Process for the production of optically active compounds

Abstract

Provided is a method for producing an optically active pyrimidine amide derivative which can be produced on an industrial scale. Compound (I), compound (V) or a salt thereof is subjected to an asymmetric reduction reaction, the obtained compound (II) or a salt thereof is subjected to a deprotection reaction, the obtained compound (III) or a salt thereof is reacted with compound (IV) or a salt thereof, and compound (V) or a salt thereof is obtained. (In the formulae, the symbols are as defined in the description.)

Description

[0001] This application is a divisional application of Chinese patent application No. 201880050913.0, filed on May 29, 2018, entitled "Method for producing optically active compounds" (the corresponding PCT application was filed on May 29, 2018, with application number (PCT / IB2018 / 053822). [Technical Field]

[0002] This invention relates to a method for producing an optically active amine compound that can be used to produce optically active pyrimidinamide derivatives, and a method for producing optically active pyrimidinamide derivatives using the optically active amine compound. (Background of the Invention)

[0003] The pyrimidine amide derivatives represented by formula (V) mentioned below are known as Raf protein kinase inhibitors and therapeutic agents for cancer and similar diseases.

[0004] The following method is referred to as the production method of the optically active form.

[0005] Patent Document 1 discloses the production of an optically active form of an amine compound represented by formula (III) mentioned below by sequentially subjecting the corresponding ketone compound to oxime, reduction and optical resolution with di-p-toluyl-(D)-tartaric acid, and the production of a target optically active form of a pyrimidine amide derivative represented by formula (V) mentioned below from the optically active amine compound.

[0006] As a method for producing optically active amine compounds, Non-Patent Document 1 discloses a reducing asymmetric amination reaction of arylacetone with diphenylmethylamine using an iridium complex as a catalyst, and Non-Patent Document 2 discloses an asymmetric reduction reaction of a compound having a diphenylmethylimino group.

[0007] [List of References]

[0008] [Patent Literature]

[0009] [Patent Document 1] WO 2009 / 006389

[0010] [Non-patent literature]

[0011] [Non-Patent Literature 1] Huang et al., Angew. Chem. int. Ed. (2016), 55, 5309-5317

[0012] [Non-Patent Literature 2] Jiang Xiao-bin et al., Org. Lett. (2003), 5, 1503 [Invention Overview]

[0013] [The problem this invention aims to solve]

[0014] The purpose of this invention is to provide a method for producing optically active pyrimidine amide derivatives on an industrial scale.

[0015] In order to produce the optically active form of the amine compound represented by formula (III) mentioned below by the asymmetric reduction of the corresponding imino compound, which is necessary for the production of the optically active form of the pyrimidine amide derivative represented by (V) mentioned below, it is important to introduce a suitable protecting group into the imino compound and to develop an asymmetric reduction reaction.

[0016] The diphenylmethyl group as a protecting group was previously little known. In the method of Non-Patent Literature 1, an optically active compound having a diphenylmethylamino group is obtained as a product of a reductive asymmetric amination reaction, which is structurally very different from the optically active form of the amine compound represented by formula (II) mentioned below. In the method of Non-Patent Literature 2, the asymmetric reduction reaction of the compound having a diphenylmethylimino group results in extremely low yields and low enantioselectivity.

[0017] [Problem-solving methods]

[0018] The inventors have conducted in-depth research to address the problems mentioned above and have discovered that by subjecting an imino compound with a suitable protecting group (represented by formula (I) mentioned below, or a salt thereof) to an asymmetric reduction reaction followed by deprotection, the optically active form of an amine compound represented by formula (III) mentioned below, or a salt thereof (which is a key intermediate) can be produced in good yield and with good optical purity. Therefore, the optically active form of a pyrimidine amide derivative represented by formula (V) mentioned below (which is the target compound) can be produced on an industrial scale, and the present invention is based on these findings.

[0019] Therefore, the present invention provides the following.

[0020] [1] A method for producing an optically active form of a compound represented by the following formula (II) or a salt thereof:

[0021]

[0022] in

[0023] R 1 It is C 1-6 alkyl groups;

[0024] R 2 It is a hydrogen atom or a halogen atom;

[0025] R3 It is a hydrogen atom or an optional halogenated C atom. 1-6 alkyl groups;

[0026] PG is a protecting group; and

[0027] The carbon atom marked with * is an asymmetric carbon atom (in the following text, the optically active form of the compound represented by formula (II) is referred to as compound (II)).

[0028] The method involves subjecting a compound or a salt thereof, represented by formula (I), to an asymmetric reduction reaction:

[0029]

[0030] Each of these symbols is as defined above (hereinafter referred to as compound (I)).

[0031] [2] A method for producing an optically active form of a compound represented by the following formula (V) or a salt thereof:

[0032]

[0033] in

[0034] R 1 It is C 1-6 alkyl groups;

[0035] R 2 It is a hydrogen atom or a halogen atom;

[0036] R 3 It is a hydrogen atom or an optional halogenated C atom. 1-6 alkyl groups;

[0037] R 4 and R 5 Each of these groups independently comprises a hydrogen atom, a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted aminosulfonyl group, an optionally substituted hydroxyl group, an optionally substituted thioalkyl (SH) group, or an optionally substituted silyl group; and

[0038] The carbon atom marked with * is an asymmetric carbon atom (in the following text, the optically active form of the compound represented by formula (V) is referred to as compound (V)).

[0039] The method includes the step of subjecting a compound represented by formula (I) or a salt thereof to an asymmetric reduction reaction to obtain an optically active form of a compound represented by formula (II) or a salt thereof.

[0040]

[0041] in

[0042] PG is a protecting group, and

[0043] And other symbols are as defined above;

[0044]

[0045] Each symbol is defined as described above.

[0046] [3] As mentioned above in [2], the method further includes:

[0047] The step of subjecting the optically active form of a compound represented by the following formula (II) or its salt to a deprotection reaction;

[0048]

[0049] in

[0050] R 1 It is C 1-6 alkyl groups;

[0051] R 2 It is a hydrogen atom or a halogen atom;

[0052] R 3 It is a hydrogen atom or an optional halogenated C atom. 1-6 alkyl groups;

[0053] PG is a protecting group; and

[0054] Carbon atoms marked with an asterisk (*) are asymmetric carbon atoms.

[0055] The steps of reacting the optically active form of the obtained compound represented by formula (III) or a salt thereof with the compound represented by formula (IV) or a salt thereof;

[0056]

[0057] Each symbol is as defined above (in the following text, the optically active form of the compound represented by formula (III) is referred to as compound (III)).

[0058]

[0059] in

[0060] X is a leaving group; and

[0061] R 4 and R 5Each of the following is independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted aminosulfonyl group, an optionally substituted hydroxyl group, an optionally substituted thioalkyl (SH) group, or an optionally substituted silyl group (hereinafter referred to as compound (IV)).

[0062] [4] The method described in [3] mentioned above, wherein the optically active form of the compound represented by formula (III) or a salt thereof is the optically active form of the compound represented by formula (III) and a salt of mandelic acid.

[0063] [5] The method described in [3] or [4] mentioned above, wherein X is a hydroxyl group.

[0064] [6] The method described in any one of [1] to [5] above, wherein the asymmetric reduction reaction is an asymmetric hydrogenation reaction in the presence of a transition metal complex.

[0065] [7] The method described in [6] above, wherein the transition metal complex is an iridium complex.

[0066] [8] The method as described in any one of [1] to [7] above, wherein PG is represented by the following formula (VI):

[0067]

[0068] in

[0069] Ar 1 It is a hydrogen atom or an optional substituted C atom 6-14 aryl groups; and

[0070] Ar 2 C is arbitrarily replaced 6-14 Aryl group.

[0071] [9] As mentioned above in [8], where Ar 1 and Ar 2 Each is an optional substituted phenyl group.

[0072]

[10] A compound or a salt thereof represented by the following formula (VII):

[0073]

[0074] Among them, Ar 3 and Ar 4 Each of them is independently and arbitrarily replaced by C.6-14 Aryl group (hereinafter referred to as compound (VII)).

[0075]

[11] The optically active form of a compound represented by the following formula (VIII) or a salt thereof:

[0076]

[0077] in

[0078] Ar 5 and Ar 6 Each of them is independently and arbitrarily replaced by C. 6-14 aryl groups, and

[0079] The carbon atom marked with * is an asymmetric carbon atom (in the following text, the optically active form of the compound represented by formula (VIII) is referred to as compound (VIII)).

[0080]

[12] A method for producing an optically active form of a compound represented by formula (III) or a salt thereof, the method comprising subjecting a compound represented by formula (Ac) or a salt thereof to an asymmetric reductive amination reaction.

[0081]

[0082] in

[0083] R 1 It is C 1-6 alkyl groups;

[0084] R 2 It is a hydrogen atom or a halogen atom; and

[0085] R 3 It is a hydrogen atom or an optional halogenated C atom. 1-6 alkyl groups

[0086] (Hereinafter referred to as compound (Ac)).

[0087]

[13] The method described in

[12] above, wherein the asymmetric reductive amination reaction is carried out by reacting a compound represented by formula (Ac) or a salt thereof with an amine source and a reducing agent in the presence of an organometallic complex.

[0088] [Invention Effects]

[0089] According to the present invention, compound (III) or its salt, which is a key intermediate, can be produced in good yield and with good optical purity by subjecting compound (I) or its salt to an asymmetric reduction reaction followed by deprotection. In particular, after deprotection, the salt of compound (III) can be produced with even better optical purity by crystallizing the diastereomer salt with optically active di-p-toluyl tartaric acid or optically active mandelic acid. Therefore, the target compound (V) or its salt can be produced on an industrial scale. (Detailed Description of the Invention)

[0090] The present invention is described in detail below.

[0091] The definition of each substituent used in this specification is described in detail below. Unless otherwise stated, each substituent has the following definition.

[0092] In this specification, examples of "halogen atoms" include fluorine, chlorine, bromine, and iodine.

[0093] In this specification, "C" 1-6 Examples of "alkyl groups" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.

[0094] In this specification, "C optionally halogenated" 1-6 Examples of "alkyl groups" include C groups that optionally have 1 to 7, preferably 1 to 5 halogen atoms. 1-6 Alkyl groups. Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, and 6,6,6-trifluorohexyl.

[0095] In this specification, "C" 2-6 Examples of "alkenyl groups" include vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, and 5-hexenyl.

[0096] In this specification, "C" 2-6Examples of "alkynyl groups" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and 4-methyl-2-pentynyl.

[0097] In this specification, "C" 3-10 Examples of “cycloalkyl groups” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl.

[0098] In this specification, "C optionally halogenated" 3-10 Examples of "cycloalkyl groups" include C groups that optionally have 1 to 7, preferably 1 to 5 halogen atoms. 3-10 Cycloalkyl groups. Specific examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0099] In this specification, "C" 3-10 Examples of "cycloalkenyl groups" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0100] In this specification, "C" 6-14 Examples of "aryl groups" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthrayl, 2-anthrayl, and 9-anthrayl.

[0101] In this specification, "C" 7-16 Examples of "aralkyl groups" include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

[0102] In this specification, "C" 1-6 Examples of "alkoxy groups" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, and hexoxy.

[0103] In this specification, "C optionally halogenated" 1-6 Examples of "alkoxy groups" include C groups that optionally have 1 to 7, preferably 1 to 5 halogen atoms. 1-6 Alkoxy groups. Specific examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentoxy, and hexoxy.

[0104] In this specification, "C" 3-10Examples of “cycloalkyloxy groups” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

[0105] In this specification, "C" 1-6 Examples of "alkyl thio groups" include methyl thio, ethyl thio, propyl thio, isopropyl thio, butyl thio, sec-butyl thio, tert-butyl thio, pentyl thio, and hexyl thio.

[0106] In this specification, "C optionally halogenated" 1-6 Examples of "alkyl thio groups" include C groups optionally having 1 to 7, preferably 1 to 5 halogen atoms. 1-6 Alkyl thio groups. Specific examples include methyl thio, difluoromethyl thio, trifluoromethyl thio, ethyl thio, propyl thio, isopropyl thio, butyl thio, 4,4,4-trifluorobutyl thio, pentyl thio, and hexyl thio.

[0107] In this specification, "C" 1-6 Examples of "alkyl-carbonyl groups" include acetyl, propionyl, butyryl, 2-methylpropionyl, valeryl, 3-methylbutyryl, 2-methylbutyryl, 2,2-dimethylpropionyl, hexanoyl, and heptanoyl.

[0108] In this specification, "C optionally halogenated" 1-6 Examples of "alkyl-carbonyl groups" include C groups that optionally have 1 to 7, preferably 1 to 5 halogen atoms. 1-6 Alkyl-carbonyl groups. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propionyl, butyryl, valeryl, and hexanoyl.

[0109] In this specification, "C" 1-6 Examples of "alkoxy-carbonyl groups" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, and hexoxycarbonyl.

[0110] In this specification, "C" 6-14 Examples of "aryl-carbonyl groups" include benzoyl, 1-naphthoyl, and 2-naphthoyl.

[0111] In this specification, "C" 7-16 Examples of "aralkyl-carbonyl groups" include phenylacetyl and phenylpropionyl.

[0112] Examples of “5- to 14-membered aromatic heterocyclic carbonyl groups” in this specification include nicotinyl, isonicotinyl, thenoyl, and furoyl.

[0113] Examples of “3- to 14-membered non-aromatic heterocyclic carbonyl groups” in this specification include morpholinocarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.

[0114] In this specification, "single- or double-C" 1-6 Examples of "alkyl-carbamoyl group" include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

[0115] In this specification, "single- or double-C" 7-16 Examples of "aralkyl-carbamoyl group" include benzylcarbamoyl and phenylethylcarbamoyl.

[0116] In this specification, "C" 1-6 Examples of "alkyl sulfonyl groups" include methyl sulfonyl, ethyl sulfonyl, propyl sulfonyl, isopropyl sulfonyl, butyl sulfonyl, sec-butyl sulfonyl, and tert-butyl sulfonyl.

[0117] In this specification, "C optionally halogenated" 1-6 Examples of "alkyl sulfonyl groups" include C groups that optionally have 1 to 7, preferably 1 to 5 halogen atoms. 1-6 Alkyl sulfonyl groups. Specific examples include methyl sulfonyl, difluoromethyl sulfonyl, trifluoromethyl sulfonyl, ethyl sulfonyl, propyl sulfonyl, isopropyl sulfonyl, butyl sulfonyl, 4,4,4-trifluorobutyl sulfonyl, pentyl sulfonyl, and hexyl sulfonyl.

[0118] In this specification, "C" 6-14 Examples of "arylsulfonyl groups" include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

[0119] In this specification, examples of "substituents" include halogen atoms, cyano groups, nitro groups, optionally substituted hydrocarbon groups, optionally substituted heterocyclic groups, acyl groups, optionally substituted amino groups, optionally substituted carbamoyl groups, optionally substituted thiocarbamoyl groups, optionally substituted aminosulfonyl groups, optionally substituted hydroxyl groups, optionally substituted thioalkyl (SH) groups, and optionally substituted silyl groups.

[0120] In this specification, examples of "hydrocarbon group" (including "hydrocarbon group" of "optionally substituted hydrocarbon group") include C 1-6 alkyl groups, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-10 Cycloalkyl groups, C3-10 cycloalkenyl group, C 6-14 aryl group and C 7-16 Aryl group.

[0121] In this specification, examples of "optionally substituted hydrocarbon groups" include hydrocarbon groups that optionally have substituents selected from substituent group A below.

[0122] [Substituted base set A]

[0123] (1) Halogen atom,

[0124] (2) Nitro group,

[0125] (3) Cyano group,

[0126] (4) Oxide group,

[0127] (5) Hydroxyl group,

[0128] (6) C that is optionally halogenated 1-6 alkoxy group,

[0129] (7)C 6-14 Aryloxy groups (e.g., phenoxy, naphthoxy),

[0130] (8)C 7-16 Arylalkyloxy groups (e.g., benzyloxy groups),

[0131] (9) 5- to 14-membered aromatic heterocyclic oxy groups (e.g., pyridyloxy groups),

[0132] (10) 3- to 14-membered non-aromatic heterocyclic oxy groups (e.g., morpholinyloxy, piperidinyloxy),

[0133] (11)C 1-6 Alkyl-carbonyloxy groups (e.g., acetoxy, propionyloxy),

[0134] (12)C 6-14 Aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy),

[0135] (13)C 1-6 Alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),

[0136] (14) Single or double C 1-6 Alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy),

[0137] (15)C 6-14 Aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy),

[0138] (16) 5- to 14-membered aromatic heterocyclic carbonyloxy groups (e.g., nicotinyloxy groups),

[0139] (17) 3- to 14-membered non-aromatic heterocyclic carbonyloxy groups (e.g., morpholinyl carbonyloxy, piperidinyl carbonyloxy),

[0140] (18) C that is optionally halogenated 1-6 Alkylsulfonyloxy group (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy),

[0141] (19) Optional location C 1-6 C with alkyl group substitution 6-14 Arylsulfonyloxy group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),

[0142] (20) C arbitrarily halogenated 1-6 alkyl thio groups,

[0143] (21) 5- to 14-membered aromatic heterocyclic groups,

[0144] (22) 3- to 14-membered non-aromatic heterocyclic groups

[0145] (23) Formyl group,

[0146] (24) Carboxyl group,

[0147] (25) C arbitrarily halogenated 1-6 alkyl-carbonyl groups,

[0148] (26)C 6-14 aryl-carbonyl group,

[0149] (27) 5- to 14-membered aromatic heterocyclic carbonyl groups

[0150] (28) 3- to 14-membered non-aromatic heterocyclic carbonyl groups

[0151] (29)C 1-6 alkoxy-carbonyl group,

[0152] (30)C 6-14 Aryloxy-carbonyl groups (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),

[0153] (31)C 7-16Arylalkyloxy-carbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl),

[0154] (32) Carbamoyl group

[0155] (33) Thiocarbamoyl group.

[0156] (34) Single or double C 1-6 alkyl-carbamoyl group,

[0157] (35)C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl),

[0158] (36) 5- to 14-membered aromatic heterocyclic carbamoyl groups (e.g., pyridylcarbamoyl, thiophenylcarbamoyl),

[0159] (37) 3- to 14-membered non-aromatic heterocyclic carbamoyl groups (e.g., morpholinocarbamoyl, piperidinylcarbamoyl),

[0160] (38) C that is arbitrarily halogenated 1-6 alkylsulfonyl group,

[0161] (39)C 6-14 arylsulfonyl group,

[0162] (40) 5- to 14-membered aromatic heterocyclic sulfonyl groups (e.g., pyridylsulfonyl, thienylsulfonyl),

[0163] (41) C that is optionally halogenated 1-6 alkyl sulfinyl group,

[0164] (42)C 6-14 Aryl sulfinyl groups (e.g., phenyl sulfinyl, 1-naphthyl sulfinyl, 2-naphthyl sulfinyl),

[0165] (43) 5- to 14-membered aromatic heterocyclic sulfinyl groups (e.g., pyridyl sulfinyl, thienyl sulfinyl),

[0166] (44) Amino group,

[0167] (45) Single or double C 1-6 Alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino),

[0168] (46) Single or double C 6-14 Aryl amino groups (e.g., phenylamino),

[0169] (47) 5- to 14-membered aromatic heterocyclic amino groups (e.g., pyridylamino),

[0170] (48)C 7-16 Arylamino groups (e.g., benzylamino),

[0171] (49) Formylamino group.

[0172] (50)C 1-6 Alkyl-carbonylamino groups (e.g., acetylamino, propionylamino, butyrylamino),

[0173] (51)(C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino),

[0174] (52)C 6-14 Aryl-carbonylamino groups (e.g., phenylcarbonylamino, naphthylcarbonylamino),

[0175] (53)C 1-6 Alkoxy-carbonylamino groups (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino),

[0176] (54)C 7-16 Arylalkyloxy-carbonylamino groups (e.g., benzyloxycarbonylamino),

[0177] (55)C 1-6 Alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino),

[0178] (56) Optional land cover C 1-6 C with alkyl group substitution 6-14 Arylsulfonylamino group (e.g., phenylsulfonylamino, toluenesulfonylamino),

[0179] (57) C that is arbitrarily halogenated 1-6 alkyl groups,

[0180] (58)C 2-6 alkenyl group,

[0181] (59)C 2-6 acetylation group,

[0182] (60)C 3-10 Cycloalkyl groups,

[0183] (61)C 3-10 Cycloalkenyl groups, and

[0184] (62)C 6-14 Aryl group.

[0185] The number of substituents mentioned above in "optionally substituted hydrocarbon groups" is, for example, one to five, preferably one to three. When the number of substituents is two or more, the corresponding substituents may be the same or different.

[0186] In this specification, examples of "heterocyclic groups" (including "heterocyclic groups with optional substitution") include (i) aromatic heterocyclic groups, (ii) non-aromatic heterocyclic groups and (iii) 7- to 10-membered bridging heterocyclic groups, each containing one to four heteroatoms selected from nitrogen, sulfur and oxygen atoms as ring-forming atoms other than carbon atoms.

[0187] In this specification, examples of "aromatic heterocyclic groups" (including "5- to 14-membered aromatic heterocyclic groups") include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups, which contain one to four heteroatoms selected from nitrogen, sulfur and oxygen atoms as ring-forming atoms other than carbon atoms.

[0188] Preferred examples of "aromatic heterocyclic groups" include 5- or 6-membered monocyclic aromatic heterocyclic groups, such as thiophene, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and similar groups; and

[0189] 8- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic groups, such as benzothiophene, benzofuran, benzimidazol, benzoxazol, benzoisoxazol, benzothiazolyl, benzoisothiazolyl, benzotriazol, imidazopyridyl, thienopyridyl, furanopyridyl, pyrrolopyridyl, pyrazololopyridyl, oxazololopyridyl, thiazonopyridyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furanopyrimidinyl, pyrrolopyrimidinyl, pyrazololopyrimidinyl, oxazololopyrimidinyl, Thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thiophenyl, phenoxathiinyl, indole, isoindole, 1H-indazolyl, purine, isoquinolinyl, quinolinyl, phthalazinyl, naphridinyl, quinoxolinyl, quinoxolinyl, cyclophosphinyl, carbazolyl, β-carbazolyl, phenanthidyl, acridineyl, phenazinyl, phenothiazinyl, phenoxazinyl, and similar groups.

[0190] In this specification, examples of “non-aromatic heterocyclic groups” (including “3- to 14-membered non-aromatic heterocyclic groups”) include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic groups, which contain one to four heteroatoms selected from nitrogen, sulfur and oxygen atoms as ring-forming atoms other than carbon atoms.

[0191] Preferred examples of “non-aromatic heterocyclic groups” include 3- to 8-membered monocyclic non-aromatic heterocyclic groups, such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothiopheneyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, and imidazoline. Imidazolyl, oxazolinyl, oxazolyl, pyrazolinyl, pyrazolyl, thiazolinyl, thiazolinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepanyl Azepinyl, oxepanyl, azocanyl, diazocanyl and similar groups; and

[0192] Nine to fourteen fused polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocyclic groups, such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 4H-quinazinyl, indololinyl, isoindololinyl, tetrahydrothieno[2,3-c]pyridyl, tetrahydrobenzozazepine Tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridine, hexahydrophenthiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthidyl, tetrahydroquinazolinyl, tetrahydrocinnaphthyl, tetrahydrocarbazole, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthyl, octahydroisoquinolinyl and similar groups.

[0193] In this specification, preferred examples of “7- to 10-membered bridging heterocyclic groups” include quinuclidinyl and 7-azabicyclo[2.2.1]heptyl.

[0194] In this specification, examples of "nitrogen-containing heterocyclic groups" include "heterocyclic groups" that contain at least one nitrogen atom as a ring-forming atom.

[0195] In this specification, examples of "optionally substituted heterocyclic groups" include heterocyclic groups that optionally have substituents selected from the substituent group A mentioned above.

[0196] The number of substituents in the "optionally substituted heterocyclic group" is, for example, one to three. When the number of substituents is two or more, the corresponding substituents may be the same or different.

[0197] In this specification, examples of "acyl group" include formyl group, carboxyl group, carbamoyl group, thiocarbamoyl group, sulfinyl group, sulfonyl group, aminosulfonyl group, and phosphonyl group, each optionally having "one or two substituents selected from the following: C 1-6 alkyl groups, C 2-6 alkenyl group, C 3-10 Cycloalkyl groups, C 3-10 cycloalkenyl group, C 6-14 aryl group, C 7-16 Aryl groups, 5- to 14-membered aromatic heterocyclic groups, and 3- to 14-membered non-aromatic heterocyclic groups, each optionally having one to three substituents selected from: halogen atoms, optionally halogenated C atoms, etc. 1-6 Alkoxy groups, hydroxy groups, nitro groups, cyano groups, amino groups, and carbamoyl groups.

[0198] Examples of “acyl groups” also include hydrocarbon sulfonyl groups, heterocyclic sulfonyl groups, hydrocarbon sulfinyl groups, and heterocyclic sulfinyl groups.

[0199] Here, alkyl-sulfonyl group refers to a sulfonyl group bonded to a hydrocarbon group, heterocyclic sulfonyl group refers to a sulfonyl group bonded to a heterocyclic group, alkyl-sulfinyl group refers to a sulfinyl group bonded to a hydrocarbon group, and heterocyclic sulfinyl group refers to a sulfinyl group bonded to a heterocyclic group.

[0200] Preferred examples of "acyl groups" include formyl groups, carboxyl groups, and C. 1-6 alkyl-carbonyl group, C 2-6 Alkenyl-carbonyl groups (e.g., crotonyl), C 3-10 Cycloalkyl-carbonyl groups (e.g., cyclobutane carbonyl, cyclopentane carbonyl, cyclohexane carbonyl, cycloheptane carbonyl), C 3-10 Cycloalkenyl-carbonyl groups (e.g., 2-cyclohexenecarbonyl), C 6-14 aryl-carbonyl group, C 7-16Aryl alkyl-carbonyl groups, 5- to 14-membered aromatic heterocyclic carbonyl groups, 3- to 14-membered non-aromatic heterocyclic carbonyl groups, C 1-6 alkoxy-carbonyl group, C 6-14 Aryloxy-carbonyl groups (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), C 7-16 Arylalkyloxycarbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl groups, mono- or di-C 1-6 alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl groups (e.g., cyclopropylcarbamoyl), mono- or di-C 6-14 aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aryl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C 1-6 Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl group (e.g., diallyl-thiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aryl alkyl-thiocarbamoyl groups (e.g., benzyl thiocarbamoyl, phenethyl thiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (e.g., pyridyl thiocarbamoyl), sulfinyl groups, C 1-6 alkyl sulfinyl groups (e.g., methyl sulfinyl, ethyl sulfinyl), sulfonyl groups, C 1-6 alkylsulfonyl group, C 6-14 arylsulfonyl groups, phosphonyl groups, and mono- or di-C 1-6 Alkyl phosphono groups (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

[0201] In this specification, examples of "optionally substituted amino groups" include those optionally having the following amino groups: "one or two substituents selected from the following: C 1-6 alkyl groups, C 2-6 alkenyl group, C 3-10Cycloalkyl groups, C 6-14 aryl group, C 7-16 Aryl groups, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7-16 Aryl alkyl-carbonyl groups, 5- to 14-membered aromatic heterocyclic carbonyl groups, 3- to 14-membered non-aromatic heterocyclic carbonyl groups, C 1-6 Alkoxy-carbonyl groups, 5- to 14-membered aromatic heterocyclic groups, carbamoyl groups, mono- or di-C 1-6 alkyl-carbamoyl group, mono- or di-C 7-16 Aryl-carbamoyl group, C 1-6 alkylsulfonyl groups and C 6-14 "Arylsulfonyl groups, each optionally having one to three substituents selected from substituent group A."

[0202] Preferred examples of optionally substituted amino groups include amino groups, mono- or di-(optionally halogenated C) groups. 1-6 Alkyl)amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6 alkenyl amino groups (e.g., diallylamino), mono- or di-C 3-10 Cycloalkylamino groups (e.g., cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 aryl amino groups (e.g., phenylamino), mono- or di-C 7-16 Aryl alkyl amino groups (e.g., benzylamino, dibenzylamino), mono- or di- (optionally halogenated C) 1-6 Alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), mono- or di-C 6-14 aryl-carbonylamino groups (e.g., benzoylamino), mono- or di-C 7-16 Arylalkyl-carbonylamino groups (e.g., benzylcarbonylamino), mono- or di-5- to 14-membered aromatic heterocyclic carbonylamino groups (e.g., nicotinylamino, isonicotinylamino), mono- or di-3- to 14-membered non-aromatic heterocyclic carbonylamino groups (e.g., piperidinylcarbonylamino), mono- or di-C 1-6 Alkoxy-carbonylamino groups (e.g., tert-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino groups (e.g., pyridylamino), carbamoylamino groups, (mono- or di-C) 1-6 alkyl-carbamoyl)amino group (e.g., methylcarbamoylamino), (mono- or di-C) 7-16 Arylalkyl-carbamoyl)amino group (e.g., benzylcarbamoylamino), C1-6 Alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), C 6-14 arylsulfonylamino group (e.g., phenylsulfonylamino), (C 1-6 Alkyl)(C 1-6 alkyl-carbonyl) amino groups (e.g., N-acetyl-N-methylamino) and (C 1-6 Alkyl)(C 6-14 Aryl-carbonyl)amino group (e.g., N-benzoyl-N-methylamino).

[0203] In this specification, examples of "optionally substituted carbamoyl groups" include those optionally having the following carbamoyl groups: "one or two substituents selected from the following: C 1-6 alkyl groups, C 2-6 alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 aryl group, C 7-16 Aryl groups, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7-16 Aryl alkyl-carbonyl groups, 5- to 14-membered aromatic heterocyclic carbonyl groups, 3- to 14-membered non-aromatic heterocyclic carbonyl groups, C 1-6 Alkoxy-carbonyl groups, 5- to 14-membered aromatic heterocyclic groups, carbamoyl groups, mono- or di-C 1-6 alkyl-carbamoyl groups and mono- or di-C 7-16 "Aryl-carbamoyl groups, each optionally having one to three substituents selected from substituent group A."

[0204] Preferred examples of optionally substituted carbamoyl groups include carbamoyl groups, mono- or di-C groups. 1-6 alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl groups (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C 6-14 aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aryl-carbamoyl group, mono- or di-C 1-6 Alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14Aryl-carbonyl-carbamoyl groups (e.g., benzoylcarbamoyl) and 5- to 14-membered aromatic heterocyclic carbamoyl groups (e.g., pyridylcarbamoyl).

[0205] In this specification, examples of "optionally substituted thiocarbamoyl groups" include those optionally having the following thiocarbamoyl groups: "one or two substituents selected from the following: C 1-6 alkyl groups, C 2-6 alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 aryl group, C 7-16 Aryl groups, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7-16 Aryl alkyl-carbonyl groups, 5- to 14-membered aromatic heterocyclic carbonyl groups, 3- to 14-membered non-aromatic heterocyclic carbonyl groups, C 1-6 Alkoxy-carbonyl groups, 5- to 14-membered aromatic heterocyclic groups, carbamoyl groups, mono- or di-C 1-6 alkyl-carbamoyl groups and mono- or di-C 7-16 "Aryl-carbamoyl groups, each optionally having one to three substituents selected from substituent group A."

[0206] Preferred examples of optionally substituted thiocarbamoyl groups include thiocarbamoyl groups, mono- or di-C groups. 1-6 Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl group (e.g., diallyl-thiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aryl alkyl-thiocarbamoyl group (e.g., benzyl thiocarbamoyl, phenethyl thiocarbamoyl), mono- or di-C 1-6 Alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di-C 6-14 Aryl-carbonyl-thiocarbamoyl groups (e.g., benzoylthiocarbamoyl) and 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (e.g., pyridylthiocarbamoyl).

[0207] In this specification, examples of "optionally substituted aminosulfonyl groups" include those optionally having the following aminosulfonyl groups: "one or two substituents selected from the following: C 1-6 alkyl groups, C 2-6 alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 aryl group, C 7-16 Aryl groups, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7-16 Aryl alkyl-carbonyl groups, 5- to 14-membered aromatic heterocyclic carbonyl groups, 3- to 14-membered non-aromatic heterocyclic carbonyl groups, C 1-6 Alkoxy-carbonyl groups, 5- to 14-membered aromatic heterocyclic groups, carbamoyl groups, mono- or di-C 1-6 alkyl-carbamoyl groups and mono- or di-C 7-16 "Aryl-carbamoyl groups, each optionally having one to three substituents selected from substituent group A."

[0208] Preferred examples of optionally substituted aminosulfonyl groups include aminosulfonyl groups, mono- or di-C groups. 1-6 Alkyl-aminosulfonyl groups (e.g., methylaminosulfonyl, ethylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl), mono- or di-C 2-6 Alkenyl-aminosulfonyl group (e.g., diallylaminosulfonyl), mono- or di-C 3-10 Cycloalkyl-aminosulfonyl groups (e.g., cyclopropylaminosulfonyl, cyclohexylaminosulfonyl), mono- or di-C 6-14 aryl-aminosulfonyl groups (e.g., phenylaminosulfonyl), mono- or di-C 7-16 Aryl alkyl aminosulfonyl groups (e.g., benzyl aminosulfonyl, phenethyl aminosulfonyl), mono- or di-C 1-6 Alkyl-carbonyl-aminosulfonyl group (e.g., acetylaminosulfonyl, propionylaminosulfonyl), mono- or di-C 6-14 Aryl-carbonyl-aminosulfonyl groups (e.g., benzoylaminosulfonyl) and 5- to 14-membered aromatic heterocyclic aminosulfonyl groups (e.g., pyridylaminosulfonyl).

[0209] In this specification, examples of "optionally substituted hydroxyl groups" include those optionally having the following hydroxyl groups: "substituents selected from the following: C 1-6 alkyl groups, C 2-6 alkenyl group, C 3-10 Cycloalkyl groups, C 6-14aryl group, C 7-16 Aryl groups, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7-16 Aryl alkyl-carbonyl groups, 5- to 14-membered aromatic heterocyclic carbonyl groups, 3- to 14-membered non-aromatic heterocyclic carbonyl groups, C 1-6 Alkoxy-carbonyl groups, 5- to 14-membered aromatic heterocyclic groups, carbamoyl groups, mono- or di-C 1-6 alkyl-carbamoyl group, mono- or di-C 7-16 Aryl-carbamoyl group, C 1-6 alkylsulfonyl groups and C 6-14 "Arylsulfonyl groups, each optionally having one to three substituents selected from substituent group A."

[0210] Preferred examples of optionally substituted hydroxyl groups include hydroxyl groups, C 1-6 alkoxy group, C 2-6 Alkenyloxy group (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), C 3-10 Cycloalkyloxy groups (e.g., cyclohexyloxy), C 6-14 Aryloxy groups (e.g., phenoxy, naphthyloxy), C 7-16 Arylalkyloxy groups (e.g., benzyloxy, phenethyloxy), C 1-6 Alkyl-carbonyloxy groups (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C 6-14 aryl-carbonyloxy group (e.g., benzoyloxy), C 7-16 Arylalkyl-carbonyloxy groups (e.g., benzylcarbonyloxy), 5- to 14-membered aromatic heterocyclic carbonyloxy groups (e.g., nicotinyloxy), 3- to 14-membered non-aromatic heterocyclic carbonyloxy groups (e.g., piperidinylcarbonyloxy), C 1-6 Alkoxy-carbonyloxy groups (e.g., tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclic oxy groups (e.g., pyridyloxy), carbamoyloxy groups, C 1-6 alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), C 7-16 Aryl alkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), C 1-6 alkylsulfonyloxy groups (e.g., methylsulfonyloxy, ethylsulfonyloxy) and C 6-14 Arylsulfonyloxy group (e.g., phenylsulfonyloxy).

[0211] In this specification, examples of "optionally substituted thioalkyl groups" include those optionally having the following thioalkyl groups: "substituents selected from the following: C 1-6 alkyl groups, C 2-6 alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 aryl group, C 7-16 Aryl groups, C 1-6 alkyl-carbonyl group, C 6-14 The aryl-carbonyl group and the 5- to 14-membered aromatic heterocyclic group, each optionally having one to three substituents selected from substituent group A; and the halogenated thioalkyl group.

[0212] Preferred examples of optionally substituted thioalkyl groups include thioalkyl (-SH) groups, C 1-6 alkyl thio groups, C 2-6 Alkenyl thio groups (e.g., allyl thio, 2-butenyl thio, 2-pentenyl thio, 3-hexenyl thio), C 3-10 Cycloalkyl thio groups (e.g., cyclohexyl thio), C 6-14 Aryl thio groups (e.g., phenyl thio, naphthio), C 7-16 Aryl thio groups (e.g., benzyl thio, phenethyl thio), C 1-6 Alkyl-carbonyl thio groups (e.g., acetyl thio, propionyl thio, butyryl thio, isobutyryl thio, pivaloylthio), C 6-14 Aryl-carbonyl thio groups (e.g., benzoyl thio), 5- to 14-membered aromatic heterocyclic thio groups (e.g., pyridyl thio), and halogenated thio groups (e.g., pentafluorothio).

[0213] In this specification, examples of "optionally substituted silyl groups" include those optionally having the following silyl groups: "1 to 3 substituents selected from the following: C 1-6 alkyl groups, C 2-6 alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 aryl group and C 7-16 "Aryl groups, each optionally having one to three substituents selected from substituent group A."

[0214] Preferred examples of optionally substituted silyl groups include tri-C 1-6 Alkyl silyl groups (e.g., trimethylsilyl, tert-butyl(dimethyl)silyl).

[0215] The definitions of each symbol in formulas (I), (II), (III), (IV), (V), (VII), and (VIII), as well as the compounds associated with them, are explained in detail below.

[0216] R 1 It is C 1-6 Alkyl group, preferably methyl.

[0217] R 2 It is a hydrogen atom or a halogen atom, preferably a chlorine atom.

[0218] R 3 It is a hydrogen atom or an optional halogenated C atom. 1-6 Alkyl groups, preferably fluorinated C4 groups. 1-6 Alkyl groups, particularly preferably trifluoromethyl groups.

[0219] PG is a protecting group. Examples of "protecting groups" include...

[0220] Groups represented by formula (VI-1):

[0221]

[0222] in

[0223] R 7 C is arbitrarily replaced 6-14 The aryl group or optionally substituted C 1-6 Alkoxy groups, and

[0224] Groups represented by formula (VI):

[0225]

[0226] in

[0227] Ar 1 It is a hydrogen atom or an optional substituted C atom 6-14 aryl groups; and

[0228] Ar 2 C is arbitrarily replaced 6-14 Aryl group.

[0229] By R 7 The term "C that is optionally replaced" indicates 6-14 Examples of "substituents" for "aryl groups" include the "substituents" mentioned above. (The last part, "by R," appears to be a fragment and doesn't translate directly.) 7 The term "C that is optionally replaced" indicates 6-14 The number of substituents at the substituted positions in the aryl group is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, the corresponding substituents may be the same or different.

[0230] By R 7 The term "C that is optionally replaced" indicates 1-6 Examples of "substituents" for "alkoxy groups" include the "substituents" mentioned above. (The last part, "by R," appears to be a fragment and doesn't translate directly.) 7 The term "C that is optionally replaced" indicates 1-6 The number of substituents at the substituted positions in the "alkoxy group" is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, the corresponding substituents may be the same or different.

[0231] R 7 Preferably, it is a C without substituents. 6-14 aryl group or unsubstituent C 1-6 The alkoxy group is more preferably phenyl or tert-butoxy, and particularly preferably phenyl.

[0232] By Ar 1 Or Ar 2 The term "C that is optionally replaced" indicates 6-14 The substituents and their number of "aryl groups" are similar to those mentioned above, which are derived from R. 7 The term "C that is optionally replaced" indicates 6-14 Those exemplified in "aryl group". Preferably, C 1-6 Alkoxy groups, and particularly preferably methoxy groups.

[0233] PG is preferably a group represented by formula (VI). In this case, Ar 1 and Ar 2 Preferably, each of the Cs is independently and optionally replaced. 6-14 The aryl group, more preferably each independently of the optionally substituted phenyl group, and even more preferably each independently of the optionally C-substituted phenyl group, is further preferred to be C-substituted. 1-6 The alkoxy-substituted phenyl groups are particularly preferably all phenyl.

[0234] As a preferred implementation scheme

[0235] The compound represented by formula (I) is the compound represented by formula (VII):

[0236]

[0237] in

[0238] Ar 3 and Ar 4 Each of the Cs is independently and arbitrarily replaced. 6-14 aryl groups, and

[0239] The optically active form of the compound represented by formula (II) is the optically active form of the compound represented by formula (VIII):

[0240]

[0241] in

[0242] Ar 5 and Ar 6 Each of them is independently and arbitrarily replaced by C. 6-14 aryl group, and

[0243] Carbon atoms marked with an asterisk (*) are asymmetric carbon atoms.

[0244] By Ar 3 Ar 4 Ar 5 Or Ar 6 The term "C that is optionally replaced" indicates 6-14 The substituents and their number of "aryl groups" are similar to those mentioned above, which are derived from R. 7 The term "C that is optionally replaced" indicates 6-14 Those exemplified in "aryl group". Preferably C 1-6 Alkoxy groups, and particularly preferably methoxy groups.

[0245] Ar 3 and Ar 4 Preferably, each is independently a phenyl group that is optionally substituted; more preferably, each is independently a phenyl group that is optionally C-substituted. 1-6 The alkoxy-substituted phenyl groups are particularly preferably all phenyl.

[0246] Ar 5 and Ar 6 Preferably, each is independently a phenyl group that is optionally substituted; more preferably, each is independently a phenyl group that is optionally C-substituted. 1-6 The alkoxy-substituted phenyl groups are particularly preferably all phenyl.

[0247] As the optimal implementation plan

[0248] The compound represented by formula (I) is (E)-2-(1-(diphenylmethylimino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide; and

[0249] The optically active form of the compound represented by formula (II) is 2-((1R)-1-(diphenylmethylamino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide.

[0250] R 4 and R5 Each of these groups is independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted aminosulfonyl group, an optionally substituted hydroxyl group, an optionally substituted thioalkyl (SH) group, or an optionally substituted silyl group.

[0251] By R 4 Or R 5 Examples of “optionally substituted hydrocarbon groups” include those exemplified as “optionally substituted hydrocarbon groups” mentioned above.

[0252] By R 4 Or R 5 Examples of “optionally substituted heterocyclic groups” include those exemplified as “optionally substituted heterocyclic groups” mentioned above.

[0253] By R 4 Or R 5 Examples of “acyl group” include those exemplified as “acyl group” mentioned above.

[0254] By R 4 Or R 5 Examples of “optionally substituted amino groups” include those exemplified as “optionally substituted amino groups” mentioned above.

[0255] By R 4 Or R 5 Examples of “optionally substituted carbamoyl groups” include those exemplified as “optionally substituted carbamoyl groups” mentioned above.

[0256] By R 4 Or R 5 Examples of “optionally substituted thiocarbamoyl groups” include those exemplified as “optionally substituted thiocarbamoyl groups” mentioned above.

[0257] By R 4 Or R 5 Examples of "optionally substituted aminosulfonyl groups" include those exemplified as "optionally substituted aminosulfonyl groups" mentioned above.

[0258] By R 4 Or R 5 Examples of “optionally substituted hydroxyl groups” include those exemplified as “optionally substituted hydroxyl groups” mentioned above.

[0259] By R 4 Or R 5 Examples of “optionally substituted thioalkyl (SH) groups” include those exemplified as “optionally substituted thioalkyl (SH) groups” mentioned above.

[0260] By R 4 Or R 5 Examples of "optionally substituted silyl groups" include those exemplified as "optionally substituted silyl groups" mentioned above.

[0261] R 4 Preferably, it is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted hydrocarbon group, an acyl group, or an optionally substituted hydroxyl group, more preferably a hydrogen atom or a halogen atom, and particularly preferably a chlorine atom.

[0262] R 5 Preferably, it is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted hydroxyl group, or an optionally substituted thioalkyl (SH) group, more preferably a hydrogen atom or an optionally substituted amino group, and particularly preferably an amino group.

[0263] Examples of leaving groups represented by X include halogen atoms, optionally substituted hydroxyl groups, azide groups, and optionally substituted imidazole groups.

[0264] Examples of “optionally substituted hydroxyl groups” represented by X include those exemplified as “optionally substituted hydroxyl groups” mentioned above.

[0265] Examples of substituents for "optionally substituted imidazole groups" represented by X include C. 1-6 Alkyl groups. Methyl groups are preferred.

[0266] X is preferably a hydroxyl group.

[0267] As the optimal implementation plan

[0268] The compound represented by formula (IV) is 6-amino-5-chloropyrimidine-4-carboxylic acid; and

[0269] The optically active form of the compound represented by formula (V) is 6-amino-5-chloro-N-((1R)-1-(5-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)-1,3-thiazolyl)ethyl)pyrimidin-4-carboxamide.

[0270] Compounds represented by formula (I), formula (II), formula (IV), formula (V), formula (VII) or formula (VIII) can be salts.

[0271] Examples of salts of compounds represented by formula (I), formula (II), formula (IV), formula (V), formula (VII) or formula (VIII) include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.

[0272] Preferred examples of metal salts include alkali metal salts, such as sodium, potassium and the like; alkaline earth metal salts, such as calcium, magnesium, barium and the like; aluminum and the like.

[0273] Preferred examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picolin, 2,6-dimethylpyridine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, and the like.

[0274] Preferred examples of salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid, carbonic acid, bicarbonic acid, and the like.

[0275] Preferred examples of salts with organic acids include salts with: carboxylic acids (i.e., organic compounds having one or more carboxyl groups; specific examples include formic acid, acetic acid, benzoic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, tartaric acid derivatives, mandelic acid, maleic acid, citric acid, succinic acid, malic acid and the aforementioned basic or acidic amino acids, and the like, wherein the amino group is protected); and sulfonic acids (i.e., organic compounds having one or more sulfonic groups; specific examples include methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and the like).

[0276] Examples of salts with tartaric acid derivatives include salts with di-p-toluyl tartaric acid, dibenzoyl tartaric acid, di-p-anestoyl tartaric acid, and the like.

[0277] Preferred examples of salts with basic amino acids include salts with arginine, lysine, ornithine, and the like. Preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like.

[0278] Examples of protecting groups for basic or acidic amino acids in which the amino group is protected include tert-butoxycarbonyl, acetyl, and similar groups.

[0279] The optically active form of the compound represented by formula (III) is preferably in the form of a salt.

[0280] Examples of salts of the optically active form of the compound represented by formula (III) include salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.

[0281] Preferred examples of the optically active form of the compound represented by formula (III) and the salt of the inorganic acid include those exemplified as the salt of the compound represented by formula (I), formula (II), formula (IV), formula (V), formula (VII) or formula (VIII) and the salt of the inorganic acid.

[0282] Preferred examples of the optically active form of the compound represented by formula (III) and the salt of the organic acid include those exemplified as the salt of the compound represented by formula (I), formula (II), formula (IV), formula (V), formula (VII) or formula (VIII) and the salt of the organic acid.

[0283] Preferred examples of the optically active form of the compound represented by formula (III) and a salt of a basic or acidic amino acid include those exemplified as compounds represented by formula (I), (II), (IV), (V), (VII) or (VIII) and a salt of a basic or acidic amino acid.

[0284] The optically active form of the compound represented by formula (III) is preferably in the form of a salt, more preferably in the form of a salt of an optically active organic acid or a salt of an optically active basic or acidic amino acid, even more preferably in the form of a salt of optically active di-p-toluyl tartaric acid (preferably di-p-toluyl-(D)-tartaric acid when the optically active form of the compound represented by formula (III) is (R)-form), or in the form of a salt of optically active mandelic acid (preferably (S)-mandelic acid when the optically active form of the compound represented by formula (III) is (R)-form), particularly preferably in the form of a salt of optically active mandelic acid (preferably (S)-mandelic acid when the optically active form of the compound represented by formula (III) is (R)-form).

[0285] As the optimal implementation plan

[0286] The optically active form of the compound represented by formula (III) is 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide; and

[0287] The optically active form of the compound represented by formula (V) is 6-amino-5-chloro-N-((1R)-1-(5-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)-1,3-thiazolyl)ethyl)pyrimidin-4-carboxamide.

[0288] In the most preferred embodiment, the salt of the optically active form of the compound represented by formula (III) is a salt of (S)-mandelic acid.

[0289] The compounds or salts thereof represented by formula (I), (II), (III), (IV), (V), (VII), or (VIII) may each be solvates (e.g., hydrates, ethanolates, etc.) or nonsolvents (e.g., nonhydrates, etc.), and are included in the compounds or salts thereof represented by formula (I), (II), (III), (IV), (V), (VII), or (VIII).

[0290] Compounds labeled with isotopes and analogs or their salts are also included in compounds or their salts represented by formula (I), (II), (III), (IV), (V), (VII) or (VIII).

[0291] in 1 H is converted to 2 The deuterium transformation form of H(D) is also included in compounds or salts thereof represented by formula (I), (II), (III), (IV), (V), (VII) or (VIII).

[0292] The production method of compound (III) or its salt (production method (A)) and the production method of compound (V) or its salt using compound (III) or its salt obtained in production method (A) (production method (B)) are described in detail below.

[0293] [Production Method (A)]

[0294] Compound (III) or its salt can be produced according to the production method (A) shown in the following scheme.

[0295]

[0296] Where X A It is a leaving group, and other symbols are as defined above.

[0297] By X A Examples of leaving groups include those exemplified above as leaving groups represented by X.

[0298] X A Preferably, it is a hydroxyl group or a chlorine atom.

[0299] The reagents and conditions used in each step of the production method (A) are described in detail.

[0300] [Step A-1]

[0301] Step A-1 is a step in which a compound represented by formula (Aa) (hereinafter referred to as compound (Aa)) or a salt thereof is produced by forming an amide bond between a compound represented by formula (Aa) (hereinafter referred to as compound (Aa)) or a salt thereof and a compound represented by formula (Ab) (hereinafter referred to as compound (Ab)) or a salt thereof.

[0302] The compound (Aa) or its salt may be a commercially available product.

[0303] Examples of salts of compound (Aa) include metal salts, ammonium salts, salts with organic bases, salts with basic amino acids, and the like.

[0304] Preferred examples of metal salts of compound (Aa) include those exemplified as metal salts of compounds (I), (II), (IV), (V), (VII), or (VIII).

[0305] Preferred examples of salts of compound (Aa) and organic bases include those exemplified as salts of compound (I), compound (II), compound (IV), compound (V), compound (VII) or compound (VIII) and organic bases.

[0306] Preferred examples of salts of compound (Aa) and basic amino acids include those exemplified as salts of compounds (I), (II), (IV), (V), (VII), or (VIII) and basic amino acids.

[0307] The compound (Ab) can be produced, for example, according to the method described in WO 2009-006389.

[0308] Examples of salts of compounds (Ab) include salts with inorganic acids, salts with organic acids, salts with acidic amino acids, and the like.

[0309] Preferred examples of salts of compounds (Ab) and inorganic acids include those exemplified as salts of compounds (I), (II), (IV), (V), (VII), or (VIII) and inorganic acids.

[0310] Preferred examples of salts of compounds (Ab) and organic acids include those exemplified as salts of compounds (I), (II), (IV), (V), (VII), or (VIII) and organic acids.

[0311] Preferred examples of salts of compounds (Ab) and acidic amino acids include those exemplified as salts of compounds (I), (II), (IV), (V), (VII), or (VIII) and acidic amino acids.

[0312] The salts of compound (Ab) are particularly preferably hydrochloride salts.

[0313] The method mentioned above, “forming amide bonds,” can be carried out using methods known per se, such as those described in Tetrahedoron, Vol. 61, p. 10827, 2005.

[0314] The method of "forming an amide bond" is preferably achieved by passing X in it. A This is a method for producing compound (Ac) or a salt thereof by condensing a compound (Aa) (an acyl halide) with a compound (Ab) or a salt thereof. Wherein, X is used... A The method of using compounds (Aa) (acyl chloride) containing chlorine atoms is particularly preferred.

[0315] To prepare acyl chloride, X A The hydroxyl group is converted into a chlorine atom by using a chlorinating agent, such as thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, and the like.

[0316] As a "chlorinating agent", thionyl chloride, oxalyl chloride and phosphorus oxychloride are preferred, and oxalyl chloride is particularly preferred.

[0317] When oxalyl chloride is used as a "chlorinating agent", the reaction is preferably carried out in the presence of N,N-dimethylformamide. The amount of N,N-dimethylformamide to be used is a catalytic amount, preferably 0.0001 mol to 0.1 mol per mol of oxalyl chloride, more preferably 0.001 mol to 0.01 mol.

[0318] Although the amount of oxalyl chloride to be used varies depending on the type of solvent and other reaction conditions, it is typically 0.1 mol to 10 mol per mol of substrate compound (Aa) or its salt, preferably 0.8 mol to 1.2 mol.

[0319] Although the reaction using oxalyl chloride as a "chlorinating agent" to prepare acyl chlorides can be carried out without a solvent, the reaction is usually carried out in a solvent. The solvent is not particularly limited, as long as it does not inhibit the reaction and can dissolve the starting compound and additives, and examples include ethers such as diethyl ether, diisopropyl ether, tert-butylmethyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, anisole, and the like; aromatic hydrocarbons such as benzene, toluene, xylene, cumene, chlorobenzene, and similar compounds. Alternatives; saturated hydrocarbons, such as hexane, heptane, pentane, cyclohexane, methylcyclohexane, isooctane, petroleum ether, and the like; halogenated hydrocarbons, such as chloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethane, and the like; nitriles, such as acetonitrile, propionitrile, and the like; sulfoxides, such as dimethyl sulfoxide, and the like; sulfones, such as dimethyl sulfone, sulfolane, and the like; ketones, such as acetone, ethyl methyl ketone, methyl isopropyl ketone, methyl butyl ketone, and the like; nitromethane, and the like. These solvents can be mixed in appropriate proportions. Ethers are preferred as solvents used in reactions that use oxalyl chloride as a "chlorinating agent" to prepare acyl chlorides, and 1,2-dimethoxyethane is particularly preferred.

[0320] The amount of solvent to be used is appropriately determined based on the solubility of the substrate compound (Aa) or its salt, and other factors. For example, when an ether (preferably 1,2-dimethoxyethane) is used as the solvent, the reaction can be carried out with almost no solvent or in a solvent containing 100 parts by weight or less of the substrate compound (Aa) or its salt per part by weight, preferably in a solvent containing 1 to 10 parts by weight of the substrate compound (Aa) or its salt per part by weight.

[0321] The temperature in the reaction for preparing acyl chloride using oxalyl chloride as a "chlorinating agent" is typically -10°C to 80°C, preferably 0°C to 40°C. The reaction time is typically 0.1 hours to 12 hours, preferably 0.5 hours to 4 hours.

[0322] The acyl chloride of the obtained compound (Aa) can be purified by means known per se (e.g., by concentration, distillation, or evaporation of low-boiling components such as solvents). Preferably, the reaction solution is used directly for the condensation reaction with the compound (Ab) or its salt.

[0323] Although the amount of compound (Ab) or its salt to undergo condensation reaction with the acyl chloride of compound (Aa) varies depending on the type of solvent and other reaction conditions, it is generally 0.1 mol to 10 mol per mol of compound (Aa) or its salt, preferably 0.8 mol to 1.2 mol.

[0324] When using a salt of compound (Ab), it is preferable to pre-convert it to its free form by reacting with a base prior to the condensation reaction with the acyl chloride of compound (Aa). Examples of bases include inorganic and organic bases.

[0325] Examples of inorganic bases include alkali metal hydroxides, such as lithium hydroxide, potassium hydroxide, sodium hydroxide, cesium hydroxide, and the like; alkali metal alkoxides having one to six carbon atoms, such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium propoxide, sodium propoxide, potassium propoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, potassium tert-butoxide, and the like; alkali metal thioalkoxides having one to six carbon atoms, such as sodium methanethiol and the like; carbonates, such as sodium carbonate, potassium carbonate, cesium carbonate, and the like; bicarbonates, such as sodium bicarbonate, potassium bicarbonate, and the like; acetates, such as sodium acetate, potassium acetate, and the like; phosphates, such as tripotassium phosphate, sodium phosphate, and the like; and monohydrogen phosphates, such as dipotassium hydrogen phosphate, disodium hydrogen phosphate, and the like.

[0326] Examples of organic bases include aliphatic amines such as trimethylamine, triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, diethylamine, diisopropylamine, cyclohexylamine, ethylenediamine, 1,8-diazabicyclo[5.4.0]undecene and the like; aromatic amines such as pyridine, picolinate, N,N-dimethylaniline and the like; and basic amino acids such as arginine, lysine, ornithine and the like. These bases can be mixed in appropriate proportions.

[0327] Pyridine is particularly preferred as a base for converting the salt of compound (Ab) into its free form.

[0328] Although the amount of base to be used varies depending on the type of solvent and other reaction conditions, it is typically 0.1 mol to 100 mol of salt per mol of substrate compound (Ab), preferably 0.5 mol to 20 mol, and more preferably 0.8 mol to 5 mol. When the base is liquid, it can also be used as a solvent.

[0329] Although the reaction used to convert the salt of compound (Ab) to its free form can be carried out without a solvent, it is generally carried out in a solvent. The solvent is not particularly limited, as long as it does not inhibit the reaction and can dissolve the starting compound and additives, and examples include ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, anisole, and the like; alcohols such as methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, benzyl alcohol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, and the like; aromatic hydrocarbons such as benzene, toluene, xylene, cumene, chlorobenzene, and the like; and saturated hydrocarbons such as hexane, heptane, pentanol, etc. Alkanes, cyclohexane, methylcyclohexane, isooctane, petroleum ether, and the like; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, formamide, hexamethylphosphoramide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolium ketone, and the like; halogenated hydrocarbons, such as chloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethane, and the like; nitriles, such as acetonitrile, propionitrile, and the like; sulfoxides, such as dimethyl sulfoxide, and the like; sulfones, such as dimethyl sulfone, sulfolane, and the like; ketones, such as acetone, ethyl methyl ketone, methyl isopropyl ketone, methyl butyl ketone, and the like; esters, such as ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate, ethyl formate, and the like; nitromethane; water, and the like. These solvents can be mixed in appropriate proportions. Nitriles are preferred as solvents for reactions used to convert the salt of compound (Ab) into its free form, and acetonitrile is particularly preferred.

[0330] The amount of solvent to be used is appropriately determined based on the solubility of the salt of the substrate compound (Ab) and other factors. For example, when a nitric acid (preferably acetonitrile) is used as the solvent, the reaction can be carried out with almost no solvent or in a solvent of 100 parts by weight or less per part by weight of the salt of the substrate compound (Ab), preferably in a solvent of 1 to 10 parts by weight per part by weight of the salt of the substrate compound (Ab).

[0331] The temperature used in the reaction to convert to the free form is typically -20°C to 40°C, preferably -10°C to 20°C. The reaction time is typically 0.01 hours to 2 hours, preferably 0.1 hours to 1 hour.

[0332] The compound (Ab) obtained in the reaction used to convert it to its free form can be separated and purified by means known per se (concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, and similar methods). Alternatively, the reaction solution can be used directly for the condensation reaction with the acyl chloride of the compound (Aa).

[0333] Condensation reactions are typically carried out in a solvent. The solvent is not particularly limited, as long as it does not inhibit the reaction and can dissolve the starting compound and additives. Examples include ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, anisole, and the like; aromatic hydrocarbons such as benzene, toluene, xylene, cumene, chlorobenzene, and similar compounds. Alternatives; saturated hydrocarbons, such as hexane, heptane, pentane, cyclohexane, methylcyclohexane, isooctane, petroleum ether, and the like; halogenated hydrocarbons, such as chloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethane, and the like; nitriles, such as acetonitrile, propionitrile, and the like; sulfoxides, such as dimethyl sulfoxide and the like; sulfones, such as dimethyl sulfone, sulfolane, and the like; ketones, such as acetone, ethyl methyl ketone, methyl isopropyl ketone, methyl butyl ketone, and the like; nitromethane and the like. These solvents can be mixed in appropriate proportions. Ethers are preferred as solvents used in the “condensation reaction” mentioned above, and 1,2-dimethoxyethane is particularly preferred.

[0334] The amount of solvent to be used depends appropriately on the solubility of the acyl chloride of the substrate compound (Aa) and the compound (Ab) or its salt, among other factors. For example, when an ether (preferably 2-dimethoxyethane) is used as the solvent, the reaction can be carried out with almost no solvent or in a solvent containing 100 parts by weight or less of the acyl chloride of the substrate compound (Aa) per part by weight, preferably in a solvent containing 1 to 10 parts by weight of the acyl chloride of the substrate compound (Aa) per part by weight.

[0335] The temperature in the condensation reaction is typically from 0°C to 120°C, preferably from 10°C to 70°C. The reaction time is typically from 0.1 hours to 12 hours, preferably from 0.5 hours to 6 hours.

[0336] The compound (Ac) or its salt obtained in the condensation reaction can be separated and purified by means known per se (concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, and similar means). The compound (Ac) or its salt is preferably separated and purified by crystallization, particularly preferably by crystallization in the presence of water.

[0337] [Step A-2]

[0338] Step A-2 is the step of producing compound (I) or its salt as a substrate for asymmetric reduction by subjecting compound (Ac) or its salt to imine.

[0339] When PG is a group represented by formula (VI-1), react the compound (Ac) or a salt thereof with the compound or a salt thereof represented by formula (VI-1'):

[0340]

[0341] Each of these symbols is as defined above (hereinafter referred to as compound (VI-1')).

[0342] When PG is a group represented by formula (VI), react the compound (Ac) or a salt thereof with the compound or a salt thereof represented by formula (VI'):

[0343]

[0344] Each of these symbols is as defined above (hereinafter referred to as compound (VI')).

[0345] Examples of salts of compound (VI-1') or compound (VI') include salts with inorganic acids, salts with organic acids, salts with acidic amino acids, and the like.

[0346] Preferred examples of salts of compound (VI-1') or compound (VI') with inorganic acids include those exemplified as salts of compounds (I), (II), (IV), (V), (VII), or (VIII) with inorganic acids.

[0347] Preferred examples of salts of compound (VI-1') or compound (VI') with organic acids include those exemplified as salts of compound (I), compound (II), compound (IV), compound (V), compound (VII) or compound (VIII) with organic acids.

[0348] Preferred examples of a salt of compound (VI-1') or compound (VI') with an acidic amino acid include those exemplified as salts of compound (I), compound (II), compound (IV), compound (V), compound (VII) or compound (VIII) with an acidic amino acid.

[0349] Although the amount of compound (VI-1') or its salt, or compound (VI') or its salt, used varies depending on the type of solvent and other reaction conditions, it is generally from 0.1 mol to 100 mol per mol of compound (Ac) or its salt, preferably from 0.5 mol to 20 mol, and more preferably from 0.8 mol to 5 mol. When compound (VI-1') or compound (VI') is a liquid, it can also be used as a solvent.

[0350] When using a salt of compound (VI-1') or compound (VI'), it is preferably converted to its free form beforehand by reacting with a base or acid.

[0351] In the reaction of step A-2, additives such as bases, acids, salts, and others may be added if necessary. Additives may be used in mixtures of two or more. Additives may be added to the reaction vessel before or during the reaction.

[0352] Examples of bases that can be added to the reaction system in step A-2 include inorganic bases and organic bases.

[0353] Examples of inorganic bases include alkali metal hydroxides, such as lithium hydroxide, potassium hydroxide, sodium hydroxide, cesium hydroxide, and the like; alkali metal alkoxides having one to six carbon atoms, such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium propoxide, sodium propoxide, potassium propoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, potassium tert-butoxide, and the like; alkali metal thioalkoxides having one to six carbon atoms, such as sodium methanethiol and the like; carbonates, such as sodium carbonate, potassium carbonate, cesium carbonate, and the like; bicarbonates, such as sodium bicarbonate, potassium bicarbonate, and the like; acetates, such as sodium acetate, potassium acetate, and the like; phosphates, such as tripotassium phosphate, sodium phosphate, and the like; and monohydrogen phosphates, such as dipotassium hydrogen phosphate, disodium hydrogen phosphate, and the like.

[0354] Examples of organic bases include aliphatic amines such as trimethylamine, triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, diethylamine, diisopropylamine, cyclohexylamine, ethylenediamine, and the like; aromatic amines such as pyridine, picolinate, N,N-dimethylaniline, and the like; and basic amino acids such as arginine, lysine, ornithine, and the like.

[0355] Although the amount of base to be used varies depending on the type of solvent and other reaction conditions, it is typically about 0.01 mol or more per mol of substrate compound (Ac) or its salt. Base can also be used as a solvent.

[0356] Examples of acids that can be added to the reaction system in step A-2 include inorganic acids (particularly hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid, carbonic acid, bicarbonate, and the like); carboxylic acids (i.e., compounds having one or more carboxyl groups; particularly formic acid, acetic acid, trifluoroacetic acid, benzoic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, and the like); acidic amino acids (particularly aspartic acid, glutamic acid, and the like); sulfonic acids (i.e., compounds having one or more sulfonyl groups; particularly methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and the like); and Lewis acids (particularly aluminum chloride, tin chloride, zinc chloride, zinc bromide, titanium tetrachloride, boron trifluoride-ethyl ether complex, and the like). When necessary, acids can be used as a mixture of two or more acids.

[0357] Although the amount of acid to be used varies depending on the type of solvent and other reaction conditions, it is typically about 0.01 mol or more per mol of substrate compound (Ac) or its salt. Acids can also be used as solvents.

[0358] In addition to the salts exemplified as “inorganic bases” mentioned above, examples of salts that can be added to the reaction system of step A-2 include salts containing “acids” mentioned above as acid components.

[0359] Although the amount of salt to be used varies depending on the type of solvent and other reaction conditions, it is typically about 0.01 mol to 100 mol per mol of substrate compound (Ac) or its salt.

[0360] As an additive used in the reaction of step A-2, an acid is preferred, with acetic acid, p-toluenesulfonic acid (which can be used as a monohydrate) and zinc chloride being more preferred, and acetic acid being particularly preferred.

[0361] Although the reaction in step A-2 can be carried out without a solvent, it is typically carried out in a solvent. The solvent is not particularly limited, provided it does not inhibit the reaction and can dissolve the starting material compounds and additives. Examples include ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, anisole, and the like; alcohols such as methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, benzyl alcohol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, and the like; and aromatic hydrocarbons such as benzene, toluene, xylene, cumene, chlorobenzene, and the like. The solvents include: saturated hydrocarbons such as hexane, heptane, pentane, cyclohexane, methylcyclohexane, isooctane, petroleum ether, and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, formamide, hexamethylphosphoramide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolium ketone, and the like; halogenated hydrocarbons such as chloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethane, and the like; nitriles such as acetonitrile, propionitrile, and the like; sulfoxides such as dimethyl sulfoxide and the like; sulfones such as dimethyl sulfone, sulfolane, and the like; esters such as ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate, ethyl formate, and the like; nitromethane; and water and the like. These solvents can be mixed in appropriate proportions.

[0362] Ethers, alcohols, and aromatic hydrocarbons are preferred solvents for the reaction in step A-2, with tetrahydrofuran, methanol, ethanol, and toluene being more preferred, and ethanol being particularly preferred.

[0363] The amount of solvent to be used depends appropriately on the solubility of compound (Ac) or its salt, compound (VI-1') or its salt, or compound (VI') or its salt, and others. For example, when an ether (preferably tetrahydrofuran), an alcohol (preferably methanol, ethanol), or an aromatic hydrocarbon (preferably toluene) is used as a solvent, the reaction can be carried out with almost no solvent or in a solvent of 100 parts by weight or less per part by weight of the substrate compound (Ac) or its salt, preferably in a solvent of 1 to 10 parts by weight per part by weight of the substrate compound (Ac) or its salt.

[0364] The temperature in the reaction of step A-2 is typically from 0°C to 180°C, preferably from 20°C to 120°C. The reaction time is typically from 0.1 hours to 24 hours, preferably from 0.5 hours to 12 hours.

[0365] Since water is generated during the reaction process in step A-2, dehydration can be achieved by adding molecular sieves to the reaction solution during the reaction or by using a Dean-Stark water separator or other methods.

[0366] The compound (I) or its salt in the reaction of step A-2 can be separated and purified by means known to them (concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and similar means).

[0367] [Step A-3]

[0368] Step A-3 is the step of producing compound (II) or its salt by subjecting compound (I) or its salt to an asymmetric reduction reaction.

[0369] The “asymmetric reduction reaction” is preferably carried out by subjecting compound (I) or its salt to a hydrogenation reaction in the presence of an organometallic complex.

[0370] In addition to "transition metal complexes (organo-transition metal complexes)," examples of "organo-metal complexes" include typical metal complexes such as boron complexes, aluminum complexes, gallium complexes, and the like.

[0371] "Organometallic complex" is preferably "transition metal complex (organotransition metal complex)".

[0372] Examples of “transition metal complexes” include compounds prepared by coordinating a “ligand” (preferably an optically active “ligand”) with a “transition metal” capable of catalyzing asymmetric hydrogenation reactions. Examples of “ligands” include monophosphine ligands, diphosphine ligands, amine ligands, diamine ligands, phosphineamine ligands, and the like, and include the specific examples described herein and their optical isomers. The valence of the “transition metal” is, for example, 0 to 6, preferably 0 to 4, and particularly preferably 0 to 3.

[0373] Preferred examples of "transition metal complexes" include rhodium complexes, ruthenium complexes, iridium complexes, palladium complexes, nickel complexes, copper complexes, osmium complexes, platinum complexes, iron complexes, gold complexes, silver complexes, zinc complexes, titanium complexes, cobalt complexes, zirconium complexes, samarium complexes, and the like; more preferably, rhodium complexes, ruthenium complexes, iridium complexes, palladium complexes, nickel complexes, and copper complexes; even more preferably, rhodium complexes, ruthenium complexes, palladium complexes, and iridium complexes; still more preferably, rhodium complexes and iridium complexes; and particularly preferred, iridium complexes.

[0374] Specific examples of rhodium, ruthenium, iridium, palladium, nickel, and copper complexes in the term "transition metal complex" are shown below, wherein, in the transition metal complex, L is a diphosphine ligand, a PN ligand, or two phosphine ligands (two monophosphine ligands, each monophosphine ligand being the same or different), and Ar is a benzene optionally having a substituent (preferably C). 1-6 alkyl groups), Cp * It is pentamethylcyclopentadienyl, Cp is cyclopentadienyl, cod is 1,5-cyclooctadiene, Tf is trifluoromethanesulfonyl, nbd is norbornene, Ph is phenyl, Ac is acetyl, Et is ethyl, dmf is N,N-dimethylformamide, and 2-methylallyl is n- 3 -2-Methylallyl, en is ethylenediamine, dpen is 1,2-diphenylethylenediamine, daipen is 1,1-di(4-anisinyl)-2-isopropyl-1,2-ethylenediamine, and n is an integer of 1 or greater. 1,2-Diphenylethylenediamine and 1,1-di(4-anisinyl)-2-isopropyl-1,2-ethylenediamine can be in (R)-form, (S)-form, and mixtures of (R)-form and (S)-form (the ratio is not limited), preferably in optically active form.

[0375] Rhodium complexes: [RhCl(L)]2, [RhBr(L)]2, [RhI(L)]2, [RhCp] * (L)]2, [Rh(cod)(L)]OTf, [Rh(cod)(L)]BF4, [Rh(cod)(L)]ClO4, [Rh(cod)(L)]PF6, [Rh(cod)(L)]SbF6, [R h(cod)(L)]BPh4, [Rh(cod)(L)]B{3,5-(CF3)2C6H3}4, [Rh(nbd)(L)]OTf, [Rh(nbd)(L)]BF4, [Rh(nbd)(L)]C lO4, [Rh(nbd)(L)]PF6, [Rh(nbd)(L)]SbF6, [Rh(nbd)(L)]BPh4, [Rh(nbd)(L)]B{3,5-(CF3)2C6H3}4, [Rh(L) (CH3OH)2]OTf, [Rh(L)(CH3OH)2]BF4, [Rh(L)(CH3OH)2]ClO4, [Rh(L)(CH3OH)2]PF6, [Rh(L)(CH3OH)2]BPh4;

[0376] Ruthenium complex: [RuCl2(L)] n [RuBr2(L)] n [RuI2(L)] n、[Ru(OAc)2(L)]、[Ru(OCOCF3)2(L)]、(NH2Me2)[{RuCl(L)}2(μ-Cl) 3]、(NH2Et2)[{RuCl(L)}2(μ-Cl)3]、(NH2Me2)[{RuBr(L)}2(μ-Br)3 ]、(NH2Et2)[{RuBr(L)}2(μ-Br)3]、(NH2Me2)[{RuI(L)}2(μ-I)3]、( NH2Et2)[{RuI(L)}2(μ-I)3]、[Ru2Cl4(L)2(NEt3)]、[RuCl2(L)(dmf) n, [Ru(2-methylallyl)2(L)], [RuCl(Ar)(L)]Cl, [RuCl(Ar)(L)]Br, [RuCl(Ar)(L)]I, [RuCl(Ar)(L)]OTf, [RuCl(Ar)(L)]ClO4, [RuCl(Ar)(L)]PF6, [RuCl(Ar)(L)]BF4, [RuCl(Ar)(L)]BPh4, [RuBr(Ar)(L)]Cl, [RuBr(Ar)(L)]Br, [RuBr(Ar)(L)]I, [RuI(Ar)(L)]Cl, [RuI(Ar)(L)]Br, [RuI(Ar)(L)]I, [Ru(L)](OTf)2, [Ru(L)](BF4)2, [Ru(L)](ClO4)2, [Ru(L)](PF6)2, [Ru(L)](BPh4)2, [RuH(L)2]Cl, [RuH(L)2]OTf, [RuH(L)2]BF4, [RuH(L)2]ClO4, [RuH(L)2]PF6, [RuH(L)2]BPh4, [RuH(CH3CN)(L)]Cl, [RuH(CH3CN)(L)]OTf, [RuH(CH3CN)(L)]BF4, [RuH(CH3CN)(L)]ClO4, [RuH(CH3CN)(L)]PF6, [RuH(CH3CN)(L)]BPh4, [RuCl(L)]OTf, [RuCl(L)]BF4, [RuCl(L)]ClO4, [RuCl(L)]PF6, [RuCl(L)]BPh4, [RuBr(L)]OTf, [RuBr(L)]BF4, [RuBr(L)]ClO4, [RuBr(L)]PF6, [RuBr(L)]BPh4, [RuI(L)]OTf, [RuI(L)]BF4, [RuI(L)]ClO4, [RuI(L)]PF6, [RuI(L)]BPh4, [RuCl2(L)(en)], [RuCl2(L)(dpen)], [RuCl2(L)(daipen)], [RuH(η 1 -BH4)(L)(en)], [RuH(η 1 -BH4)(L)(daipen)], [RuH(η 1 -BH4)(L)(dpen)]

[0377] (Besides en, dpen, and daipen, examples of diamine ligands corresponding to en, dpen, and daipen as diamine ligands in [RuCl2(L)(en)], [RuCl2(L)(dpen)], and [RuCl2(L)(daipen)] include 1,2-cyclohexanediamine, 1,2-cycloheptanediamine, 2,3-dimethylbutanediamine, 1-methyl-2,2-diphenyl-1,2-ethylenediamine, 1-isobutyl ...diphenyl-2,2-diphenyl-2,2-diphenyl-2,2-diphenyl-2,2-diphenyl-2,2-diphenyl-2,2-diphenyl-2,2-diphenyl-2,2-diphenyl-2,2-diphenyl-2,2-diphenyl-2,2-diphenyl-2,2-diphenyl-2,2-diphenyl-2,2-diphenyl-2,2-diphenyl-2,2-diphenyl-2,2-diphenyl-2,2-diphenyl Propyl-2,2-diphenyl-1,2-ethylenediamine, 1,1-di(4-anisinyl)-2-methyl-1,2-ethylenediamine, 1,1-di(4-anisinyl)-2-isobutyl-1,2-ethylenediamine, 1,1-di(4-anisinyl)-2-benzyl-1,2-ethylenediamine, 1-methyl-2,2-dinathyl-1,2-ethylenediamine, 1-isobutyl-2,2-dinathyl-1,2-ethylenediamine, 1-isopropyl-2,2-dinathyl-1,2-ethylenediamine, propylenediamine, butylenediamine, phenylenediamine and the like);

[0378] Iridium complexes: [IrCl(L)]2, [IrBr(L)]2, [IrI(L)]2, [IrCp] * (L)]2, [Ir(cod)(L)]OTf, [Ir(cod)(L)]BF4, [Ir(cod)(L)]ClO4, [Ir(cod)(L)]PF6, [Ir (cod)(L)]SbF6, [Ir(cod)(L)]BPh4, [Ir(nbd)(L)]B{3,5-(CF3)2C6H3}4, [Ir(nbd)(L)] OTf, [Ir(nbd)(L)]BF4, [Ir(nbd)(L)]ClO4, [Ir(nbd)(L)]PF6, [Ir(nbd)(L)]SbF6, [Ir(nbd)(L)]BPh4, [Ir(nbd)(L)]B{3,5-(CF3)2C6H3}4, [Ir(π-allyl)(L)((C,O)-substituted benzoate)];

[0379] Palladium complexes: [PdCl2(L)], [PdBr2(L)], [PdI2(L)], [Pd(π-allyl)(L)]Cl, [Pd(π-allyl)(L)]OTf, [Pd(π-allyl)(L)]BF4, [Pd(π-allyl)(L)]ClO4, [Pd(π-allyl)(L)]PF6, [Pd(π-allyl)(L)]BPh4, [Pd(L)](OTf)2, [Pd(L)](BF4)2, [Pd(L)](ClO4)2, [Pd(L)](PF6)2, [Pd(L)](BPh4)2, [Pd(L)2], [Pd(L) )2](OAc)2, [Pd(L)(H2O)2](OTf)2, [Pd(L)(H2O)2](BF4)2, [Pd(L)(H2O)2](ClO4)2, Pd(L)(H2O)2](PF6)2, [Pd(L)(H2O)2](BPh4)2, [{Pd( L)}2(μ-OH)2](OTf)2, [{Pd(L)}2(μ-OH)2](BF4)2, [{Pd(L)}2(μ-OH)2](ClO4)2, [{Pd(L)}2(μ-OH)2](PF6)2, [{Pd(L)}2(μ-OH)2](BPh4)2;

[0380] Nickel complexes: [NiCl2(L)], [NiBr2(L)], [NiI2(L)], [Ni(π-allyl)(L)]Cl, [Ni(cod)(L)], [Ni(nbd)(L)];

[0381] Copper complexes: [CuCl(L)], [CuBr(L)], [CuI(L)], [CuH(L)], [Cu(η)] 1 -BH4)(L)], [Cu(Cp)(L)], [Cu(Cp * )(L)], [Cu(L)(CH3CN)2]OTf, [Cu(L)(CH3CN)2]BF4, [Cu(L)(CH3CN)2]ClO4, [Cu(L)(CH3CN)2]PF6, [Cu(L)(CH3CN)2]BPh4

[0382] Examples of the diphosphine ligands mentioned above, represented by L, include:

[0383] 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as BINAP);

[0384] BINAP derivatives, which have substituents such as C on the naphthyl ring of BINAP. 1-6 alkyl groups, C 6-14Aryl groups and similar groups, for example, 2,2'-bis(diphenylphosphino)-6,6'-dimethyl-1,1'-binaphthyl;

[0385] BINAP derivatives, wherein the naphthyl ring of BINAP is partially hydrogenated, for example, 2,2'-bis(diphenylphosphino)-5,6,7,8,5',6',7',8'-octahydro-1,1'-binaphthyl (H8BINAP);

[0386] BINAP derivatives having one to five substituents, such as C, on the benzene ring bonded to the phosphorus atom of BINAP. 1-6 Alkyl groups, halogen atoms, single or double carbon atoms 1-6 alkylamino group, C 1-6 Alkoxy groups, pyrrolyl groups, and similar groups, such as 2,2'-bis[bis(4-chlorophenyl)phosphino]-1,1'-binaphthyl, 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl (tol-BINAP), 2,2'-bis[bis(3,5-dimethylphenyl)phosphino]-1,1'-binaphthyl (xyl-BINAP), 2,2'-bis[bis(3,5-diethylphenyl)phosphino]-1,1'-binaphthyl, 2,2'-bis[bis(3,5-diisopropylphenyl)phosphino]-1,1'-binaphthyl, 2,2'-bis[bis(3,5-diisopropylphenyl)phosphino]-1,1'-binaphthyl, 2,2'-bis[bis(3,5-di-tert-butylphenyl)phosphino]-1,1'-binaphthyl, 2,2'-bis[bis(4-dimethylaminophenyl)phosphino]-1,1'-binaphthyl, 2,2'-bis[bis(4-dimethylamino-3-diethyl ... [5-Dimethylphenyl)phosphino]-1,1'-binaphine, 2,2'-bis[bis(4-dimethylamino-3,5-diethylphenyl)phosphino]-1,1'-binaphine, 2,2'-bis[bis(4-dimethylamino-3,5-diisopropylphenyl)phosphino]-1,1'-binaphine, 2,2'-bis[bis(4-diethylamino ... [4-(pyrrolidone-1-yl)phenyl]phosphino]-1,1'-binaphine, 2,2'-bis(di-p-methoxyphenylphosphino)-1,1'-binaphine, 2,2'-bis[bis(3,5-dimethyl-4-methoxyphenyl)phosphino]-1,1'-binaphine, 2,2'-bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-1,1'-binaphine (DTBM-BINAP);

[0387] 2,2'-bis(dicyclohexylphosphino)-6,6'-dimethyl-1,1'-biphenyl (BICHEP), 2,2'-bis(diphenylphosphino)-6,6'-dimethoxybiphenyl (MeO-BIPHEP), 2,3-bis(diphenylphosphino)butane (CHIRAPHOS), 1-cyclohexyl-1,2-bis(diphenylphosphino)ethane (CYCPHOS), 1,2-bis[(2-methoxyphenyl)phenylphosphino]ethane (DIPAMP), 1,2-bis(diphenylphosphino)propane (PROPHOS), 2,4-bis(diphenylphosphino)pentane (SKEWPHOS), and those with one to five substituents, such as C, on the benzene ring bonded to the phosphorus atom of SKEWPHOS. 1-6 SKEWPHOS derivatives with alkyl groups and similar groups, 1-[1',2-bis(diphenylphosphino)ferrocene]ethylenediamine (BPPFA), 1-substituted -3,4-bis(diphenylphosphino)pyrrolidine (DEGPHOS), 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane (DIOP), substituted -1,2-bis-n-phosphine (DuPHOS), substituted -1,2-bis-n-phosphine ethane ( BPE), 5,6-bis(diphenylphosphino)-2-norbornene (NORPHOS), N,N'-bis(diphenylphosphino)-N,N'-bis(1-phenylethyl)ethylenediamine (PNNP), 2,2'-diphenylphosphino-1,1'-dicyclopentyl (BICP), 4,12-bis(diphenylphosphino)-[2,2]-p-cycloarane (PhanePHOS), N-substituted-N-diphenylphosphino-1-[2-(diphenylphosphino)ferrocene Ethylamine (BoPhoz), 1-[2-(disubstituted phosphino)ferrocene]ethyl-disubstituted phosphine (Josiphos), 1-[2-(2'-disubstituted phosphinophenyl)ferrocene]ethyl-disubstituted phosphine (Walphos), 2,2'-bis(α-N,N-dimethylaminophenylmethyl)-1,1'-bis(disubstituted phosphino)ferrocene (Mandyphos), disubstituted phosphino-2-[α-(N,N-dimethylaminophenylmethyl)-1,1'-bis(disubstituted phosphino)ferrocene (Mandyphos), disubstituted phosphino-2-[α-(N,N-dimethylaminophenylmethyl)-1,1'-bis(disubstituted phosphino)ferrocene [-dimethylamino)-o-disubstituted phosphinophenyl-methyl] ferrocene (Taniaphos), 1,1-bis(disubstituted phosphino)ferrocene (FerroTANE), 7,7'-bis(diphenylphosphino)-3,3',4,4'-tetrahydro-4,4'-dimethyl-8,8'-bis(2H-1,4-benzoxazine) (Solphos), substituted -1,1'-bis-phosphinoferrocene (Ferrocelane), and the like.

[0388] The diphosphine ligands mentioned above are preferably in an optically active form.

[0389] The examples of two phosphine ligands (two monophosphine ligands, each monophosphine ligand may be the same or different) denoted by L mentioned above include:

[0390] Compounds represented by formula (IX):

[0391]

[0392] in

[0393] A is an optically active framework; and

[0394] R 8a and R 8b Each of the Cs is independently and arbitrarily replaced. 1-6 Alkyl groups, or optionally substituted C groups 6-14 aryl group;

[0395] Compounds represented by formula (X):

[0396]

[0397] in

[0398] A 1 and A 2 Each is an independent optically activated carbon framework;

[0399] R 9 It is a hydrogen atom, with the C atoms optionally substituted. 1-6 alkyl groups, optionally substituted C 6-14 aryl group, optionally substituted amino group, optionally substituted hydroxyl group, ferrocene or ferrocene methyl group; and

[0400] A 1 and A 2 The atoms can be combined with adjacent atoms to form 4- to 8-membered rings;

[0401] Compounds represented by formula (XI):

[0402]

[0403] in

[0404] R 10 and R 11 Each of the Cs is independently and arbitrarily replaced. 1-6 Alkyl groups, or optionally substituted C groups 6-14 aryl group;

[0405] R 12 It is a hydrogen atom, with the C atoms optionally substituted. 1-6 alkyl groups, optionally substituted C 6-14An aryl group, an optionally substituted hydroxyl group, or an optionally substituted ferrocene group; and

[0406] R 10 and R 11 Combining, optionally, with adjacent atoms, they form 4- to 8-membered rings; and

[0407] Compounds represented by formula (XII):

[0408]

[0409] in

[0410] R 13 and R 14 Each is an independent hydrogen atom, and the C atoms are optionally substituted. 1-6 Alkyl groups or optionally substituted C 6-14 aryl group;

[0411] R 15 and R 16 Each of them is independently and arbitrarily replaced by C. 1-6 Alkyl groups, or optionally substituted C groups 6-14 aryl group;

[0412] R 13 and R 14 Combining, optionally, with adjacent atoms, they form 4- to 8-membered rings; and

[0413] R 15 and R 16 They can be combined with adjacent atoms to form 4- to 8-membered rings.

[0414] The examples of optically active frameworks represented by A mentioned above include frameworks represented by the following formula.

[0415]

[0416] in

[0417] Carbon atoms marked with an asterisk (*) are asymmetric carbon atoms; and

[0418] The bond axis marked with an asterisk (*) is an asymmetric axis.

[0419] By R 8a Or R 8b The term "C that is optionally replaced" indicates 1-6 Examples of "substituents" for "alkyl groups" include the "substituents" mentioned above. (The last part, "by R," appears to be a fragment and doesn't translate directly.) 8a Or R 8b The term "C that is optionally replaced" indicates 1-6The number of substituents at the substituted positions in the "alkyl group" is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, the corresponding substituents may be the same or different.

[0420] By R 8a Or R 8b The term "C that is optionally replaced" indicates 6-14 The substituents and their number in the "aryl group" are similar to those mentioned above, which are composed of R. 7 The term "C that is optionally replaced" indicates 6-14 Those exemplified in "aryl groups".

[0421] By A 1 Or A 2 Examples of optically active frameworks include those represented by the following formula.

[0422]

[0423] Each symbol is defined as described above.

[0424] When A 1 and A 2 Examples of compounds (X) that combine with adjacent atoms to form 4- to 8-membered rings include:

[0425] Compounds represented by formula (Xa):

[0426]

[0427] in

[0428] R Xa and R Xb Each is C independently 1-6 alkyl groups, C 3-10 Cycloalkyl groups, optionally substituted C 6-14 aryl group, C 7-16 Aryl group, optionally substituted ferrocene or ferrocene methyl group, and

[0429] Other symbols are as defined above;

[0430] Compounds represented by formula (Xb):

[0431]

[0432] in

[0433] R Xc and R Xd Each is an independent hydrogen atom, C 1-6 alkyl groups, C 3-10 Cycloalkyl groups, optionally substituted C6-14 aryl group or C 7-16 Aryl groups;

[0434] R Xe and R Xf Each is independently a hydrogen atom or an optionally substituted hydroxyl group, and

[0435] Other symbols are as defined above;

[0436] Compounds represented by formula (Xc):

[0437]

[0438] Each symbol is as defined above;

[0439] Compounds represented by formula (Xd):

[0440]

[0441] in

[0442] R Xg and R Xh Each is an independent hydrogen atom, C 1-6 alkyl groups, C 3-10 Cycloalkyl groups, optionally substituted C 6-14 aryl group or C 7-16 Aryl groups, and

[0443] Other symbols are as defined above; and

[0444] Compounds represented by formula (Xe):

[0445]

[0446] in

[0447] R Xi and R Xj Each is an independent hydrogen atom, C 1-6 alkyl groups, C 3-10 Cycloalkyl groups, optionally substituted C 6-14 aryl group or C 7-16 Aryl groups, and

[0448] Other symbols are as defined above.

[0449] By R Xa R Xb R Xc R Xd R Xg R Xh R Xi Or RXj The term "C that is optionally replaced" indicates 6-14 Preferred examples of substituents for the "aryl group" include halogen atoms, C atoms, and C atoms. 1-6 alkyl groups and C 1-6 Alkoxy group.

[0450] By R Xa Or R Xb Preferred examples of substituents in the term "optionally substituted ferrocene" include C. 1-6 Alkyl groups.

[0451] By R Xe Or R Xf Preferred examples of substituents representing "optionally substituted hydroxyl groups" include C 1-6 alkyl groups and C 7-16 Aryl group.

[0452] R 9 Preferably, it is a hydrogen atom, or optionally, a substituted C atom. 1-6 alkyl groups, optionally substituted C 6-14 An aryl group, an optionally substituted amino group, or an optionally substituted hydroxyl group.

[0453] "C can be arbitrarily replaced" 1-6 Preferred examples of substituents for "alkyl group" include C 6-14 Aryl group.

[0454] "C can be arbitrarily replaced" 6-14 Preferred examples of substituents for the "aryl group" include halogen atoms, C atoms, and C atoms. 1-6 alkyl groups and C 1-6 Alkoxy group.

[0455] Preferred examples of substituents for “optionally substituted amino groups” include:

[0456] (1)Optionally having 1 to 3 Cs 1-6 alkoxy group or C 1-6 C of alkyl group 6-14 C with aryl group substitution 1-6 alkyl groups, and

[0457] (2) Optionally having 1 to 3 Cs 1-6 alkoxy group or C 1-6 C of alkyl group 6-14 Aryl group.

[0458] Preferred examples of substituents for “optionally substituted hydroxyl groups” include

[0459] (1)Optionally having 1 to 3 Cs1-6 alkoxy group or C 1-6 C of alkyl group 6-14 C with aryl group substitution 1-6 alkyl groups, and

[0460] (2) Optionally having 1 to 3 Cs 1-6 alkoxy group or C 1-6 C of alkyl group 6-14 Aryl group.

[0461] When R 10 and R 11 When combined with adjacent atoms to form 4- to 8-membered rings, the cyclic structure portion in the compound (XI), and when R 13 and R 14 Examples of cyclic structures in compounds (XII) that combine with adjacent atoms to form 4- to 8-membered rings include

[0462] The ring-shaped structural portion represented by equation (XI-1), equation (XI-2), or equation (XI-3):

[0463]

[0464] Each symbol is as defined above;

[0465] The ring-shaped structure represented by equation (XI-a):

[0466]

[0467] in

[0468] R XIa1 R XIa2 R XIa3 and R XIa4 Each of them is independently and arbitrarily replaced by C. 6-14 aryl group, and

[0469] Other symbols are as defined above;

[0470] The ring-shaped structure represented by equation (XI-b):

[0471]

[0472] in

[0473] R XIb1 R XIb2 R XIb3 R XIb4 R XIb5 R XIb6 R XIb7 R XIb8 RXIb9 and R XIb10 Each is independently a hydrogen atom, a halogen atom, and a carbon atom. 1-6 alkyl groups, optionally substituted C 6-14 aryl group or C 1-6 alkoxy group;

[0474] R XIb1 and R XIb3 The atoms can be combined with adjacent atoms to form 4- to 8-membered rings;

[0475] R XIb2 and R XIb4 The atoms can be combined with adjacent atoms to form 4- to 8-membered rings;

[0476] R XIb5 and R XIb7 The atoms can be combined with adjacent atoms to form 4- to 8-membered rings;

[0477] R XIb6 and R XIb8 Combining, optionally, with adjacent atoms, they form 4- to 8-membered rings; and

[0478] Other symbols are as defined above;

[0479] The ring-shaped structure represented by equation (XI-c):

[0480]

[0481] in

[0482] R XIc1 and R XIc2 Each is independently a hydrogen atom, a halogen atom, and a carbon atom. 1-6 alkyl groups, optionally substituted C 6-14 aryl group or C 1-6 alkoxy group; and

[0483] Other symbols are as defined above;

[0484] The ring-shaped structure represented by equation (XI-d):

[0485]

[0486] Where R XId1 R XId2 R XId3 R XId4 R XId5 and R XId6 Each is independently a hydrogen atom, a halogen atom, and a carbon atom. 1-6 alkyl groups, optionally substituted C 6-14 aryl group or C1-6 alkoxy group; and

[0487] Other symbols are as defined above;

[0488] The ring-shaped structure represented by equation (XI-e):

[0489]

[0490] in

[0491] R XIe1 R XIe2 R XIe3 and R XIe4 Each is independently a hydrogen atom, a halogen atom, and a carbon atom. 1-6 alkyl groups, optionally substituted C 6-14 aryl group or C 1-6 Alkoxy group;

[0492] R XIe5 and R XIe6 Each is an independent hydrogen atom, C 1-6 Alkyl groups or optionally substituted C 6-14 aryl group; and

[0493] Other symbols are as defined above; and

[0494] The ring-shaped structure represented by equation (XI-f):

[0495]

[0496] in

[0497] R XIf1 and R XIf2 Each is independently a hydrogen atom, a halogen atom, or a carbon atom. 1-6 alkyl groups; and

[0498] Other symbols are as defined above.

[0499] By R XIa1 R XIa2 R XIa3 R XIa4 R XIb1 R XIb2 R XIb3 R XIb4 R XIb5 R XIb6 R XIb7 R XIb8 R XIb9 R XIb10 R XIc1 R XIc2 R XId1R XId2 R XId3 R XId4 R XId5 R XId6 R XIe1 R XIe2 R XIe3 R XIe4 R XIe5 or R XIe6 The term "C that is optionally replaced" indicates 6-14 Preferred examples of substituents for the "aryl group" include halogen atoms, C atoms, and C atoms. 1-6 alkyl groups and C 1-6 Alkoxy group.

[0500] Preferably, R 10 and R 11 They are combined with adjacent atoms to form 4- to 8-membered rings, and the ring structure is preferably represented by the structure of formula (XI-1).

[0501] Preferably, R 13 and R 14 They are combined with adjacent atoms to form 4- to 8-membered rings, and the ring structure is preferably represented by the structure of formula (XI-1).

[0502] R 12 Preferably, C is optionally substituted. 1-6 alkyl groups, optionally substituted C 6-14 An aryl group or an optionally substituted hydroxyl group.

[0503] "C can be arbitrarily replaced" 1-6 Preferred examples of substituents for "alkyl group" include C 6-14 Aryl group.

[0504] "C can be arbitrarily replaced" 6-14 Preferred examples of substituents for the "aryl group" include halogen atoms, C atoms, and C atoms. 1-6 alkyl groups and C 1-6 Alkoxy group.

[0505] Preferred examples of substituents for “optionally substituted hydroxyl groups” include

[0506] (1) C can be optionally replaced by the following 1-6 Alkyl groups:

[0507] (a) Optionally having 1 to 3 Cs 1-6 alkoxy group or C 1-6 C of alkyl group 6-14 aryl group, or

[0508] (b) Optionally having one or two Cs 1-6 The amino group of the alkyl group,

[0509] (2) Optionally having 1 to 3 Cs 1-6 alkoxy group or C 1-6 C of alkyl group 3-10 Cycloalkyl groups, and

[0510] (3) Optionally having 1 to 3 Cs 1-6 alkoxy group or C 1-6 C of alkyl group 6-14 Aryl group.

[0511] R 15 and R 16 Preferably, each of the Cs is independently and optionally replaced. 1-6 Alkyl groups.

[0512] "C can be arbitrarily replaced" 1-6 The number of substituents at the substituted positions in the "alkyl group" is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, the corresponding substituents may be the same or different.

[0513] "C can be arbitrarily replaced" 1-6 Preferred examples of substituents for the "alkyl group" include those optionally having 1 to 3 carbon atoms. 1-6 alkoxy group or C 1-6 C of alkyl group 6-14 Aryl group.

[0514] When R 15 and R 16 Examples of cyclic structures in compounds (XII) that combine with adjacent atoms to form 4- to 8-membered rings include

[0515] The ring structure portion represented by equation (XI-g):

[0516]

[0517] in

[0518] R XIg1 and R XIg2 Each is an independent hydrogen atom, and the C atoms are optionally substituted. 1-6 alkyl groups, optionally substituted C 3-10 Cycloalkyl groups or optionally substituted C 6-14 aryl group;

[0519] Y is -(CH2)2-, -(CH2)3-, or -CH2-O-CH2-; and

[0520] Other symbols are as defined above; and

[0521] The ring-shaped structure represented by equation (XI-h):

[0522]

[0523] in

[0524] R XIh1 It is a hydrogen atom, a halogen atom, and a carbon atom. 1-6 alkyl groups, optionally substituted C 6-14 aryl group or C 1-6 Alkoxy group;

[0525] R XIh2 It is a hydrogen atom, C 1-6 Alkyl groups or optionally substituted C 6-14 aryl group; and

[0526] Other symbols are as defined above.

[0527] By R XIg1 Or R XIg2 The term "C that is optionally replaced" indicates 1-6 Examples of "substituents" of "alkyl groups" include those mentioned above. At the substituted position, the number of substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, the corresponding substituents may be the same or different.

[0528] By R XIg1 Or R XIg2 The term "C that is optionally replaced" indicates 1-6 Preferred examples of "substituents" of "alkyl groups" include C 1-6 alkyl groups, C 3-10 cycloalkyl groups and C 6-14 Aryl group.

[0529] By R XIg1 Or R XIg2 The term "C that is optionally replaced" indicates 3-10 The "substituents" of the "cycloalkyl group" and their number are similar to those mentioned above, which are composed of R. XIg1 Or R XIg2 The term "C that is optionally replaced" indicates 1-6 Those exemplified in the "alkyl group" section. Preferably, C... 1-6 alkyl groups, C 3-10 cycloalkyl groups and C 6-14 Aryl group.

[0530] By R XIg1 Or R XIg2 The term "C that is optionally replaced" indicates6-14 The "substituents" of the "aryl group" and their number are similar to those mentioned above, which are composed of R. XIg1 Or R XIg2 The term "C that is optionally replaced" indicates 1-6 Those exemplified in the term "alkyl group". Preferably, halogen atoms, C 1-6 alkyl groups, C 3-10 cycloalkyl groups and C 6-14 Aryl group.

[0531] By R XIh1 The term "C that is optionally replaced" indicates 6-14 Preferred examples of "substituents" for "aryl groups" include halogen atoms, C atoms, and C atoms. 1-6 alkyl groups, C 3-10 cycloalkyl groups and C 6-14 Aryl group.

[0532] R XIh1 Preferably, it is a hydrogen atom or a halogen atom.

[0533] By R XIh2 The term "C that is optionally replaced" indicates 6-14 Preferred examples of "substituents" for "aryl groups" include halogen atoms, C atoms, and C atoms. 1-6 alkyl groups, C 3-10 cycloalkyl groups and C 6-14 Aryl group.

[0534] R XIh2 Preferably, it is a hydrogen atom or a carbon atom. 1-6 Alkyl groups.

[0535] The specific examples of the two phosphine ligands (two monophosphine ligands, each monophosphine ligand may be the same or different) denoted by L mentioned above include:

[0536] (3,5-Dioxa-4-phosphacycloheptan[2,1-a;3,4-a']dinaphthyl-4-yl)dimethylamine (MonoPhos)

[0537] (3,5-Dioxa-4-phosphacyclohepta[2,1-a;3,4-a']dinaphthyl-4-yl)benzyl(methyl)amine

[0538] (3,5-Dioxa-4-phosphacyclohepta[2,1-a;3,4-a']dinaphthyl-4-yl)-(1-phenylethyl)amine,

[0539] (3,5-Dioxa-4-phosphacyclohepta[2,1-a;3,4-a']dinaphthyl-4-yl)bis(1-phenylethyl)amine,

[0540] (3,5-dioxa-4-phosphacycloheptan[2,1-a;3,4-a']dinaphthyl-4-yl)-2,5-diphenylpyrrolidine

[0541] (3,5-dioxa-4-phosphacycloheptan[2,1-a;3,4-a']dinaphthyl-4-yl)morpholine (Morfphos)

[0542] (3,5-dioxa-4-phosphacycloheptan[2,1-a;3,4-a']dinaphthyl-4-yl)piperidine (PipPhos),

[0543] 2-(diphenylphosphino)-2'-methoxy-1,1'-binaphthyl (MOP)

[0544] 1-(2-Diphenylphosphino-1-naphthyl)isoquinoline (QUINAP),

[0545] N-Dimethyl-[1,1-spirodiindane-7,7'-diyl]phosphoramide (SIPHOS),

[0546] N-Di[(1-Phenylacetyl]-[1,1-spirodiindane-7,7-diyl]phosphite (SIPHOS-PE),

[0547] (3aR,8aR)-(-)-(2,2-dimethyl-4,4,8,8-tetraphenyl-tetrahydro-[1,3]dioxacyclopenteno[4,5-e][1,3,2]dioxaphosphaheptan-6-yl)dimethylamine,

[0548] (3aS,8aS)-(-)-(2,2-dimethyl-4,4,8,8-tetraphenyl-tetrahydro-[1,3]dioxacyclopenteno[4,5-e][1,3,2]dioxaphosphaheptan-6-yl)dimethylamine,

[0549] 5-[(3aR,8aR)-tetrahydro-2,2-dimethyl-4,4,8,8-tetraphenyl-1,3-dioxacyclopenteno[4,5-e][1,3,2]dioxaphosphaheptan-6-yl]-5H-dibenzo[b,f]azepine,

[0550] 5-[(3aS,8aS)-tetrahydro-2,2-dimethyl-4,4,8,8-tetraphenyl-1,3-dioxacyclopenteno[4,5-e][1,3,2]dioxaphosphaheptan-6-yl]-5H-dibenzo[b,f]azacycloheptantriene,

[0551] N-[(2S,5S)-4,4-diphenyl-3-oxa-1-aza-2-phosphabicyclo[3.3.0]oct-2-yl]dibenzo[b,f]azacycloheptatriene

[0552] And similar items.

[0553] The two phosphine ligands represented by L (two monophosphine ligands, each monophosphine ligand may be the same or different) are preferably in the optically active form.

[0554] Specific examples of PN ligands represented by L include:

[0555] 2-[(6-(diphenylphosphino)spiro[4.4]non-1,6-dien-1-yl]-4,5-dihydro-4-benzyloxazole (Bn-SpinPHOX),

[0556] 2-(2-(diphenylphosphino)phenyl)-4-isopropyl-4,5-dihydrooxazole (iPr-Phox)

[0557] And similar items.

[0558] The PN ligand represented by L is preferably in an optically active form.

[0559] The "ligand" used for "transition metal complexes" is preferably an optically active ligand.

[0560] "Transition metal complexes" can be prepared by means known to themselves from "ligands" and other complexes that serve as transition metal sources (Preparation of rhodium complexes; Journal of the American Chemical Society (J.Am.Chem.Soc.), Vol. 94, p. 6429, 1972; Organic Synthesis (Org.Synth.), Vol. 67, p. 33, 1989; Preparation of ruthenium complexes; Journal of Organic Chemistry (J.Org.Chem.), Vol. 57, p. 4053, 1992; Tetrahedron Asymmetry (Tetrahedron Asym.), Vol. 2, p. 43, 1991; Journal of Organic Chemistry (J.Org.Chem.), Vol. 59, p. 3064, 1994; Angewandte Chemie International). Edition (Angew. Chem. Int. Ed.), Vol. 37, p. 1703, 1998: Preparation of iridium complexes; Journal of Organometallic Chemistry (J. Organomet. Chem.), Vol. 428, p. 213, 1992: Preparation of palladium complexes; Organometallics, Vol. 12, p. 4188, 1993; Journal of the American Chemical Society (J. Am. Chem. Soc.), Vol. 121, p. 5450, 1999: Preparation of nickel complexes; "5th Edition, Jikken Kagaku Koza", Vol. 21, organic transition metal compound, Supermolecular Complex, pp. 293-294 (2004), edited by Japan Chemical Society (Maruzen): Preparation of copper complexes; "5th Edition, Jikken Kagaku Koza", Vol. 21, organic transition metal compound, Supermolecular Complex, pp. 293-294 (2004), edited by Japan Chemical Society (Maruzen): Preparation of copper complexes; KagakuKoza, Vol. 21, organic transition metal compound, Supermolecular Complex, p. 357 (2004), Journal of Organic Chemistry (J.Org.Chem).(Volume 63, page 6090, 1998), and can be separated and purified by known means (e.g., concentration, solvent extraction, fractionation, crystallization, recrystallization, chromatography).

[0561] In the “diphosphine ligand” denoted by L, SKEWPHOS derivatives can be synthesized according to the method described in patent document WO 2013 / 146987, wherein the SKEWPHOS derivatives have one to five substituents, such as C, on a benzene ring bonded to the phosphorus atom of SKEWPHOS. 1-6 Alkyl groups and similar groups.

[0562] Two phosphine ligands represented by L (two monophosphine ligands, each monophosphine ligand may be the same or different) can be prepared by means known per se (Wiley, Phosphorus Ligands in Asymmetric Catalysis, Vol. 1, pp. 5-69, (2008)), and can be separated or purified by means known per se (e.g., concentration, solvent extraction, fractionation, crystallization, recrystallization, chromatography).

[0563] "Transition metal complexes" can also be prepared by adding "ligands" and other complexes that serve as transition metal sources to the reaction system. The "transition metal complexes" can be added directly to the reaction vessel, or they can be prepared by adding the aforementioned "transition metal source" and "ligands" to the reaction vessel. When preparing "transition metal complexes" by adding "transition metal sources" and "ligands" to the vessel, the "ligands" are used in an amount from 1 to 100 times, preferably 1 to 5 times, and even more preferably 1.01 to 2.02 times, relative to the theoretical molar amount required for the preparation of the "transition metal complex," on a molar basis.

[0564] Although the amount of the “transition metal complex” to be used varies depending on the reaction vessel, the manner of the reaction, and other factors, it is, for example, about 1.0 mol to about 0.00001 mol per mol of substrate compound (I) or its salt.

[0565] In step A-3, the “hydrogenation reaction”, hydrogen, metal hydrides, isopropanol, formic acid, benzothiazoline, Hantzsch esters, and the like can be used as hydrogen donors. Hydrogen is preferred.

[0566] When using hydrogen, the hydrogenation reaction can be carried out by a batch process or a continuous process. When the hydrogenation reaction is carried out in the presence of hydrogen, the hydrogen pressure is, for example, from 0.001 atm to 200 atm, preferably from 0.1 atm to 15 atm.

[0567] In step A-3, the “hydrogenation reaction”, additives such as bases, acids, salts, and others may be added if necessary. Additives may be used in mixtures of two or more. Additives may be added to the reaction vessel before or during the “hydrogenation reaction.”

[0568] Examples of bases that can be added to the “hydrogenation reaction” system in step A-3 include inorganic and organic bases.

[0569] Examples of inorganic bases include alkali metal hydroxides, such as lithium hydroxide, potassium hydroxide, sodium hydroxide, cesium hydroxide, and the like; alkali metal alkoxides having one to six carbon atoms, such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium propoxide, sodium propoxide, potassium propoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, potassium tert-butoxide, and the like; alkali metal thioalkoxides having one to six carbon atoms, such as sodium methanethiol and the like; carbonates, such as sodium carbonate, potassium carbonate, cesium carbonate, and the like; bicarbonates, such as sodium bicarbonate, potassium bicarbonate, and the like; acetates, such as sodium acetate, potassium acetate, and the like; phosphates, such as tripotassium phosphate, sodium phosphate, and the like; and monohydrogen phosphates, such as dipotassium hydrogen phosphate, disodium hydrogen phosphate, and the like.

[0570] Examples of organic bases include aliphatic amines such as trimethylamine, triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, diethylamine, diisopropylamine, cyclohexylamine, ethylenediamine, and the like; aromatic amines such as pyridine, picolinate, N,N-dimethylaniline, and the like; and basic amino acids such as arginine, lysine, ornithine, and the like.

[0571] Although the amount of base to be used varies depending on the type of solvent and other reaction conditions, it is typically about 0.01 mol or more per mol of substrate compound (I) or its salt. The base can also be used as a solvent.

[0572] Examples of acids that can be added to the “hydrogenation reaction” system in step A-3 include inorganic acids (particularly hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid, carbonic acid, bicarbonate, and the like); carboxylic acids (i.e., compounds having one or more carboxyl groups; particularly formic acid, acetic acid, trifluoroacetic acid, benzoic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, and the like); acidic amino acids (particularly aspartic acid, glutamic acid, and the like); and sulfonic acids (i.e., compounds having one or more sulfonyl groups; particularly methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and the like). When necessary, acids can be used as a mixture of two or more acids.

[0573] Although the amount of acid to be used varies depending on the type of solvent and other reaction conditions, it is typically about 0.01 mol or more per mol of substrate compound (I) or its salt. The acid can also be used as a solvent.

[0574] Besides the salts exemplified as “inorganic bases” mentioned above, examples of salts that can be added to the “hydrogenation reaction” system in step A-3 include salts containing “acids” mentioned above as acid components.

[0575] Although the amount of salt to be used varies depending on the type of solvent and other reaction conditions, it is typically about 0.01 mol to 100 mol per mol of substrate compound (I) or its salt.

[0576] The “hydrogenation reaction” in step A-3 is typically carried out in a solvent. The solvent is not particularly limited, provided it does not inhibit the reaction and can dissolve the starting material compounds, organometallic complexes, and additives. Examples include ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, anisole, and the like; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, benzyl alcohol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, and the like; aromatic hydrocarbons such as benzene, toluene, xylene, cumene, chlorobenzene, and the like; and saturated hydrocarbons such as hexane, heptane, etc. Alkanes, pentanes, cyclohexanes, methylcyclohexanes, isooctanes, petroleum ethers, and the like; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, formamide, hexamethylphosphoramide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolium ketone, and the like; halogenated hydrocarbons, such as chloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethane, and the like; nitriles, such as acetonitrile, propionitrile, and the like; sulfoxides, such as dimethyl sulfoxide, and the like; sulfones, such as dimethyl sulfone, sulfolane, and the like; ketones, such as acetone, ethyl methyl ketone, methyl isopropyl ketone, methyl butyl ketone, and the like; esters, such as ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate, ethyl formate, and the like; nitromethanes; water, and the like. These solvents can be mixed in appropriate proportions.

[0577] The amount of solvent to be used depends appropriately on the solubility of the substrate compound (I) or its salt, and other factors. The reaction can be carried out with almost no solvent or in a solvent of 100 parts by weight or less per part by weight of the substrate compound (I) or its salt, preferably in a solvent of about 2 to about 100 parts by weight per part by weight of the substrate compound (I) or its salt.

[0578] The temperature in the "hydrogenation reaction" of step A-3 is typically -30°C to 160°C, preferably 0°C to 120°C, and more preferably 10°C to 80°C. The reaction time is typically 0.1 hours to 120 hours, preferably 1 hour to 72 hours.

[0579] The compound (II) or its salt obtained in the "hydrogenation reaction" can be purified by means known to them (e.g., fractional recrystallization, chiral column method, diastereomer salt method).

[0580] Alternatively, if necessary, the compound (II) or its salt obtained in the “hydrogenation reaction” can be processed by means known per se (e.g., concentration, solvent extraction, chromatography), and the resulting solution can then be used directly in the next step A-4 without separation.

[0581] [Step A-4]

[0582] Step A-4 is the step of producing compound (III) or its salt by subjecting compound (II) or its salt to a deprotection reaction.

[0583] When PG is a group represented by formula (VI-1), the deprotection reaction can be carried out according to methods known per se (e.g., methods described in Synthetic Communications, Vol. 10, p. 253, 1980; Tetrahedron, Vol. 50, p. 4399, 1994).

[0584] When PG is a group represented by formula (VI), the deprotection reaction can be carried out by methods known per se (e.g., the method described in Protective Group in Organic Synthesis, 3rd Edition, pp. 579-583, 1999).

[0585] In the preferred embodiment where compound (I) or a salt thereof is compound (VII) or a salt thereof, and compound (II) or a salt thereof is compound (VIII) or a salt thereof, steps A-3 and A-4 in the method for producing compound (III) or a salt thereof are described in detail below.

[0586] In a preferred embodiment, the "transition metal complex" used in the "hydrogenation reaction" of step A-3 is particularly preferably an iridium complex.

[0587] The ligand used for the "iridium complex" is preferably a monophosphine ligand, more preferably a compound represented by formula (XI) or formula (XII), even more preferably a compound represented by formula (XII), and particularly preferably a compound having a cyclic moiety represented by formula (XI-b). Specific examples include...

[0588] (3,5-dioxa-4-phosphacycloheptane[2,1-a;3,4-a']dinaphthyl-4-yl)dimethylamine (MonoPhos);

[0589] (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a']dinaphthyl-4-yl)benzyl(methyl)amine;

[0590] (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a']dinaphthyl-4-yl)-(1-phenylethyl)amine;

[0591] (3,5-dioxa-4-phosphacycloheptane[2,1-a;3,4-a']dinaphthyl-4-yl)bis(1-phenylethyl)amine;

[0592] (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a']dinaf-4-yl)-2,5-diphenylpyrrolidine; (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a']dinaf-4-yl)morpholine (Morfphos); and

[0593] (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a']dinaphth-4-yl)piperidine (PipPhos).

[0594] The preferred option is

[0595] (3,5-dioxa-4-phosphacyclohepta[2,1-a; 3,4-a']dinaf-4-yl)dimethylamine (MonoPhos); (3,5-dioxa-4-phosphacyclohepta[2,1-a; 3,4-a']dinaf-4-yl)morpholine (Morfphos); and

[0596] (3,5-dioxa-4-phosphacycloheptan[2,1-a;3,4-a']dinaphthyl-4-yl)piperidine (PipPhos),

[0597] A particularly preferred option is (3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a']dinaphthyl-4-yl)dimethylamine (MonoPhos).

[0598] The “iridium complex” is preferably prepared by adding a “ligand” and other iridium complexes as iridium metal sources to the reaction system.

[0599] "Other iridium complexes as iridium metal sources" are particularly preferably bis(cyclooctadiene)iridium(I)tetra(3,5-bis(trifluoromethyl)phenyl)borate.

[0600] Preferred examples of solvents used in the "hydrogenation reaction" include toluene and dichloromethane, with dichloromethane being particularly preferred.

[0601] In a preferred embodiment, the “deprotection reaction” in step A-4 can be carried out according to methods known per se (i.e., methods described in Synthesis, Vol. 4, p. 570, 2003; Organic Letters, Vol. 1, p. 1395, 1999; Tetrahedron, Vol. 52, p. 10685, 1996; Tetrahedron Letters, Vol. 32, p. 5865, 1991).

[0602] The “deprotection reaction” is preferably carried out by reacting compound (VIII) or its salt with triethylsilane in the presence of an acid.

[0603] Examples of "acids" include inorganic acids (particularly hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid, carbonic acid, bicarbonate, and the like); carboxylic acids (i.e., compounds having one or more carboxyl groups; particularly formic acid, acetic acid, trifluoroacetic acid, benzoic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, and the like); acidic amino acids (particularly aspartic acid, glutamic acid, and the like); sulfonic acids (i.e., compounds having one or more sulfonyl groups; particularly methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and the like); and Lewis acids (particularly aluminum chloride, tin chloride, zinc chloride, zinc bromide, titanium tetrachloride, boron trifluoride-ethyl ether complexes, and the like). When necessary, acids can be used in mixtures of two or more of these. Trifluoroacetic acid and Lewis acids are preferred, Lewis acids are more preferred, and aluminum chloride is particularly preferred.

[0604] Although the amount of triethylsilane to be used in the "method of reaction with triethylsilane" varies depending on the type of solvent and other reaction conditions, it is generally from 0.1 mol to 30 mol per mol of substrate compound (VIII) or its salt, preferably from 1.5 mol to 10 mol.

[0605] Although the amount of acid to be used in the "method of reaction with triethylsilane" varies depending on the type of solvent and other reaction conditions, it is generally from 0.1 mol to 30 mol per mol of substrate compound (VIII) or its salt, preferably from 1.5 mol to 10 mol.

[0606] Although the "method of reaction with triethylsilane" can be carried out without a solvent, it is generally carried out in a solvent. The solvent is not particularly limited, as long as it does not inhibit the reaction and can dissolve the starting compound and additives, and examples include ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, anisole, and the like; alcohols such as methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, benzyl alcohol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, and the like; aromatic hydrocarbons such as benzene, toluene, xylene, cumene, chlorobenzene, and the like; and saturated hydrocarbons such as hexane, heptane, pentanol, etc. Alkanes, cyclohexane, methylcyclohexane, isooctane, petroleum ether, and the like; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, formamide, hexamethylphosphoramide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolium ketone, and the like; halogenated hydrocarbons, such as chloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethane, and the like; nitriles, such as acetonitrile, propionitrile, and the like; sulfoxides, such as dimethyl sulfoxide, and the like; sulfones, such as dimethyl sulfone, sulfolane, and the like; ketones, such as acetone, ethyl methyl ketone, methyl isopropyl ketone, methyl butyl ketone, and the like; esters, such as ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate, ethyl formate, and the like; nitromethane; water, and the like. These solvents can be mixed in appropriate proportions. As solvents used in the "method of reaction with triethylsilane" mentioned above, halogenated hydrocarbons and aromatic hydrocarbons are preferred, toluene, dichloromethane and 1,2-dichloroethane are more preferred, and 1,2-dichloroethane is particularly preferred.

[0607] The amount of solvent to be used is appropriately determined based on the solubility of the substrate compound (VIII) or its salt, and other factors. For example, when a haloalkane (preferably 1,2-dichloroethane) is used as the solvent, the reaction can be carried out with almost no solvent or in a solvent of 100 parts by weight or less per part by weight of the substrate compound (VIII) or its salt, preferably in a solvent of 1 to 30 parts by weight per part by weight of the substrate compound (VIII) or its salt.

[0608] The temperature in the above-mentioned "method of reaction with triethylsilane" is typically from 10°C to 180°C, preferably from 30°C to 120°C. The reaction time is typically from 0.1 hours to 96 hours, preferably from 0.5 hours to 48 hours.

[0609] The R obtained in the "method of reaction with triethylsilane" mentioned above 2 It is a chlorine atom and R 3 The trifluoromethyl compound (III) or its salt can be purified by means known to them (e.g., fractional recrystallization, chiral column method, diastereomer salt method).

[0610] To obtain the aforementioned compound (III) or its salt with high optical purity, it is preferably purified by fractional recrystallization or diastereomeric salt method, preferably by crystallizing ditolyl-(D)-tartaric acid (when the aforementioned compound (III) is in the (R)-form, preferably ditolyl-(D)-tartaric acid) or optically active mandelic acid (when the aforementioned compound (III) is in the (R)-form, preferably (S)-mandelic acid) diastereomeric salt, particularly preferably by crystallizing optically active mandelic acid (when the aforementioned compound (III) is in the (R)-form, preferably (S)-mandelic acid) diastereomeric salt.

[0611] The "deprotection reaction" is also preferably carried out by reacting compound (VIII) or its salt with an oxidizing agent.

[0612] Preferred examples of “oxidizing agents” include N-bromosuccinimide and N-chlorosuccinimide, with N-bromosuccinimide being particularly preferred.

[0613] Although the amount of “oxidant” to be used varies depending on the type of oxidant and solvent and other reaction conditions, it is typically 0.8 mol to 30 mol per mol of substrate compound (VIII) or its salt, preferably 0.9 mol to 2 mol.

[0614] The additive is preferably used in the reaction by means of an oxidizing agent. Water and acid are preferred as the additive.

[0615] Examples of "acids" include inorganic acids (particularly hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid, carbonic acid, bicarbonate, and the like); carboxylic acids (i.e., compounds having one or more carboxyl groups; particularly formic acid, acetic acid, trifluoroacetic acid, benzoic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, and the like); acidic amino acids (particularly aspartic acid, glutamic acid, and the like); and sulfonic acids (i.e., compounds having one or more sulfonyl groups; particularly methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and the like). When necessary, acids may be used as mixtures of two or more acids.

[0616] Water, acetic acid, citric acid and hydrochloric acid are preferred as additives used in the reaction by "reaction with an oxidant", and water is particularly preferred.

[0617] Although the amount of “additive” to be used varies depending on the type of additive and solvent and other reaction conditions, it is typically 0.8 mol to 100 mol per mol of substrate compound (VIII) or its salt, preferably 5 mol to 50 mol.

[0618] Although the reaction by means of an oxidizing agent can be carried out without a solvent, it is usually carried out in a solvent. The solvent is not particularly limited, as long as it does not inhibit the reaction and can dissolve the raw material compound and additives, and examples include ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, anisole, and the like; alcohols such as methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, benzyl alcohol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, and the like; aromatic hydrocarbons such as benzene, toluene, xylene, cumene, chlorobenzene, and the like; and saturated hydrocarbons such as hexane, heptane, pentanol, etc. Alkanes, cyclohexane, methylcyclohexane, isooctane, petroleum ether, and the like; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, formamide, hexamethylphosphoramide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolium ketone, and the like; halogenated hydrocarbons, such as chloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethane, and the like; nitriles, such as acetonitrile, propionitrile, and the like; sulfoxides, such as dimethyl sulfoxide, and the like; sulfones, such as dimethyl sulfone, sulfolane, and the like; ketones, such as acetone, ethyl methyl ketone, methyl isopropyl ketone, methyl butyl ketone, and the like; esters, such as ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate, ethyl formate, and the like; nitromethane; water, and the like. These solvents can be mixed in suitable proportions. Acetonitrile is preferred as the solvent used in the reaction by means of "reaction with an oxidizing agent".

[0619] The amount of solvent to be used depends on the solubility of the substrate compound (VIII) or its salt, and other factors, and is appropriately determined. For example, when water is used as an additive and acetonitrile is used as a solvent, the reaction can be carried out with almost no solvent or in a solvent of 100 parts by weight or less per part by weight of the substrate compound (VIII) or its salt, preferably in a solvent of 1 to 20 parts by weight per part by weight of the substrate compound (VIII) or its salt.

[0620] The temperature in the reaction by means of "reaction with an oxidant" is typically from -10°C to 120°C, preferably from 0°C to 60°C. The reaction time is typically from 0.1 hours to 96 hours, preferably from 0.5 hours to 48 hours.

[0621] R was obtained through the "method of reaction with oxidant" mentioned above. 2 It is a chlorine atom and R 3The trifluoromethyl compound (III) or its salt can be purified by means known to them (e.g., fractional recrystallization, chiral column method, diastereomer salt method).

[0622] To obtain compound (III) or its salt with high optical purity, it is preferably purified by fractional recrystallization or diastereomeric salt method.

[0623] Although undesirable enantiomers can be removed as crystals by fractional recrystallization, compound (III) or its salts are preferably purified by crystallization of di-p-toluyl tartaric acid (preferably di-p-toluyl-(D)-tartaric acid when compound (III) mentioned above is in the (R)-form) or optically active mandelic acid (preferably (S)-mandelic acid when compound (III) mentioned above is in the (R)-form), particularly preferably by crystallization of diastereomer salts with optically active mandelic acid (preferably (S)-mandelic acid when compound (III) mentioned above is in the (R)-form).

[0624] [Production Methods (AX)]

[0625] Compound (III) or its salt can also be synthesized directly by subjecting compound (Ac) or its salt to an asymmetric reductive amination reaction according to the production method (AX) shown in the following scheme.

[0626]

[0627] Each symbol is defined as described above.

[0628] The reagents and conditions used in step AX are described in detail.

[0629] [Step (AX)]

[0630] Step AX is the step of producing compound (III) or its salt by subjecting compound (Ac) or its salt to an asymmetric reductive amination reaction.

[0631] The “asymmetric reductive amination reaction” is preferably carried out by reacting a compound (Ac) or its salt with an amine source and a reducing agent in the presence of an organometallic complex.

[0632] A hydrogen donor is used as a "reducing agent." Hydrogen gas, metal hydrides, isopropanol, formic acid, benzothiazoline, Hantzsch esters, and similar substances can be used as the hydrogen donor. Hydrogen gas is preferred.

[0633] When hydrogen is used, the reaction can be carried out by batch or continuous processes. When the "asymmetric reductive amination reaction" is carried out in the presence of hydrogen, the hydrogen pressure is, for example, from 0.001 atm to 200 atm, preferably from 0.1 atm to 80 atm.

[0634] The "amine source" is preferably an ammonium salt. Preferred examples of acids to be used to form the ammonium salt include optionally substituted salicylic acid, optionally substituted nicotinic acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, and benzoic acid.

[0635] Examples of substituents in optionally substituted salicylic acid include those mentioned above as "substituents". At the substituted position, the number of substituents is, for example, 1 to 4, preferably 1.

[0636] Preferred examples of salicylic acid that may be optionally substituted include the compounds shown below.

[0637]

[0638] Examples of substituents in nicotinic acid that may be optionally substituted include those referred to above as "substituents". At the substituted position, the number of substituents is, for example, 1 to 4, preferably 1.

[0639] Examples of “organometallic complexes” include those similar to the “organometallic complexes” used in “step (A-3)” mentioned above.

[0640] "Organometallic complex" is preferably "transition metal complex (organotransition metal complex)".

[0641] Examples of “transition metal complexes” include compounds prepared by coordinating a “ligand” (preferably an optically active “ligand”) with a “transition metal” capable of catalyzing asymmetric hydrogenation reactions. Examples of “ligands” include monophosphine ligands, diphosphine ligands, amine ligands, diamine ligands, phosphineamine ligands, and the like, and include the specific examples described herein and their optical isomers. The valence of the “transition metal” is, for example, 0 to 6, preferably 0 to 4, and particularly preferably 0 to 3.

[0642] Preferred examples of "transition metal complexes" include rhodium complexes, ruthenium complexes, iridium complexes, palladium complexes, nickel complexes, copper complexes, osmium complexes, platinum complexes, iron complexes, gold complexes, silver complexes, zinc complexes, titanium complexes, cobalt complexes, zirconium complexes, samarium complexes, and the like; more preferably, rhodium complexes, ruthenium complexes, iridium complexes, palladium complexes, nickel complexes, and copper complexes; even more preferably, rhodium complexes, ruthenium complexes, palladium complexes, and iridium complexes; still more preferably, rhodium complexes and iridium complexes; and particularly preferred, iridium complexes.

[0643] In the category of “transition metal complexes,” specific examples of rhodium complexes, ruthenium complexes, iridium complexes, palladium complexes, nickel complexes, and copper complexes include those similar to specific examples of “organometallic complexes” used in “step (A-3)” mentioned above.

[0644] The "transition metal complex" can also be prepared by adding a "ligand" and other complexes as a transition metal source to the reaction system. The "transition metal complex" can be added directly to the reaction vessel, or it can be prepared by adding the aforementioned "transition metal source" and "ligand" to the reaction vessel. When the "transition metal complex" is prepared by adding the "transition metal source" and "ligand" to the reaction vessel, the "ligand" is used in an amount of 1 to 100 times, preferably 1 to 5 times, and even more preferably 1.01 to 2.02 times, relative to the theoretical molar amount required for the preparation of the "transition metal complex" on a molar basis.

[0645] Although the amount of the “transition metal complex” to be used varies depending on the reaction vessel, the manner of the reaction, and other factors, it is, for example, about 1.0 mol to about 0.00001 mol per mol of substrate compound (I) or its salt.

[0646] In the asymmetric reductive amination reaction of step AX, additives such as bases, acids, salts, and others may be added if necessary. Additives may be used in mixtures of two or more additives. Additives may be added to the reaction vessel before or during the asymmetric reductive amination reaction.

[0647] Examples of bases that can be added to the “asymmetric reductive amination” system in step AX include inorganic and organic bases.

[0648] Examples of inorganic bases include alkali metal hydroxides, such as lithium hydroxide, potassium hydroxide, sodium hydroxide, cesium hydroxide, and the like; alkali metal alkoxides having one to six carbon atoms, such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium propoxide, sodium propoxide, potassium propoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, potassium tert-butoxide, and the like; alkali metal thioalkoxides having one to six carbon atoms, such as sodium methanethiol and the like; carbonates, such as sodium carbonate, potassium carbonate, cesium carbonate, and the like; bicarbonates, such as sodium bicarbonate, potassium bicarbonate, and the like; acetates, such as sodium acetate, potassium acetate, and the like; phosphates, such as tripotassium phosphate, sodium phosphate, and the like; and monohydrogen phosphates, such as dipotassium hydrogen phosphate, disodium hydrogen phosphate, and the like.

[0649] Examples of organic bases include aliphatic amines such as trimethylamine, triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, diethylamine, diisopropylamine, cyclohexylamine, ethylenediamine, and the like; aromatic amines such as pyridine, picolinate, N,N-dimethylaniline, and the like; and basic amino acids such as arginine, lysine, ornithine, and the like.

[0650] Although the amount of base to be used varies depending on the type of solvent and other reaction conditions, it is typically about 0.01 mol or more per mol of substrate compound (Ac) or its salt. Base can also be used as a solvent.

[0651] Examples of acids that can be added to the “asymmetric reductive amination” system in step AX include inorganic acids (particularly hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid, carbonic acid, bicarbonate, and the like); carboxylic acids (i.e., compounds having one or more carboxyl groups; particularly formic acid, acetic acid, trifluoroacetic acid, benzoic acid, salicylic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, and the like); acidic amino acids (particularly aspartic acid, glutamic acid, and the like); and sulfonic acids (i.e., compounds having one or more sulfonyl groups; particularly methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and the like). When necessary, acids can be used as a mixture of two or more acids.

[0652] Although the amount of acid to be used varies depending on the type of solvent and other reaction conditions, it is typically about 0.01 mol or more per mol of substrate compound (Ac) or its salt. Acids can also be used as solvents.

[0653] Besides the salts exemplified as “inorganic bases” mentioned above, examples of salts that can be added to the “asymmetric reductive amination” system of step AX include salts containing “acids” mentioned above as acid components.

[0654] Although the amount of salt to be used varies depending on the type of solvent and other reaction conditions, it is typically about 0.01 mol to 100 mol per mol of substrate compound (I) or its salt.

[0655] The “asymmetric reductive amination” in step AX is typically carried out in a solvent. The solvent is not particularly limited, provided it does not inhibit the reaction and can dissolve the starting compound, organometallic complex, and additives. Examples include ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, anisole, and the like; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, benzyl alcohol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, and the like; aromatic hydrocarbons such as benzene, toluene, xylene, cumene, chlorobenzene, and the like; and saturated hydrocarbons such as hexane, heptane, etc. Alkanes, pentanes, cyclohexanes, methylcyclohexanes, isooctanes, petroleum ethers, and the like; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, formamide, hexamethylphosphoramide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolium ketone, and the like; halogenated hydrocarbons, such as chloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethane, and the like; nitriles, such as acetonitrile, propionitrile, and the like; sulfoxides, such as dimethyl sulfoxide, and the like; sulfones, such as dimethyl sulfone, sulfolane, and the like; ketones, such as acetone, ethyl methyl ketone, methyl isopropyl ketone, methyl butyl ketone, and the like; esters, such as ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate, ethyl formate, and the like; nitromethanes; water, and the like. These solvents can be mixed in appropriate proportions.

[0656] The amount of solvent to be used depends appropriately on the solubility of the substrate compound (Ac) or its salt, and other factors. The reaction can be carried out with almost no solvent or in a solvent of 100 parts by weight or less per part by weight of the substrate compound (Ac) or its salt, preferably in a solvent of about 2 to about 100 parts by weight per part by weight of the substrate compound (Ac) or its salt.

[0657] The temperature in the "asymmetric reductive amination reaction" of step AX is typically -30°C to 160°C, preferably 0°C to 120°C, and more preferably 10°C to 80°C. The reaction time is typically 0.1 hours to 120 hours, preferably 1 hour to 72 hours.

[0658] The compound (III) or its salt obtained in the “asymmetric reductive amination reaction” can be purified by means known to them (e.g., fractional recrystallization, chiral column method, diastereomer salt method).

[0659] As the optimal implementation plan

[0660] The compound represented by formula (Ac) is 2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide; and

[0661] The optically active form of the compound represented by formula (III) is 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide.

[0662] Step AX in the production method (AX) of the preferred embodiment is described in detail below.

[0663] In the most preferred embodiment, the transition metal complex used as a catalyst in the asymmetric reductive amination reaction of step AX is particularly preferably an iridium complex.

[0664] The ligand used for the "iridium complex" is preferably a diphosphine ligand; more preferably, it is 2,4-bis(diphenylphosphino)pentane (SKEWPHOS) having one to five substituents, such as C, on the benzene ring bonded to the phosphorus atom of SKEWPHOS. 1-6 SKEWPHOS derivatives with alkyl groups and similar groups, 4,12-bis(diphenylphosphino)-[2,2]-p-cycloarane (PhanePHOS), substituted -1,1'-bis-phosphinoferrocene (Ferrocelane), and 1-[2-(disubstituted -phosphino)ferrocene]ethyl-disubstituted -phosphine (Josiphos); more preferably 2,4-bis(diphenylphosphino)pentane (SKEWPHOS) and benzene rings having one to five substituents, such as C, on the phosphorus atom bonded to SKEWPHOS. 1-6 SKEWPHOS derivatives with alkyl groups and similar groups; and particularly preferred are pentane-2,4-diylbis(bis(4-(tert-butyl)phenyl)phosphine), and use of its optically active form, namely (R,R)-pentane-2,4-diylbis(bis(4-(tert-butyl)phenyl)phosphine), results in the optically active form in the most preferred embodiment (compound (III) is the (R)-form).

[0665] The “iridium complex” is preferably prepared shortly before use by mixing the “ligand” and other iridium complexes as iridium metal sources in a solvent before the addition of hydrogen. During the preparation shortly before use, the iridium complex is preferably coexisting with the substrate compound (Ac) or its salt and an ammonium salt as an amine source. The solvent used in the preparation shortly before use is preferably the same as the solvent used in the subsequent “asymmetric reductive amination reaction”. The temperature for the preparation of the “iridium complex” shortly before use is typically 10°C to 80°C; more preferably 30°C to 60°C; particularly preferably 35°C to 55°C. The preparation time for the “iridium complex” shortly before use is typically 30 min to 360 min; more preferably 60 min to 120 min. The preparation procedure for the “iridium complex” shortly before use is preferably carried out under an inert gas atmosphere such as argon or nitrogen.

[0666] Preferred examples of “other iridium complexes as iridium metal sources” include bis(1,5-cyclooctadiene)iridium(I)tetrafluoroborate, chloro(1,5-cyclooctadiene)iridium(I) (dimer), bis(1,5-cyclooctadiene)iridium(I)tetra(3,5-bis(trifluoromethyl)phenyl)borate, iodo(1,5-cyclooctadiene)iridium(I) (dimer), (1,5-cyclooctadiene)(methoxy)iridium(I) (dimer), and (acetylacetonyl)(1,5-cyclooctadiene)iridium(I); and chloro(1,5-cyclooctadiene)iridium(I) (dimer) is particularly preferred.

[0667] The acid to be used to form the ammonium salt used in the "asymmetric reductive amination reaction" is preferably a substituted salicylic acid. The most preferred ammonium salt is ammonium salicylate. The amount of ammonium salicylate to be added in the "asymmetric reductive amination reaction" is preferably 1.1 to 5 equivalents, more preferably 2 to 4 equivalents, relative to the substrate compound (Ac) or its salt.

[0668] Preferred examples of solvents for the “asymmetric reductive amination reaction” include tetrahydrofuran, 1,4-dioxane, methanol, isopropanol, 2-methyl-2-butanol and toluene, with tetrahydrofuran being particularly preferred.

[0669] In the "asymmetric reductive amination reaction", additives may be added. Preferred examples of additives include water, zinc chloride, lithium chloride, and terpyridine, with water being particularly preferred.

[0670] When water is added to the “asymmetric reductive amination reaction” system, the amount is limited to a small amount, such that the water concentration in the reaction solution is 4000 ppm or lower, preferably 1000 ppm to 3000 ppm; most preferably 1500 ppm to 2500 ppm.

[0671] In the "asymmetric reductive amination reaction", the hydrogen pressure is preferably 8 atm to 80 atm, more preferably 4 atm to 80 atm.

[0672] In the "asymmetric reductive amination reaction", the reaction temperature is preferably 30°C to 60°C, more preferably 35°C to 55°C.

[0673] In the "asymmetric reductive amination reaction", the reaction time is preferably 12 hours to 50 hours; more preferably 20 hours to 30 hours.

[0674] In the most preferred embodiment, compound (III) or its salt can be purified by means known per se (e.g., fractional recrystallization, chiral column method, diastereomer salt method).

[0675] To obtain the aforementioned compound (III) or its salt with high optical purity, it is preferably purified by fractional recrystallization or diastereomeric salt method. In particular, compound (III) or its salt is preferably purified by crystallizing ditolyl-(D)-tartaric acid with optically active ditolyl-tartaric acid (preferably ditolyl-(D)-tartaric acid when the aforementioned compound (III) is in the (R)-form) or optically active mandelic acid (preferably (S)-mandelic acid when the aforementioned compound (III) is in the (R)-form), and particularly preferably by crystallizing diastereomeric salt with optically active mandelic acid (preferably (S)-mandelic acid when the aforementioned compound (III) is in the (R)-form).

[0676] [Production Method (B)]

[0677] Compound (V) or its salt can be produced by reacting compound (III) or its salt obtained in production method (A) with compound (IV) or its salt in order to form an amide bond, according to production method (B) shown in the following scheme.

[0678]

[0679] Each symbol is defined as described above.

[0680] Compound (IV) or its salts can be produced, for example, according to the methods described in WO 2009-006389.

[0681] Although the amount of compound (IV) or its salt to be used in the process of “forming amide bonds” in production method (B) varies depending on the reaction conditions, it is generally from 0.5 mol to 30 mol of compound (III) or its salt per mol, preferably from 0.9 mol to 2 mol.

[0682] In the production method (B) mentioned above, although the salt of compound (III) obtained in production method (A) can be used directly for the condensation reaction, it is preferred to convert it into its free form by reacting it with a base. Examples of bases include inorganic bases and organic bases.

[0683] Examples of inorganic bases include alkali metal hydroxides, such as lithium hydroxide, potassium hydroxide, sodium hydroxide, cesium hydroxide, and the like; alkali metal alkoxides having one to six carbon atoms, such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium propoxide, sodium propoxide, potassium propoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, potassium tert-butoxide, and the like; alkali metal thioalkoxides having one to six carbon atoms, such as sodium methanethiol and the like; carbonates, such as sodium carbonate, potassium carbonate, cesium carbonate, and the like; bicarbonates, such as sodium bicarbonate, potassium bicarbonate, and the like; acetates, such as sodium acetate, potassium acetate, and the like; phosphates, such as tripotassium phosphate, sodium phosphate, and the like; and monohydrogen phosphates, such as dipotassium hydrogen phosphate, disodium hydrogen phosphate, and the like.

[0684] Examples of organic bases include aliphatic amines such as trimethylamine, triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, diethylamine, diisopropylamine, cyclohexylamine, ethylenediamine, 1,8-diazabicyclo[5.4.0]undecene and the like; aromatic amines such as pyridine, picolinate, N,N-dimethylaniline and the like; and basic amino acids such as arginine, lysine, ornithine and the like. These bases can be mixed in appropriate proportions.

[0685] Sodium bicarbonate is particularly preferred as a base for use in the reaction to convert the salt of compound (III) into its free form.

[0686] Although the amount of base to be used varies depending on the type of solvent and other reaction conditions, it is typically 0.5 mol to 100 mol of salt per mol of substrate compound (III), preferably 1.0 mol to 10 mol, and particularly preferably 1.5 mol to 4 mol. When the base is liquid, it can also be used as a solvent.

[0687] Although the reaction used to convert the salt of compound (III) to its free form can be carried out without a solvent, it is generally carried out in a solvent. The solvent is not particularly limited, provided it does not inhibit the reaction and can dissolve the starting compound and additives, and examples include ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, anisole, and the like; alcohols such as methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, benzyl alcohol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, and the like; aromatic hydrocarbons such as benzene, toluene, xylene, cumene, chlorobenzene, and the like; saturated hydrocarbons such as hexane, heptane, pentanol, etc. Alkanes, cyclohexane, methylcyclohexane, isooctane, petroleum ether, and the like; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, formamide, hexamethylphosphoramide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolium ketone, and the like; halogenated hydrocarbons, such as chloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethane, and the like; nitriles, such as acetonitrile, propionitrile, and the like; sulfoxides, such as dimethyl sulfoxide, and the like; sulfones, such as dimethyl sulfone, sulfolane, and the like; ketones, such as acetone, ethyl methyl ketone, methyl isopropyl ketone, methyl butyl ketone, and the like; esters, such as ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate, ethyl formate, and the like; nitromethane; water, and the like. These solvents can be mixed in appropriate proportions. Ethers, alcohols, and nitriles are preferred as solvents for the reaction used to convert the salt of compound (III) into its free form, and acetonitrile is particularly preferred.

[0688] The solvent is preferably used as a mixed solvent. When a nitrile (preferably acetonitrile) is used as the solvent, it is particularly preferably mixed with water.

[0689] The amount of solvent to be used depends on the solubility of the salt of substrate compound (III) and other factors to be appropriately determined. For example, when the salt of compound (III) is a salt of mandelic acid and a nitrile (preferably acetonitrile) is used as the solvent, the reaction can be carried out with almost no solvent or in a solvent of 100 parts by weight or less per part by weight of the salt of substrate compound (III), preferably in a solvent of 5 to 30 parts by weight per part by weight of the salt of substrate compound (III).

[0690] The temperature used in the reaction to convert to the free form is typically from -10°C to 80°C, preferably from 0°C to 40°C. The reaction time is typically from 0.01 hours to 2 hours, preferably from 0.1 hours to 1 hour.

[0691] Compound (III) obtained in the reaction used to convert it to its free form can be separated and purified by means known per se (concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, and similar methods). Alternatively, the reaction solution can be used directly for the condensation reaction with compound (IV) or its salt.

[0692] The method of “forming amide bonds” in production method (B) can be carried out by methods known per se, such as those described in Tetrahedoron, Vol. 61, p. 10827, 2005.

[0693] The method of “forming an amide bond” is preferably carried out by using a compound (IV) in which X is a hydroxyl group and a condensing agent.

[0694] Examples of "condensing agents" include

[0695] Carbodiimide condensing agent (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide);

[0696] 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0697] N,N'-Dicyclohexylcarbodiimide;

[0698] N,N'-Diisopropylcarbodiimide);

[0699] Imidazole condensing agent (N,N'-carbonyldiimidazole);

[0700] 1,1'-carbonylbis(1,2,4-triazole);

[0701] Triazine condensing agent (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate;

[0702] (4,6-Dimethoxy-1,3,5-triazin-2-yl)-(2-octyloxy-2-oxoethyl)dimethyltrifluoromethanesulfonate ammonium);

[0703] Phosphorus condensing agent (1H-benzotriazol-1-yloxytris(dimethylamino)phosphorus hexafluorophosphate);

[0704] 1H-benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate;

[0705] (7-azabenzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate;

[0706] Chloropyrrolidinephosphonium hexafluorophosphate;

[0707] Bromotri(dimethylamino)phosphonium hexafluorophosphate;

[0708] 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4(3H)-one;

[0709] Ureun condensing agent (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylureun hexafluorophosphate);

[0710] O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylureon hexafluorophosphate;

[0711] O-(N-succinimide)-N,N,N',N'-tetramethylureon tetrafluoroborate;

[0712] O-(N-succinimide)-N,N,N',N'-tetramethylureon hexafluorophosphate;

[0713] O-(3,4-dihydro-4-oxo-1,2,3-benzotriazine-3-yl)-N,N,N',N'-tetramethylureon tetrafluoroborate;

[0714] S-(1-Oxide-2-pyridyl)-N,N,N',N'-Tetramethylureon tetrafluoroborate;

[0715] O-[2-oxo-1(2H)-pyridyl]-N,N,N',N'-tetramethylureon tetrafluoroborate;

[0716] {{[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy}-4-morpholinylmethylene}dimethylammonium hexafluorophosphate); and

[0717] Halouronium condensing agent (2-chloro-1,3-dimethylimidazoline hexafluorophosphate);

[0718] 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate;

[0719] 2-Fluoro-1,3-Dimethylimidazoline hexafluorophosphate;

[0720] Fluoro-N,N,N',N'-Tetramethylformamide hexafluorophosphate).

[0721] As a "condensing agent", carbodiimide condensing agents are preferred, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N,N'-dicyclohexylcarbodiimide are more preferred, and N,N'-dicyclohexylcarbodiimide is particularly preferred.

[0722] Although the amount of “condensing agent” to be used varies depending on the type of condensing agent and solvent and other reaction conditions, it is generally 0.8 mol to 10 mol per mol of compound (IV) or its salt, preferably 0.9 mol to 2 mol.

[0723] In the reaction of method "forming amide bonds" in production method (B), additives are preferably used.

[0724] Examples of “additives” include 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, N-hydroxysuccinimide, and N,N'-disuccinimidyl carbonate. 1-hydroxybenzotriazole is preferred.

[0725] Although the amount of “additive” to be used varies depending on the type of additive, condensing agent and solvent and other reaction conditions, it is generally 0.01 mol to 1.0 mol per mol of compound (IV) or its salt, preferably 0.05 mol to 0.5 mol.

[0726] Although the reaction via the "formation of amide bonds" in production method (B) can be carried out with almost no solvent, it is generally carried out in a solvent. The solvent is not particularly limited, provided it does not inhibit the reaction and can dissolve the raw material compound and additives, and examples include ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, anisole, and the like; alcohols such as methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, benzyl alcohol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, and the like; aromatic hydrocarbons such as benzene, toluene, xylene, cumene, chlorobenzene, and the like; and saturated hydrocarbons such as hexane, heptane, pentanol, etc. Alkanes, cyclohexane, methylcyclohexane, isooctane, petroleum ether, and the like; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, formamide, hexamethylphosphoramide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolium ketone, and the like; halogenated hydrocarbons, such as chloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethane, and the like; nitriles, such as acetonitrile, propionitrile, and the like; sulfoxides, such as dimethyl sulfoxide, and the like; sulfones, such as dimethyl sulfone, sulfolane, and the like; ketones, such as acetone, ethyl methyl ketone, methyl isopropyl ketone, methyl butyl ketone, and the like; esters, such as ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate, ethyl formate, and the like; nitromethane; water, and the like. These solvents can be mixed in appropriate proportions. As a solvent used in the reaction of "forming amide bonds" in production method (B), an amide is preferred, and N,N-dimethylacetamide is more preferred.

[0727] The amount of solvent to be used depends appropriately on the solubility of compound (III) or its salt and compound (IV) or its salt, among other factors. For example, when N,N-dimethylacetamide is used as a solvent, the reaction can be carried out with almost no solvent or in a solvent containing 100 parts by weight or less of compound (III) or its salt per part by weight, preferably in a solvent containing 1 to 20 parts by weight of substrate compound (III) or its salt per part by weight.

[0728] The temperature in the reaction by the method of "forming amide bonds" is typically from -10°C to 120°C, preferably from 0°C to 60°C. The reaction time is typically from 0.1 hours to 48 hours, preferably from 0.5 hours to 16 hours.

[0729] The compound (V) or its salt obtained in the production method (B) by the reaction of forming an amide bond can be separated and purified by means known per se (concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and similar means).

[0730] "Separation and purification" preferably means crystallization, particularly preferably crystallization from a mixed solvent of n-butanol and water.

[0731] The isolated and purified compound (V) or its salt is preferably further purified by recrystallization to give a compound with high purity. The solvent used for recrystallization is particularly preferably dimethyl sulfoxide, 2-propanol, or a mixture of solvent and water.

[0732] [Production Method (C)]

[0733] In addition to the production of compound (II) or its salts, the asymmetric hydrogenation reaction in the presence of transition metal complexes in this invention can be applied to the production of optically active amine compounds.

[0734] Preferred examples of the production of optically active amine compounds are shown below.

[0735] The compound represented by formula (B) or its salt can be obtained by subjecting the compound represented by formula (A) or its salt to an asymmetric hydrogenation reaction in the presence of a transition metal complex with a trivalent phosphine ligand:

[0736]

[0737] in

[0738] Ar X and Ar Y Each of them is independently and arbitrarily replaced by C. 6-14 aryl group;

[0739] Ar Z C is arbitrarily replaced 6-14 Aryl groups, or optionally substituted heterocyclic groups;

[0740] R x C is arbitrarily replaced 1-6 alkyl groups;

[0741] R x and Ar Z Combinatorially and optionally together with adjacent atoms, they form optionally substituted 8-14 member fused polycyclic rings; and

[0742] Carbon atoms marked with an asterisk (*) are asymmetric carbon atoms.

[0743]

[0744] Each symbol is defined as above.

[0745] This invention provides, but is not limited to, the following embodiments:

[0746] 1. A method for producing an optically active form of a compound represented by formula (II) or a salt thereof:

[0747]

[0748] in

[0749] R 1 It is C 1-6 alkyl groups;

[0750] R 2 It is a hydrogen atom or a halogen atom;

[0751] R 3 It is a hydrogen atom or an optional halogenated C atom. 1-6 alkyl groups;

[0752] PG is a protecting group; and

[0753] Carbon atoms marked with an asterisk (*) are asymmetric carbon atoms.

[0754] The method involves subjecting a compound or a salt thereof, represented by the following formula (I), to an asymmetric reduction reaction:

[0755]

[0756] Each symbol is defined as described above.

[0757] 2. A method for producing an optically active form of a compound represented by the following formula (V) or a salt thereof:

[0758]

[0759] in

[0760] R 1 It is C 1-6 alkyl groups;

[0761] R 2 It is a hydrogen atom or a halogen atom;

[0762] R 3 It is a hydrogen atom or an optional halogenated C atom. 1-6 alkyl groups;

[0763] R 4 and R 5Each of these groups independently comprises a hydrogen atom, a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted aminosulfonyl group, an optionally substituted hydroxyl group, an optionally substituted thioalkyl (SH) group, or an optionally substituted silyl group; and

[0764] Carbon atoms marked with an asterisk (*) are asymmetric carbon atoms.

[0765] The method includes the step of subjecting a compound represented by formula (I) or a salt thereof to an asymmetric reduction reaction to obtain an optically active form of a compound represented by formula (II) or a salt thereof;

[0766]

[0767] in

[0768] PG is a protecting group, and

[0769] And other symbols are as defined above,

[0770]

[0771] Each symbol is defined as described above.

[0772] 3. The method as described in Embodiment 2, the method further includes...

[0773] The step of subjecting the optically active form of a compound represented by the following formula (II) or its salt to a deprotection reaction;

[0774]

[0775] in

[0776] R 1 It is C 1-6 alkyl groups;

[0777] R 2 It is a hydrogen atom or a halogen atom;

[0778] R 3 It is a hydrogen atom or an optional halogenated C atom. 1-6 alkyl groups;

[0779] PG is a protecting group; and

[0780] Carbon atoms marked with an asterisk (*) are asymmetric carbon atoms.

[0781] as well as

[0782] The step of reacting the optically active form of the obtained compound represented by formula (III) or a salt thereof with the compound represented by formula (IV) or a salt thereof;

[0783]

[0784] Each symbol is as defined above.

[0785]

[0786] in

[0787] X is a leaving group; and

[0788] R 4 and R 5 Each of these groups is independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted aminosulfonyl group, an optionally substituted hydroxyl group, an optionally substituted thioalkyl (SH) group, or an optionally substituted silyl group.

[0789] 4. The method as described in Embodiment 3, wherein the optically active form of the compound represented by formula (III) or a salt thereof is a salt of the optically active form of the compound represented by formula (III) and mandelic acid.

[0790] 5. The method as described in embodiment 3 or 4, wherein X is a hydroxyl group.

[0791] 6. The method of any one of embodiments 1 to 5, wherein the asymmetric reduction reaction is an asymmetric hydrogenation reaction in the presence of a transition metal complex.

[0792] 7. The method as described in Embodiment 6, wherein the transition metal complex is an iridium complex.

[0793] 8. The method as described in any one of embodiments 1 to 7, wherein PG is represented by the following formula (VI):

[0794]

[0795] in

[0796] Ar 1 It is a hydrogen atom or an optional substituted C atom 6-14 aryl groups; and

[0797] Ar 2 C is arbitrarily replaced 6-14 Aryl group.

[0798] 9. The method as described in embodiment 8, wherein Ar 1 and Ar 2 Each is an optional substituted phenyl group.

[0799] 10. A compound or a salt thereof represented by the following formula (VII):

[0800]

[0801] Among them, Ar 3 and Ar 4 Each of the Cs is independently and arbitrarily replaced. 6-14 Aryl group.

[0802] 11. An optically active form of a compound represented by the following formula (VIII) or a salt thereof:

[0803]

[0804] in

[0805] Ar5 and Ar6 are each independently optional substituted C6-14 aryl groups, and

[0806] Carbon atoms marked with an asterisk (*) are asymmetric carbon atoms. [Example]

[0807] The invention is described in detail below with reference to reference to referenced embodiments and examples, which are merely exemplary and not to be construed as limiting, and the invention may be varied within the scope of the invention.

[0808] In the following reference examples and embodiments, "room temperature" generally means about 10°C to about 35°C.

[0809] In the reaction scheme, s / c refers to the substrate-catalyst ratio (substrate (mol) / catalyst (mol)), and s / s refers to the substrate-solvent ratio (solvent (ml) / substrate (g)).

[0810] Chemical yield is the separation yield (mol / mol%) or the yield measured by high performance liquid chromatography. Optical purity (asymmetric yield) of the optically active form is assessed by enantiomeric excess (%ee). Enantiomeric excess is calculated according to the following formula.

[0811] Enantiomer excess (%ee) = 100 × [(R) - (S)] / [(R) + (S)] or 100 × [(S) - (R)] / [(R) + (S)], where (R) and (S) are the areas of each enantiomer as measured by high performance liquid chromatography.

[0812] In addition, the amount of solvent used in the chromatography is shown in % by volume, and the amount of another solvent is shown in % by weight.

[0813] Regarding enantiomers, compounds whose absolute configuration is determined are described as R or S. For compounds whose absolute configuration is not determined, the enantiomer excess (optical purity) is calculated based on the results of high-performance liquid chromatography.

[0814] Enantiomer excess (%ee) = 100 × [(initial peak) - (subsequent peak)] / [(initial peak) + (subsequent peak)]

[0815] In proton NMR spectra, broad and unidentified protons, such as OH protons and NH protons and analogs, are not described in the data.

[0816] The abbreviations used in this manual refer to the following technical terms or structures.

[0817] s: single peak

[0818] d: Bimodal

[0819] t: triple peak

[0820] q: Four Peaks

[0821] m: multiple peaks

[0822] br: broad peak

[0823] J: Coupling constant

[0824] Hz: Hertz

[0825] CDCl3: Deuterated chloroform

[0826] DMSO-d6: Deuterated dimethyl sulfoxide

[0827] CD3OD: Deuterated methanol

[0828] 1 H NMR: Proton nuclear magnetic resonance

[0829] 13 C NMR: 13 C NMR

[0830] 19 F NMR: 19 F nuclear magnetic resonance

[0831] 31 P NMR: 31 P nuclear magnetic resonance

[0832] [RhCl(cod)]2: Chloro(1,5-cyclooctadiene)rhodium(I) dimer

[0833] [Rh(cod)2]OTf: Bis(1,5-cyclooctadiene)rhodium(I)trifluoromethanesulfonate

[0834] [Rh(cod)(R)-(S)-josiphos]OTf:(1,5-cyclooctadiene){(R)-(-)-1-[(S)-2-(diphenylphosphino)ferrocene]ethyldicyclohexylphosphine}rhodium(I)trifluoromethanesulfonate

[0835] [Rh(nbd)(R)-(S)-josiphos]BF4:{(R)-(-)-1-[(S)-2-(diphenylphosphino)ferrocene]ethyldicyclohexylphosphine}(norbornadiene)rhodium(I)tetrafluoroborate

[0836] [Rh(cod)(S,S)-skewphos]OTf:{(2S,4S)-(-)-2,4-bis(diphenylphosphino)pentane}(1,5-cyclooctadiene)rhodium(I)trifluoromethanesulfonate

[0837] [Rh(nbd)(S,S)-bisP*]BF4:{(S,S)-1,2-bis-(tert-butyl(methyl)phosphino)ethane}(norbornadiene)rhodium(I)tetrafluoroborate

[0838] [Rh(cod)(R,R)-dipamp]BF4: (R,R)-1,2-bis[(2-methoxyphenyl)phenylphosphino]ethane(1,5-cyclooctadiene)rhodium(I)tetrafluoroborate

[0839] [Rh(cod)(S)-xyl-binap]OTf:{(S)-(-)-2,2'-bis[bis(3,5-dimethylyl)phosphino]-1,1'-binaphthyl}(1,5-cyclooctadiene)rhodium(I)trifluoromethanesulfonate

[0840] RuCl2{(R)-binap}: Dichloro[(R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]ruthenium(II)

[0841] RuCl2{(R)-binap}{R,R-dpen}:Dichloro[(R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]{(1R,2R)-(+)-1,2-diphenylmethyldiamine}ruthenium(II)

[0842] RuCl2{(R)-binap}{R,R-dach}:Dichloro[(R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]{(1R,2R)-(+)-1,2-diaminocyclohexane}ruthenium(II)

[0843] RuCl2{(R)-binap}{R-daipen}:Dichloro{(R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl}[(2R)-(-)-1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine]ruthenium(II)

[0844] RuCl2{(R)-xyl-binap}{R,R-dpen}:Dichloro{(R)-(+)-2,2'-bis[bis(3,5-dimethylyl)phosphino]-1,1'-binaphthyl}{(1R,2R)-(+)-1,2-diphenylmethyldiamine}ruthenium(II)

[0845] RuCl2{(R)-xyl-binap}{R,R-dach}:Dichloro{(R)-(+)-2,2'-bis[bis(3,5-dimethylyl)phosphino]-1,1'-binaphthyl}{(1R,2R)-(+)-1,2-diaminocyclohexane}ruthenium(II)

[0846] RuCl2{(R)-xyl-binap}{R-daipen}:Dichloro{(R)-(+)-2,2'-bis[bis(3,5-xylyl)phosphino]-1,1'-binaphthyl}[(2R)-(-)-1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine]ruthenium(II)

[0847] [Ir(cod)2]BARF: Bis(1,5-cyclooctadiene)iridium(I)tetra[3,5-bis(trifluoromethyl)phenyl]borate

[0848] [Ir(cod)2]BF4: Bis(1,5-cyclooctadiene)iridium(I)tetrafluoroborate

[0849] [IrCl(cod)]2: Chloro(1,5-cyclooctadiene)iridium(I) dimer

[0850] [IrOMe(cod)]2: (1,5-cyclooctadiene)methoxyiridium(I) dimer

[0851] Ir(acac)(cod): (acetylacetonyl)(1,5-cyclooctadiene)iridium(I)

[0852] Pd(OCOCF3)2: Palladium(II) trifluoroacetate

[0853] Pd(OAC)2: Palladium(II) acetate

[0854] (R)-(S)-Josiphos(SL-J001-1): (R)-(-)-1-[(S)-2-(diphenylphosphino)ferrocene]ethyldicyclohexylphosphine

[0855] SL-M001-1: (αR,αR)-2,2'-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1'-bis(diphenylphosphino)ferrocene

[0856] SL-W001-1: (R)-1-[(R)-2-(2'-diphenylphosphinophenyl)ferrocene]ethyl di(bis-3,5-trifluoromethylphenyl)phosphine

[0857] SL-W002-1: (R)-1-[(R)-2-(2'-diphenylphosphinophenyl)ferrocene]ethyldiphenylphosphine

[0858] SL-W003-1: (R)-1-[(R)-2-(2'-diphenylphosphine)ferrocene]ethyldicyclohexylphosphine

[0859] SL-T001-1: (S)-1-Diphenylphosphino-2-[(R)-α-(N,N-dimethylamino)-o-diphenylphosphinophenyl-methyl]ferrocene

[0860] SL-T002-1: (S)-1-Dicyclohexylphosphino-2-[(R)-α-(N,N-dimethylamino)-o-dicyclohexylphosphinophenyl-methyl]ferrocene

[0861] SL-J004-1: (R)-1-[(1S)-2-(dicyclohexylphosphino)ferrocene]ethyldiphenylphosphine

[0862] (S)(R)-SL-J002-02:(S)-1-[(R)-2-(diphenylphosphino)ferrocene]ethyl di-tert-butylphosphine

[0863] (R)(S)-SL-J502-1:(R)-1-[(S)-2-(di-tert-butylphosphino)ferrocene]ethyldiphenylphosphine

[0864] (R)(S)-SL-J009-1:(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyl di-tert-butylphosphine

[0865] (R)(S)-SL-J005-1:(R)-1-[(S)-2-(diphenylphosphino)ferrocene]ethyldi-3,5-dimethylphosphine

[0866] (R)(S)-SL-J011-1: (R)-1-[(S)-2-[bis-(4-trifluoromethylphenyl)phosphinyl]ferrocene]ethyl di-tert-butylphosphine

[0867] (R)(S)-SL-J013-1:(R)-1-[(S)-2-[bis-(3,5-dimethyl-4-methoxyphenyl)phosphine]ferrocene]ethyl di-tert-butylphosphine

[0868] (R)(S)-SL-J014-1:(R)-1-[(S)-2-[di-(4-fluorophenyl)phosphino]ferrocene]ethyl di-tert-butylphosphine

[0869] (R)(S)-SL-J212-1:(R)-1-[(S)-2-(di-2-furanylphosphino)ferrocene]ethyl di-tert-butylphosphine

[0870] (R)(S)-SL-J216-1:(R)-1-[(S)-2-(bi-1-naphthylphosphino)ferrocene]ethyl di-tert-butylphosphine

[0871] (R)(S)-SL-J202-1:(R)-1-[(S)-2-[di-(4-methoxyphenyl)phosphinyl]ferrocene]ethyl di-tert-butylphosphine

[0872] (R)(S)-SL-J203-1:(R)-1-[(S)-2-[bis-(3,5-di-tert-butyl-4-methoxyphenyl)phosphine]ferrocene]ethyldi-tert-butylphosphine

[0873] (R)(S)-SL-J210-1:(R)-1-[(S)-2-[bis-(3,5-bis-trifluoromethylphenyl)phosphinyl]ferrocene]ethyl di-tert-butylphosphine

[0874] (S)(R)-SL-J210-2:(S)-1-[(R)-2-[bis-(3,5-bis-trifluoromethylphenyl)phosphino]ferrocene]ethyl di-tert-butylphosphine

[0875] (R,R)-Skewphos: (2R,4R)-(+)-2,4-bis(diphenylphosphino)pentane

[0876] (R)-BINAP: (R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[0877] (R)-xylyl-BINAP:(R)-(+)-2,2'-bis[bis(3,5-dimethylyl)phosphino]-1,1'-binaphthyl

[0878] (S)-H8-BINAP:(S)-(-)-2,2'-bis(diphenylphosphino)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl

[0879] (R,R)-Me-Duphos:(-)-1,2-bis[(2R,5R)-2,5-dimethylphosphine]benzene

[0880] (R,R)-Et-Duphos:(-)-1,2-bis[(2R,5R)-2,5-diethylphosphine]benzene

[0881] (R,R)-iPr-Duphos:(-)-1,2-bis[(2R,5R)-2,5-diisopropylphosphine]benzene

[0882] (R,R)-Ph-BPE: (-)-1,2-bis((2R,5R)-2,5-diphenylphosphine)ethane

[0883] (R)-Phanephos: (R)-(-)-4,12-bis(diphenylphosphino)-[2,2]-p-cycloarane

[0884] (S)-xyl-Phanephos:(S)-(+)-4,12-bis(bis(3,5-dimethylyl)phosphino)-[2,2]-p-cycloaramine

[0885] (S,S)-Et-Ferrotane: (-)-1,1'-bis[(2S,4S)-2,4-diethylphosphonobutane]ferrocene; (R,R)-DIPAMP: (R,R)-1,2-bis[(2-methoxyphenyl)phenylphosphino]ethane

[0886] (R,R)-Quinox-P*:(R,R)-(-)-2,3-bis(tert-butylmethylphosphino)quinoxaline

[0887] (S)-DTBM-Segphos:(S)-(+)-5,5'-bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4'-bis-1,3-benzodioxane-pentene

[0888] (R)-C3-Tunephos: (R)-(-)-1,13-bis(diphenylphosphino)-7,8-dihydro-6H-dibenzo[f,h][1,5]dioxonine

[0889] (S)-MeO-BIPHEP:(S)-(-)-2,2'-bis(diphenylphosphino)-6,6'-dimethoxy-1,1'-biphenyl

[0890] (S)-ShiP: Phenyl-[(S)-1,1-spirodiindane-7,7-diyl]phosphite

[0891] (S)-MOP: (S)-(-)-2-diphenylphosphino-2'-methoxy-1,1'-binaphthyl

[0892] (R)-QuINAP:(R)-1-[2-(diphenylphosphino)-1-naphthyl]isoquinoline

[0893] (S)-Monophos: (S)-(+)-(3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4-a']dinaphthyl-4-yl)dimethylamine

[0894] (S)-Me-Monophos: (S)-(+)-(2,6-dimethyl-3,5-dioxa-4-phospha-cycloheptano[2,1-a;3,4-a']dinaphthyl-4-yl)dimethylamine

[0895] (R,R)-Taddol-type: (3aR,8aR)-(-)-(2,2-dimethyl-4,4,8,8-tetraphenyl-tetrahydro-[1,3]dioxacyclopenteno[4,5-e][1,3,2]dioxaphosphaheptan-6-yl)dimethylamine

[0896] (S)-BnMe: (S)-(+)-(3,5-dioxa-4-phospha-cycloheptano[2,1-a;3,4-a']dinaphthyl-4-yl)benzyl(methyl)amine

[0897] (S,R,R)-α-phenylethyl:(S)-(+)-(3,5-dioxa-4-phospha-cycloheptano[2,1-a;3,4-a']dinaphthyl-4-yl)bis[(1R)-1-phenylethyl]amine

[0898] (S)-Et-Monophos: (S)-(+)-(2,6-dimethyl-3,5-dioxa-4-phospha-cycloheptano[2,1-a;3,4-a']dinaphthyl-4-yl)diethylamine

[0899] (S)-Morphos: (S)-(+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a']dinaphthyl-4-yl)morpholine

[0900] (S)-α-phenethylH: (S)-(+)-(3,5-dioxa-4-phospha-cycloheptano[2,1-a;3,4-a']dinafnaphthyl-4-yl)[(1R)-1-phenylethyl]amine

[0901] (S)-Pipphos: (S)-(+)-(3,5-dioxa-4-phosphacycloheptan[2,1-a;3,4-a']dinaphthyl-4-yl)piperidine

[0902] (S)-H8-Monophos:(S)-(+)-(8,9,10,11,12,13,14,15-octahydro-3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4-a']dinafnaphthyl-4-yl)dimethylamine

[0903] (R,R)-cataciumM(R): (-)-2,3-bis[(2R,5R)-2,5-dimethylphosphino]maleic anhydride cataASium T3: (+)-{4-[(1R,4S)-3-(diphenylphosphino)-1,7,7-trimethylbicyclo[2.2.1]heptene-2-en-2-yl]-2,5-dimethyl-3-thienyl}bis(3,5-dimethylphenyl)phosphine

[0904] (R,R)-Norphos:(2R,3R)-(-)-2,3-bis(diphenylphosphino)bicyclo[2.2.1]hept-5-ene

[0905] (R)-iPr-PHOX:(R)-(+)-2-[2-(diphenylphosphino)phenyl]-4-isopropyl-2-oxazoline

[0906] DMF: N,N-dimethylformamide

[0907] CPME: Cyclopentylmethyl ether

[0908] DME: Dimethyl ether

[0909] MeCN: Acetonitrile

[0910] AcOH: Acetic acid

[0911] EtOH: Ethanol

[0912] NBS: N-bromosuccinimide

[0913] Et3N: Triethylamine

[0914] EDC: 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride

[0915] HOBT: 1-Hydroxybenzotriazole

[0916] DMAc: N,N-dimethylacetamide

[0917] 1-BuOH: n-Butanol

[0918] IPA: 2-Propanol

[0919] DMSO: Dimethyl sulfoxide

[0920] THF: Tetrahydrofuran

[0921] DCM: Dichloromethane

[0922] MeOH: Methanol

[0923] p-TsOH: p-Toluenesulfonic acid

[0924] TMSCl: Trimethylchlorosilane

[0925] DCE: 1,2-Dichloroethane

[0926] Et3SiH: Triethylsilane

[0927] (S)-MA: (S)-Mandrine

[0928] MS4A: Molecular sieve 4A

[0929] TMEDA: Tetramethylethylenediamine

[0930] AHN: Ammonium 2-hydroxynicotinate

[0931] APC: Ammonium picolinate

[0932] ATFA: Ammonium trifluoroacetate

[0933] (-)-CSA:(-)-10-Camphorsulfonic acid

[0934]

[0935] In the following reference examples and examples, nuclear magnetic resonance (NMR) spectra were measured under the following conditions.

[0936] 1 H nuclear magnetic resonance spectrum ( 1 H-NMR: BRUKER AVANCE 500 (500MHz) manufactured by Bruker Corporation, internal standard: tetramethylsilane

[0937] 13 C nuclear magnetic resonance spectrum ( 13 C-NMR: BRUKER AVANCE 500 (125MHz) manufactured by Bruker Corporation, internal standard material: CDCl3

[0938] 19 F nuclear magnetic resonance spectrum ( 19F-NMR: BRUKER AVANCE 500 (202MHz) manufactured by Bruker Corporation; external standard material: trifluoroacetic acid.

[0939] 31 p-nuclear magnetic resonance spectrum ( 31 P-NMR: BRUKER AVANCE 500 (471MHz) manufactured by Bruker Corporation, external standard material: 85% H3PO4 aqueous solution

[0940] Refer to Example 1

[0941] Synthesis of 2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide

[0942]

[0943] 2-Acetyl-1,3-thiazolyl-5-carboxylic acid (24.7 g), 1,2-dimethoxyethane (43 mL), N,N-dimethylformamide (0.047 g), and oxalyl chloride (17.8 g) were placed in a four-necked flask (100 mL), and the mixture was stirred at room temperature for 2 hours (reaction solution 1). Separately, 5-chloro-4-(trifluoromethyl)pyridine-2-amine hydrochloride (30.0 g), acetonitrile (96 mL), and pyridine (30.8 g) were placed in a four-necked flask (500 mL), and the mixture was cooled to approximately 5°C (reaction solution 2). At 35°C or lower, reaction solution 1 was added to reaction solution 2, along with 1,2-dimethoxyethane (15 mL). The mixture was stirred at room temperature for 1 hour, then heated to approximately 50°C and stirred for another 1 hour. Water (210 mL) was added to the mixture at approximately 50 °C, and the mixture was cooled to room temperature and stirred for 30 min. The crystallized material was collected by filtration, washed with a mixture of acetonitrile (22.5 mL) and water (67.5 mL), washed with water (180 mL), and dried under reduced pressure at 50 °C to give the title compound. 43.4 g, light brown powder, yield 96%, purity 99.0% (HPLC).

[0944] Conditions for high-performance liquid chromatography analysis (area normalization)

[0945] Column: Inertsil ODS-3 5μm, 4.6mm id×150mm

[0946] UV detection wavelength: 254nm

[0947] Column temperature: 25℃

[0948] Mobile phase:

[0949] Table 1

[0950]

[0951] Flow rate: 1.0 mL / min

[0952] Retention time: 8.9 min (title compound)

[0953] 1 ¹H NMR (DMSO-d6) δ 2.67 (s, 3H), 8.58 (s, 1H), 8.80 (s, 1H), 9.00 (s, 1H), 12.00 (s, 1H). Regarding C... 12 H8ClF3N3O2S[(M+H) + The calculated HRMS(ESI) is 349.9972, and the measured value is 349.9977. Melting point: 165℃.

[0954] Refer to Example 2

[0955] Synthesis of (E)-2-(1-(diphenylmethylimino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide

[0956]

[0957] 40.0 g of 2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide, 200 mL of ethanol, 23.1 g of diphenylmethylamine, and 1.96 mL of acetic acid were placed into a 300 mL four-necked flask equipped with a Dean-Stark separator, and the mixture was heated under reflux for 6.5 hours. The mixture was cooled to room temperature and stirred for 1 hour. The crystals were collected by filtration, washed with 100 mL of ethanol, and dried under reduced pressure at 50 °C to give crystals. All the obtained crystals (59.4 g) and toluene (300 mL) were placed into a 2 L four-necked flask, and the mixture was heated under reflux until 60 mL of solvent was evaporated. Toluene (60 mL) was added to the residue, and the mixture was heated under reflux until 60 mL of solvent was evaporated. This procedure was repeated a total of three times. Heptane (900 mL) was added to the mixture at approximately 80 °C, and the mixture was cooled to room temperature and stirred for 1 hour. The crystallized material was collected by filtration, washed with a mixed solvent of toluene (40 mL) and heptane (200 mL), and dried under reduced pressure at 60 °C to give the title compound. White powder, 51.4 g, yield 87%, purity 99.7% (HPLC).

[0958] Conditions for high-performance liquid chromatography analysis (area normalization)

[0959] Column: Inertsil C8-4, HP 3μm, 4.6mm id × 150mm

[0960] UV detection wavelength: 254nm

[0961] Column temperature: 25℃

[0962] Mobile phase:

[0963] Table 2

[0964]

[0965] Flow rate: 1.0 mL / min

[0966] Retention time: 20.8 min (title compound)

[0967] 1 H NMR(CDCl3)δ2.46(s,3H),5.90(s,1H),7.24(m,2H),7.33(m,4H),7.45(m,4H),8.36(s,1H),8.43(brs,1H),8.44(s,1H),8.69(s,1H). About C 25 H 19 ClF3N4OS[(M+H) + The calculated HRMS(ESI) is 515.0915, and the measured value is 515.0914. Melting point: 175℃.

[0968] Example 1

[0969] Synthesis of 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (S)-mandelate

[0970]

[0971] (E)-2-(1-(diphenylmethylimino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (45.0 g), [Ir(cod)2]BARF (0.167 g), and (S)-Monophos (0.104 g) were placed in an autoclave (1 L). The atmosphere in the autoclave was reduced to a reduced pressure and replaced with argon, and dehydrated dichloromethane (500 mL) was added. The mixture was stirred at room temperature for 10 min, and hydrogen was fed into the autoclave until the pressure reached 0.65 MPa. The mixture was heated to approximately 50 °C, and hydrogen was fed into the autoclave until the pressure reached 0.80 MPa, and the mixture was stirred for 24 h. The mixture was cooled to room temperature, the hydrogen was released, and the atmosphere was replaced with argon. The mixture was concentrated under reduced pressure by adding acetonitrile (135 mL), and the mixture was concentrated under reduced pressure. Acetonitrile (135 mL) and water (22.5 mL) were added, and then N-bromosuccinimide (17.1 g) was added at room temperature, and the mixture was stirred for 18 hours. Triethylamine (9.73 g) and acetonitrile (900 mL) were added at room temperature, and then (S)-mandelic acid (16.0 g) dissolved in acetonitrile (270 mL) was added dropwise at room temperature. The crystallized material was collected by filtration, washed with acetonitrile (180 mL), and dried under reduced pressure at 50 °C to give the title compound. White powder, 32.9 g, yield 75%, purity 99.9% (HPLC), optical purity 98.6% de (chiral HPLC).

[0972] Conditions for high-performance liquid chromatography analysis (area normalization)

[0973] Column: L-column2 ODS, S-5μm, 4.6mm id×250mm

[0974] UV detection wavelength: 220nm

[0975] Column temperature: 25℃

[0976] Mobile phase:

[0977] Table 3

[0978] 0.00min. 90％ 10％ 2.00 min. 90％ 10％ 30.00 min. 10％ 90％ 40.00 min. 10％ 90％

[0979] Flow rate: 1.0 mL / min

[0980] Retention time: 14.9 min (title compound)

[0981] Conditions for high-performance liquid chromatography analysis (optical purity)

[0982] Column: CROWNPAK CR-I(+), S-5μm, 3.0mm id.×150mm

[0983] UV detection wavelength: 305nm

[0984] Column temperature: 25℃

[0985] Mobile phase:

[0986] Table 4

[0987] 0.00min. 60％ 40％ 2.00 min. 60％ 40％ 15.00 min. 40％ 60％ 16.00 min. 10％ 90％ 20.00 min. 10％ 90％

[0988] Flow rate: 0.5 mL / min

[0989] Retention time: 5.2 min (R), 8.1 min (S)

[0990] 1 ¹H NMR (DMSO-d₆) δ 1.43 (d, J = 6.5 Hz, 3H), 4.33 (m, 1H), 4.91 (s, 1H), 7.25 (m, 1H), 7.32 (m, 1H), 7.40 (m, 1H), 8.59 (s, 1H), 8.73 (s, 1H), 8.77 (s, 1H), 11.66 (brs, 1H). Melting point 152 °C.

[0991] Example 2

[0992] Synthesis of 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide

[0993]

[0994] Water (145 mL), sodium bicarbonate (8.35 g), acetonitrile (145 mL), and 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide(S)-mandelate (25.0 g) were placed in a four-necked flask (500 mL), and the mixture was stirred at room temperature for 15 min. Activated carbon SHIRASAGI A (2.5 g) was added, and the mixture was stirred at room temperature for 15 min. The activated carbon was removed by filtration and washed with a mixture of acetonitrile (12.5 mL) and water (12.5 mL). Water (250 mL) was added to the filtrate and washings at room temperature, and the mixture was stirred at room temperature for 1 hour. The crystallized material was collected by filtration, washed with water (300 mL), and dried under reduced pressure at 50 °C to give the title compound. White powder, 15.1 g, yield 87%, purity 99.9% (HPLC). Optical purity 98.6% ee (chiral HPLC).

[0995] Conditions for high-performance liquid chromatography analysis (area normalization)

[0996] Column: L-column2 ODS, S-5μm, 4.6mm id×250mm

[0997] UV detection wavelength: 220nm

[0998] Column temperature: 25℃

[0999] Mobile phase:

[1000] Table 5

[1001]

[1002]

[1003] Flow rate: 1.0 mL / min

[1004] Retention time: 14.9 min (title compound)

[1005] Conditions for high-performance liquid chromatography analysis (optical purity)

[1006] Column: CROWNPAK CR-I(+), S-5μm, 3.0mm id.×150mm

[1007] UV detection wavelength: 305nm

[1008] Column temperature: 25℃

[1009] Mobile phase:

[1010] Table 6

[1011] 0.00min. 60％ 40％ 2.00 min. 60％ 40％ 15.00 min. 40％ 60％ 16.00 min. 10％ 90％ 20.00 min. 10％ 90％

[1012] Flow rate: 0.5 mL / min

[1013] Retention time: 5.2 min (R), 8.1 min (S)

[1014] 1 ¹H NMR (DMSO-d⁶) δ 1.39 (d, J = 7.0 Hz, 3H), 4.21 (q, J = 7.0 Hz, 1H), 8.59 (s, 1H), 8.70 (s, 1H), 8.76 (s, 1H), 11.59 (brs, 1H). Regarding C… 12 H 11 ClF3N4OS[(M+H) + The calculated HRMS(ESI) is 351.0289, and the measured value is 351.0290. Melting point: 154℃.

[1015] Example 3

[1016] Synthesis of 6-amino-5-chloro-N-((1R)-1-(5-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)-1,3-thiazo-2-yl)ethyl)pyrimidin-4-carboxamide

[1017]

[1018] 1-Hydroxybenzotriazole monohydrate (1.31 g), 6-amino-5-chloropyrimidin-4-carboxylic acid (8.16 g), 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (15.0 g), and N,N-dimethylacetamide (75 mL) were placed in a four-necked flask (500 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.61 g) was added, and the mixture was stirred at room temperature for 4 hours. n-Butanol (75 mL) was added at room temperature, and the mixture was heated to approximately 55 °C. Water (180 mL) was added, and the mixture was stirred for 40 min. Water (45 mL) was added at approximately 55 °C, and the mixture was cooled to room temperature and stirred for 30 min. The crystalline substance was collected by filtration, washed with water (150 mL), and dried under reduced pressure at 60 °C to give the title compound. White powder, 19.1 g, yield 88%, purity 99.9% (HPLC). Optical purity 96.1% ee (chiral HPLC).

[1019] Conditions for high-performance liquid chromatography analysis (area normalization)

[1020] Column: Waters XTerra RP18, 5μm, 3.9×150mm

[1021] UV detection wavelength: 254nm

[1022] Column temperature: 30℃

[1023] Mobile phase:

[1024] Table 7

[1025] 0.00min. 80％ 20％ 1.00 min. 80％ 20％ 26.00 min. 15％ 85％ 31.00 min. 15％ 85％

[1026] Flow rate: 0.6 mL / min

[1027] Retention time: 16.0 min (title compound)

[1028] Conditions for high-performance liquid chromatography analysis (optical purity)

[1029] Column: CHIRALPAK IC-3, 3μm, 4.6×150mm

[1030] UV detection wavelength: 277nm

[1031] Column temperature: 40℃

[1032] Mobile phase: formic acid aqueous solution (pH 2.0) / acetonitrile = 6 / 4

[1033] Flow rate: 1.0 mL / min

[1034] Retention time: 14.1 min (R), 16.7 min (S)

[1035] 1 ¹H NMR (DMSO-d⁶) δ 1.59 (d, J = 7.0 Hz, 3H), 5.35 (m, 1H), 7.41 (brs, 1H), 7.81 (brs, 1H), 8.37 (s, 1H), 8.58 (s, 1H), 8.76 (s, 1H), 8.78 (s, 1H), 9.51 (d, J = 8.0 Hz, 3H), 11.76 (s, 1H). Regarding C... 17 H 13 Cl2F3N7O2S[(M+H) + The calculated HRMS(ESI) is 506.0175, and the measured value is also 506.0175. Melting point: 206℃.

[1036] Example 4

[1037] Purification of 6-amino-5-chloro-N-((1R)-1-(5-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)-1,3-thiazo-2-yl)ethyl)pyrimidin-4-carboxamide

[1038]

[1039] 15.0 g of 6-amino-5-chloro-N-((1R)-1-(5-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)-1,3-thiazo-2-yl)ethyl)pyrimidin-4-carboxamide, 25.5 mL of dimethyl sulfoxide, and 102 mL of 2-propanol were placed in a four-necked flask (200 mL), and the mixture was heated to approximately 75 °C. Insoluble substances were removed by filtration and washed with a mixture of dimethyl sulfoxide (4.5 mL) and 2-propanol (18 mL). Water (45 mL) was added to the filtrate and washings at approximately 75 °C, and seed crystals (15.0 mg) of 6-amino-5-chloro-N-((1R)-1-(5-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)-1,3-thiazolyl)ethyl)pyrimidine-4-carboxamide were added, and the mixture was stirred for 30 min. The mixture was cooled to approximately 45 °C and stirred for 1 h. The mixture was heated to approximately 75 °C, and water (90 mL) was added. The mixture was cooled to room temperature and stirred for 1 h. The crystallized material was collected by filtration, washed with 2-propanol (150 mL), and dried under reduced pressure at 60 °C to give the title compound. White powder, 13.8 g, yield 91%, purity 99.9% (HPLC). Optical purity 97.5% ee (chiral HPLC).

[1040] Conditions for high-performance liquid chromatography analysis (area normalization)

[1041] Column: Waters XTerra RP18, 5μm, 3.9×150mm

[1042] UV detection wavelength: 254nm

[1043] Column temperature: 30℃

[1044] Mobile phase:

[1045] Table 8

[1046] 0.00min. 80％ 20％ 1.00 min. 80％ 20％ 26.00 min. 15％ 85％ 31.00 min. 15％ 85％

[1047] Flow rate: 0.6 mL / min

[1048] Retention time: 16.0 min (title compound)

[1049] Conditions for high-performance liquid chromatography analysis (optical purity)

[1050] Column: CHIRALPAK IC-3, 3μm, 4.6×150mm

[1051] UV detection wavelength: 277nm

[1052] Column temperature: 40℃

[1053] Mobile phase: formic acid aqueous solution (pH 2.0) / acetonitrile = 6 / 4

[1054] Flow rate: 1.0 mL / min

[1055] Retention time: 14.1 min (R), 16.7 min (S)

[1056] 1 ¹H NMR (DMSO-d⁶) δ 1.59 (d, J = 7.0 Hz, 3H), 5.35 (m, 1H), 7.41 (brs, 1H), 7.81 (brs, 1H), 8.37 (s, 1H), 8.58 (s, 1H), 8.76 (s, 1H), 8.78 (s, 1H), 9.51 (d, J = 8.0 Hz, 3H), 11.76 (s, 1H). Regarding C... 17 H 13 Cl2F3N7O2S[(M+H) + The calculated HRMS(ESI) is 506.0175, and the measured value is also 506.0175. Melting point: 206℃.

[1057] Example 5

[1058] Synthesis of 2-((1R)-1-(diphenylmethylamino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide

[1059]

[1060] (E)-2-(1-(diphenylmethylimino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (290.66 g), [Ir(cod)2]BARF (1.44 g), and (S)-MONOPHOS (0.89 g) were placed into a 10 L autoclave. The atmosphere in the autoclave was reduced until the pressure dropped to -0.90 MPa or lower, and then the pressure was restored to approximately 0.1 MPa using argon. This procedure was repeated a total of seven times. The pressure in the autoclave was restored to normal, and dehydrated dichloromethane (3 L) for organic synthesis was fed into it under argon pressure. The mixture was stirred for 10 min. After stirring was stopped, hydrogen was fed into the autoclave until the pressure increased to 0.1 MPa, and then the pressure was restored to normal. This procedure was repeated a total of ten times. Hydrogen was fed into an autoclave up to 0.90 MPa, and the mixture was stirred at an internal temperature of 50 °C for 23 hours. The mixture was cooled to approximately 20 °C, and the hydrogen was released. The atmosphere was replaced with argon, and the reaction solution was removed. The reaction solution was concentrated under reduced pressure to give the title compound. A brown oil, 304.77 g, yield 104.5%, HPLC area normalized 99.3%, optical purity 89.9% ee.

[1061] Conditions for high-performance liquid chromatography analysis (area normalization)

[1062] Column: YMC-Pack ODS-A (manufactured by YMC.CO.,LTD.), 4.6*150mm

[1063] UV detection wavelength: 254nm

[1064] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1065] Flow rate: 1.0 mL / min

[1066] Retention times: 6.9 min (title compound), 9.3 min (substrate)

[1067] Conditions for high-performance liquid chromatography analysis (optical purity)

[1068] Column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150mm

[1069] UV detection wavelength: 254nm

[1070] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1071] Flow rate: 1.0 mL / min

[1072] Retention time: 8.8 min (s), 14.3 min (R)

[1073] Example 6

[1074] Synthesis of 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide hydrobromide

[1075]

[1076] (E)-2-(1-(diphenylmethylimino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (5.00 g), [Ir(cod)2]BARF (0.0247 g), and (S)-MONOPHOS (0.0154 g) were placed in an autoclave (120 mL). The atmosphere in the autoclave was reduced, and the pressure was restored with argon. This procedure was repeated a total of seven times. The pressure in the autoclave was restored to normal, and dehydrated toluene (50 mL) for organic synthesis was fed into it under argon pressure. Hydrogen was fed into the autoclave until the pressure increased by 0.1 MPa, and the pressure was restored to normal. This procedure was repeated a total of ten times. Hydrogen was fed into the autoclave until the pressure reached 1.20 MPa, and the mixture was stirred at an internal temperature of 80 °C for 18 hours. The mixture was cooled to an internal temperature of approximately 20°C, hydrogen was released, and the atmosphere was replaced with argon. The reaction solution was stirred at near room temperature for 2 hours, and insoluble substances were removed by filtration and washed with toluene (10 mL). Water (0.874 mL) and N-bromosuccinimide (1.73 g) were added to the filtrate and washings at near room temperature, and the mixture was stirred for 19 hours. The crystalline substance was collected by filtration, washed with toluene (30 mL), and dried under reduced pressure at 60°C to give the title compound. Yellow powder, 3.86 g, yield 92.1%, purity 74.4%, optical purity 98.5% ee.

[1077] Conditions (purity) for high-performance liquid chromatography analysis

[1078] Column: YMC-Pack ODS-A (manufactured by YMC.CO.,LTD.), 4.6*150mm

[1079] UV detection wavelength: 254nm

[1080] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1081] Flow rate: 1.0 mL / min

[1082] Retention times: 2.6 min (title compound), 9.3 min (raw material)

[1083] Conditions for high-performance liquid chromatography analysis (optical purity)

[1084] Column: CHIRALPAK IA (manufactured by Daicel Chemical Industries), 4.6*250mm

[1085] UV detection wavelength: 254nm

[1086] Mobile phase: Acetonitrile for HPLC / Methanol for HPLC / Distilled water for HPLC = 80 / 15 / 5

[1087] Flow rate: 2.0 mL / min

[1088] Retention time: 10.2 min (R), 14.4 min (S)

[1089] 1 H NMR (DMSO-d6) δ1.67 (d, J = 6.6 Hz, 3H), 5.01 (brs, 1H), 8.58 (s, 1H), 8.75 (brs, 3H), 8.80 (s, 1H), 8.90 (s, 1H), 11.88 (s, 1H).

[1090] Example 7

[1091] Synthesis of 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (S)-mandelate

[1092]

[1093] 1.00 g of 2-(1R)-1-((diphenylmethylamino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide and 0.516 g of aluminum trichloride were placed in a Schlenk flask (50 mL). The atmosphere in the Schlenk flask was reduced under reduced pressure and then restored to pressure with argon. This procedure was repeated three times in total. 20 mL of dichloromethane and 0.924 mL of triethylsilane were added to the flask under an argon atmosphere, and the reaction mixture was stirred at 80 °C for 23 hours. The reaction mixture was cooled to room temperature, and the reaction was quenched with 20 mL of 30 wt% aqueous sodium hydroxide solution. The mixture was extracted three times with THF. The obtained organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give a pale yellow solid. This solid was suspended in acetonitrile (13.5 mL), and the suspension was heated to 50 °C. (S)-mandelic acid (0.294 g) was added to the mixture at 50 °C, and the mixture was heated under reflux for 15 min. The mixture was cooled to room temperature and stirred at the same temperature for 1.5 h. The precipitate was collected by filtration through a glass filter, and the resulting white solid was washed with acetonitrile (3.5 mL) and dried under reduced pressure at 50 °C for 2 h to give the title compound (0.655 g). Yield 68%. HPLC area normalized 100%. 99.3% de.

[1094] Conditions for high-performance liquid chromatography analysis (HPLC area normalization)

[1095] Column: YMC-Pack ODS-A (manufactured by YMC.CO.,LTD.), 4.6*150mm

[1096] UV detection wavelength: 254nm

[1097] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1098] Flow rate: 1.4 mL / min

[1099] Retention times: 1.6 min (title compound); 5.5 min (raw material)

[1100] Conditions for high-performance liquid chromatography analysis (optical purity)

[1101] Column: IA (manufactured by Daicel Chemical Industries), 4.6*250mm

[1102] UV detection wavelength: 254nm

[1103] Mobile phase: Acetonitrile / methanol / water = 80 / 15 / 5 for high performance liquid chromatography

[1104] Flow rate: 2.0 mL / min

[1105] Column temperature: 40℃

[1106] Retention time: 11.4 min (R-form); 16.4 min (S-form)

[1107] 1 H NMR(DMSO-d6)δ1.40(d,J=6.5Hz,3H),4.26(q,J=6.5Hz,1H),4.72(s,1H),7.18-7.22 (m,1H),7.25-7.29(m,2H),7.36-7.40(m,2H),8.59(s,1H),8.72(s,1H),8.77(s,1H).

[1108] Example 8

[1109] Synthesis of 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide hydrochloride

[1110]

[1111] 0.80 g of 2-((1R)-1-((diphenylmethylamino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide was placed in a Schlenk flask (50 mL). The atmosphere in the Schlenk flask was reduced under reduced pressure and then restored to pressure with argon. This procedure was repeated a total of three times. Dichloromethane (16 mL) was added under an argon atmosphere. The solution was cooled in an ice bath and N-bromosuccinimide (0.414 g) was added. The reaction mixture was stirred at 0 °C for 1 hour and then at room temperature for 2 hours, with the reaction proceeding at 15 wt%. Quenching was performed with an aqueous sodium hydroxide solution (40 mL). The mixture was extracted three times with dichloromethane. The resulting organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give a pale yellow solid. The solid was added to acetonitrile (6 mL), and the mixture was stirred at 0 °C for 30 min. The resulting solid was collected by filtration to give the corresponding imine (0.524 g, 66% yield). The imine was suspended in acetonitrile / water = 20 / 1 (3.78 mL), and a 1 mol / L hydrogen chloride-ether solution (1.02 mL) was added to it at room temperature. The mixture was stirred at room temperature for 15 h, and filtered using a Hirsch funnel to give a white solid. The solid was washed with acetonitrile (2 mL) and dried under reduced pressure at 50 °C for 8 h to give the title compound (63% yield in two steps). The remaining benzophenone (2%) in the compound was collected by filtration. 1 H NMR analysis confirmed this.

[1112] Conditions for high-performance liquid chromatography analysis (HPLC area normalization)

[1113] Column: YMC-Pack ODS-A (manufactured by YMC.CO.,LTD.), 4.6*150mm

[1114] UV detection wavelength: 254nm

[1115] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1116] Flow rate: 1.4 mL / min

[1117] Retention times: 1.6 min (title compound); 2.3 min (benzophenone); 5.5 min (raw material).

[1118] Conditions for high-performance liquid chromatography analysis (optical purity)

[1119] Column: IA (manufactured by Daicel Chemical Industries), 4.6*250mm

[1120] UV detection wavelength: 254nm

[1121] Mobile phase: Acetonitrile / methanol / water = 80 / 15 / 5 for high performance liquid chromatography

[1122] Flow rate: 2.0 mL / min

[1123] Column temperature: 40℃

[1124] Retention time: 11.4 min (R-form); 16.4 min (S-form)

[1125] 1 H NMR (DMSO-d6) δ1.65 (d, J = 6.5 Hz, 3H), 4.92 (q, J = 6.5 Hz, 1H), 8.58 (s, 1H), 8.80 (s, 1H), 8.88 (s, 1H), 8.91 (br, 3H), 11.89 (s, 1H).

[1126] Examples 9-54

[1127] Synthesis of 2-((1R)-1-((diphenylmethylamino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide

[1128]

[1129] (E)-2-(1-(diphenylmethylimino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (0.0386 g), catalyst (corresponding to s / c = 20), and ligand (1.1 or 2.2 equivalents relative to iridium catalyst) were placed in a test tube. The test tube was placed in an autoclave. The atmosphere in the autoclave was reduced in pressure, and the pressure was restored with nitrogen. These procedures were repeated a total of three times. The pressure in the autoclave was restored to normal, and solvent (0.75 mL) was added. Hydrogen was fed into the autoclave until the pressure increased by 0.1 MPa, and the pressure was restored to normal. These procedures were repeated a total of ten times. Hydrogen was fed into the autoclave until 3.0 MPa, and the mixture was stirred at an internal temperature of 50 °C for 2 hours. The mixture was cooled to an internal temperature of approximately 20 °C, and the hydrogen was released. The conversion and enantiomeric excess were measured by HPLC. The results are shown in Table 9.

[1130] Conversion rate can be calculated using the following formula.

[1131] Conversion rate = 100 × desired compound / (desired compound + raw material compound)

[1132] The desired compounds and raw materials refer to each area in high-performance liquid chromatography.

[1133] Conditions for high-performance liquid chromatography analysis (HPLC area normalization)

[1134] Column: YMC-Pack ODS-A (manufactured by YMC.CO.,LTD.), 4.6*150mm

[1135] UV detection wavelength: 254nm

[1136] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1137] Flow rate: 1.4 mL / min

[1138] Retention time: 5.5 min (title compound), 7.2 min (raw material).

[1139] Conditions for high-performance liquid chromatography analysis (optical purity)

[1140] Column: OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150mm

[1141] UV detection wavelength: 254nm

[1142] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1143] Flow rate: 1.2 mL / min

[1144] Retention time: 8.3 min (S-form), 13.6 min (R-form).

[1145] 1 H NMR(CDCl3)δ1.56(d,J=6.5Hz,3H),2.19(s,1H),4.05(q,J=6.5Hz,1H),4.98(s,1H),7.19-7.24( m,1H),7.27-7.32(m,3H),7.33-7.44(m,6H),8.26(s,1H),8.41(s,1H),8.44(s,1H),8.69(s,1H).

[1146] Table 9-1

[1147]

[1148] Table 9-2

[1149]

[1150] Table 9-3

[1151]

[1152] Reference Example 3

[1153] Synthesis of (E)-2-(1-(bis(4-methoxyphenyl)methyl)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide

[1154]

[1155] 13.00 g of 2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide, 10.00 g of 4,4'-dimethoxydiphenylmethylamine, 65 mL of ethanol, and 0.642 mL of acetic acid were placed in a 200 mL four-necked flask and stirred under reflux for 8 hours at a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 10 mL of ethanol was added, and the mixture was filtered. The remaining white solid was washed with 30 mL of ethanol, and the filtrate and washings were combined and concentrated under reduced pressure to give a solid. Toluene (80 mL) was added to the solid, and the mixture was heated to 99 °C. Hexane (190 mL) was added dropwise from 73 °C to 99 °C, and the mixture was stirred at 73 °C (reflux temperature) for 10 min and cooled to room temperature. The resulting crystals were aged at room temperature. The crystals were collected by filtration, washed with a mixed solvent of hexane and toluene (1:3) (60 mL), and dried under reduced pressure at 60 °C to give the title compound as a light brown solid (16.57 g, 77% yield).

[1156] 1 H NMR(CDCl3)δ2.45(s,3H),3.78(s,6H),5.82(s,1H),6.86(d,J=9.0Hz,4H), 7.33(d,J=9.0Hz,4H),8.36(s,1H),8.44(s,1H),8.57(bs,1H),8.69(s,1H); 13C NMR (CDCl3) δ14.62, 55.26, 67.42, 111.89 (q, J = 5.4Hz), 114.01, 121.45 (q, J = 275.2Hz), 124.06, 128. 30,135.16,135.91,137.81(q,J=32.7Hz),145.41,149.48,149.92,158.68,158.81,159.67,176.60.

[1157] Refer to Example 4

[1158] Synthesis of (E)-2-(1-(2-benzoylhydrazono))ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide

[1159]

[1160] 2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (1.00 g), benzoyl hydrazine (0.408 g), and p-toluenesulfonic acid monohydrate (0.0272 g) were placed in a four-necked flask (50 mL). Methanol (15 mL) was added under a nitrogen atmosphere, and the mixture was stirred at 60 °C for 1 hour. The reaction mixture was cooled in a water bath, and the precipitate was collected by filtration through a glass filter. The resulting white solid was washed with methanol (5 mL) and dried under reduced pressure at 50 °C to give the title compound (1.21 g). Yield 91%, HPLC area normalized 99.3%. E / Z isomer ratio 11 / 1.

[1161] Conditions for high-performance liquid chromatography analysis (area normalization)

[1162] Column: YMC-Pack ODS-A (manufactured by YMC.CO.,LTD.), 4.6*150mm

[1163] UV detection wavelength: 254nm

[1164] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1165] Flow rate: 1.0 mL / min

[1166] Retention times: 1.47 min (benzoyl hydrazide), 4.36 min (title compound), 4.48 min (raw material)

[1167] 1H NMR(DMSO-d6)δ2.48(s,3H),7.50-7.57(m,2H),7.58-7.65(m,1H),7.81-7.94 (m,2H),8.59(s,1H),8.78(s,1H),8.86(s,1H),11.22(bs,1H),11.81(bs,1H).

[1168] Refer to Example 5

[1169] Synthesis of (E)-(S)-2-(1-(5-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)-1,3-thiazo-2-yl)ethylene)hydrazine carboxylic acid tert-butyl ester

[1170]

[1171] 6.00 g of 2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide was placed in a four-necked flask (100 mL). The atmosphere in the container was reduced to a reduced pressure, and the pressure was restored with nitrogen. This procedure was repeated three times in total. Toluene (18 mL), acetic acid (3.6 mL), and tert-butoxycarbonylhydrazine (0.408 g) were added to the mixture under a nitrogen atmosphere, and the mixture was stirred at 60 °C for 2 hours. The reaction mixture was cooled in a water bath, and the target product was precipitated. The mixture was aged at room temperature for 1 hour, and the precipitate was collected by filtration using a glass filter. The resulting white solid was washed with toluene / hexane = 1 / 1 (50 mL) and dried at 50 °C under reduced pressure to give the title compound (7.18 g). Yield 89%, HPLC area normalized 93.9%.

[1172] Conditions for high-performance liquid chromatography analysis (area normalization)

[1173] Column: YMC-Pack ODS-A (manufactured by YMC.CO.,LTD.), 4.6*150mm

[1174] UV detection wavelength: 254nm

[1175] Mobile phase: Acetonitrile for high performance liquid chromatography / 0.025 mol / L potassium dihydrogen phosphate aqueous solution = 7 / 3

[1176] Flow rate: 1.0 mL / min

[1177] Retention times: 4.48 min (raw material); 5.66 min (title compound)

[1178] 1H NMR(DMSO-d6)δ1.51(s,9H),2.31(s,3H),8.58(s,1H),8.75(s,1H),8.80(s,1H),10.46(s,1H),11.74(s,1H); 13 C NMR(DMSO-d6)δ12.59,27.95,80.33,111.81(q,J=5.4Hz),121.58(q,J=274.3Hz),121 .62,134.85,135.32(q,J=31.8Hz),145.51,149.70,151.33,152.23,159.69,172.44; 19 F NMR (DMSO-d6) δ -63.81.

[1179] Refer to Example 6

[1180] Synthesis of (E)-2-(1-(benzylimino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide

[1181]

[1182] 6.00 g of 2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide was placed in a 100 mL four-necked flask. Toluene (30 mL), benzyl alcohol (1.97 mL), and acetic acid (0.196 mL) were added under a nitrogen atmosphere, and the mixture was stirred at 90 °C for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude target product was suspended in a 9 / 1 mixture of hexane and ethyl acetate (60 mL), and the suspension was heated to dissolve at 90 °C. The solution was then cooled to 0 °C to precipitate crystals. The mixture was aged at 0 °C for 30 min, and the precipitate was collected by filtration through a glass filter. The resulting pale orange solid was washed with a 9 / 1 mixture of hexane and ethyl acetate (30 mL) and dried under reduced pressure at 50 °C to give the title compound (6.83 g). Yield: 91%, HPLC area normalized: 84.7%.

[1183] Conditions for high-performance liquid chromatography analysis (area normalization)

[1184] Column: YMC-Pack ODS-A (manufactured by YMC.CO.,LTD.), 4.6*150mm

[1185] UV detection wavelength: 254nm

[1186] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1187] Flow rate: 1.0 mL / min

[1188] Retention times: 4.48 min (raw material), 16.4 min (title compound)

[1189] Refer to Example 7

[1190] Synthesis of (E)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-2-(1-((4-methoxybenzyl)imino)ethyl)-1,3-thiazolyl-5-carboxamide

[1191]

[1192] 6.00 g of 2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide was placed in a 100 mL four-necked flask. Toluene (30 mL), 2.35 mL of 4-methoxybenzylamine, and 0.196 mL of acetic acid were added under a nitrogen atmosphere, and the mixture was stirred at 85 °C for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude target product was suspended in 48 mL of ethanol, and the suspension was dissolved by heating at 70 °C. The solution was cooled to room temperature to precipitate crystals. The precipitate was collected by filtration through a glass filter, washed with 20 mL of ethanol, and dried under reduced pressure at 60 °C to give the title compound (5.64 g) as a single isomer. A pale orange solid, 70% yield, HPLC area normalized 99.4%.

[1193] Conditions for high-performance liquid chromatography analysis (HPLC area normalization)

[1194] Column: YMC-Pack ODS-A (manufactured by YMC.CO.,LTD.), 4.6*150mm

[1195] UV detection wavelength: 254nm

[1196] Mobile phase: Acetonitrile for high performance liquid chromatography / 0.025 mol / L potassium dihydrogen phosphate aqueous solution = 7 / 3

[1197] Flow rate: 1.0 mL / min

[1198] Retention time: 4.7 min (raw material); 11.2 min (title compound).

[1199] 1H NMR(CDCl3)δ2.47(s.3H),3.82(s,3H),4.74(s,2H),6.92(d,J=8.5Hz,2H), 7.33(d,J=8.5Hz,2H),8.37(s,1H),8.40(s,1H),8.44(s,1H),8.67(s,1H).

[1200] Synthesis according to Example 8

[1201] (E)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-2-(1-((2,4-dimethoxybenzyl)imino)ethyl)-1,3-thiazolyl-5-carboxamide

[1202]

[1203] The title compound (6.81 g) was obtained as a single isomer in the same manner as in Reference Example 7. It was a yellow solid, 75% yield, with a normalized HPLC area of ​​96.2%.

[1204] Conditions for high-performance liquid chromatography analysis (HPLC area normalization)

[1205] Column: YMC-Pack ODS-A (manufactured by YMC.CO.,LTD.), 4.6*150mm

[1206] UV detection wavelength: 254nm

[1207] Mobile phase: Acetonitrile for high performance liquid chromatography / 0.025 mol / L potassium dihydrogen phosphate aqueous solution = 7 / 3

[1208] Flow rate: 1.0 mL / min

[1209] Retention time: 4.7 min (raw material); 12.1 min (title compound).

[1210] 1 H NMR(CDCl3)δ2.47(s.3H),3.82(s,3H),3.84(s,3H),4.70(s,2H),6.49(d,J=2.5Hz,1H),6.52(d d,J=8.5,2.5Hz,1H),7.36(d,J=8.5Hz,1H),8.37(s,1H),8.41(s,1H),8.43(s,1H),8.68(s,1H).

[1211] Reference Example 9

[1212] Synthesis of (E)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-2-(1-((4-methoxyphenyl)imino)ethyl)-1,3-thiazolyl-5-carboxamide

[1213]

[1214] 2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (1.00 g), p-toluenesulfonic acid monohydrate (0.0272 g), and p-anisidine (0.369 g) were placed in a four-necked flask (50 mL). Toluene (6 mL) was added under a nitrogen atmosphere, and the mixture was stirred at 90 °C for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude target product was suspended in ethanol (10 mL), and the suspension was dissolved by heating at 65 °C. Water (10 mL) was added dropwise at the same temperature, and the mixture was cooled to room temperature. The resulting reddish-brown suspension was stirred at room temperature for 30 min, and the precipitate was collected by filtration through a glass filter, washed with ethanol / water = 1 / 1 (10 mL), and dried under reduced pressure at 50 °C to give the title compound (1.08 g) as a single isomer. Brown solid, yield 83%, HPLC area normalized 91.7%.

[1215] Conditions for high-performance liquid chromatography analysis (HPLC area normalization)

[1216] Column: YMC-Pack ODS-A (manufactured by YMC.CO.,LTD.), 4.6*150mm

[1217] UV detection wavelength: 254nm

[1218] Mobile phase: Acetonitrile for high performance liquid chromatography / 0.025 mol / L potassium dihydrogen phosphate aqueous solution = 7 / 3

[1219] Flow rate: 1.0 mL / min

[1220] Retention time: 4.7 min (raw material); 28.0 min (title compound).

[1221] 1 H NMR(DMSO-d6)δ2.37(s.3H),3.78(s,3H),6.86-7.05(m,4H),8.59(s,1H),8.78(s,1H),8.93(s,1H),11.85(s,1H); 13C NMRδ16.18,55.22,111.89,114.19,122.08(q,J=274.28Hz),121.79,122.00,135.36(q ,J=32.7Hz),136.93,141.46,146.01,149.74,151.27,156.78,159.61,160.61,174.22; 19 F NMRδ-63.81.

[1222] Example 55

[1223] Synthesis of 2-((1R)-1-((bis(4-methoxyphenyl)methyl)amino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide

[1224]

[1225] (E)-2-(1-((bis(4-methoxyphenyl)methyl)imino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (3.00 g), [Ir(cod)2]BARF (0.0664 g), and (S)-MONOPHOS (0.0412 g) were placed in an autoclave (120 mL). The atmosphere in the autoclave was reduced, and the pressure was restored with argon. This procedure was repeated a total of five times. The pressure in the autoclave was restored to normal, and dehydrated dichloromethane (30 mL) for organic synthesis was fed into it under argon pressure. Hydrogen was fed into the autoclave until the pressure increased by 0.1 MPa, and the pressure was restored to normal. This procedure was repeated a total of ten times. Hydrogen was fed into the autoclave until the pressure reached 1.0 MPa, and the mixture was stirred at an internal temperature of 50 °C for 24 hours. The mixture was cooled to an internal temperature of approximately 20°C, hydrogen was released, and the atmosphere was replaced with argon (conversion 73.7%, optical purity 93.7% ee). The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound. 1.54 g of light brown solid, yield 50%, HPLC area normalized 96.2%.

[1226] Conditions for high-performance liquid chromatography analysis (area normalization)

[1227] Column: YMC-Pack ODS-A (manufactured by YMC.CO.,LTD.), 4.6*150mm

[1228] UV detection wavelength: 254nm

[1229] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1230] Flow rate: 1.0 mL / min

[1231] Retention time: 2.4 min (title compound)

[1232] 1 H NMR (CDCl3) δ1.54 (d, J = 6.6 Hz, 3H), 4.42 (q, J = 6.6 Hz, 1H), 7.23 (d, J = 3.2 Hz, 1H), 7.70 (d, J = 3.2 Hz, 1H).

[1233] 13 C NMR (CDCl3) δ24.66, 49.65, 118.36, 142.38, 178.38.

[1234] Example 56

[1235] Synthesis of 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide hydrochloride

[1236]

[1237] 2-((1R)-1-((bis(4-methoxyphenyl)methyl)amino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (0.150 g) was dissolved in a mixed solvent of acetonitrile and water (9:1, 3.0 mL), and a 1 mol / L hydrogen chloride-diethyl ether solution (0.312 mL) was added dropwise to this solution. The mixture was heated to 50 °C and stirred overnight at the same temperature. The mixture was cooled to room temperature, and the resulting crystals were collected by filtration to give the title compound. Colorless solid, 0.0776 g, yield 77%.

[1238] Examples 57-101

[1239] Synthesis of 2-((1R)-1-(2-benzoylhydrazine)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide

[1240]

[1241] (E)-2-(1-(2-benzoylhydrazine)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (0.0702 g), catalyst (corresponding to s / c = 20), ligand (1.1 or 2 equivalents relative to the catalyst), and additive (potassium butoxide was used in an amount of 1 equivalent relative to the substrate in Examples 57-62, and no additive was used in Examples 63-101) were placed in a test tube. Solvent (1 mL) was added under a nitrogen atmosphere, the test tube was placed in an autoclave, and the reaction system was purged with hydrogen. Hydrogen was fed into the autoclave up to 5.0 MPa, and the mixture was stirred at 50 °C for 16 hours. The formation of the title compound was confirmed by HPLC analysis of the reaction solution. The results are shown in Table 10.

[1242] Conditions for high-performance liquid chromatography analysis (optical purity)

[1243] Column: OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150mm

[1244] UV detection wavelength: 254nm

[1245] Mobile phase: Acetonitrile for high performance liquid chromatography / 0.025 mol / L potassium dihydrogen phosphate aqueous solution = 1 / 1

[1246] Flow rate: 1.0 mL / min

[1247] Retention time: 5.4 min (S-form); 6.1 min (R-form); 7.6 min (raw materials)

[1248] Table 10-1

[1249]

[1250] Table 10-2

[1251]

[1252] Example 102

[1253] Synthesis of 2-((1S)-1-(2-benzoylhydrazyl)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide

[1254]

[1255] Rh(cod)2]OTf (0.0020 g) and (S)(R)-SL-J210-2 (0.0037 g) were placed into a Schlenk flask (20 mL). The atmosphere in the container was reduced in pressure and then restored to pressure with argon. This procedure was repeated a total of five times. The pressure in the container was restored to normal, and dehydrated methanol (20 mL) for organic synthesis was added. The mixture was stirred at room temperature for 1 hour. Separately, (E)-2-(1-(2-benzoylhydrazine)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (2.00 g) was placed into an autoclave. The atmosphere in the container was reduced in pressure and then restored to pressure with argon. This procedure was repeated a total of seven times. The pressure in the container was restored to normal, and the rhodium catalyst methanol solution prepared above was fed into it under argon pressure. The Schlenk container was washed with methanol (20 mL) and the washing solution was added under argon pressure. Hydrogen was fed into the container up to 1.0 MPa, and the mixture was stirred at an internal temperature of 50 °C for 20 hours. The mixture was cooled to an internal temperature of approximately 20 °C, and the hydrogen was released. The formation of the title compound was confirmed by HPLC analysis of the reaction solution (conversion 99% or higher, 90% ee). The reaction mixture was concentrated to give a yellow solid. The solid was suspended in acetonitrile (4 mL) / diisopropyl ether (16 mL), and the suspension was stirred at 60 °C for 1 hour, cooled to room temperature, and stirred overnight. The precipitate was collected by filtration through a glass filter and washed with acetonitrile (2 mL) / diisopropyl ether (8 mL). The obtained solid was dried at 60 °C under reduced pressure to give the title compound (yield 86%, 91% ee). HPLC area normalization was 98.3%.

[1256] Conditions for high-performance liquid chromatography analysis (optical purity)

[1257] Column: OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150mm

[1258] UV detection wavelength: 254nm

[1259] Mobile phase: Acetonitrile for high performance liquid chromatography / 0.025 mol / L potassium dihydrogen phosphate aqueous solution = 1 / 1

[1260] Flow rate: 1.0 mL / min

[1261] Retention time: 5.4 min (S-form); 6.1 min (R-form); 7.6 min (raw material)

[1262] 1H NMR(CDCl3)δ1.62(d,J=6.5Hz,3H),4.64(qd,J=6.5,2.0Hz,1H),5.31(dd,1H),7.43(t,J=7.5Hz,2H),7.53(tt ,J=8.0,1.5Hz,1H),7.71(dd,J=8.0,1.5Hz,2H),7.84(d,J=5.5Hz,1H),8.29(s,1H),8.43(s,1H),8.67(s,2H); 19 F NMR (CDCl3) δ -64.77; 13 CNMR(CDCl3)δ20.43,59.12,111.96(q,J=5.4Hz),121.4(q,J=275.2Hz),123.97,126.96,128.78, 132.16, 132.37, 133.55, 137.79 (q, J = 33.6Hz), 144.67, 149.42, 150.04, 158.94, 168.02, 180.68.

[1263] Example 103

[1264] Synthesis of 2-((1S)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide hydrochloride

[1265]

[1266] 2-((1S)-1-(2-benzoylhydrazido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (0.0500 g) and zinc powder (0.0152 g) were placed in a Schlenk flask (10 mL). The atmosphere in the container was reduced under reduced pressure, and the pressure was restored with argon. This procedure was repeated a total of three times. Methanol (2.0 mL) and trimethylchlorosilane (0.002 mL) were added at room temperature. After confirming that the reaction solution had turned gray, benzoic acid (0.029 g) was added, and the reaction mixture was stirred at room temperature for 17 hours. The formation of the title compound was confirmed by HPLC (55.8% ee).

[1267] Conditions for high-performance liquid chromatography analysis (optical purity)

[1268] Column: OJ-H (manufactured by Daicel Chemical Industries), 4.6*150mm

[1269] UV detection wavelength: 270nm

[1270] Mobile phase: Hexane / isopropanol / methanol / diethylamine = 80 / 15 / 5 / 0.1 for high-performance liquid chromatography.

[1271] Flow rate: 1.0 mL / min

[1272] Retention time: 5.7 min (S-form); 8.6 min (R-form)

[1273] Examples 104-111

[1274] Synthesis of tert-butyl 2-((1S)-1-(5-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)-1,3-thiazolyl)ethyl)hydrazine carboxylate

[1275]

[1276] 0.0696 g of 2-(1-(5-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)-1,3-thiazolyl)ethylene)hydrazine carboxylic acid tert-butyl ester, a catalyst (corresponding to s / c = 20), and a ligand (1.1 equivalents relative to the catalyst) were placed in a test tube. Solvent (1.5 mL) was added under a nitrogen atmosphere, and the test tube was placed in an autoclave, with the reaction system purged with hydrogen. Hydrogen was fed into the autoclave up to 1.0 MPa, and the mixture was stirred at 50 °C for 15 hours. The formation of the title compound was confirmed by HPLC analysis of the reaction solution. The results are shown in Table 11.

[1277] Conditions for high-performance liquid chromatography analysis (optical purity)

[1278] Column: OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150mm

[1279] UV detection wavelength: 254nm

[1280] Mobile phase: Acetonitrile for high performance liquid chromatography / 0.025 mol / L potassium dihydrogen phosphate aqueous solution = 1 / 1

[1281] Flow rate: 0.5 mL / min

[1282] Retention times: 12.8 min (enantiomer-A); 14.6 min (raw material); 16.1 min (enantiomer-B)

[1283] Table 11

[1284]

[1285] Examples 112-149

[1286] Synthesis of 2-(1-(benzylamino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide

[1287]

[1288] (E)-2-(1-(benzylimino)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (0.0658 g), catalyst (corresponding to s / c = 20), ligand (1.1 or 2 equivalents relative to the catalyst), and additive (potassium butoxide was used in an amount of 1 equivalent relative to the substrate in Examples 113-118, and no additive was used in Examples 119-149) were placed in a test tube. Solvent (1 mL) was added under a nitrogen atmosphere, the test tube was placed in an autoclave, and the reaction system was purged with hydrogen. Hydrogen was fed into the autoclave up to 5.0 MPa, and the mixture was stirred at 50 °C for 20 hours. The formation of the title compound was confirmed by HPLC analysis of the reaction solution. The results are shown in Table 12.

[1289] Conditions for high-performance liquid chromatography analysis (HPLC area normalization)

[1290] Column: YMC-Pack ODS-A (manufactured by YMC.CO.,LTD.), 4.6*150mm

[1291] UV detection wavelength: 254nm

[1292] Mobile phase: Acetonitrile for high performance liquid chromatography / 0.025 mol / L potassium dihydrogen phosphate aqueous solution = 7 / 3

[1293] Flow rate: 1.4 mL / min

[1294] Retention time: 7.2 min (title compound); 12.0 min (raw material).

[1295] Conditions for high-performance liquid chromatography analysis (optical purity)

[1296] Column: OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150mm

[1297] UV detection wavelength: 254nm

[1298] Mobile phase: Acetonitrile for high performance liquid chromatography / 0.025 mol / L potassium dihydrogen phosphate aqueous solution = 7 / 3

[1299] Flow rate: 1.0 mL / min

[1300] Retention times: 4.8 min (title compound); 7.2 min (raw material); 11.9 min (title compound)

[1301] Table 12-1

[1302]

[1303] Table 12-2

[1304]

[1305] Examples 150-156

[1306] Synthesis of N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-2-(1-((4-methoxybenzyl)amino)ethyl)-1,3-thiazolyl-5-carboxamide

[1307]

[1308] N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-2-(1-((4-methoxybenzyl)imino)ethyl)-1,3-thiazolyl-5-carboxamide (0.0351 g), catalyst (corresponding to s / c = 20), and ligand (1.1 or 2 equivalents relative to the catalyst) were placed in a test tube. Solvent (0.75 mL) was added under a nitrogen atmosphere, and the test tube was placed in an autoclave, with the reaction system purged with hydrogen. Hydrogen was fed into the autoclave up to 3.0 MPa, and the mixture was stirred at 50 °C for 2 hours. The formation of the title compound was confirmed by HPLC analysis of the reaction solution. The results are shown in Table 13.

[1309] Conditions for high-performance liquid chromatography analysis (HPLC area normalization)

[1310] Column: YMC-Pack ODS-A (manufactured by YMC.CO.,LTD.), 4.6*150mm

[1311] UV detection wavelength: 254nm

[1312] Mobile phase: Acetonitrile for high performance liquid chromatography / 0.025 mol / L potassium dihydrogen phosphate aqueous solution = 7 / 3

[1313] Flow rate: 1.0 mL / min

[1314] Retention time: 6.9 min (title compound); 11.2 min (raw material).

[1315] Conditions for high-performance liquid chromatography analysis (optical purity)

[1316] Column: OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150mm

[1317] UV detection wavelength: 254nm

[1318] Mobile phase: Acetonitrile for high performance liquid chromatography / 0.025 mol / L potassium dihydrogen phosphate aqueous solution = 7 / 3

[1319] Flow rate: 1.0 mL / min

[1320] Retention times: 5.0 min (title compound); 6.0 min (title compound); 7.4 min (raw material)

[1321] Table 13

[1322]

[1323] Examples 157-162

[1324] Synthesis of N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-2-(1-((2,4-dimethoxybenzyl)amino)ethyl)-1,3-thiazolyl-5-carboxamide

[1325]

[1326] N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-2-(1-((2,4-dimethoxybenzyl)imino)ethyl)-1,3-thiazolyl-5-carboxamide (0.0351 g), catalyst (corresponding to s / c = 20), and ligand (1.1 or 2 equivalents relative to the catalyst) were placed in a test tube. Solvent (0.75 mL) was added under a nitrogen atmosphere, and the test tube was placed in an autoclave, with the reaction system purged with hydrogen. Hydrogen was fed into the autoclave up to 3.0 MPa, and the mixture was stirred at 50 °C for 2 hours. The formation of the title compound was confirmed by HPLC analysis of the reaction solution. The results are shown in Table 15.

[1327] Conditions for high-performance liquid chromatography analysis (HPLC area normalization)

[1328] Column: YMC-Pack ODS-A (manufactured by YMC.CO.,LTD.), 4.6*150mm

[1329] UV detection wavelength: 254nm

[1330] Mobile phase: Acetonitrile for high performance liquid chromatography / 0.025 mol / L potassium dihydrogen phosphate aqueous solution = 7 / 3

[1331] Flow rate: 1.0 mL / min

[1332] Retention time: 6.3 min (title compound); 12.1 min (raw material).

[1333] Conditions for high-performance liquid chromatography analysis (optical purity)

[1334] Column: OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150mm

[1335] UV detection wavelength: 254nm

[1336] Table 14

[1337] Mobile phase:

[1338]

[1339] Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 4 / 6, 10 min

[1340] Flow rate: 1.2 mL / min

[1341] Retention times: 6.0 min (title compound); 6.5 min (title compound); 10.8 min (raw material)

[1342] Table 15

[1343]

[1344] Reference Example 10

[1345] Synthesis of (E)-1,1-diphenyl-N-(1-phenylethylidene)methylamine

[1346]

[1347] Acetophenone (4.92 g), toluene (50 mL), diphenylmethylamine (7.88 g), and acetic acid (0.5 mL) were placed into a 100 mL four-necked flask equipped with a Dean-Stark separator, and the mixture was stirred at an external temperature of 135 °C for 6 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give an oil. Hexane was added to the oil, and the mixture was stirred at 0 °C for 2 hours. The resulting solid was collected by filtration, washed with hexane (20 mL), and dried under reduced pressure at 50 °C to give the title compound (4.13 g, 35% yield) as a white solid.

[1348] 1H NMR(CDCl3)δ2.26(s,3H),5.84(s,1H),7.12-7.21(m,2H),7.24-7.30(m,4H),7.33-7.39(m,3H),7.42-7.50(m,4H),7.88-7.96(m,2H); 13 CNMR(CDCl3)δ16.03,68.52,126.81,127.08,127.70,128.25,128.52,129.73,141.33,144.97,164.51.

[1349] Refer to Example 11

[1350] Synthesis of (E)-N-(1-(4-methoxyphenyl)ethylene)-1,1-diphenylmethylamine

[1351]

[1352] Molecular sieve 4A (5.00 g) was placed in a four-necked flask (100 mL) and dried under reduced pressure at 100 °C for 30 min, with the reaction system purged with nitrogen. The flask was cooled to room temperature, and toluene (30 mL), 4'-methoxyacetophenone (5.00 g), diphenylmethylamine (6.03 mL), and acetic acid (0.38 mL) were added. The mixture was stirred at an internal temperature of 90 °C for 22 h. The reaction mixture was cooled to room temperature and filtered using a Hertzsprung funnel. The filtrate was concentrated under reduced pressure to give an oil. Hexane (30 mL) was added to the oil, and the oil was dissolved at 90 °C. The mixture was cooled to room temperature and stirred for 1 h. The resulting solid was collected by filtration, washed with hexane (20 mL), and dried under reduced pressure at 40 °C. The resulting white solid (5.55 g) was dissolved again in n-hexane (20 mL) under heating at 90 °C, and the solution was cooled to room temperature and stirred overnight at room temperature. The resulting solid was collected by filtration, washed with n-hexane (10 mL), and dried under reduced pressure at 40 °C to give the title compound as a white solid (4.81 g, yield 46%).

[1353] 1 H NMR(CDCl3)δ2.27(s,3H),3.82(s,3H),5.83(s,1H),6.90(d,J=9.0Hz,2H),7.19(t ,J=7.5Hz,2H),7.29(t,J=7.5Hz,4H),7.46(d,J=7.5Hz,4H),7.92(d,J=9.0Hz,2H); 13C NMR (CDCl3) δ15.60,55.31,68.23,113.40,126.60,127.56,128.35,128.44,133.98,145.08,160.92,163.47.

[1354] Refer to Example 12

[1355] Synthesis of (E)-N-(1-(4-chlorophenyl)ethylidene)-1,1-diphenylmethylamine

[1356]

[1357] Molecular sieve 4A (5.00 g) was placed in a four-necked flask (100 mL) and dried under reduced pressure at 100 °C for 30 min, with the reaction system purged with nitrogen. The flask was cooled to room temperature, and toluene (30 mL), 4'-chloroacetophenone (5.00 mL), diphenylmethylamine (7.97 mL), and acetic acid (0.44 mL) were added. The mixture was stirred at an internal temperature of 100 °C for 25 h. Seven hours after stirring began, additional diphenylmethylamine (1.3 mL) was added. The reaction mixture was cooled to room temperature and filtered using a Hertz funnel. The filtrate was concentrated under reduced pressure to give a white solid. Hexane (50 mL) was added to the solid, and the mixture was heated under reflux for 20 min, cooled to 0 °C, and stirred at the same temperature for 1 h. The obtained solid was collected by filtration, washed with n-hexane (30 mL) cooled to 0 °C, and dried under reduced pressure at 40 °C to give the title compound as a white solid (8.25 g, yield 67%).

[1358] 1 H NMR(CDCl3)δ2.29(s,3H),5.85(s,1H),7.20(t,J=7.5Hz,2H),7.30(t,J=7.5Hz,4H),7.35(d,J=8.5Hz,2H),7.44(d,J=7.5Hz,4H),7.88(d,J=8.5Hz); 13 C NMR(CDCl3)δ15.75,68.50,126.79, 127.51,128.31,128.45 ,135.75,139.52,144.64,163.16 (two peaks overlap in one of the underlined peaks).

[1359] Refer to Example 13

[1360] Synthesis of (E)-1,1-diphenyl-N-(1-(4-trifluoromethylphenyl)ethylidene)methylamine

[1361]

[1362] Molecular sieve 4A (5.00 g) was placed in a four-necked flask (100 mL) and dried under reduced pressure at 100 °C for 30 min, while purging the reaction system with nitrogen. The flask was cooled to room temperature, and toluene (30 mL), 4'-trifluoromethylacetophenone (5.00 g), diphenylmethylamine (5.72 mL), and acetic acid (0.31 mL) were added. The mixture was stirred at an internal temperature of 100 °C for 16 h. The reaction mixture was cooled to room temperature and filtered using a Hertz funnel. The filtrate was concentrated under reduced pressure to give a white solid. Hexane (30 mL) was added to the solid, and the mixture was stirred at 90 °C, cooled to 0 °C, and stirred at the same temperature for 1 h. The resulting solid was collected by filtration, washed with hexane (20 mL) cooled to 0 °C, and dried under reduced pressure at 40 °C to give the title compound as a white solid (4.68 g, 50% yield). The residual filtrate was concentrated under reduced pressure, and the residue was recrystallized from n-hexane (15 mL) at -20 °C to give the title compound as a white solid (1.45 g, 15% yield).

[1363] 1 H NMR(CDCl3)δ2.33(s,3H),5.88(s,1H),7.21(t,J=7.5Hz,2H),7.31(d,J=7.5 Hz,4H),7.45(d,J=7.5Hz,4H),7.64(d,J=8.5Hz,2H),8.03(d,J=8.5Hz,2H); 19 F NMR (CDCl3) δ -62.65; 13 C NMR(CDCl3)δ15.99,68.67,124.13(q,J=272.4Hz),125.13(q,J=4.5Hz),126 .89,127.28,127.49,128.51,131.41(q,J=31.8Hz),144.30,144.43,163.23.

[1364] Refer to Example 14

[1365] Synthesis of (E)-N-(1-(naphthyl-1-yl)ethylidene)-1,1-diphenylmethylamine

[1366]

[1367] Molecular sieve 4A (5.00 g) was placed in a four-necked flask (100 mL) and dried under reduced pressure at 100 °C for 30 min, while purging the reaction system with nitrogen. The flask was cooled to room temperature, and toluene (25 mL), 1-naphthyl ethylone (5.00 mL), diphenylmethylamine (5.95 mL), and acetic acid (0.38 mL) were added. The mixture was stirred at an internal temperature of 100 °C for 28 h. The reaction mixture was cooled to 90 °C and filtered using a Hertzsprung funnel. The filtrate was concentrated under reduced pressure to give a brown solid. Hexane (60 mL) was added to the solid, and the mixture was heated under reflux for 10 min, cooled to -20 °C, and stirred at the same temperature for 1 h. The resulting solid was collected by filtration, washed with hexane (40 mL) cooled to -20 °C, and dried under reduced pressure at 40 °C to give the title compound (7.82 g, 71% yield) as a white solid.

[1368] 1 H NMR(CDCl3)δ2.50(s,3H),5.22(s,1H),7.02-7.05(m,1H),7.06-7.11(m,2H),7.13-7.21(m,6H),7.22-7. 27(m,2H),7.30-7.36(m,1H),7.40-7.44(m,1H),7.46-7.51(m,2H),7.82-7.86(m,1H),7.87-7.90(m,1H); 13 CNMR(CDCl3)δ29.61,70.19,123.13,125.12,125.20,126.31,126.47,126.56,126.59,127.5 2,127.74,128.00,128.09,128.22,128.45,129.09,133.43,137.91,144.04,144.48,168.46.

[1369] Refer to Example 15

[1370] Synthesis of (E)-N-(1-(furan-2-yl)ethylidene)-1,1-diphenylmethylamine

[1371]

[1372] Molecular sieve 4A (4.00 g) was placed in a four-necked flask (100 mL) and dried under reduced pressure at 100 °C for 30 min, with the reaction system purged with nitrogen. The flask was cooled to room temperature, and toluene (20 mL), 2-acetylfuran (3.44 mL), diphenylmethylamine (6.20 mL), and acetic acid (0.39 mL) were added. The mixture was stirred at an internal temperature of 90 °C for 4 h. The reaction mixture was cooled to 60 °C and filtered using a Hertzsprung funnel. The filtrate was concentrated under reduced pressure to give a mixture of a brown liquid and a white solid. Toluene (20 mL) was added to the residue, and the mixture was heated to 90 °C, cooled to 0 °C, and stirred at the same temperature for 1 h. The resulting solid was collected by filtration and washed with toluene (20 mL) cooled to 0 °C. The resulting filtrate was concentrated under reduced pressure, toluene (10 mL) was added, and the mixture was heated to 90 °C, cooled, and stirred at -20 °C for 1 h. The resulting solid was collected by filtration, washed with toluene (8 mL) cooled to -20 °C, and dried under reduced pressure at 40 °C to give the title compound as a white solid (1.50 g, yield 16%).

[1373] 1 H NMR(CDCl3)δ2.24(s,3H),5.83(s,1H),6.45(dd,J=3.5,2.0Hz,1H),6.89(d,J=3.5Hz,1H), 7.20(t,J=7.0Hz,2H),7.29(t,J=7.0Hz,4H),7.41(d,J=7.0Hz,4H),7.50(d,J=2.0Hz,1H); 13 C NMR(CDCl3)δ15.22,67.91,111.13,111.45,126.75, 127.68,128.42, 143.90, 144.43, 156.22 (two peaks overlap in one of the underlined peaks).

[1374] Refer to Example 16

[1375] Synthesis of (E)-1,1-diphenyl-N-(1-(pyridin-2-yl)ethylidene)methylamine

[1376]

[1377] Toluene (50 mL), 2-acetylpyridine (5.00 mL), diphenylmethylamine (8.07 mL), and acetic acid (0.51 mL) were placed in a 100 mL four-necked flask purged with nitrogen, and the mixture was stirred at an internal temperature of 80 °C for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give an oily substance. Hexane (50 mL) was added to the residue, and the mixture was stirred at 85 °C for 15 min, cooled to room temperature, and stirred at the same temperature for 1.5 h. The resulting solid was collected by filtration and washed with hexane (20 mL). The resulting filtrate was concentrated under reduced pressure until the volume was reduced to about 40 mL and allowed to stand at -5 °C for 1 h in a freezer. The resulting solid was washed with hexane (40 mL) cooled to -5 °C and dried under reduced pressure at 50 °C to give the title compound (7.22 g, 57% yield) as light brown crystals.

[1378] 1 H NMR(CDCl3)δ2.46(s,3H),5.93(s,1H),7.21(t,J=7.5Hz,2H),7.26-7.33(m,5H),7.46( d,J=7.5Hz,4H),7.73(td,J=8.0,2.0Hz,1H),8.37(d,J=7.5Hz,1H),8.56-8.60(m,1H); 13 C NMR (CDCl3) δ14.38,68.72,121.39,124.19,126.80,127.57,128.43,136.17,144.46,148.14,157.83,166.06.

[1379] Refer to Example 17

[1380] Synthesis of (E)-1,1-diphenyl-N-(1-(pyridin-3-yl)ethylene)methylamine

[1381]

[1382] Molecular sieve 4A (5.00 g) was placed in a four-necked flask (100 mL) and dried under reduced pressure at 100 °C for 30 min, with the reaction system purged with nitrogen. The flask was cooled to room temperature, and toluene (25 mL), 3-acetylpyridine (5.00 mL), diphenylmethylamine (8.72 mL), and acetic acid (0.52 mL) were added. The mixture was stirred at an internal temperature of 100 °C for 2 h. The reaction mixture was cooled to 80 °C and filtered using a Hertzsprung funnel. The filtrate was concentrated under reduced pressure to give an oily substance. Toluene (20 mL) was added to the residue, and the mixture was stirred at 100 °C for 10 min, cooled to -20 °C, and stirred at the same temperature for 1 h. The resulting solid was collected by filtration and washed with toluene (20 mL) cooled to -20 °C. The resulting filtrate was concentrated under reduced pressure and solvent-displaced with n-hexane. The residue was dissolved in a mixed solvent of hexane:toluene = 1:2 (15 mL), and the solution was cooled to -78 °C and stirred for 5 hours. The resulting solid was collected by filtration, washed with a mixed solvent of hexane:toluene = 10:1 (15 mL) cooled to -78 °C, and dried under reduced pressure at 40 °C to give the title compound as a white solid (4.85 g, yield 37%).

[1383] 1 H NMR(CDCl3)δ2.33(s,3H),5.88(s,1H),7.21(tt,J=7.5,1.5Hz,2H),7.28-7.33(m,5H),7.46(dd,J =8.0,1.5Hz,4H),8.26(dt,J=8.0,2.0Hz,1H),8.62(dd,J=4.5,2.0Hz,1H),9.11(d,J=2.0Hz,1H); 13 C NMR(CDCl3)δ5.72,68.49,123.07,126.87,127.46,128.49,134.27,136.26,144.39,148.56,150.58,162.23.

[1384] Refer to Example 18

[1385] Synthesis of (E)-1,1-diphenyl-N-(1-(thiazolyl-2-yl)ethylene)methylamine

[1386]

[1387] Molecular sieve 4A (5.00 g) was placed in a four-necked flask (100 mL) and dried under reduced pressure at 100 °C for 30 min, while purging the reaction system with nitrogen. The flask was cooled to room temperature, and toluene (25 mL), 2-acetylthiazol (5.00 mL), diphenylmethylamine (8.72 mL), and acetic acid (0.55 mL) were added. The mixture was stirred at an internal temperature of 100 °C for 4 h. The reaction mixture was cooled to 70 °C and filtered using a Hertzsprung funnel. The filtrate was concentrated under reduced pressure to give an oily substance. Hexane (50 mL) was added to the residue, and the mixture was stirred at 50 °C for 10 min, cooled to -11 °C, and stirred at the same temperature for 30 min. The resulting solid was collected by filtration, washed with hexane (40 mL) cooled to -11 °C, and dried under reduced pressure at 40 °C to give the title compound (10.64 g, 75% yield) as a white solid.

[1388] 1 H NMR(CDCl3)δ2.46(s,3H),5.89(s,1H),7.22(t,J=7.0Hz,2H),7.31(t,J=7.0 Hz,4H),7.38(d,J=3.0Hz,1H),7.45(d,J=7.0Hz,4H),7.84(d,J=3.0Hz,1H); 13 C NMR (CDCl3) δ15.08, 68.29, 122.39, 126.97, 127.43, 128.52, 143.29, 143.95, 160.62, 172.10.

[1389] Refer to Example 19

[1390] Synthesis of (E)-2-((1-diphenylmethylimino)ethyl)-1,3-thiazol-5-carboxylic acid methyl ester

[1391]

[1392] Molecular sieve 4A (5.00 g) was placed in a four-necked flask (100 mL) and dried under reduced pressure at 100 °C for 30 min, with the reaction system purged with nitrogen. The flask was cooled to room temperature, and toluene (30 mL), methyl 2-acetyl-5-thiazolyl carboxylate (5.00 g), diphenylmethylamine (4.90 mL), and acetic acid (0.31 mL) were added. The mixture was stirred at an internal temperature of 100 °C for 22 h. Four hours after stirring began, additional diphenylmethylamine (0.70 mL) was added. The reaction mixture was cooled to 70 °C and filtered using a Hertzsprung funnel. The filtrate was concentrated under reduced pressure to give an oily residue. A 2:1 mixture of hexane and toluene (30 mL) was added to the residue, and the mixture was cooled to -78 °C, then heated to -20 °C and stirred for 1 h. The obtained solid was collected by filtration, washed with a 20 mL mixture of n-hexane and toluene cooled to -20 °C (2:1), and dried under reduced pressure at 40 °C to give the title compound as a light brown solid (4.78 g, 51% yield). The residual filtrate was concentrated under reduced pressure, and the residue was recrystallized at 0 °C from a 6:1 (14 mL) mixture of n-hexane and toluene. The obtained solid was collected by filtration, washed with a 10:1 mixture of n-hexane and toluene cooled to 0 °C, and dried under reduced pressure at 40 °C to give the title compound as a light brown solid (2.51 g, 26% yield).

[1393] 1 H NMR(CDCl3)δ2.44(s,3H),3.92(s,3H),5.88(s,1H),7.23(t,J=7.5Hz,2H),7.32(t,J=7.5Hz,4H),7.44(d,J=7.5Hz,4H),8.39(s,1H); 13 C NMR (CDCl3) δ14.73,52.49,68.59,127.14,127.35,128.60,131.41,143.55,148.62,160.55,161.94,176.52.

[1394] Reference Example 20

[1395] Synthesis of (E)-N-(3,4-dihydronaphthalene-1(2H)-ylidene)-1,1-diphenylmethylamine

[1396]

[1397] Molecular sieve 4A (5.00 g) was placed in a four-necked flask (100 mL) and dried under reduced pressure at 100 °C for 30 min, while purging the reaction system with nitrogen. The flask was cooled to room temperature, and toluene (30 mL), α-tetrahydronaphthone (5.00 mL), diphenylmethylamine (8.10 mL), and acetic acid (0.43 mL) were added. The mixture was stirred at an internal temperature of 100 °C for 18 h. The reaction mixture was cooled to 70 °C and filtered using a Hertzsprung funnel. The filtrate was concentrated under reduced pressure to give a brown oily substance. Hexane (30 mL) was added to the residue, and the mixture was heated under reflux, cooled to 0 °C, and stirred for 2.5 h. The resulting solid was collected by filtration, washed with hexane (35 mL) cooled to 0 °C, and dried under reduced pressure at 40 °C to give the title compound (5.90 g, 50% yield) as a white solid.

[1398] 1 H NMR(CDCl3)δ1.90(quint,J=6.5Hz,2H),2.64(t,J=6.5Hz,2H),2.78(t,J=6.5Hz,2H),5.88(s,1H),7.12 (d,J=7.5Hz,1H),7.18(t,J=7.5Hz,2H),7.25-7.32(m,6H),7.47(d,J=7.5Hz,4H),8.50(d,J=8.0Hz,1H); 13 C NMR(CDCl3)δ22.65,28.28,29.77,67.05,126.27,126.34,126.61,127.56,128.27,128.35,129.72,135.10,140.59,145.11,163.73.

[1399] Refer to Example 21

[1400] Synthesis of (E)-N-(benzodihydropyran-4-ylidene)-1,1-diphenylmethylamine

[1401]

[1402] A four-necked flask (100 mL) equipped with a Dean-Stark separator was purged with nitrogen. Toluene (30 mL), 4-benzodihydropyranone (5.00 g), diphenylmethylamine (7.27 mL), and acetic acid (0.39 mL) were added, and the mixture was heated under reflux at an external temperature of 140 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and solvent-displaced with ethanol to give an oily substance. Ethanol (30 mL) was added to the residue, and the mixture was stirred at 50 °C, cooled to room temperature, and stirred at the same temperature for 1 hour. The resulting solid was collected by filtration, washed with ethanol (50 mL), and dried under reduced pressure at 50 °C to give the title compound (3.71 g, 35% yield) as a white solid.

[1403] 1 H NMR(CDCl3)δ2.79(t,J=6.0Hz,2H),4.26(t,J=6.0Hz,2H),5.81(s,1H),6.85-6.90(m,1H),6. 97-7.03(m,1H),7.17-7.22(m,2H),7.26-7.32(m,5H),7.42-7.48(m,4H),8.34-8.79(m,1H); 13 C NMR(CDCl3)δ27.75,65.68,67.09,117.27,121.22,122.92,126.36,126.78,127.47,128.44,131.85,144.66,158.09,158.13.

[1404] Refer to Example 22

[1405] Synthesis of N-diphenylmethyl-(1R)-1-phenylethylamine

[1406]

[1407] (E)-1,1-diphenyl-N-(1-phenylethylene)methylamine (0.075 g), [Ir(cod)2]BARF (0.0033 g), and (S)-MONOPHOS (0.0020 g) were placed into sample tubes for a 24-well autoclave, and the tubes were placed inside the autoclave. The autoclave was placed in a glove box, and dichloromethane (1.5 mL) was added to it under a nitrogen atmosphere. The autoclave was sealed, removed from the glove box, and the reaction system was purged with hydrogen ten times. Hydrogen was fed into the autoclave until 3.0 MPa was reached, and the mixture was stirred at 50 °C for 20 hours. The reaction solution was cooled to room temperature, and the hydrogen was released. The reaction was then analyzed by high-performance liquid chromatography and... 11H NMR analysis of the reaction solution confirmed the production of the title compound (100% conversion, 79.4% ee).

[1408] Conditions for high performance liquid chromatography analysis

[1409] Column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150mm

[1410] UV detection wavelength: 254nm

[1411] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1412] Flow rate: 1.0 mL / min

[1413] Retention time: 5.1 min (enantiomer-A), 5.9 min (enantiomer-B)

[1414] 1 ¹H NMR (CDCl₃) δ 1.36 (d, J = 7.0 Hz, 3H), 3.67 (q, J = 7.0 Hz, 1H), 4.63 (s, 1H), 7.15–7.19 (m, 1H), 7.22–7.29 (m, 8H), 7.31–7.36 (m, 6H) (No protons originating from NH were detected).

[1415] Reference Example 23

[1416] Synthesis of N-diphenylmethyl-(1R)-1-(4-methoxyphenyl)ethylamine

[1417]

[1418] (E)-N-(1-(4-methoxyphenyl)ethylene)-1,1-diphenylmethylamine (0.075 g), [Ir(cod)2]BARF (0.0030 g), and (S)-MONOPHOS (0.0018 g) were placed into sample tubes for a 24-well autoclave, and the tubes were placed inside the autoclave. The autoclave was placed in a glove box, and dichloromethane (1.5 mL) was added to it under a nitrogen atmosphere. The autoclave was sealed, removed from the glove box, and the reaction system was purged with hydrogen ten times. Hydrogen was fed into the autoclave until 3.0 MPa was reached, and the mixture was stirred at 50 °C for 20 hours. The reaction solution was cooled to room temperature, and the hydrogen was released. The reaction was then analyzed by high performance liquid chromatography and... 1 1H NMR analysis of the reaction solution confirmed the production of the title compound (100% conversion, 87.9% ee).

[1419] Conditions for high performance liquid chromatography analysis

[1420] Column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150mm

[1421] UV detection wavelength: 254nm

[1422] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1423] Flow rate: 1.2 mL / min

[1424] Retention time: 4.7 min (enantiomer-A), 5.5 min (enantiomer-B)

[1425] 1 ¹H NMR (CDCl₃) δ 1.34 (d, J = 6.5 Hz, 3H), 3.63 (q, J = 6.5 Hz, 1H), 3.82 (s, 3H), 4.62 (s, 1H), 6.87 (d, J = 8.5 Hz, 2H), 7.14–7.19 (m, 3H), 7.21–7.29 (m, 5H), 7.30–7.34 (m, 4H) (No protons originating from NH were detected).

[1426] Refer to Example 24

[1427] Synthesis of N-diphenylmethyl-(1R)-1-(4-chlorophenyl)ethylamine

[1428]

[1429] (E)-N-(1-(4-chlorophenyl)ethylene)-1,1-diphenylmethylamine (0.075 g), [Ir(cod)2]BARF (0.0030 g), and (S)-MONOPHOS (0.0018 g) were placed into sample tubes for a 24-well autoclave, and the tubes were placed inside the autoclave. The autoclave was placed in a glove box, and dichloromethane (1.5 mL) was added to it under a nitrogen atmosphere. The autoclave was sealed, removed from the glove box, and the reaction system was purged with hydrogen ten times. Hydrogen was fed into the autoclave until 3.0 MPa was reached, and the mixture was stirred at 50 °C for 20 hours. The reaction solution was cooled to room temperature, and the hydrogen was released. The reaction was then analyzed by high performance liquid chromatography and... 1 1H NMR analysis of the reaction solution confirmed the production of the title compound (100% conversion, 96.0% ee).

[1430] Conditions for high performance liquid chromatography analysis

[1431] Column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150mm

[1432] UV detection wavelength: 254nm

[1433] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1434] Flow rate: 1.2 mL / min

[1435] Retention time: 7.6 min (enantiomer-A), 8.8 min (enantiomer-B)

[1436] 1 1H NMR (CDCl3) δ 1.34 (d, J = 7.0 Hz, 3H), 3.66 (q, J = 7.0 Hz, 1H), 4.58 (s, 1H), 7.16–7.21 (m, 3H), 7.22–7.35 (m, 11H) (No protons originating from NH were detected).

[1437] Reference Example 25

[1438] Synthesis of N-diphenylmethyl-(1R)-1-(4-trifluoromethylphenyl)ethylamine

[1439]

[1440] (E)-1,1-diphenyl-N-(1-(4-trifluoromethylphenyl)ethylene)methylamine (0.075 g), [Ir(cod)2]BARF (0.0027 g), and (S)-MONOPHOS (0.0016 g) were placed into sample tubes for a 24-well autoclave, and the tubes were placed inside the autoclave. The autoclave was placed in a glove box, and dichloromethane (1.5 mL) was added to it under a nitrogen atmosphere. The autoclave was sealed, removed from the glove box, and the reaction system was purged with hydrogen ten times. Hydrogen was fed into the autoclave until 3.0 MPa was reached, and the mixture was stirred at 50 °C for 20 hours. The reaction solution was cooled to room temperature, and the hydrogen was released. The reaction was then analyzed by high performance liquid chromatography and... 1 1H NMR analysis of the reaction solution confirmed the production of the title compound (100% conversion, 95.5% ee).

[1441] Conditions for high performance liquid chromatography analysis

[1442] Column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150mm

[1443] UV detection wavelength: 254nm

[1444] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1445] Flow rate: 1.2 mL / min

[1446] Retention time: 4.0 min (enantiomer-A), 5.4 min (enantiomer-B)

[1447] 1 ¹H NMR (CDCl₃) δ 1.36 (d, J = 7.0 Hz, 3H), 3.75 (q, J = 7.0 Hz, 1H), 4.58 (s, 1H), 7.18 (tt, J = 7.0, 1.5 Hz, 1H), 7.22–7.35 (m, 9H), 7.38 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H) (No protons originating from NH were detected).

[1448] Reference Example 26

[1449] Synthesis of N-diphenylmethyl-(1R)-1-(naphth-1-yl)ethylamine

[1450]

[1451] (E)-N-(1-(naphthyl-1-yl)ethylene)-1,1-diphenylmethylamine (0.075 g), [Ir(cod)2]BARF (0.0028 g), and (S)-MONOPHOS (0.0017 g) were placed into sample tubes for a 24-well autoclave, and the tubes were placed inside the autoclave. The autoclave was placed in a glove box, and dichloromethane (1.5 mL) was added to it under a nitrogen atmosphere. The autoclave was sealed, removed from the glove box, and the reaction system was purged with hydrogen ten times. Hydrogen was fed into the autoclave until 3.0 MPa was reached, and the mixture was stirred at 50 °C for 20 hours. The reaction solution was cooled to room temperature, and the hydrogen was released. The reaction was then analyzed by high performance liquid chromatography and... 1 1H NMR analysis of the reaction solution confirmed the production of the title compound (100% conversion, 70.1% ee).

[1452] Conditions for high performance liquid chromatography analysis

[1453] Column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150mm

[1454] UV detection wavelength: 254nm

[1455] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1456] Flow rate: 1.0 mL / min

[1457] Retention time: 7.4 min (enantiomer-A), 9.0 min (enantiomer-B)

[1458] 1 ¹H NMR (CDCl₃) δ 1.49 (d, J = 7.0 Hz, 3H), 4.56 (q, J = 7.0 Hz, 1H), 4.74 (s, 1H), 7.16–7.35 (m, 10H), 7.36–7.41 (m, 1H), 7.42–7.47 (m, 1H), 7.47–7.52 (m, 1H), 7.66–7.70 (m, 1H), 7.74–7.78 (m, 1H), 7.84–7.91 (m, 2H) (No protons originating from NH were detected).

[1459] Reference Example 27

[1460] Synthesis of N-diphenylmethyl-(1R)-1-(furan-2-yl)ethylamine

[1461]

[1462] (E)-N-(1-(furan-2-yl)ethylene)-1,1-diphenylmethylamine (0.075 g), [Ir(cod)2]BARF (0.0035 g), and (S)-MONOPHOS (0.0021 g) were placed into sample tubes for a 24-well autoclave, and the tubes were placed inside the autoclave. The autoclave was placed in a glove box, and dichloromethane (1.5 mL) was added to it under a nitrogen atmosphere. The autoclave was sealed, removed from the glove box, and the reaction system was purged with hydrogen ten times. Hydrogen was fed into the autoclave until 3.0 MPa was reached, and the mixture was stirred at 50 °C for 20 hours. The reaction solution was cooled to room temperature, and the hydrogen was released. The reaction was then analyzed by high performance liquid chromatography and... 1 1H NMR analysis of the reaction solution confirmed the production of the title compound (100% conversion, 70.0% ee).

[1463] Conditions for high performance liquid chromatography analysis

[1464] Column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150mm

[1465] UV detection wavelength: 254nm

[1466] Mobile phase: Acetonitrile for high performance liquid chromatography / 0.025 mol / L potassium dihydrogen phosphate aqueous solution = 7 / 3

[1467] Flow rate: 1.0 mL / min

[1468] Retention time: 5.6 min (enantiomer-A), 6.5 min (enantiomer-B)

[1469] 1 ¹H NMR (CDCl₃) δ 1.42 (d, J = 7.0 Hz, 3H), 3.73 (q, J = 7.0 Hz, 1H), 4.75 (s, 1H), 6.06 (d, J = 3.5 Hz, 1H), 6.31 (dd, J = 3.5, 1.5 Hz, 1H), 7.15–7.19 (m, 1H), 7.20–7.27 (m, 3H), 7.29–7.33 (m, 4H), 7.36 (d, J = 1.5 Hz, 1H), 7.40–7.44 (m, 2H) (No protons originating from NH were detected).

[1470] Reference Example 28

[1471] Synthesis of N-diphenylmethyl-(1R)-1-(pyridin-2-yl)ethylamine

[1472]

[1473] (E)-1,1-diphenyl-N-(1-(pyridin-2-yl)ethylidene)methylamine (0.075 g), [Ir(cod)2]BARF (0.0033 g), and (S)-MONOPHOS (0.0020 g) were placed into sample tubes for a 24-well autoclave, and the tubes were placed inside the autoclave. The autoclave was placed in a glove box, and dichloromethane (1.5 mL) was added to it under a nitrogen atmosphere. The autoclave was sealed, removed from the glove box, and the reaction system was purged with hydrogen ten times. Hydrogen was fed into the autoclave until 3.0 MPa was reached, and the mixture was stirred at 50 °C for 20 hours. The reaction solution was cooled to room temperature, and the hydrogen was released. The reaction was then analyzed by high performance liquid chromatography and... 1 1H NMR analysis of the reaction solution confirmed the production of the title compound (conversion 55%, 76.7% ee).

[1474] Conditions for high performance liquid chromatography analysis

[1475] Column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150mm

[1476] UV detection wavelength: 254nm

[1477] Mobile phase: Acetonitrile for high performance liquid chromatography / 0.025 mol / L potassium dihydrogen phosphate aqueous solution = 1 / 1

[1478] Flow rate: 1.0 mL / min

[1479] Retention time: 6.5 min (enantiomer-A), 8.0 min (enantiomer-B)

[1480] 1 ¹H NMR (CDCl₃) δ 1.39 (d, J = 6.5 Hz, 3H), 3.78 (q, J = 6.5 Hz, 1H), 4.60 (s, 1H), 7.13–7.18 (m, 3H), 7.20–7.33 (m, 7H), 7.38 (d, J = 7.5 Hz, 2H), 7.61 (td, J = 7.5, 2.0 Hz, 1H), 8.57–8.60 (m, 1H) (No protons originating from NH were detected).

[1481] Reference Example 29

[1482] Synthesis of N-diphenylmethyl-(1R)-1-(pyridin-3-yl)ethylamine

[1483]

[1484] (E)-1,1-diphenyl-N-(1-(pyridin-3-yl)ethylene)methylamine (0.075 g), [Ir(cod)2]BARF (0.0033 g), and (S)-MONOPHOS (0.0020 g) were placed into sample tubes for a 24-well autoclave, and the tubes were placed inside the autoclave. The autoclave was placed in a glove box, and dichloromethane (1.5 mL) was added to it under a nitrogen atmosphere. The autoclave was sealed, removed from the glove box, and the reaction system was purged with hydrogen ten times. Hydrogen was fed into the autoclave until 3.0 MPa was reached, and the mixture was stirred at 50 °C for 20 hours. The reaction solution was cooled to room temperature, and the hydrogen was released. The reaction was then analyzed by high performance liquid chromatography and... 1 ¹H NMR analysis of the reaction solution confirmed a conversion rate of 0%.

[1485] Conditions for high performance liquid chromatography analysis

[1486] Column: CHIRALCEL OD-RH (manufactured by Daicel Chemical Industries), 4.6*150mm

[1487] UV detection wavelength: 254nm

[1488] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography (HPLC) = 3 / 7, 35 min → Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for HPLC = 8 / 2, 10 min

[1489] Flow rate: 1.2 mL / min

[1490] Retention time: 25.1 min (enantiomer-A), 27.6 min (enantiomer-B)

[1491] Reference Example 30

[1492] Synthesis of N-diphenylmethyl-(1R)-1-(thiazol-2-yl)ethylamine

[1493]

[1494] (E)-1,1-diphenyl-N-(1-(thiazolyl-2-yl)ethylene)methylamine (0.075 g), [Ir(cod)2]BARF (0.0033 g), and (S)-MONOPHOS (0.0019 g) were placed into sample tubes for a 24-well autoclave, and the tubes were placed inside the autoclave. The autoclave was placed in a glove box, and dichloromethane (1.5 mL) was added to it under a nitrogen atmosphere. The autoclave was sealed, removed from the glove box, and the reaction system was purged with hydrogen ten times. Hydrogen was fed into the autoclave until 3.0 MPa was reached, and the mixture was stirred at 50 °C for 20 hours. The reaction solution was cooled to room temperature, and the hydrogen was released. The reaction was then analyzed by high performance liquid chromatography and... 1 1H NMR analysis of the reaction solution confirmed the production of the title compound (100% conversion, 82.8% ee).

[1495] Conditions for high performance liquid chromatography analysis

[1496] Column: CHIRALCEL OD-RH (manufactured by Daicel Chemical Industries), 4.6*150mm

[1497] UV detection wavelength: 254nm

[1498] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography (HPLC) = 4 / 6, 35 min → Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for HPLC = 8 / 2, 10 min

[1499] Flow rate: 1.2 mL / min

[1500] Retention time: 31.3 min (enantiomer-A), 33.2 min (enantiomer-B)

[1501] 1 ¹H NMR (CDCl₃) δ 1.53 (d, J = 6.5 Hz, 3H), 4.07 (q, J = 6.5 Hz, 1H), 4.92 (s, 1H), 7.17–7.21 (m, 1H), 7.23–7.29 (m, 4H), 7.33 (t, J = 7.5 Hz, 2H), 7.36–7.40 (m, 4H), 7.73 (d, J = 2.5 Hz, 1H) (No protons originating from NH were detected).

[1502] Reference Example 31

[1503] Synthesis of methyl 2-((1R)-1-(diphenylmethylamino)ethyl)-1,3-thiazol-5-carboxylic acid

[1504]

[1505] Methyl (E)-2-((1-diphenylmethylimino)ethyl)-1,3-thiazolyl-5-carboxylic acid (0.075 g), [Ir(cod)2]BARF (0.0027 g), and (S)-MONOPHOS (0.0016 g) were placed into sample tubes for a 24-well autoclave, and the tubes were placed inside the autoclave. The autoclave was placed in a glove box, and dichloromethane (1.5 mL) was added to it under a nitrogen atmosphere. The autoclave was sealed, removed from the glove box, and the reaction system was purged with hydrogen ten times. Hydrogen was fed into the autoclave until 3.0 MPa was reached, and the mixture was stirred at 50 °C for 20 hours. The reaction solution was cooled to room temperature, and the hydrogen was released. The reaction was then analyzed by high performance liquid chromatography and... 1 1H NMR analysis of the reaction solution confirmed the production of the title compound (100% conversion, 79.7% ee).

[1506] Conditions for high performance liquid chromatography analysis

[1507] Column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150mm

[1508] UV detection wavelength: 254nm

[1509] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1510] Flow rate: 1.0 mL / min

[1511] Retention time: 4.4 min (enantiomer-A), 5.1 min (enantiomer-B)

[1512] 1 ¹H NMR (CDCl₃) δ 1.53 (d, J = 6.5 Hz, 3H), 3.91 (s, 3H), 4.01 (q, J = 6.5 Hz, 1H), 4.95 (s, 1H), 7.18–7.23 (m, 1H), 7.23–7.30 (m, 3H), 7.32–7.36 (m, 2H), 7.36–7.42 (m, 4H), 8.31 (s, 1H) (No protons originating from NH were detected).

[1513] Reference Example 32

[1514] Synthesis of N-diphenylmethyl-1,2,3,4-tetrahydronaphthyl-(1R)-1-amine

[1515]

[1516] (E)-N-(3,4-dihydronaphthyl-1(2H)-ylidene)-1,1-diphenylmethylamine (0.075 g), [Ir(cod)2]BARF (0.0031 g), and (S)-MONOPHOS (0.0018 g) were placed into sample tubes for a 24-well autoclave, and the tubes were placed inside the autoclave. The autoclave was placed in a glove box, and dichloromethane (1.5 mL) was added to it under a nitrogen atmosphere. The autoclave was sealed, removed from the glove box, and the reaction system was purged with hydrogen ten times. Hydrogen was fed into the autoclave until 3.0 MPa was reached, and the mixture was stirred at 50 °C for 20 hours. The reaction solution was cooled to room temperature, and the hydrogen was released. The reaction was then analyzed by high performance liquid chromatography and... 1 1H NMR analysis of the reaction solution confirmed the production of the title compound (100% conversion, 23.0% ee).

[1517] Conditions for high performance liquid chromatography analysis

[1518] Column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150mm

[1519] UV detection wavelength: 254nm

[1520] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1521] Flow rate: 1.2 mL / min

[1522] Retention time: 5.5 min (enantiomer-A), 8.1 min (enantiomer-B)

[1523] 1 ¹H NMR (CDCl₃) δ 1.66–1.75 (m, 1H), 1.81–2.01 (m, 3H), 2.66–2.74 (m, 1H), 2.77–2.84 (m, 1H), 3.67–3.72 (m, 1H), 5.11 (s, 1H), 7.03–7.08 (m, 1H), 7.11–7.24 (m, 4H), 7.25–7.30 (m, 2H), 7.30–7.36 (m, 2H), 7.43–7.49 (m, 3H), 7.49–7.53 (m, 2H) (No protons originating from NH were detected).

[1524] Reference Example 33

[1525] Synthesis of N-diphenylmethylbenzodihydropyran-(4R)-4-amine

[1526]

[1527] (E)-N-(benzodihydropyran-4-yl)-1,1-diphenylmethylamine (0.075 g), [Ir(cod)2]BARF (0.0031 g), and (S)-MONOPHOS (0.0018 g) were placed into sample tubes for a 24-well autoclave, and the tubes were placed inside the autoclave. The autoclave was placed in a glove box, and dichloromethane (1.5 mL) was added to it under a nitrogen atmosphere. The autoclave was sealed, removed from the glove box, and the reaction system was purged with hydrogen ten times. Hydrogen was fed into the autoclave until 3.0 MPa was reached, and the mixture was stirred at 50 °C for 20 hours. The reaction solution was cooled to room temperature, and the hydrogen was released. The reaction was then analyzed by high performance liquid chromatography and... 1 1H NMR analysis of the reaction solution confirmed the production of the title compound (100% conversion, 16.1% ee).

[1528] Conditions for high performance liquid chromatography analysis

[1529] Column: CHIRALCEL OJ-RH (manufactured by Daicel Chemical Industries), 4.6*150mm

[1530] UV detection wavelength: 254nm

[1531] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1532] Flow rate: 1.2 mL / min

[1533] Retention time: 4.0 min (enantiomer-A), 4.8 min (enantiomer-B)

[1534] 1 ¹H NMR (CDCl₃) δ 1.90–1.98 (m, 1H), 2.00–2.09 (m, 1H), 3.76 (t, J = 5.0 Hz, 1H), 4.15–4.21 (m, 1H), 4.36 (td, J = 10.5, 3.0 Hz, 1H), 5.09 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.87 (td, J = 7.5, 1.5 Hz, 1H), 7.13 (td, J = 7.5, 1.0 Hz, 1H), 7.18–7.32 (m, 5H), 7.35 (t, J = 7.5 Hz, 2H), 7.42–7.50 (m, 4H) (No protons originating from NH were detected).

[1535] Refer to Example 34

[1536] Synthesis of (1R)-1-(thiazol-2-yl)ethylamine

[1537]

[1538] (E)-1,1-diphenyl-N-(1-(thiazolyl-2-yl)ethylene)methylamine (2.00 g), [Ir(cod)2]BARF (0.0870 g), and (S)-MONOPHOS (0.0540 g) were placed in an autoclave (120 mL). The atmosphere in the autoclave was reduced in pressure and then restored to pressure with argon. This procedure was repeated a total of seven times. The pressure in the autoclave was restored to normal, and dehydrated dichloromethane (20 mL) for organic synthesis was fed into it under argon pressure. Hydrogen was fed into the autoclave until the pressure increased by 0.1 MPa, and then the pressure was restored to normal. This procedure was repeated a total of ten times. Hydrogen was fed into the autoclave until the pressure reached 1.10 MPa, and the mixture was stirred at an internal temperature of 50 °C for 19 hours. The mixture was cooled to an internal temperature of approximately 20 °C, the hydrogen was released, and the atmosphere was replaced with argon (100% conversion, 82.7% ee optical purity). The reaction solution was concentrated under reduced pressure, and acetonitrile (18 mL) and water (2 mL) were added. N-bromosuccinimide (1.83 g) was added at near room temperature, and the mixture was stirred for 7 hours. The mixture was concentrated under reduced pressure, and the residue was partitioned with 1 mol / L hydrochloric acid (10 mL) and ethyl acetate (20 mL) (organic layer (1) and aqueous layer (1)). Aqueous layer (1) was adjusted to pH 5 with 5 mol / L sodium hydroxide aqueous solution (about 3 mL) and extracted with ethyl acetate (20 mL) (organic layer (2) and aqueous layer (2)). Aqueous layer (2) was partitioned with 5 mol / L sodium hydroxide aqueous solution (1 mL) and ethyl acetate (20 mL) (organic layer (3) and aqueous layer (3)). Organic layer (3) was washed with saturated brine (10 mL) (organic layer (4) and aqueous layer (4)). Organic layer (1) was washed with saturated brine (10 mL) (organic layer (5) and aqueous layer (5)). Aqueous layers (4) and (5) were combined and extracted with ethyl acetate (30 mL) (organic layer (6) and aqueous layer (6)). Organic layers (4), (5), and (6) were combined and dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound. Brown oil, 0.61 g, yield 70.1%, HPLC area normalized 89.7%.

[1539] Conditions for high-performance liquid chromatography analysis (area normalization)

[1540] Column: YMC-Pack ODS-A (manufactured by YMC.CO.,LTD.), 4.6*150mm

[1541] UV detection wavelength: 254nm

[1542] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1543] Flow rate: 1.0 mL / min

[1544] Retention time: 2.4 min (title compound)

[1545] 1 H NMR (CDCl3) δ1.54 (d, J = 6.6 Hz, 3H), 4.42 (q, J = 6.6 Hz, 1H), 7.23 (d, J = 3.2 Hz, 1H), 7.70 (d, J = 3.2 Hz, 1H).

[1546] 13 C NMR (CDCl3) δ24.66, 49.65, 118.36, 142.38, 178.38.

[1547] Reference Example 35

[1548] Synthesis of (R)-methyl-2-(1-aminoethyl)-1,3-thiazol-5-carboxylic acid ester p-toluenesulfonate

[1549]

[1550] (E)-methyl 2-((1-diphenylmethylimino)ethyl)-1,3-thiazol-5-carboxylic acid ester (1.00 g), [Ir(cod)2]BARF (0.0363 g), and (S)-MONOPHOS (0.0226 g) were placed in an autoclave (120 mL). The atmosphere in the autoclave was reduced in pressure and then restored to pressure with argon. This procedure was repeated a total of seven times. The pressure in the autoclave was restored to normal, and dehydrated dichloromethane (20 mL) for organic synthesis was fed into it under argon pressure. Hydrogen was fed into the autoclave until the pressure increased by 0.1 MPa, and then the pressure was restored to normal. This procedure was repeated a total of ten times. Hydrogen was fed into the autoclave until the pressure reached 1.0 MPa, and the mixture was stirred at an internal temperature of 50 °C for 18 hours. The mixture was cooled to an internal temperature of approximately 20°C, hydrogen was released, and the atmosphere was replaced with argon (conversion 100%, optical purity 80.1% ee). The reaction solution was concentrated under reduced pressure, and acetonitrile (9 mL), water (1 mL), and N-bromosuccinimide (0.61 g) were added to it near room temperature, and the mixture was stirred for 23 hours. The mixture was concentrated under reduced pressure, and the residue was partitioned with water (3 mL) and ethyl acetate (10 mL) (organic layer (1) and aqueous layer (1)). Aqueous layer (1) was partitioned with 1 mol / L sodium hydroxide aqueous solution (3 mL) and ethyl acetate (15 mL) (organic layer (2) and aqueous layer (2)). Aqueous layer (2) was partitioned with 1 mol / L sodium hydroxide aqueous solution (1 mL) and ethyl acetate (10 mL) (organic layer (3) and aqueous layer (3)). Organic layers (2) and (3) were combined, and p-toluenesulfonic acid monohydrate (0.56 g) was added to it. The mixture was concentrated under reduced pressure, acetonitrile (10 mL) was added, and the mixture was stirred at near room temperature for 1 hour. The crystallized material was collected by filtration, washed with acetonitrile, and dried under reduced pressure at 50 °C to give the title compound. A pale yellow powder, 0.6412 g, yield 62.7%, HPLC area normalized 100%, optical purity 80.3% ee.

[1551] Conditions for high-performance liquid chromatography analysis (HPLC area normalization)

[1552] Column: YMC-Pack ODS-A (manufactured by YMC.CO.,LTD.), 4.6*150mm

[1553] UV detection wavelength: 254nm

[1554] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1555] Flow rate: 1.0 mL / min

[1556] Retention time: 2.2 min (title compound)

[1557] Conditions for high-performance liquid chromatography analysis (optical purity)

[1558] Column: CHIRALPAK IA (manufactured by Daicel Chemical Industries), 4.6*250mm

[1559] UV detection wavelength: 254nm

[1560] Mobile phase: Acetonitrile for HPLC / Methanol for HPLC / Distilled water for HPLC = 80 / 15 / 5

[1561] Flow rate: 1.0 mL / min

[1562] Retention time: 4.5 min (enantiomer-A), 5.7 min (enantiomer-B)

[1563] 1 H NMR(DMSO-d6)δ1.61(d,J=6.9Hz,3H),2.29(s,3H),3.87(s,3H),4.95(q,J=6.8H z, 1H), 7.12 (d, J = 7.9Hz, 2H), 7.48 (d, J = 7.9Hz, 2H), 8.51 (s, 1H), 8.64 (brs, 3H).

[1564] 13 C NMR(DMSO-d6)δ19.76,20.74,47.62,52.79,125.45,128.04,130.01,137.73,145.44,147.56,160.80,172.89.

[1565] Examples 163-368

[1566] Synthesis of 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide

[1567]

[1568] 2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (substrate, 0.0350 g), ammonium salt (amine source, 10 equivalents relative to the substrate), metal source (0.05 equivalents relative to the substrate), and ligand (1.1 equivalents relative to the metal source) were weighed separately and placed into test tubes for a 24-well autoclave. Solvent (1.5 mL) was added under a nitrogen atmosphere, and the atmosphere in the autoclave was purged with hydrogen. Hydrogen was fed into the autoclave up to 3.0 MPa, and the mixture was stirred at 50 °C for 22 hours. After the reaction was complete, the autoclave was cooled, and the hydrogen was released. The selectivity of the title compound (containing both R- and S-forms) and the enantiomeric excess (ee) of the title compound (R-form) were calculated by HPLC. The results are shown in Tables 16–20. The structures of the ligands used above are shown above. In Examples 348-355 and Examples 359-361, (-)-CSA was used as an additive in an amount of 0.1 equivalents relative to the substrate.

[1569] Conditions for high-performance liquid chromatography analysis (area normalization)

[1570] Column: YMC-Pack ODS-A (manufactured by YMC.CO.,LTD.), 4.6*150mm

[1571] UV detection wavelength: 254nm

[1572] Mobile phase: Acetonitrile / 0.025 mol / L potassium dihydrogen phosphate aqueous solution for high performance liquid chromatography = 8 / 2

[1573] Flow rate: 1.0 mL / min

[1574] Retention times: 2.3 min (title compound (including R- and S-forms)), 2.9 min (alcohol form), 4.8 min (substrate)

[1575] Conditions for high-performance liquid chromatography analysis (optical purity)

[1576] Column: IA (manufactured by Daicel Chemical Industries), 4.6*250mm

[1577] UV detection wavelength: 254nm

[1578] Mobile phase: Acetonitrile / methanol / water = 80 / 15 / 5 for high performance liquid chromatography

[1579] Flow rate: 1.0 mL / min

[1580] Column temperature: 40℃

[1581] Retention times: 4.6 min (substrate), 5.8 min (alcoholic form), 11.6 min (alcoholic form), 16.2 min (title compound (R-form)), 24.2 min (enantiomer of title compound (S-form)).

[1582] Table 16-1

[1583]

[1584] Table 16-2

[1585]

[1586] Table 16-3

[1587]

[1588] Table 16-4

[1589]

[1590] Table 16-5

[1591]

[1592] Table 16-6

[1593]

[1594] Table 16-7

[1595]

[1596] Table 17-1

[1597]

[1598] Table 17-2

[1599]

[1600] Table 17.3

[1601]

[1602] Table 17-4

[1603]

[1604] Table 17-5

[1605]

[1606] Table 17-6

[1607]

[1608] Table 17-7

[1609]

[1610] Table 17-8

[1611]

[1612] Table 18-1

[1613]

[1614] Table 18-2

[1615]

[1616] Table 19-1

[1617]

[1618] Table 19-2

[1619]

[1620] Table 20

[1621]

[1622] Examples 369-380

[1623] Synthesis of 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide

[1624]

[1625] The reaction was carried out in the same manner as in Examples 163-368, except that ammonium salicylate (0.155 g) was used as the amine source, [IrCl(cod)]₂ (0.0017 g) as the metal source, (R,R)-PTBP-Skewphos (0.0037 g) as the ligand, and IPA (1.4 mL) as the solvent, and an additive (10 equivalents relative to the iridium catalyst) was added to the test tubes used in the 24-well autoclave. Under the same conditions as in Examples 163-368, the selectivity of the title compound (containing both R- and S-forms) and the enantiomeric excess of the title compound (R-form) were calculated by HPLC. The results are shown in Table 21.

[1626] Table 21

[1627]

[1628] Examples 381-385

[1629] Synthesis of 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide

[1630]

[1631] 2-Acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (substrate, 0.100 g), ammonium salicylate (0.444 g), [IrCl(cod)]2 (0.0048 g), and (R,R)-PTBP-Skewphos (0.0105 g) were weighed separately and placed into an autoclave (120 mL). The atmosphere in the autoclave was reduced and then restored to pressure under an argon atmosphere. This procedure was repeated a total of five times. Under an argon atmosphere, dehydrated isopropanol (4.0 mL) was added using a syringe, and the mixture was stirred under the given premixing conditions (temperature and time). After stirring, the atmosphere in the autoclave was purged with hydrogen. Hydrogen was fed into the autoclave up to 3.0 MPa, and the mixture was stirred under hydrogen pressure at the given temperature for 20 hours. After the reaction was complete, the autoclave was cooled and hydrogen was released. The enantiomeric excess of the title compound (R-form) was calculated by HPLC. The results are shown in Table 22. The HPLC conditions were the same as in Examples 163-368.

[1632] Table 22

[1633]

[1634] Examples 386-400

[1635] Synthesis of 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide

[1636]

[1637] The amounts of each reactant to be used are as follows: 2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (0.100 g), ammonium salicylate (0.444 g), [IrCl(cod)]2 (0.0048 g), and (R,R)-PTBP-Skewphos (0.0105 g). Reactants marked with 〇 in Table 23 are placed into Schlenk flasks (10 mL). Reactants marked with ◎ (if present) are placed into another Schlenk flask (10 mL). Isopropanol is added to each Schlenk flask containing the reactants under an argon atmosphere, and each mixture is stirred at a given temperature for a given time to prepare the reaction solution. Reactants not marked with 〇 or ◎ in the table were placed in an autoclave (120 mL), the atmosphere of which was replaced with argon, and the previously heated reaction solution under stirring was fed into it. The atmosphere in the autoclave was purged with hydrogen, and hydrogen was fed into the autoclave up to 3.0 MPa, and the mixture was stirred at the given temperature under hydrogen pressure for 20 hours. After the reaction was complete, the autoclave was cooled and the hydrogen was released. The enantiomeric excess of the title compound (R-form) was calculated by HPLC. The results are shown in Table 23. The HPLC conditions were the same as in Examples 163-368. Specific procedures are described in the notes to Table 23.

[1638] Table 23-1

[1639]

[1640] Table 23-2

[1641]

[1642] Examples 401-412

[1643] Synthesis of 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide

[1644]

[1645] The reaction was carried out in the same manner as in Examples 381-385, except that ammonium salicylate was used in an amount of 5 equivalents (0.222 g) relative to the substrate, and the solvents shown in Table 24 were used as the dehydration solvents after recovery under an argon atmosphere. The selectivity of the title compound (containing both R- and S-forms) and the enantiomeric excess of the title compound (R-form) were calculated by HPLC. The results are shown in Table 24.

[1646] Table 24

[1647]

[1648] Examples 413-415

[1649] Synthesis of 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide

[1650]

[1651] The reaction was carried out in the same manner as in Examples 401-412, except that the S / C ratio of [IrCl(cod)]2 was 50 or 100. The results are shown in Table 25.

[1652] Table 25

[1653]

[1654] Example 416

[1655] Synthesis of 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (S)-mandelate

[1656]

[1657] A hydrogenation reaction solution containing 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (2.82 mmol, 59.6% ee) was concentrated under reduced pressure, and the residue was partitioned between a 1 / 1 toluene / ethyl acetate mixture (30 mL) and an aqueous triethylamine solution (prepared by diluting 5.26 mL of triethylamine with 40 mL of water). The organic layers were separated, and the aqueous layer was washed twice with a 1 / 1 toluene / ethyl acetate mixture (30 mL). The three organic layers were combined and washed with an aqueous triethylamine solution (prepared by diluting 0.478 mL of triethylamine with 40 mL of water). The organic layers were separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to solvent displacement with acetonitrile, and acetonitrile (27.8 mL) and water (0.96 mL) were added to the residue, which was then dissolved by heating at 60 °C. (S)-mandelic acid (0.399 g) was added to the residue at 60 °C, and the mixture was cooled to room temperature. The resulting crystals were aged at room temperature for 3 hours. The crystals were collected by filtration using a Hertzsprung funnel, washed with acetonitrile (4.0 mL), and dried overnight at 50 °C under reduced pressure to give 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (S)-mandelic acid salt (93.4 HPLC area % and 98.9% de). Acetonitrile (72 mL) was added to the obtained wet crystals, and the mixture was heated under reflux for 30 min and then cooled to room temperature again. The resulting crystals were collected by filtration through a Hertzsprung funnel, washed with acetonitrile (18 mL), and dried overnight under reduced pressure at 50 °C to give 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (S)-mandelate (1.01 g). Yield 77%, 94.4% de.

[1658] Example 417

[1659] Synthesis of 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (S)-mandelate

[1660]

[1661] A hydrogenation reaction solution containing 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (2.21 mmol, 80.5% ee) was concentrated under reduced pressure, and the residue was partitioned between a 1 / 1 mixture of toluene and ethyl acetate (30 mL) and an aqueous solution of triethylamine (prepared by diluting 5.38 mL of triethylamine with 40 mL of water). The organic layers were separated, and the aqueous layer was washed twice with a 1 / 1 mixture of toluene and ethyl acetate (30 mL). The three organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to solvent displacement with acetonitrile, to which acetonitrile (22.1 mL) and water (0.76 mL) were added, and the residue was dissolved by heating at 60 °C. (S)-mandelic acid (0.361 g) was added to the residue at 60 °C, and the mixture was cooled to room temperature. The resulting crystals were aged at room temperature for 3 hours. The crystals were collected by filtration through a Hertzner funnel, washed with acetonitrile (4.0 mL), and dried overnight at 50 °C under reduced pressure to give (R)-2-(1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazolyl-5-carboxamide (S)-mandelate (93.4 HPLC area % and 98.9% de). Acetonitrile (72 mL) was added to the obtained wet crystals, and the mixture was heated under reflux for 30 min and then cooled again to room temperature. The resulting crystals were collected by filtration through a Hertzner funnel, washed with acetonitrile (18 mL), and dried overnight at 50 °C under reduced pressure to give 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (S)-mandelate (0.87 g). Yield 79%, 97.1% de.

[1662] Example 418

[1663] Synthesis of 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (S)-mandelate

[1664]

[1665] A hydrogenation reaction solution containing 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (2.79 mmol, 63.6% ee) was concentrated under reduced pressure, and the residue was partitioned between a 1 / 1 mixture of toluene and ethyl acetate (30 mL) and a 1 mol / L aqueous solution of sodium hydroxide (40 mL). The organic layers were separated, and the aqueous layer was washed twice with a 1 / 1 mixture of toluene and ethyl acetate (30 mL). The three organic layers were combined and washed with a 0.1 mol / L aqueous solution of sodium hydroxide (40 mL). The three organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to solvent displacement with acetonitrile, to which acetonitrile (22.2 mL) and water (0.77 mL) were added, and the residue was dissolved by heating at 60 °C. (S)-mandelic acid (0.327 g) was added to the mixture at 60 °C, and the mixture was cooled to room temperature. The resulting crystals were aged overnight at room temperature. The crystals were collected by filtration using a Hertzsprung funnel, washed with acetonitrile (4.0 mL), and dried overnight at 50 °C under reduced pressure to give 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (S)-mandelic acid salt (0.81 g). Yield 57%, 96.0% de.

[1666] Example 419

[1667] Synthesis of 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (S)-mandelate

[1668]

[1669] A hydrogenation reaction solution containing 2-((1R)-1-aminoethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazolyl-5-carboxamide (2.94 mmol, 64.6% ee) was concentrated under reduced pressure, and the residue was partitioned between a 1 / 1 mixture of toluene and ethyl acetate (30 mL) and a 0.5 mol / L aqueous sodium hydroxide solution (80 mL). The organic layers were separated, and the aqueous layer was washed twice with a 1 / 1 mixture of toluene and ethyl acetate (30 mL). The three organic layers were combined and washed with a 0.05 mol / L aqueous sodium hydroxide solution (80 mL). The three organic lay...

Claims

1. A method for producing an optically active form of a compound represented by formula (III) or a salt thereof, in R 1 It is methyl; R 2 It is -Cl; R 3 It is -CF3; and The marked The carbon atom is an asymmetric carbon atom; This method involves subjecting a compound or a salt thereof, represented by the following formula (Ac), to an asymmetric reductive amination reaction. Each symbol is defined as described above. The asymmetric reductive amination reaction is carried out in the presence of an amine source, a reducing agent, and an organometallic complex. The organometallic complex is [IrCl(cod)]2 and contains ligands. The ligand is (R,R)-PTBP-Skewphos, the amine source is ammonium salicylate, the reducing agent is hydrogen, and the asymmetric reductive amination reaction is carried out under a nitrogen or argon atmosphere.

2. A method for producing an optically active form of a compound represented by the following formula (V) or a salt thereof: in R 1 It is methyl; R 2 It is -Cl; R 3 It is -CF3; R 4 It is -Cl; R 5 It is -NH2; and Marked The carbon atom is an asymmetric carbon atom, or a salt thereof. The method involves subjecting a compound or its salt represented by formula (Ac) to an asymmetric reduction reaction in the presence of an amine source, a reducing agent, and an organometallic complex. Each symbol is defined as described above. To obtain the optically active form of the compound represented by the following formula (III) or a salt thereof; Each symbol is defined as described above. The method further includes the step of reacting an optically active form of the compound represented by formula (III) or a salt thereof with a compound represented by formula (IV) or a salt thereof; in X is a leaving group; and Other symbols are as defined above. The organometallic complex is [IrCl(cod)]2 and contains ligands. The ligand is (R,R)-PTBP-Skewphos, the amine source is ammonium salicylate, the reducing agent is hydrogen, and the asymmetric reductive amination reaction is carried out under a nitrogen or argon atmosphere.

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