Selective manufacturing method of single axially chiral compound

Abstract

The present invention relates to, as one embodiment thereof, a method for producing a compound of formula (I) as defined in the description or a salt thereof. The production method comprises a step for obtaining a compound of formula (I) or a salt thereof by reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof, or by reacting a compound of formula (IIB) or a salt thereof with a compound of formula (IIIB) or a salt thereof. In the compound of formula (I), preferably R4 is formula (VI) or (VII), and R5 is formula (VIII) or (IX) (all the formulas, R4 and R5 are defined in the specification).

Description

TECHNICAL FIELD

[0001] The present application relates to a method for selectively producing one of compounds having axial chirality, and the like. More specifically, it relates to a method for selectively producing one of compounds of formula (I) having axial chirality or a salt thereof, and the like.

[0002] Further, the present application also relates to a method for efficiently producing a compound used in a selective production method for an axial chiral compound, and an axial chiral compound obtained by a selective production method for an axial chiral compound. BACKGROUND

[0003] In Patent Literature 1 (International Publication No. 2022 / 173032), as a quinazoline compound for inducing decomposition of G12D mutant KRAS protein, a compound represented by the following formula (A) or a salt thereof, and a method for producing the same, and the like are described.

[0004] [Chemical Formula 1]

[0005] (Note that the definition of each group in the formula is described in Patent Literature 1.)

[0006] PRIOR ART DOCUMENTS

[0007] PATENT LITERATURE

[0008] Patent Literature 1: International Publication No. 2022 / 173032 SUMMARY

[0009] As described above, in Patent Literature 1, a method of producing the compound represented by the above formula (A) is described, but in the production process, a compound having a chiral axis is obtained, and thus, it is possible to synthesize an intermediate, a target compound in the form of a stereoisomer mixture based thereon. For example, in Production Example 11 of Patent Literature 1, it is described that by reacting (1S,4S)-tert-butyl 5-{8-(benzyloxy)-7-bromo-6-cyclopropyl-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.15 g) and 6-fluoro-5-methyl-l-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole (1.92 g), it is possible to obtain (1S,4S)-tert-butyl 5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.42 g) as an M body and (1S,4S)-tert-butyl 5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.37 g) as a P body, and the M:P ratio in Production Example 11 is about 1:1. Even if synthesized in the form of a stereoisomer mixture, it is possible to separate each stereoisomer by performing a general fractionation operation, such as fractionation using an ODS column or silica gel column chromatography, but from the viewpoint of improving the yield of the target compound and reducing the fractionation step, it is more desirable to establish a method of selectively obtaining one axially chiral compound.

[0010] In addition, if a single axially chiral compound represented by formula (IIA) is obtained, it is possible to efficiently produce the compound of formula (A).

[0011] Furthermore, from the viewpoint of reducing costs, it is desirable to establish a new synthesis method of the compound represented by formula (IIA) for a selective production method of an axially chiral compound.

[0012] An object of the present application is to develop a production method of selectively obtaining one axially chiral compound or a salt thereof in the synthesis of the compound represented by the above formula (A).

[0013] The present inventors have found a method for selectively obtaining an axially chiral compound or a salt thereof by controlling the axial chirality using a chiral auxiliary group. In addition, the present inventors have also found a method for efficiently producing a compound used in the selective production method of an axially chiral compound, an axially chiral compound obtained by the selective production method of an axially chiral compound in the course of developing the above method.

[0014] In addition, the present inventors have also found a method for producing a compound of the following formula (#1) or a salt thereof by reacting a compound of the following formula (#2) with a diazo transfer reagent.

[0015] The present application encompasses the following modes, but is not limited thereto. [1]

[0017] A method for producing a compound of the following formula (I) or a salt thereof, [Chemical Formula 2]

[0018] [In the formula, A is N or CH, Y is a bond, -CH2-, -O-, -S-, or -NR Y -, R Y is H or a C 1-3 alkyl group which can be substituted, R 1 is the following formula (IV) or (V), [Chemical Formula 3]

[0019] Ring A is a 7- to 9-membered bridge-heterocycloalkane which can be substituted and contains 1 to 2 nitrogen atoms, or a 4- to 6-membered heterocycloalkane which can be substituted and contains 1 to 2 nitrogen atoms, Z is a bond, -CH2-, -O-, -S-, or -N(R Z1 )-, R Z1 is H or a C 1-3 alkyl group which can be substituted, PG 1 is a protecting group for NH included in Ring A, PG 2 is a protecting group for OH, R 2 is a C 1-15 alkyl group which can be substituted or a heterocycloalkyl group which can be substituted, R 3 is halogen, C 3-6 cycloalkyl, vinyl, or a C 1-3 alkyl group which can be substituted, R 4 is the following formula (Vl) or (VII), [Chem. 4]

[0020] R 4A is C 1-3 alkyl, R 4B is naphthyl, phenanthryl or phenyl which can be substituted, R 5 is the following formula (VIII) or (IX), [Chem. 5]

[0021] PG 3 is a protecting group of NH, R 5A is H, methyl, F or Cl, R 5B is Cl, methyl, ethyl or vinyl, indicates a chiral axis wherein, the method comprises the step of reacting a compound of the following formula (IIA) or a salt thereof with a compound of the following formula (IIIA) or a salt thereof, or reacting a compound of the following formula (IIB) or a salt thereof with a compound of the following formula (IIIB) or a salt thereof, to obtain a compound of the formula (I) or a salt thereof, [Chem. 6]

[0022] [In the formula, A, Y, R Y , R 1 , ring A, Z, R Z1 , PG 1 , PG 2 , R 2 , R 3 , R 4 , R 4A , R 4B , R 5 , PG 3 , R 5A , R 5B and as defined above, X is Cl, Br, I, methanesulfonyloxy or p-toluenesulfonyloxy, BLG is a boronic acid group, a boronic ester group, a trifluoroborate group or a triol borate group Herein, one of the compounds of the above formula (I) or a salt thereof having an axial chirality is selectively produced or a salt thereof. [2]

[0024] The method according to [1], wherein the reaction comprises reacting a compound of the formula (IIA) or a salt thereof with a compound of the formula (IIIA) or a salt thereof, Herein, X is Cl or Br, Y is -O- or -S-, R 1 is a group selected from the group consisting of the following formulae (IV-1), (IV-2), (IV-3) and (V), [Chemical Formula 7]

[0025] R 2 is tetrahydropyranyl or C 1-3 alkyl which can be substituted with -OCH3, R 3 is cyclopropyl, R 4 is a group selected from the group consisting of the following formulae (VI-1), (VI-2) and (VI-3), [Chemical Formula 8]

[0026] R 5 is a group selected from the group consisting of the following formulae (VIII-1) and (IX-1).

[0027] [Chemical Formula 9] [3]

[0029] The method according to [2], wherein the reaction comprises reacting a compound of the formula (IIA) or a salt thereof with a compound of the formula (IIIA) or a salt thereof, Herein, A is N, R 1 is a group selected from the group consisting of the following formulae (IV-1), (IV-2) and (V), [Chemical Formula 10]

[0030] R 5 is a group represented by the following formula (VIII-1).

[0031] [Chemical Formula 11] [4]

[0033] The method according to [3], wherein the compound of the formula (IIA) or a salt thereof is a compound represented by the following formula (IIA-1), [Chemical Formula 12]

[0034] The compound of the formula (IIIA) or a salt thereof is a compound represented by the following formula (IIIA-1), [Chemical Formula 13]

[0035] The method includes a step of obtaining a compound represented by the following formula (I-1) by the following steps.

[0036] [Chemical Formula 14] [5]

[0038] The method according to [4], wherein the compound (1) or a salt thereof is obtained by the following steps.

[0039] [Chemical Formula 15] [6]

[0041] The method according to [5], wherein the compound (14) is obtained from the following compound (16) and the following compound (17) by the following steps.

[0042] [Chemical Formula 16] [7]

[0044] The method according to [5], wherein the compound of the formula (IIA-1) is obtained from the following compound (2) by the following steps.

[0045] [Chemical Formula 17] [8]

[0047] The method according to [6], wherein the compound (20) is obtained from the following compound (24) and the following compound (25) by the following steps.

[0048] [Chemical Formula 18] [9]

[0050] The method according to any one of [4] to [8], wherein the compound of formula (IIIA-1) is obtained from the following compound (27) by the following steps.

[0051] [Chemical Formula 19]

[10]

[0053] The method according to [3], wherein the compound of formula (IIA) or a salt thereof is a compound represented by the following formula (IIA-2), [Chemical Formula 20]

[0054] The compound of formula (IIIA) or a salt thereof is a compound represented by the following formula (IIIA-1), [Chemical Formula 21]

[0055] The method includes a step of obtaining a compound represented by formula (I-1) by the following steps.

[0056] [Chemical Formula 22]

[11]

[0058] The method according to

[10] , wherein the compound (1) or a salt thereof is obtained by the following steps.

[0059] [Chemical Formula 23]

[12]

[0061] The method according to

[10] or

[11] , wherein the compound of formula (IIA-2) is obtained by the following steps.

[0062] [Chemical Formula 24]

[13]

[0064] The compound represented by any one of the following or a salt thereof.

[0065] [Chemical Formula 25-1]

[0066] [Chemical Formula 25-2]

[0067] [Chemical Formula 25-3]

[14]

[0069] the method according to [1], wherein the reaction comprises reacting a compound of formula (IIB) or a salt thereof with a compound of formula (IIIB) or a salt thereof, Herein, X is Cl or Br, Y is -O- or -S-, R 1 is a group selected from the group consisting of the following formulae (IV-1), (IV-2), (IV-3) and (V), [Chem. 26]

[0070] R 2 is tetrahydropyranyl or C 1-3 alkyl which can be substituted with -OCH3, R 3 is cyclopropyl, R 4 is a group selected from the group consisting of the following formulae (VI-1), (VI-2) and (VI-3), [Chem. 27]

[0071] R 5 is a group selected from the group consisting of the following formulae (VIII-1) and (IX-1).

[0072] [Chem. 28]

[15]

[0074] the method according to

[14] , wherein the reaction comprises reacting a compound of formula (IIB) or a salt thereof with a compound of formula (IIIB) or a salt thereof, Herein, A is N, R 1 is a group selected from the group consisting of the following formulae (IV-1), (IV-2) and (V), [Chem. 29]

[0075] R 5 is a group represented by the following formula (VIII-1).

[0076] [Chem. 30]

[16]

[0078] The method according to

[15] , wherein The compound of the formula (IIB) or a salt thereof is a compound represented by the following formula (IIB-1), [Chemical Formula 31]

[0079] The compound of the formula (IIIB) or a salt thereof is a compound represented by the following formula (IIIB-1), [Chemical Formula 32]

[0080] The method includes a step of obtaining a compound represented by the formula (I-1) by the following steps.

[0081] [Chemical Formula 33]

[17]

[0083] The method according to any one of [1] to [4] and

[14] to

[16] , wherein the producing is performed in the presence of a palladium catalyst or a palladium catalyst precursor and a ligand.

[18]

[0085] The method according to

[17] , wherein the producing is performed in the presence of a base.

[19]

[0087] The method according to

[18] , wherein the producing is performed at 20°C to 140°C in a solvent that is inert to the reaction.

[20]

[0089] The method according to [1], wherein, comprising reacting a compound of the formula (IIA) or a salt thereof with a compound of the formula (IIIA) or a salt thereof, R 5 is a group selected from the group consisting of the following formulae (VIII-1) and (IX-1).

[0090] [Chemical Formula 34]

[21]

[0092] The method according to

[20] , wherein R 4 is a group selected from the group consisting of the following formulae (VI-1), (VI-2), and (VI-3).

[0093] [Chemical Formula 35]

[22]

[0095] The method according to

[20] or

[21] , wherein, R 3 is C 3-6 cycloalkyl, vinyl or C 1-3 alkyl which can be substituted, R 3 is C 3-6 cycloalkyl.

[23]

[0097] The method according to any one of

[20] to

[22] , wherein, X is Cl, Br or I, X is preferably Cl or Br.

[24]

[0099] The method according to any one of

[20] to

[23] , wherein, A is N.

[25]

[0101] The method according to any one of

[20] to

[24] , wherein, R 1 is the following formula (V).

[0102] [Chemical Formula 36]

[26]

[0104] The method according to any one of

[20] to

[25] , wherein, Y is a bond, R 2 is a heterocycloalkyl which can be substituted, the heterocycloalkyl being a 4- to 7-membered saturated heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen.

[27]

[0106] The method according to

[26] , wherein, R 2 is a group selected from the group consisting of the following formulas (X-1), (X-2), (X-3), (X-4), (X-5), (X-6) and (X-7), [Chemical Formula 37]

[0107] R 2A is H or C 1-3 alkyl which can be substituted, V is PG 4 or C 1-3 alkyl which can be substituted, PG 4 is a protecting group for NH.

[28]

[0109] The method according to any one of

[20] to

[27] , wherein R 2 is the following formula (X-1), [Chemical Formula 38]

[0110] R 2A is H or C 1-3 alkyl, V is PG 4 or C 1-3 alkyl, PG 4 is a protecting group of NH, R 3 is cyclopropyl, R 4 is the following formula (VI-1), [Chemical Formula 39]

[0111] R 5 is the following formula (VIII-1).

[0112] [Chemical Formula 40]

[29]

[0114] A method of producing a compound of the following formula (#1) or a salt thereof, [Chemical Formula 41]

[0115] [In the formula, R 11 is C 1-6 alkyl which can be substituted, C 3-6 cycloalkyl which can be substituted or a 4- to 6-membered saturated heterocyclic group which can be substituted and contains 1 hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, R 12A and R 12B are the same or different from each other, and are H or C 1-6 alkyl which can be substituted, or R 12A and R 12B together with the carbon to which they bind form C 3-6 cycloalkyl which can be substituted or a 4- to 6-membered saturated heterocycle which can be substituted and contains 1 hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, R 13 is H; halogen; C 1-3 alkyl; -SO2CH3; C3-6 cycloalkyl; a 4- to 6-membered saturated heterocyclic group optionally substituted, containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; a 5-membered heteroaryl group optionally substituted, containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; or a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms, W is a phenyl group optionally substituted or a 6-membered heteroaryl group optionally substituted, containing 1 to 3 nitrogen atoms. wherein, including the step of reacting the compound of the following formula (#2) with a diazo transfer reagent to obtain the compound of the above formula (#1) or a salt thereof.

[0116] [Chemical Formula 42]

[0117] [In the formula, R 11 , R 12A , R 12B , R 13 and W are as defined above]

[30] The method according to

[29] , wherein 2-azido-1,3-dimethylimidazole is used as the diazo transfer reagent.

[31]

[0119] The method according to

[29] or

[30] , wherein R 11 is ethyl, isopropyl, tert-butyl or C 3-6 cycloalkyl, R 12A and R 12B are the same or different from each other, H or C 1-3 alkyl optionally substituted with a group selected from the group consisting of F, OH and N(CH3)2, or R 12A and R 12B together with the carbon to which they are bonded form a cyclopropyl group, R 13 is H, halogen or a group selected from the group consisting of [Chemical Formula 43]

[0120] R 13A , R 13B are the same or different from each other, H or C 1-3 alkyl optionally substituted with OH, W is a phenyl group.

[32]

[0122] The method according to any one of

[29] to

[31] , wherein R 11 isopropyl, R 12A is H, R 12B is C 1-3 alkyl which can be substituted with OH, R 13 is a group described below, [Chemical Formula 44]

[0123] R 13A is C 1-3 alkyl, W is phenyl.

[33]

[0125] The method according to any one of

[29] to

[32] , wherein the diazo transfer reagent is a perfluoroalkylsulfonyl azide.

[34]

[0127] The method according to any one of

[29] to

[32] , wherein the diazo transfer reagent is a nonafluorobutanesulfonyl azide.

[35]

[0129] The method according to any one of

[29] to

[34] , wherein a base reagent is used.

[36]

[0131] The method according to any one of

[29] to

[35] , wherein an additive is used.

[37]

[0133] The method according to any one of

[29] to

[36] , wherein a polar solvent is used.

[38]

[0135] The method according to any one of

[29] to

[37] , wherein the reaction is carried out at a reaction temperature of 10°C to 25°C.

[39]

[0137] The method according to any one of [1] to

[28] , wherein the method according to any one of

[29] to

[38] is included as a step.

[40]

[0139] The following compound or a salt thereof.

[0140] [Chemical Formula 45]

[41]

[0142] The following compound or a salt thereof.

[0143] [Chemical Formula 46]

[0144] Inventive Effects

[0145] According to one embodiment of the present application, by introducing a chiral auxiliary group in the manufacturing step, the chiral auxiliary group is used to control the chiral axis, whereby one axially chiral compound or a salt thereof can be selectively obtained. In addition, according to the present application, a compound for a selective manufacturing method of an axially chiral compound can be efficiently manufactured, and an axially chiral compound can also be obtained by the selective manufacturing method of an axially chiral compound.

[0146] In addition, according to one embodiment of the present application, the compound of the above formula (#2) can also be reacted with a diazo transfer reagent to efficiently obtain the compound of the above formula (#1) or a salt thereof. DETAILED DESCRIPTION

[0147] Hereinafter, the present application will be described in detail.

[0148] 1. Definitions

[0149] As described above, the present application relates to a method for selectively obtaining one axially chiral compound or a salt thereof in one aspect. In the present specification, the expression "selectively obtaining one axially chiral compound or a salt thereof" means that the ratio (M:P ratio) of M body to P body is not 1:1, but one axially chiral compound or a salt thereof is obtained in a higher ratio than the other axially chiral compound or a salt thereof. In one aspect, M body is obtained in a higher ratio than P body by the method of the present application, and the ratio (M:P ratio) is not particularly limited, and is, for example, 1.3:1 or more, 1.4:1 or more, 1.5:1 or more, 1.6:1 or more, 2:1 or more, 3:1 or more, 4:1 or more, 5:1 or more, 6:1 or more, 7:1 or more, 8:1 or more, 10:1 or more, 20:1 or more, 40:1 or more, 60:1 or more, 80:1 or more, or 90:1 or more. Note that in the case where M body is obtained in a higher ratio than P body, the expression "1.3:1 or more" means that 1.3 units or more of M body is obtained with respect to 1 unit (amount in grams or amount in moles) of P body. For example, it means that 1.3 g or more of M body is obtained with respect to 1 g of P body. Note that in the present application, the molecular weight of M body and P body is the same, and therefore the M:P ratio in grams is the same as the M:P ratio in moles.

[0150] In addition, in one embodiment, the P body is obtained in a higher ratio than the M body by the method of the present application, and the ratio (M:P ratio) is not particularly limited, and is, for example, 1:1.3 or more, 1:1.4 or more, 1:1.5 or more, 1:1.6 or more, 1:2 or more, or 1:5 or more. Note that in the case where the P body is obtained in a higher ratio than the M body, as described above, the notation "1:1.3 or more" means that 1.3 units or more of the P body is obtained with respect to 1 unit of the M body.

[0151] Note that in the method for producing an axially chiral compound without using a chiral auxiliary group, the target compound is obtained as a stereoisomer mixture having an M:P ratio of about 1:1. In comparison with such a method, the method of the present application is advantageous in that the selectivity of the stereoisomer is improved when obtaining the desired axially chiral compound.

[0152] In addition, in one embodiment, the present application relates to a method for producing an axially chiral compound using a chiral auxiliary group, and an axially chiral compound having a chiral auxiliary group is obtained. Furthermore, the present inventors have found that the separation and fractionation of an axially chiral compound having a chiral auxiliary group is easy compared to an axially chiral compound not having a chiral auxiliary group. That is, the mixture of the axially chiral compound having a chiral auxiliary group (M body and P body) obtained by the production method of the present application can be easily purified to a high purity by a simple operation such as recrystallization. In addition, the axially chiral compound can be purified to a high purity by a fractionation operation such as ordinary column chromatography. That is, the production method of the present application can improve the yield of the target compound having a prescribed stereoisomer and reduce the steps of separation, fractionation, and the like, and can further contribute to the reduction of the production cost.

[0153] The method for analyzing the obtained axially chiral compound or salt thereof can be performed using a publicly known method such as HPLC or NMR. Note that there is no substantial difference between the M:P ratio calculated by HPLC-based analysis and the M:P ratio calculated by NMR-based analysis.

[0154] In the present specification, the HPLC analysis conditions use the following conditions, but are not limited to these analysis conditions as long as the target compound or salt thereof can be separated and analyzed. Note that the HPLC analysis conditions described in Tables 2 to 3 described later correspond to one of the following.

[0155] <HPLC Analysis Condition 1>

[0156] • Column: InfinityLab Poroshell 120 EC-C8, 2.1 x 100 mm, 2.7 μm (Agilent)

[0157] • Mobile phase: (A) pH 2.5 aqueous HCIO4solution; (B) iPrOH

[0158] • Elution: B) 45% (0 min) -> 45% (2 min) -> 90% (22 min) -> 90% (25 min)

[0159] • Flow rate: 0.1 mL / min

[0160] • Column temperature: 40 °C

[0161] • Detection wavelength: 254 nm

[0162] <HPLC analysis condition 2>

[0163] • Column: CORTECS C18+, 4.6 x 150 mm, 2.7 pm (Waters)

[0164] • Mobile phase: (A) 0.03% TFA in water / MeCN (95 / 5); (B) 0.03% TFA in water / MeCN (5 / 95)

[0165] • Elution: B) 45% (0 min) -> 70% (8 min) -> 70% (20 min) -> 95% (21 min) -> 95% (23 min)

[0166] • Flow rate: 1.0 mL / min

[0167] • Column temperature: 40 °C

[0168] • Detection wavelength: 210 nm

[0169] <HPLC analysis condition 3>

[0170] • Column: InfinityLab Poroshell 120 EC-C8, 2.1 x 100 mm, 2.7 pm (Agilent)

[0171] • Mobile phase: (A) pH 2.5 aqueous HCIO4-NaCIO4buffer solution; (B) MeOH

[0172] • Elution: B) 70% (0 min) -> 99% (30 min) -> 99% (33 min)

[0173] • Flow rate: 0.15 mL / min

[0174] • Column temperature: 40 °C

[0175] • Detection wavelength: 254 nm

[0176] <HPLC analysis condition 4>

[0177] • Column: Ascentis Express C18, 2.1 x 100 mm, 2.7 pm (Supelco, Sigma-Aldrich)

[0178] • Mobile phase: (A) pH 2.5 aqueous HCIO4solution; (B) MeOH

[0179] • Elution: B) 95% (0 min) -» 99% (15 min) -» 99% (20 min)

[0180] • Flow rate: 0.2 mL / min

[0181] • Column temperature: 40 °C

[0182] • Detection wavelength: 254 nm

[0183] <HPLC Analysis Condition 5>

[0184] • Column: YMC-Pack C4, 4.6 x 150 mm, 3 pm (YMC Inc.)

[0185] • Mobile phase: (A) pH 7, 10 mM phosphate buffer / MeCN (95 / 5); (B) MeCN

[0186] • Elution: B) 0% (0 min) -» 79% (10 min) -» 79% (25 min)

[0187] • Flow rate: 1.5 mL / min

[0188] • Column temperature: 40 °C

[0189] • Detection wavelength: 220 nm

[0190] <HPLC Analysis Condition 6>

[0191] • Column: ZORBAX RRHD Eclipse Plus C18, 2.1 x 50 mm, 1.8 pm (Agilent)

[0192] • Mobile phase: (A) 0.1% formic acid in water; (B) 0.1% formic acid in MeCN

[0193] • Elution: B) 2% (0 min) -» 100% (10 min)

[0194] • Flow rate: 1.0 mL / min

[0195] • Column temperature: 40 °C

[0196] • Detection wavelength: 254 nm

[0197] (Note) After 1 to 2 mg of the compound was dissolved in MeOH, an appropriate amount of 4M hydrochloric acid / ethyl acetate was added, and the protecting group was removed by shaking several times, HPLC measurement was performed.

[0198] <HPLC analysis condition 7>

[0199] • Column: InfinityLab Poroshell 120 EC-C8, 2.1 x 100 mm, 2.7 μm (Agilent)

[0200] • Mobile phase: (A) pH 2.5 aqueous HCIO4 solution; (B) iPrOH

[0201] • Elution method: B) 50% (0 min) -> 65% (15 min) -> 90% (23 min) -> 90% (25 min)

[0202] • Flow rate: 0.1 mL / min

[0203] • Column temperature: 40°C

[0204] • Detection wavelength: 254 nm

[0205] <HPLC analysis condition 8>

[0206] • Column: YMC-Pack C4, 4.6 mm x 150 mm, 3 μm (YMC)

[0207] • Mobile phase: (A) pH 7, 10 mM aqueous K2HPO4 buffer solution / MeCN (95 / 5); (B) MeCN

[0208] • Elution method: B) 0% (0 min) -> 79% (10 min) -> 79% (45 min)

[0209] • Flow rate: 1.5 mL / min

[0210] • Column temperature: 40°C

[0211] • Detection wavelength: 220 nm

[0212] <HPLC analysis condition 9>

[0213] • Column: YMC-Pack Pro C4, 2.0 x 100 mm, 3 μm (YMC)

[0214] • Mobile phase: (A) pH 7, 10 mM aqueous K2HPO4 buffer solution / MeCN (95 / 5); (B) MeCN

[0215] • Elution method: B) 74% (0 min) → 74% (60 min)

[0216] • Flow rate: 0.4 mL / min

[0217] • Column temperature: 40°C

[0218] • Detection wavelength: 220 nm

[0219] "C 1-15 "Alkyl" means a straight-chain or branched-chain alkyl group having 1 to 15 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, dodecyl, tridecyl, tetradecyl, pentadecyl, and the like, and as one embodiment, n-propyl, and as one embodiment, ethyl (hereinafter, the same applies to the number of carbon atoms).

[0220] "C 1-6 "Alkyl" means a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like, and as one embodiment, isopropyl.

[0221] Similarly, "C 1-3 "Alkyl" means a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, and as one embodiment, n-propyl, ethyl or methyl, and as one embodiment, n-propyl, and as one embodiment, ethyl, and as one embodiment, methyl.

[0222] "C 3-6 "Cycloalkyl" means a cycloalkyl group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and as one embodiment, cyclopropyl.

[0223] "Heterocycloalkane" means a 4- to 7-membered saturated heterocycle containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, and can partially contain an unsaturated bond. In addition, the sulfur atom as a ring-constituting atom of the saturated heterocycle can be oxidized. In one embodiment, the above "heterocycloalkane" can contain 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, and can contain 1 to 2 nitrogen atoms as ring-constituting atoms. In one embodiment, the above "heterocycloalkane" can be a 4- to 6-membered saturated heterocycle, and can be a 5- to 6-membered saturated heterocycle. As one embodiment of "heterocycloalkane", "4- to 6-membered heterocycloalkane containing 1 to 2 nitrogen atoms" is mentioned, and as one embodiment, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, Alzolidine, imidazoline, piperazine, morpholine, thiomorpholine, dioxothiomorpholine, as a form of pyrrolidine.

[0224] "Heterocyclic alkyl" is a 4- to 7-membered saturated heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-forming atoms, and may also partially contain unsaturated bonds. In another embodiment, the aforementioned "heterocyclic alkyl" may contain 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-forming atoms, or may contain 1 to 2 nitrogen atoms as ring-forming atoms. In yet another embodiment, the aforementioned "heterocyclic alkyl" may be a 4- to 6-membered saturated heterocyclic group, or a 5- to 6-membered saturated heterocyclic group. Furthermore, the sulfur atom serving as the ring-forming atom of this saturated heterocyclic group may also be oxidized. Examples of "heterocyclic alkyl" include oxocyclic butyl, tetrahydrofuranyl, tetrahydropyranyl, azacyclic butyl, pyrrolidinyl, piperidinyl, etc. Azolyl, imidazolyl, piperazine, morpholino, thiomorpholino, dioxothiomorpholino, as a mode, tetrahydropyrano or piperazine, as a mode, tetrahydropyrano, as a mode, piperazine.

[0225] "Bridged heterocyclic alkanes" refer to 7- to 9-membered bridged heterocycles containing 1 to 2 nitrogen atoms as ring constituent atoms. One type of "bridged heterocyclic alkanes" is "7- to 9-membered bridged heterocyclic alkanes containing 1 to 2 nitrogen atoms," including diazabicyclo[2.2.2]octane, diazabicyclo[3.2.1]octane, diazabicyclo[3.1.1]heptane, diazabicyclo[2.2.1]heptane, and diazabicyclo[3.3.1]nonane. Another type is diazabicyclo[2.2.1]heptane, and yet another type is 2,5-diazabicyclo[2.2.1]heptane.

[0226] "Halogen" refers to F, Cl, Br, and I. One form of halogen is F, Cl, or Br; another form is F or Cl; another form is F or Br; another form is F; another form is Cl; and another form is Br.

[0227] "Protecting group of OH" refers to a substituent that protects OH to prevent specific chemical reactions. Examples of protecting groups for OH include tert-butyl, benzyl, p-methoxybenzyl, methoxymethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, acetyl, benzoyl, and triphenylmethyl. Tert-butyl is also a common protecting group.

[0228] "Protecting group of NH" refers to a substituent that protects NH to prevent specific chemical reactions. Examples of protecting groups for NH include tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, phthaloyl, 2-nitrobenzenesulfonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, triphenylmethyl, and tetrahydropyranyl.

[0229] In this specification, "substitutable" means unsubstituted or having 1 to 5 substituents. Alternatively, it means unsubstituted or having 1 to 3 substituents. It should be noted that when there are two or more substituents, these substituents can be the same or different from each other.

[0230] As in "replaceable C" 1-15 Alkyl group, substituted C 1-6 Alkyl group, substituted C 1-3 Alkyl group, substituted C 3-6 The following are permitted substituents: “cycloalkyl”, “7- to 9-membered substituted bridged heterocyclic alkanes containing 1 to 2 nitrogen atoms”, “4- to 6-membered saturated heterocyclic groups containing 1 heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen”, “4- to 6-membered substituted heterocyclic alkanes containing 1 to 2 nitrogen atoms”, “substituted heterocyclic alkyl”, “5-membered heteroaryl groups containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen”, “6-membered heteroaryl groups containing 1 to 3 nitrogen atoms”, or “substituted phenyl”, each independently being F, OH, OCH3, N(CH3)2, C 1-3 Alkyl, C 2-3 alkenyl (vinyl, 1-propenyl or 2-propenyl), C 2-3 Alkyne (ethynyl, 1-propynyl, or 2-propynyl), hydroxymethyl, methoxymethyl, difluoroethyl, substituted C 3-6 Cycloalkyl, azirmonobicyclo[3.3.0]octyl, or a substituted 4- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from oxygen, sulfur, and nitrogen, as an example, OCH3.

[0231] Depending on the kind of functional group, the mode of replacement with an appropriate protecting group (a group that can be easily converted to the functional group) during the reaction is sometimes effective in the manufacturing technique. As such a protecting group, there can be mentioned, for example, the protecting groups described in P.G.M. Wuts and T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 5th edition, John Wiley & Sons Inc., 2014, and the like, and the use thereof can be appropriately selected depending on the reaction conditions thereof. After the reaction with the introduction of the protecting group, the protecting group is removed as necessary, whereby the desired compound can be obtained. In the present specification, the “protecting group” is not particularly limited as long as the above object is achieved.

[0232] In one mode, as the protecting group, there can be mentioned benzyl, p-methoxybenzyl, benzyloxycarbonyl, tert-butyl(dimethyl)silyl, (trimethylsilyl)ethoxymethyl, acetyl, trifluoroacetyl, benzoyl, tert-butyl, tert-butoxycarbonyl, triphenylmethyl, tetrahydropyranyl, and the like.

[0233] 2. Process for the selective production of an axially chiral compound or salt thereof by controlling the axial chirality using a chiral auxiliary group 3. Diazo transfer reaction

[0234] The present application is, in one mode, a method for selectively producing one of the compounds of formula (I) or a salt thereof having an axial chirality, which comprises a step of reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof or a step of reacting a compound of formula (IIB) or a salt thereof with a compound of formula (IIIB) or a salt thereof. Further, the present application is, in one mode, a method for selectively producing one of the compounds of formula (I) or a salt thereof having an axial chirality, which comprises a step of reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof. Note that, represents a chiral axis.

[0235] [Chemical Formula 47]

[0236] In the above method, A is N or CH. Further, in one mode, A is N, and in one mode, A is CH.

[0237] In the above method, X is Cl, Br, I, methanesulfonyloxy, or p-toluenesulfonyloxy. Further, in one mode, X is Cl, Br, or I, in one mode, X is Cl or Br, in one mode, X is Cl, and in one mode, X is Br.

[0238] In the above method, Y is a bond, -CH2-, -O-, -S-, -NR Y -, -S(=O) or -SO2-, and the above R Y is H or a C 1-3 alkyl group which can be substituted. Further, as one mode, Y is a bond, -CH2-, -O-, -S- or -NR Y -, and the above R Y is H or a C 1-3 alkyl group which can be substituted. Further, in one mode, Y is -O- or -S-, in one mode, Y is -O-, in one mode, Y is -S-, and in one mode, Y is a bond.

[0239] In the above method, R 1 is the following formula (IV) or (V).

[0240] [Chemical Formula 48]

[0241] Further, in one mode, R 1 is a group selected from the group consisting of the following formulae (IV-1), (IV-2), (IV-3) and (V). Further, in one mode, R 1 is a group selected from the group consisting of the following formulae (IV-1), (IV-2) and (V), and in one mode, R 1 is the following formula (IV-1). Further, in one mode, R 1 is the following formula (V).

[0242] [Chemical Formula 49]

[0243] In the above R 1 , ring A is a 7- to 9-membered bridge-heterocycloalkane which can be substituted and contains 1 to 2 nitrogen atoms or a 4- to 6-membered heterocycloalkane which can be substituted and contains 1 to 2 nitrogen atoms, Z is a bond, -CH2-, -O-, -S- or -N(R Z1 )-, R Z1 is H or a C 1-3 alkyl group which can be substituted, and PG 1 is a protecting group for NH included in ring A, and the kind thereof is not particularly limited, and in one mode, is tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, phthaloyl, 2-nitrobenzenesulfonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl. Further, PG 2a protecting group for OH, which is not particularly limited, and in one embodiment, is a tert-butyl group, a benzyl group, a p-methoxybenzyl group, a methoxymethyl group, a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, an acetyl group, a benzoyl group, or a triphenylmethyl group.

[0244] In addition, in the above-mentioned method, R 2 is a C 1-15 alkyl group or a substituted heterocycloalkyl group. In one embodiment, R 2 is a C 1-3 alkyl group. In addition, in one embodiment, R 2 is a 4- to 7-membered heterocycloalkyl group which can be substituted.

[0245] In addition, in one embodiment, R 2 is a tetrahydropyranyl group, an ethyl group, or a C 1-3 alkyl group which can be substituted with -OCH3. In one embodiment, R 2 is a tetrahydropyranyl group. In one embodiment, R 2 is an ethyl group. In one embodiment, R 2 is a n-propyl group which can be substituted with -OCH3.

[0246] In addition, in one embodiment, R 2 is a substituted heterocycloalkyl group, and the above-mentioned heterocycloalkyl group is a 4- to 7-membered saturated heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen. In one embodiment, the heterocycloalkyl group of R 2 is a 4- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen. In addition, in one embodiment, the heterocycloalkyl group of R 2 is a 4- to 6-membered saturated heterocyclic group containing 1 to 2 nitrogen atoms. The above-mentioned "substituted heterocycloalkyl group" is cited from the above-mentioned description, and each independently is one or two or more selected from the group consisting of the above-mentioned substituents.

[0247] In one embodiment, R 2 is a group selected from the group consisting of the following formulae (X-1), (X-2), (X-3), (X-4), (X-5), (X-6), and (X-7), [Chemical Formula 50]

[0248] Herein, R 2A is H or a C 1-3 alkyl group which can be substituted, V is PG 4 or a C 1-3 alkyl group which can be substituted, PG4 It is a protecting group for NH.

[0249] In one approach, R 2 For the above equation (X-1), R 2A For H or C 1-3 alkyl, V stands for PG 4 Or C 1-3 alkyl, PG 4 It is a protecting group for NH.

[0250] In one approach, PG acts as a protecting group for NH. 4 One or more of the functional groups selected from the group consisting of the "protecting groups of NH" listed above can be used, in one manner being tert-butoxycarbonyl, triphenylmethyl, tetrahydropyranyl, and in another manner being 2-(trimethylsilyl)ethoxycarbonyl.

[0251] In addition, in the above method, R 3 Halogen, C 3-6 cycloalkyl, vinyl, or substituted C 1-3 Alkyl group. Additionally, in one embodiment, R... 3 C 3-6 cycloalkyl, in one manner, R 3 It is cyclopropyl.

[0252] In addition, in the above method, R 4 It is the following formula (VI) or (VII).

[0253] [Chemical Formula 51]

[0254] In equation (VI) or (VII) above, R 4A C 1-3 Alkyl, R 4B It can be naphthyl, phenanthryl, or a substituted phenyl group.

[0255] In one approach, R 4 For a group selected from the group consisting of the following formulas (VI-1), (VI-2), and (VI-3), in one manner, R 4 It is the following formula (VI-1).

[0256] [Chemical Formula 52]

[0257] In addition, in the above method, R 5 It is the following formula (VIII) or (IX).

[0258] [Chemical Formula 53]

[0259] In the above formula (VIII) or (IX), PG 3 is a protecting group for NH, and the kind thereof is not particularly limited, and in one embodiment, PG 5A is H, methyl, F or Cl, and R 5B is Cl, methyl, ethyl or vinyl.

[0260] In addition, in one embodiment, R 5 is the following formula (VIII-1) or (IX-1). In addition, in one embodiment, R 5 is the following formula (VIII-1).

[0261] [Chemical Formula 54]

[0262] In the above formula (VIII-1) or (IX-1), PG 3 is a protecting group for NH, and the kind thereof is not particularly limited, and in one embodiment, PG 3 is triphenylmethyl or tetrahydropyranyl, and in one embodiment, PG 3 is triphenylmethyl.

[0263] In addition, in the above method, BLG is a boronic acid group, a boronic acid ester group, a trifluoroborate group or a triol borate group. In addition, in one embodiment, BLG is a boronic acid ester group, and in one embodiment, BLG is a pinacol boronic acid ester group.

[0264] In addition, in one embodiment, BLG is any one of the substituents shown below, [Chemical Formula 55]

[0265] In addition, in one embodiment, BLG is any one of the substituents shown below.

[0266] [Chemical Formula 56]

[0267] In the method for selectively producing one axially chiral compound or salt thereof of the compound of formula (I) or salt thereof, which comprises a step of reacting the compound of the above formula (IIA) or salt thereof with the compound of formula (IIIA) or salt thereof, the reaction conditions are not particularly limited. In one mode, the production method uses the compound of formula (IIA) or salt thereof and the compound of formula (IIIA) or salt thereof in equimolar or one excess equivalent, and stirs a mixture thereof in the presence of a palladium catalyst and a ligand. In one mode, the production method uses the compound of formula (IIA) or salt thereof and the compound of formula (IIIA) or salt thereof in equimolar or one excess equivalent, and stirs a mixture thereof in the presence of a base, a palladium catalyst, and a ligand. In one mode, the production method uses the compound of formula (IIA) or salt thereof and the compound of formula (IIIA) or salt thereof in equimolar or one excess equivalent, and stirs a mixture thereof in a reaction-inert solvent in the presence of a base, a palladium catalyst, and a ligand at room temperature to heating reflux, preferably at 20°C to 140°C. In one mode, the production method uses the compound of formula (IIA) or salt thereof and the compound of formula (IIIA) or salt thereof in equimolar or one excess equivalent, and stirs a mixture thereof in a reaction-inert solvent in the presence of a base, a palladium catalyst, and a ligand at room temperature to heating reflux, preferably at 20°C to 140°C, usually for 0.1 hours to 5 days.

[0268] Examples of the solvent used herein are not particularly limited, and halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as diethyl ether, THF, DOX, 1,2-dimethoxyethane, alcohols such as MeOH, EtOH, iPrOH, tBuOH, pentanol, 2-methyl-2-butanol, DMF, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one, water, and mixtures thereof can be mentioned.

[0269] Examples of the base are not particularly limited, and anhydrous or hydrated inorganic bases such as barium hydroxide, tri-potassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide can be mentioned.

[0270] Examples of the palladium catalyst are not particularly limited, and tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, [1,1’-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane adduct, (1E,4E)-1,5-diphenylpenta-1,4-diene-3-one / palladium(3:2), palladium(II) acetate, di-μ-chlorobis(2’-amino-1,1’-biphenyl-2-yl-C,N)palladium(II), bis(tri-tert-butylphosphine)palladium, bis(bibenzylideneacetone)palladium, and the like can be mentioned.

[0271] As the ligand, SPhos, RuPhos, DPPF, and the like can be mentioned without particular limitation.

[0272] In addition, a palladium catalyst precursor can be used instead of the palladium catalyst in the production method. As the palladium catalyst precursor, a cyclopalladation catalyst precursor such as RuPhos Pd G3, SPhos Pd G3, RuPhos Pd G2, SPhos Pd G2, and the like can be mentioned without particular limitation.

[0273] In one embodiment of the palladium catalyst or the palladium catalyst precursor, palladium (II) acetate, RuPhos Pd G3, or SPhos Pd G3 is used. In one embodiment of the ligand, SPhos or RuPhos is used. In one embodiment of the base, barium hydroxide or potassium phosphate tribasic is used. In one embodiment of the solvent, DOX, 2-methyl-2-butanol, or water, and a mixture thereof is used. In one embodiment of the reaction temperature, 50°C to 90°C is used. In one embodiment of the reaction time, 1 hour to 2 days is used.

[0274] In addition, the method of heating the mixture by microwave irradiation is sometimes advantageous in terms of smoothly proceeding with the reaction.

[0275] The reaction conditions for the reaction of the compound of the formula (IIB) or a salt thereof with the compound of the formula (IIIB) or a salt thereof are also not particularly limited, and the reaction can be performed under substantially the same conditions as the above-described reaction conditions for the reaction of the compound of the formula (IIA) or a salt thereof with the compound of the formula (IIIA) or a salt thereof, and as one embodiment, the reaction conditions described in Example 23 can be used.

[0276] In one embodiment of the present application, the following method is provided: a compound of the following formula (IIA-1) as a compound of the formula (IIA) or a salt thereof is reacted with a compound of the following formula (IIIA-1) as a compound of the formula (IIIA) or a salt thereof, thereby producing a compound of the following formula (I-1). In the present specification, this reaction is described as the "sixth step".

[0277] [Chemical Formula 57]

[0278] (Sixth Step)

[0279] As described above, the present step is a method of producing a compound of the formula (I-1) by reacting a compound of the formula (IIA-1) with a compound of the formula (IIIA-1). The reaction conditions are not particularly limited as long as the reaction proceeds, and in one embodiment, the same conditions as the above-described reaction conditions for the reaction of the compound of the formula (IIA) or a salt thereof with the compound of the formula (IIIA) or a salt thereof are used. In addition, in one embodiment, the reaction conditions described in Example 3 described later can be used.

[0280] In one embodiment, the present application is a method for producing a compound of the following formula (I-1) which comprises obtaining the compound of formula (1) from a compound of the following formula (IIA-1) and a compound of the following formula (IIIA-1) by the following sixth step to the following tenth step. In one embodiment, the present application is a method for producing a compound of formula (1) from a compound of the following formula (IIA-1) and a compound of the following formula (IIIA-1) which comprises the following sixth step to the following tenth step.

[0281] [Chemical Formula 58]

[0282] (Sixth Step)

[0283] This step is a step of obtaining a compound of formula (10) by deprotection based on catalytic hydrogenation reaction of a compound of formula (I-1). This reaction can be performed by stirring a compound of formula (I-1) in a hydrogen atmosphere at normal pressure to pressurization in a solvent inert to the reaction in the presence of a metal catalyst under cooling to heating, preferably at room temperature, for 1 hour to 5 days. As the solvent, alcohols such as MeOH, EtOH, iPrOH, ethyl acetate, water and the like, and a mixture thereof can be exemplified, and there is no particular limitation. As the metal catalyst, there is no particular limitation, and a palladium catalyst such as Pd / C, palladium black, and the like can be used. In addition, a method in which the reaction is performed in the presence of an inorganic base such as sodium bicarbonate, potassium carbonate, and the like is sometimes advantageous in terms of smoothly proceeding the reaction.

[0284] In one embodiment, the reaction conditions described in Example 4 described later can be used.

[0285] (Eighth Step)

[0286] This step is a step of obtaining a compound (12) by reacting a compound (10) with a compound (11). This reaction is performed by using the compound (10) and the compound (11) in an equivalent amount or one excess equivalent amount, and stirring a mixture thereof in the presence of a base in a solvent inert to the reaction under cooling to heating reflux, preferably at 0°C to 80°C, usually for 0.1 hour to 5 days. As the solvent used here, ethers such as diethyl ether, THF, DOX, 1,2-dimethoxyethane, DMF, DMAc and the like, and a mixture thereof can be exemplified, and there is no particular limitation. As examples of the base, there is no particular limitation, and inorganic bases such as potassium carbonate, cesium carbonate, sodium hydride and the like can be exemplified.

[0287] In one embodiment, the reaction conditions described in Example 5 described later can be used.

[0288] (Ninth Step)

[0289] This step is a step of obtaining compound (13) by removing the protecting group (triphenylmethyl) of NH of compound (12).

[0290] In this reaction, compound (12) and an acidic reagent are used in an equivalent amount or an excess equivalent amount of one, and a mixture thereof is usually stirred for 30 minutes to 1 hour under cooling to heating reflux, preferably at room temperature, in a solvent inert to the reaction. As examples of the acidic reagent used here, there is no particular limitation, and 4-methylbenzene-l-sulfonic acid monohydrate and the like can be given. As the solvent, alcohols such as MeOH, EtOH, iPrOH and the like can be given, and there is no particular limitation.

[0291] In addition, in one mode, the reaction conditions described in Example 6 described later can be used.

[0292] (Tenth step)

[0293] This step is a step of obtaining compound (15) by a cycloaddition reaction of compound (13) and compound (14). In this reaction, compound (13) and compound (14) are used in an equivalent amount or an excess equivalent amount of one, and a mixture thereof is usually stirred for 0.1 hour to 5 days under cooling to heating reflux, preferably at 0°C to 100°C, preferably in the presence of a copper salt, further preferably in the presence of a copper salt and a reducing agent, in a solvent inert to the reaction or without a solvent. As examples of the solvent used here, ethers such as diethyl ether, THF, DOX, 1,2-dimethoxyethane and the like, alcohols such as MeOH, EtOH, iPrOH, tBuOH and the like, water and a mixture thereof can be given, and there is no particular limitation. As the copper salt, there is no particular limitation, and cupric iodide (I), cupric sulfate (II), cupric trifluoromethanesulfonate (II) and the like can be given. As the reducing agent, there is no particular limitation, and sodium ascorbate and the like can be given.

[0294] In addition, in one mode, the reaction conditions described in Example 11 described later can be used.

[0295] (Tenth step)

[0296] This step is a step of obtaining compound (1) by removing the protecting group (tert-butoxycarbonyl) of NH of compound (15). In this reaction, compound (15) and an acidic reagent are used in an equivalent amount or an excess equivalent amount of one, and a mixture thereof is usually stirred for 30 minutes to 5 days under cooling to heating reflux, preferably at room temperature to 60°C, in a solvent inert to the reaction. As examples of the acidic reagent used here, there is no particular limitation, and methanesulfonic acid and the like can be given. As the solvent, alcohols such as MeOH, EtOH, iPrOH, tBuOH and the like, water and a mixture thereof can be given, and there is no particular limitation.

[0297] In addition, in one embodiment, the reaction conditions described in Example 12 described later can be used.

[0298] In one embodiment, the compound (14) reacted in the tenth step can be obtained from the following compound (16) and the following compound (17) by the following twelfth to sixteenth steps.

[0299] [Chemical Formula 59]

[0300] (Twelfth Step)

[0301] This step is a step of obtaining the compound (18) by an amidation reaction of the compound (16) and the compound (17). In this reaction, the compound (16) and the compound (17) are used in an equivalent amount or in an excess amount of one, and the mixture thereof is usually stirred under cooling to heating, preferably at -20°C to 60°C, in a solvent inert to the reaction in the presence of a condensing agent. As examples of the solvent, ethers such as diethyl ether, THF, DOX, 1,2-dimethoxyethane, DMF, and a mixture thereof can be given, and there is no particular limitation. As examples of the condensing agent, there is no particular limitation, and HATU, EDCI, and the like can be given. The use of an additive (for example, 1-hydroxybenzotriazole) is sometimes preferable for the reaction. The reaction in the presence of an organic base such as TEA, DIPEA, or an inorganic base such as potassium carbonate, sodium carbonate, or potassium hydroxide is sometimes advantageous in terms of smooth progress of the reaction.

[0302] In addition, in one embodiment, the reaction conditions described in Example 8 described later can be used.

[0303] (Thirteenth Step)

[0304] This step is a step of obtaining the compound (19) by deprotection using a catalytic hydrogenation reaction of the compound (18). The reaction conditions are the same as those of the seventh step described above.

[0305] In addition, in one embodiment, the reaction conditions described in Example 9 described later can be used.

[0306] (Fourteenth Step)

[0307] This step is a step of obtaining the compound (21) by an amidation reaction of the compound (19) and the compound (20). The reaction conditions are the same as those of the twelfth step described above.

[0308] (Fifteenth Step)

[0309] This step is a step of obtaining compound (22) by cleaving the protecting group (tert-butoxycarbonyl) of NH of compound (21). This reaction is performed by generally stirring for 0.1 hour to 5 days with cooling to heating under reflux. Examples of the solvent used here are not particularly limited, and alcohols such as MeOH, EtOH, iPrOH, tBuOH, ethyl acetate, and mixtures thereof can be given. Examples of the deprotecting reagent are not particularly limited, and acids such as hydrogen chloride (DOX solution), hydrogen chloride (ethyl acetate solution), trifluoroacetic acid, methanesulfonic acid, and the like can be given.

[0310] In addition, in one mode, the reaction conditions of the above-mentioned fourteenth step to fifteenth step can use the reaction conditions described in Example 10 described later.

[0311] (Sixteenth step)

[0312] This step is a step of obtaining compound (14) by the reaction of compound (22) with a diazo transfer reagent. In this reaction, compound (22) is treated with an equivalent or excess amount of a diazo transfer reagent in a solvent inert to the reaction with cooling to heating, preferably at 0°C to 50°C, generally for 0.1 hour to 3 days. Examples of the diazo transfer reagent are not particularly limited, and can include, for example, trifluoromethanesulfonyl azide, 1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl azide, imidazole-1-sulfonyl azide or a salt thereof, ADMP, and the like. The reaction is sometimes advantageously performed in the presence of an organic base such as TEA, DMAP, 2,6-lutidine, a copper salt such as catalytic amount of copper sulfate. Examples of the solvent can include ethers such as THF, halogenated hydrocarbons such as dichloromethane, alcohols such as MeOH, MeCN, water, and mixtures thereof.

[0313] In addition, in one mode, the reaction conditions of the above-mentioned sixteenth step can use the reaction conditions described in Example 10-2 described later.

[0314] In one mode, the compound of formula (IIA-1) which is reacted in the sixth step can be obtained from the following compound (2) by the following first step to fifth step.

[0315] [Chemical Formula 60]

[0316] (First step)

[0317] This step is a step of chlorinating compound (2) to obtain compound (3). In this reaction, compound (2) and a chlorinating agent are used in an equivalent or one excess equivalent, and the mixture thereof is usually stirred at 0°C to 80°C under cooling to heating reflux, preferably under heating reflux, in a solvent inert to the reaction or without a solvent for usually 0.1 hour to 3 days. As the chlorinating agent used here, there is no particular limitation, and examples of the solvent used here can include dichloromethane, 1,2-dichloroethane, chloroform, and the like halogenated hydrocarbons, benzene, toluene, xylene, and the like aromatic hydrocarbons, diethyl ether, THF, DOX, 1,2-dimethoxyethane, and the like ethers, DMF, DMAc, DMSO, ethyl acetate, MeCN, and a mixture thereof. The reaction is sometimes favorably performed in the presence of an organic base such as TEA, DIPEA, NMM, DABCO, tBuOK, sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, and the like.

[0318] (Second step)

[0319] This step is a step of obtaining compound (5) by an in situ substitution reaction of compound (3) with compound (4). In this reaction, compound (3) and compound (4) are used in an equivalent or one excess equivalent, and the mixture thereof is usually stirred at 0°C to 80°C under cooling to heating reflux, preferably under heating reflux, in a solvent inert to the reaction or without a solvent for usually 0.1 hour to 5 days. As the solvent used here, there is no particular limitation, and examples of the solvent used here can include dichloromethane, 1,2-dichloroethane, chloroform, and the like halogenated hydrocarbons, benzene, toluene, xylene, and the like aromatic hydrocarbons, diethyl ether, THF, DOX, 1,2-dimethoxyethane, and the like ethers, DMF, DMAc, DMSO, ethyl acetate, MeCN, and a mixture thereof. The reaction is sometimes favorably performed in the presence of an organic base such as TEA, DIPEA, NMM, DABCO, tBuOK, sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, and the like.

[0320] In addition, in one mode, the reaction conditions described in International Publication No. 2022 / 173032 can be used.

[0321] (Third step)

[0322] This step is a step of obtaining compound (7) by an in situ substitution reaction of compound (5) with compound (6). The reaction conditions are the same as those of the above-mentioned second step.

[0323] In addition, in one mode, the reaction conditions described in International Publication No. 2022 / 173032 can be used.

[0324] (Fourth step)

[0325] This step is a step of obtaining compound (8) by an in situ substitution reaction of compound (7) with compound (9). The reaction conditions are the same as those of the above-mentioned second step.

[0326] In addition, in one mode, the reaction conditions described in Example 1 described later can be used.

[0327] (Fifth step)

[0328] This step is a step of reacting compound (8) with the cyclopropylboronic acid of compound (30) to obtain a compound of the formula (IIA-1). The reaction is carried out using compound (8) and the cyclopropylboronic acid of compound (30) in an equivalent or one equivalent excess, and the mixture thereof is usually stirred at room temperature to heating reflux, preferably at 20°C to 140°C, in the presence of a base and a palladium catalyst in a solvent inert to the reaction, usually for 0.1 hours to 5 days. As examples of the solvent used here, there are no particular limitations, and MeCN, water, and a mixture thereof can be mentioned. As the base, inorganic bases such as potassium phosphate tribasic, sodium carbonate, potassium carbonate, and the like can be mentioned. As the palladium catalyst, there are no particular limitations, and tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane adduct, and the like can be mentioned. The mode in which the reaction is carried out in the presence of a ligand such as DPPF is sometimes advantageous in terms of smoothly proceeding the reaction. In addition, the mode in which the mixture is heated by microwave irradiation is sometimes advantageous in terms of smoothly proceeding the reaction.

[0329] In addition, in one mode, the reaction conditions described in Example 2 described later can be used.

[0330] In addition, in one mode, the above-mentioned compound of the formula (I-1) can be obtained as follows: a compound of the following compound (2a) is subjected to the following first a step to fifth a step to obtain a compound of the formula (IIA-2), and then, the above-mentioned compound of the formula (I-1) is obtained by a sixth a step according to the same reaction conditions as the above-mentioned sixth step.

[0331] [Chemical Formula 61-1]

[0332] [Chemical Formula 61-2]

[0333] (First a step)

[0334] This step is a step of brominating compound (2a) to obtain compound (2b). In this reaction, compound (2a) and a brominating agent are used in an equivalent amount or an excess equivalent amount of one, and a mixture thereof is usually stirred at 40°C to 70°C for 1 hour to 5 days in the presence of an acidic reagent in a solvent inert to the reaction. As the brominating agent used here, there is no particular limitation, and 1,3-dibromo-5,5-dimethylhydantoin, NBS, and the like can be mentioned. As the acidic reagent used here, there is no particular limitation, and methanesulfonic acid, sulfuric acid, and the like can be mentioned. As examples of the solvent used here, there is no particular limitation, and alcohols such as MeOH, EtOH, iPrOH, tBuOH, MeCN, and the like can be mentioned.

[0335] In addition, in one mode, the reaction conditions described in Example 14 described later can be used in the first a step.

[0336] (First b step)

[0337] This step is a step of oximating compound (2b) to obtain compound (2c) and / or compound (2c'). In this reaction, compound (2b) and hydroxylamine hydrochloride are used in an equivalent amount or an excess equivalent amount of one, and a mixture thereof is usually stirred at room temperature to 60°C for 0.5 hours to 5 days in a solvent inert to the reaction. As examples of the solvent used here, there is no particular limitation, and alcohols such as MeOH, EtOH, iPrOH, tBuOH, and the like, and the like can be mentioned. The mode in which the reaction is performed in the presence of an additive such as sodium acetate is sometimes advantageous in terms of smoothly proceeding with the reaction.

[0338] In addition, in one mode, the reaction conditions described in Example 15 described later can be used in the first b step.

[0339] (First c step)

[0340] This step is a step of subjecting compound (2c) and / or compound (2c') to a ring expansion reaction to obtain compound (3a). In this reaction, compound (2c) and / or compound (2c') and a chlorinating agent are used in an equivalent amount or an excess equivalent amount of one, and a mixture thereof is usually stirred at room temperature to 110°C for 1 hour to 7 days in the presence of triphenylphosphine oxide and a base in a solvent inert to the reaction. As the chlorinating agent used here, there is no particular limitation, and thionyl chloride, phosphorus oxychloride, triphosgene, and the like can be mentioned. As the base used here, there is no particular limitation, and bases such as DIPEA can be mentioned. As examples of the solvent used here, there is no particular limitation, and aromatic hydrocarbons such as benzene, toluene, xylene, and the like, and the like can be mentioned. In addition, instead of triphenylphosphine oxide, a trialkylphosphine oxide or the like can be used, but it is not limited thereto.

[0341] In addition, in one mode, the reaction conditions described in Example 16 described later can be used in the first c-step.

[0342] The second a-step to the fifth a-step can be carried out under the same reaction conditions as the second step to the fifth step described above, respectively. In addition, the sixth a-step can be carried out using the same reaction conditions as the sixth step described above.

[0343] In addition, in one mode, the compound of the formula (IIA-2) can be obtained using the reaction conditions described in Examples 14 to 19 described later, and then the compound of the formula (I-1) can be obtained using the reaction conditions described in Example 3.

[0344] In one mode, the compound (20) on which the reaction is carried out in the fourteenth step can be obtained from the following compound (24) and the following compound (25) by the following seventeenth step to the eighteenth step.

[0345] [Chemical Formula 62]

[0346] (Seventeenth step)

[0347] This step is a step of reacting the compound (24) with the compound (25) to obtain the compound (26). In this reaction, the compound (24) and the compound (25) are used in an equivalent amount or in an excess of one equivalent, and a mixture thereof is usually stirred for 0.1 hours to 5 days at room temperature to heating reflux, preferably at 20°C to 140°C, in the presence of a base and a palladium catalyst in a solvent inert to the reaction. Examples of the solvent used here are not particularly limited, and ethers such as diethyl ether, THF, DOX, 1,2-dimethoxyethane, NMP, DMF, DMAc, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one, ethyl acetate, water, and a mixture thereof can be mentioned. As the base, an alkali such as potassium phosphate tribasic, sodium carbonate, potassium carbonate, potassium acetate, and the like can be mentioned. As the palladium catalyst, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, [1,1’-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane adduct, (1E,4E)-1,5-diphenylpenta-1,4-diene-3-one / palladium(3:2), (2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonate, palladium(II) acetate, and the like can be mentioned. In addition, a method in which the mixture is heated by microwave irradiation is sometimes advantageous in smoothly proceeding the reaction.

[0348] As a reference for the reaction, for example, the following can be referred to.

[0349] Synthesis 2020, 52, p. 2521-2527

[0350] PNAS 2016, 113, p. 7124-7129

[0351] (Eighteenth step)

[0352] This step is a step of removing the protecting group (tert-butoxycarbonyl) of NH of the compound (26) to obtain the compound of the formula (20). The reaction conditions are the same as those of the above-mentioned fifteenth step.

[0353] In one embodiment, the compound of the formula (IIIA-1) which is reacted in the sixth step can be obtained from the following compound (27) by the following nineteenth step to the twenty-first step.

[0354] [Chemical formula 63]

[0355] (Nineteenth step)

[0356] This step is a step of protecting NH of the compound (27) with triphenylmethyl to obtain the compound (28). The reaction conditions are not particularly limited as long as the reaction proceeds, and the reaction can be performed, for example, according to the method described in Preparation Example 245 of Patent Document 1.

[0357] (Twentieth step)

[0358] This step is a step of methylating the compound (28) to obtain the compound (29). The reaction conditions are not particularly limited as long as the reaction proceeds, and the reaction can be performed, for example, according to the method described in Preparation Example 246 of Patent Document 1.

[0359] (Twenty-first step)

[0360] This step is a step of substituting Br of the compound (29) with pinacol boronic acid ester to obtain the compound of the formula (IIIA-1). The reaction conditions are not particularly limited as long as the reaction proceeds, and the reaction can be performed, for example, according to the method described in Preparation Example 247 of Patent Document 1.

[0361] (Third-2 step to sixth-2 step)

[0362] In addition, in one embodiment, the present application is a method of producing the compound of the formula (I) or a salt thereof described in the above [1], wherein the step of reacting the compound of the formula (IIA) or a salt thereof with the compound of the formula (IIIA) or a salt thereof, The compound of the formula (I) is a compound represented by the following formula (I-2), [Chemical formula 64]

[0363] The compound of formula (IIA) is a compound represented by the following formula (IIA-3), [Chemical Formula 65]

[0364] The step of obtaining the compound represented by formula (I-2) includes the step of obtaining the compound represented by formula (I-2) by the following step.

[0365] [Chemical Formula 66]

[0366] In addition, in one embodiment, the compound of formula (IIIA) is a compound of the above formula (IIIA-1).

[0367] As described above, the sixth-2 step is a method of producing the compound of formula (I-2) by reacting the compound of formula (IIA-3) with the compound of formula (IIIA). The reaction conditions are not particularly limited as long as the reaction proceeds, and in one embodiment, are the same as the conditions described above for reacting the compound of formula (IIA) or a salt thereof with the compound of formula (IIIA) or a salt thereof. In addition, in one embodiment, the reaction conditions described in Example 35 described later can be used.

[0368] In one embodiment, the compound of formula (IIA-3) that is reacted in the sixth-2 step can be obtained from the following compound (5-2) by the following step.

[0369] [Chemical Formula 67]

[0370] (third-2 step)

[0371] This step is a step of obtaining the compound (7-2) from the compound (5-2). The reaction conditions are the same as those of the third step described above. In addition, in one embodiment, the reaction conditions described in Example 36 described later can be used.

[0372] (fourth-2 step)

[0373] This step is a step of obtaining the compound (8-2) from the compound (7-2). The reaction conditions are the same as those of the fourth step described above. In addition, in one embodiment, the reaction conditions described in Example 37 described later can be used.

[0374] (fifth-2 step)

[0375] This step is a step of obtaining compound (IIA-3) from compound (8-2). The reaction conditions are the same as those of the above-described fourth step. In addition, in one mode, the reaction conditions described in Example 38 described later can be used.

[0376] 4. Compounds

[0377] The present application is, in one mode, a method of producing a compound of formula (#1) or a salt thereof, [Chemical Formula 68]

[0378] [In the formula, R 11 is a C 1-6 alkyl group, a C 3-6 cycloalkyl group or a 4- to 6-membered saturated heterocyclic group optionally substituted, which contains 1 hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, R 12A and R 12B are the same or different from each other, and are H or a C 1-6 alkyl group optionally substituted, or R 12A and R 12B together with the carbon to which they bind form a C 3-6 cycloalkyl group optionally substituted or a 4- to 6-membered saturated heterocycle optionally substituted, which contains 1 hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, R 13 is H; a halogen; a C 1-3 alkyl group; -SO2CH3; a C 3-6 cycloalkyl group; a 4- to 6-membered saturated heterocyclic group optionally substituted, which contains 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; a 5-membered heteroaryl group optionally substituted, which contains 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; or a 6-membered heteroaryl group which contains 1 to 3 nitrogen atoms, W is a phenyl group optionally substituted or a 6-membered heteroaryl group optionally substituted, which contains 1 to 3 nitrogen atoms. wherein, including a step of obtaining the above-mentioned compound of formula (#1) or a salt thereof by reacting a compound of the following formula (#2) with a diazonium transfer reagent.

[0379] [Chemical Formula 69]

[0380] [In the formula, R 11 , R 12A , R 12B , R 13 and W are as defined above] In one embodiment, in the method of producing the above compound of formula (#1) or a salt thereof, R 11 is ethyl, isopropyl, tert-butyl or C 3-6 cycloalkyl, R 12A and R 12B are the same or different from each other, H or C 1-3 alkyl which can be substituted with a group selected from the group consisting of F, OH and N(CH3)2, 12A and R 12B together with the carbon to which they are bonded form a cyclopropyl group, R 13 is H, halogen or a group selected from the group consisting of [Chemical Formula 70]

[0381] R 13A , R 13B are the same or different from each other, H or C 1-3 alkyl which can be substituted with OH, W is phenyl.

[0382] Further, in one embodiment, in the method of producing the above compound of formula (#1) or a salt thereof, R 11 is isopropyl, R 12A is H, R 12B is C 1-3 alkyl which can be substituted with OH, R 13 is the following group, [Chemical Formula 71]

[0383] R 13A is C 1-3 alkyl, W is phenyl.

[0384] The kind of diazo transfer reagent is not limited as long as the above diazo transfer reaction proceeds, and for example, perfluoroalkylsulfonyl azide, imidazole-1-sulfonyl azide or a salt thereof can be used. The above perfluoroalkylsulfonyl azide is, in one embodiment, nonafluorobutanesulfonyl azide, heptafluoropropanesulfonyl azide, pentafluoroethanesulfonyl azide, trifluoromethanesulfonyl azide, in one embodiment, nonafluorobutanesulfonyl azide, and in one embodiment, 1,1,2,2,3,3,4,4,4-nonafluoro-1-butanesulfonyl azide which is one form of nonafluorobutanesulfonyl azide.

[0385] In one embodiment, a base reagent can be used in the above diazo transfer reaction. As the base reagent, inorganic bases such as potassium bicarbonate, potassium carbonate, and the like can be exemplified.

[0386] In one embodiment, in the above diazo transfer reaction, in order to make the reaction proceed, a suitable additive can be used. As the additive, metal salts such as copper salts such as CuSO4, zinc salts such as ZnSO4, and the like can be exemplified.

[0387] In one embodiment, in the above diazo transfer reaction, a polar solvent can be used. As the polar solvent, polar organic solvents such as water, acetonitrile, methanol or ethanol, DMSO, MTBE, and the like, and mixtures thereof can be exemplified.

[0388] In one embodiment, the above diazo transfer reaction can be carried out at 10°C to 25°C. In one embodiment, the above diazo transfer reaction can be carried out at 10°C to 20°C, for example, at 15°C.

[0389] In one embodiment, the above diazo transfer reaction can be carried out in the presence of a metal catalyst, or can be carried out in the absence of a metal catalyst.

[0390] 4. Abbreviations

[0391] In one embodiment, the present application is a compound represented by any one of the following or a salt thereof. They are compounds or salts thereof which can be obtained by the method of producing the above compound of formula (I) or a salt thereof, or which can be obtained in each of the above seventh step to tenth step.

[0392] [Chemical Formula 72-1]

[0393] [Chemical Formula 72-2]

[0394] [Chemical Formula 72-3]

[0395] In one embodiment, the present application is the compound (3a) or a salt thereof obtained in the above first c step.

[0396] [Chemical Formula 73]

[0397] Further, in one embodiment, the present application is the above compounds (7-2), (8-2), (IIA-3), and (I-2) or a salt thereof.

[0398] [Chemical Formula 74]

[0399] ​

[0400] In the present specification, the following abbreviations are sometimes used.

[0401] TFA: trifluoroacetic acid, DMF: N,N-dimethylformamide, THF: tetrahydrofuran, MeCN: acetonitrile, MeOH: methanol, EtOH: ethanol, iPrOH: isopropanol, tBuOH: tert-butanol, iPr2O: diisopropyl ether, DOX: 1,4-dioxane, DMSO: dimethyl sulfoxide, TEA: triethylamine, DIPEA: N,N-diisopropylethylamine, tBuOK: potassium tert-butoxide, tBuONa: sodium tert-butoxide, PdCl2(dppf)·CH2Cl2: [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane adduct, Pd / C: palladium on carbon, HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate, DABCO: 1,4-diazabicyclo[2.2.2]octane, SPhos: dicyclohexyl(2’,6’-dimethoxy-[1,1’-biphenyl]-2-yl)phosphine, RuPhos: dicyclohexyl(2’,6’-diisopropoxy-[1,1’-biphenyl]-2-yl)phosphine, SPhos Pd G2: chloro(2-dicyclohexylphosphino-2’,6’-dimethoxy-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II), RuPhos Pd G2: chloro(2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II), SPhos Pd G3: (2-dicyclohexylphosphino-2’,6’-dimethoxy-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) mesylate, RuPhos Pd G3: (2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) mesylate, DPPF: 1,1’-bis(diphenylphosphino)ferrocene), WSC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, Pd(PPh3)4: tetrakis(triphenylphosphine)palladium(0), DMAc: dimethylacetamide, NMP: N-methyl-2-pyridone, ADMP: 2-azido-1,3-dimethylimidazole hexafluorophosphate, DMAP: 4-dimethylaminopyridine, NMM: N-methylmorpholine, NBS: N-bromosuccinimide, MTBE: methyl tert-butyl ether.

[0402] In addition, in the following tables, the following abbreviations are sometimes used.

[0403] Ex: Example number, Syn: Example number manufactured by the same method (for example, Syn: 9 indicates manufactured by the same method as Example 9.), DATA: Physical and chemical data, ESI+: m / z value in mass spectrometry (ionization method ESI, [M+H] when not stated + ), ESI-: m / z value in mass spectrometry (ionization method ESI, [M-H] when not stated - ), NMR: δ value (ppm) of peak in 27°C in DMSO-d6 1 H-NMR (500MHz), NMR (100°C): δ value (ppm) of peak in 100°C in DMSO-d6 1 H-NMR (500MHz), s: singlet (spectrum), d: doublet (spectrum), dd: double doublet (spectrum), ddd: double of doublet (spectrum), t: triplet (spectrum), dt: double of triplet (spectrum), q: quartet (spectrum), m: multiplet (spectrum), br: broad (spectrum) (example: br s).

[0404] Example

[0405] Hereinafter, the present application is described in more detail by citing specific examples, but the present application is not limited to the following specific examples. Note that in this specification, in the case where not particularly stated, the concentration and the like are mass-based, and the numerical range includes the end points thereof.

[0406] Example 1

[0407] To a mixture of (1S,4S)-5-{7-bromo-8-fluoro-6-iodo-2-[(oxan-4- yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (54.8 g), (1S)-1-phenylethan-1-ol (12.4 g) and THF (400 mL) under nitrogen atmosphere, tBuOK (11.3 g) was added in portions keeping the internal temperature below 10°C under ice cooling, stirred for 30 minutes under ice cooling. The reaction was stopped by adding saturated aqueous ammonium chloride under ice cooling. Water and ethyl acetate were added, the organic and aqueous layers were separated, the aqueous layer was extracted twice with ethyl acetate, the combined organic layers were washed with saturated aqueous sodium chloride, dried over magnesium sulfate. Filtration and concentration under reduced pressure, the residue was suspended by adding hexane / iPr2O (1 / 1, 400 mL) before the solid was filtered off, dried under reduced pressure to give (1S,4S)-5-{7-bromo-6-iodo-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a solid (52.3 g).

[0408] Example 2

[0409] (1S,4S)-5-{7-bromo-6-iodo-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (52.3 g) was suspended in MeCN (1000 mL) under nitrogen atmosphere, cyclopropylboronic acid (10 g), PdCl2(dppf)·CH2Cl2(5.6 g), potassium phosphate tribasic (55 g) and water (200 mL) were added at room temperature, stirred overnight at 90°C. The reaction mixture was allowed to cool to room temperature naturally, concentrated under reduced pressure to about half of the volume, ethyl acetate was added and filtered through Celite (registered trademark). Water was added to the filtrate and extracted twice with ethyl acetate, the combined organic layers were washed with saturated aqueous sodium chloride. Amino-modified silica gel (25 g) and activated charcoal (25 g) were added to the organic layer and stirred for 1 hour at room temperature, filtered through Celite (registered trademark), the filtrate was concentrated under reduced pressure. iPrOH (250 mL) was added to the residue and powdered, after stirring for 3 hours at 90°C, gradually cooled to room temperature while stirring. The resulting powder was filtered off, dried under reduced pressure to give (1S,4S)-5-{7-bromo-6-cyclopropyl-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a solid (32.3 g).

[0410] Example 3

[0411] (1S,4S)-5-{7-bromo-6-cyclopropyl-2-[(oxan-4-yl)oxy]-8-[(1S)-1- phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1 g), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- (triphenylmethyl)-2H-indazole (1 g) were dissolved in DOX (20 mL), water (4 mL), palladium (II) acetate (35 mg), anhydrous barium hydroxide (775 mg) and SPhos (125 mg) were added. After stirring overnight at 50°C under argon atmosphere, 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- (triphenylmethyl)-2H-indazole (200 mg) was added at the temperature, further stirred for 4 hours. The reaction mixture was allowed to cool naturally, ethyl acetate and Celite (registered trademark) were added and stirred at room temperature for 30 minutes, then filtered, the filtrate was washed with saturated aqueous sodium chloride solution. Amino-modified silica gel was added to the organic layer and stirred at room temperature for 30 minutes, then filtered, concentrated. To the obtained residue, MeOH (40 mL) was added to dissolve, stirred at 50°C for 1 hour, stirred at room temperature for 2 hours. The produced solid was filtered, MeOH washed, dried under reduced pressure, to obtain (1S,4S)-5-{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-2- (triphenylmethyl)-2H-indazol-4-yl]-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (913 mg) as a solid.

[0412] Example 3-1

[0413] (1S,4S)-5-{7-bromo-6-cyclopropyl-2-[(oxan-4-yl)oxy]-8-[(1S)-1- phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (300 mg), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- (triphenylmethyl)-2H-indazole (300 mg), RuPhos Pd G3 (38 mg), RuPhos (21 mg), potassium phosphate tribasic (475 mg), DOX (5 mL) and water (1 mL) were mixed and stirred under argon atmosphere at 90°C for 2 hours. The reaction mixture was allowed to cool naturally, water and ethyl acetate were added and filtered through Celite (registered trademark), washing with ethyl acetate. The filtrate was partitioned, the aqueous layer was extracted with ethyl acetate, the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (amino modified silica gel, hexane / ethyl acetate) to give (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]- 2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylic acid tert-butyl ester (367 mg) as a foamy solid.

[0414] Example 3-2

[0415] (1S,4S)-5-{7-bromo-6-cyclopropyl-2-[(oxan-4-yl)oxy]-8-[(1S)-1- phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (200 mg), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- (triphenylmethyl)-2H-indazole (200 mg), RuPhos Pd G3 (25 mg), RuPhos (14 mg), barium hydroxide octahydrate (285 mg), DOX (3 mL), and water (0.6 mL) were mixed and stirred under an argon atmosphere at 90°C for 2 hours. The reaction mixture was allowed to cool naturally and filtered through Celite® while washing with ethyl acetate. Water was added to the filtrate and extracted twice with ethyl acetate, the combined organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (amino-modified silica gel, hexane / ethyl acetate) to give (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (291 mg) as a foamy solid.

[0416] Example 3-3

[0417] (1S,4S)-5-{7-bromo-6-cyclopropyl-2-[(oxan-4-yl)oxy]-8-[(1S)-1- phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (200 mg), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- (triphenylmethyl)-2H-indazole (200 mg), palladium(II)acetate (7 mg), RuPhos (28 mg), barium hydroxide octahydrate (285 mg), DOX (3 mL), and water (0.6 mL) were mixed and stirred under argon atmosphere at 50°C for 13 hours. The reaction mixture was allowed to cool naturally, ethyl acetate and Celite® were added and after stirring at room temperature for 30 minutes, Celite® filtration was performed, and the filtrate was concentrated. The residue was purified with silica gel column chromatography (amino-modified silica gel, hexane / ethyl acetate) to give (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (268 mg) as a foamy solid.

[0418] Example 3-4

[0419] A mixture of (1S,4S)-5-{7-bromo-6-cyclopropyl-2-[(oxan-4-yl)oxy]-8-[(1S)-1- phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (200 mg), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- (triphenylmethyl)-2H-indazole (200 mg), palladium (II) acetate (7 mg), SPhos (25 mg), anhydrous barium hydroxide (155 mg), DOX (3 mL) and water (0.6 mL) was mixed at room temperature, stirred under argon atmosphere at 50°C for 14 hours. The reaction mixture was allowed to cool naturally, ethyl acetate and Celite® were added and after stirring at room temperature for 30 minutes, Celite® filtration was performed, the filtrate was concentrated. The residue was purified by silica gel column chromatography (amino modified silica gel, hexane / ethyl acetate) to give (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (281 mg) as a foamy solid.

[0420] Example 4

[0421] A mixture of (1S,4S)-5-{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)- 2H-indazol-4-yl]-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5- diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (4.96 g), 10% Pd / C (ca. 50% water, 1 g), sodium bicarbonate (2 g), ethyl acetate (80 mL) and MeOH (20 mL) was stirred under hydrogen atmosphere at room temperature and atmospheric pressure overnight. After replacement with argon, the reaction was filtered through Celite®, the filtrate was concentrated under reduced pressure, thus giving (1S,4S)-5-{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-hydroxy-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (4.46 g) as a foamy solid.

[0422] Example 5

[0423] (1S,4S)-5-{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-hydroxy-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (34 g) and cesium carbonate (38 g) were suspended in DMF (200 mL) under nitrogen atmosphere, and 4-ethynylphenyl methanesulfonate (8.2 g) was added at room temperature, and stirred at room temperature for 2 hours. The reaction mixture was added to ice water (about 1000 mL), and stirred at room temperature for 30 minutes. The resulting solid was filtered, and dried under reduced pressure to obtain (1S,4S)-5-{(7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (35.5 g) as a solid.

[0424] Example 6

[0425] To a solution of (1S,4S)-5-{(7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (408 mg) in MeOH (8 mL) was added 4-methylbenzene-1-sulfonic acid monohydrate (145 mg) at room temperature, and stirred at room temperature for 1 hour. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate twice. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. To the resulting solid was added ethyl acetate (3 mL) / hexane (3 mL) to dissolve, and then hexane (3 mL) was added, and stirred at 90°C for 30 minutes, and at room temperature for 1 hour. The resulting solid was filtered, and dried under reduced pressure to obtain (1S,4S)-5-{(7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (408 mg) as a solid.

[0426] Example 7

[0427] To a solution of (4-ethynylphenyl)methanol (10 g) in CH2Cl2(100 mL) under ice cooling, DIPEA (33 mL) and methanesulfonic anhydride (15.3 g) were added little by little, and stirred for 1 hour under ice cooling. Methanesulfonic anhydride (3 g) was further added under ice cooling, and stirred for 30 minutes. Water and ethyl acetate / hexane (1 / 1) were added under ice cooling, and extracted twice with ethyl acetate / hexane (1 / 1). The combined organic layer was washed with saturated aqueous ammonium chloride, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated to give methanesulfonic acid (4-ethynylphenyl)methyl ester (16.0 g) as a solid.

[0428] Example 8

[0429] To a mixture of N-(tert-butoxycarbonyl)-L-valine (30.8 g), (4R)-4-hydroxy-L-proline benzyl ester hydrochloride (35 g), THF (200 mL), DMF (200 mL) and DIPEA (70 mL) under ice cooling, HATU (53.9 g) was added little by little (the internal temperature was maintained below 10°C). It was stirred for 15 minutes under ice cooling, and for 45 minutes at room temperature. Saturated aqueous sodium chloride (900 mL) was added at room temperature, and extracted twice with ethyl acetate. The combined organic layer was washed successively with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The insolubles were filtered off, and concentrated under reduced pressure to give N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-L-proline benzyl ester (107 g, containing impurities) as an oil.

[0430] Example 9

[0431] To a solution of N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-L-proline benzyl ester (107 g, containing impurities) obtained in Example 8 in MeOH (400 mL) under nitrogen atmosphere, 10% Pd / C (about 50% water content, 2.9 g) was added at room temperature. It was replaced with hydrogen gas atmosphere, and stirred overnight at room temperature. Celite (registered trademark) was added to the reaction solution, and stirred, and filtered while washing with MeOH. To the obtained residue, ethyl acetate (200 mL) was added, and stirred overnight at room temperature. The solid was filtered off to give N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-L-proline (32.7 g) as a solid.

[0432] Example 10

[0433] To a mixture of N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-L-proline (13.7 g), (2R)-2-amino-2-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethan-1-ol dihydrochloride (13.3 g), DMF (110 mL), and THF (110 mL) was added DIPEA (28 mL) and stirred. To the mixture was added HATU (16.5 g) little by little under ice-cooling (ice / saturated sodium chloride aqueous solution) (the internal temperature was maintained at 0°C or lower). After stirring for 30 minutes under ice-cooling, a half-saturated sodium chloride aqueous solution (400 mL) and ethyl acetate (200 mL) were added and stirred, and the water layer and the organic layer were separated. The water layer was extracted twice with ethyl acetate, and the combined organic layer was washed successively with a saturated sodium hydrogen carbonate aqueous solution, a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. The insolubles were filtered off, and concentrated under reduced pressure to give N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (32.6 g, containing impurities) as a foamy solid. To a solution of the obtained solid in ethyl acetate (100 mL) / MeOH (100 mL) was added 4M hydrogen chloride (ethyl acetate solution, 100 mL) little by little under ice-cooling, and stirred at room temperature overnight. The resulting solid was filtered off, and ethyl acetate (50 mL) / MeOH (100 mL) was added, and stirred at room temperature for 2 hours. The solid was filtered off to give L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide dihydrochloride (19.0 g) as a solid.

[0434] L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide dihydrochloride obtained in Example 10 was reacted with a diazo transfer reagent under the reaction conditions described in International Publication No. 2022 / 173032 to give (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

[0435] Example 10-2

[0436] A mixture of 1,1,2,2,3,3,4,4,4-nonafluoro-1-butanesulfonyl chloride (2.42 g), methyl-tert-butyl ether (19 mL), water (19 mL), MeCN (1 mL), sodium azide (0.61 g), sodium bicarbonate (0.24 g), tetrabutylammonium chloride (0.31 g) was stirred at 5°C for 20 hours, and then partitioned with 25% aqueous sodium chloride solution to give 1,1,2,2,3,3,4,4,4-nonafluoro-1-butanesulfonyl azide. The obtained organic layer was added to a mixture of L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide dihydrochloride (2.00 g) and potassium bicarbonate (1.93 g), DMSO (20 mL), water (4 mL), and stirred at 15°C for 16 hours. To the reaction solution was added 25% aqueous sodium chloride solution and ethyl acetate, and partitioned. To the obtained organic layer was added silica gel and sodium sulfate, and stirred at room temperature for 30 minutes. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure, and then crystallized from methanol and methyl-tert-butyl ether to give (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide as a solid (1.15 g).

[0437] Example 11

[0438] To a solution of (1S,4S)-5-{(7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (310 mg), (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (200 mg) in tBuOH (0.4 mL) / THF (0.5 mL) / water (0.4 mL) was added sodium ascorbate (80 mg) and copper (I) iodide (20 mg) at room temperature under nitrogen atmosphere, stirred for 4 hours. Copper (I) iodide (20 mg) was added at room temperature, further stirred for 15 hours. To the mixture, disodium ethylenediaminetetraacetate (750 mg) in water (20 mL) was added, diluted with ethyl acetate (20 mL) and stirred at room temperature for 1 hour. Extracted with ethyl acetate twice, the combined organic layer was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (amino modified silica gel, CHCl3 / MeOH) to give (1S,4S)-5-{(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (452 mg) as a solid.

[0439] Example 12

[0440] To a solution of (1S,4S)-5-{(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (200 mg) in MeOH (1 mL) under a nitrogen atmosphere, methanesulfonic acid (100 μL) was added at room temperature and stirred at 50°C for 4 hours. Concentration under reduced pressure, the residue was purified by reverse phase chromatography (ODS column, 0.1% aqueous formic acid / 0.1% formic acid in MeCN). Fractions containing the desired product were collected, 5% aqueous sodium bicarbonate solution was added and extracted twice with CHCl3 / MeOH (9 / 1). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure to give (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (139 mg) as a solid.

[0441] Example 14

[0442] Under an argon atmosphere, 6-chloro-7-fluoro-1H-indazole-2,3-dione (250.8 g), MeCN (1.25 L) were mixed at room temperature and stirred, methanesulfonic acid (24.2 g) and 1,3-dibromo-5,5-dimethylhydantoin (359.3 g) were added and stirred at room temperature for 10 minutes. After stirring at 55°C for 20 hours, cooled to below 10°C, a solution of sodium ascorbate (497.9 g) in water (2.5 L) was added. After stirring at below 10°C for 1 hour, water (2.5 L) was added at room temperature and stirred for 1 hour, the precipitate was filtered, washed with water and dried under reduced pressure at 60°C to give 5-bromo-6-chloro-7-fluoro-1H-indazole-2,3-dione (320.4 g) as a solid.

[0443] Example 15

[0444] Under an argon atmosphere, 320 g of 5-bromo-6-chloro-7-fluoro-1H-indole-2,3-dione, 2.24 L of EtOH, and 141 g of sodium acetate were mixed at room temperature and stirred for 10 minutes. Hydroxylamine hydrochloride (87.8 g) was then added, and the mixture was stirred at 50 °C for 2 hours. After adding 4.16 L of water at 50 °C, the mixture was cooled to room temperature, stirred for 30 minutes, and the solid was collected by filtration. The filtrate was washed successively with EtOH / water (1 / 2) and water, and dried under reduced pressure at 60 °C to obtain 314 g of 5-bromo-6-chloro-7-fluoro-3-(hydroxyimino)-1,3-dihydro-2H-indole-2-one as a solid.

[0445] Example 16

[0446] Under a nitrogen atmosphere, 1 g of 5-bromo-6-chloro-7-fluoro-3-(hydroxyimino)-1,3-dihydro-2H-indol-2-one, 10 mL of toluene, 192 mg of triphenylphosphine oxide, and 0.12 mL of DIPEA were mixed and stirred at room temperature. Thionyl chloride (1.24 mL) was added dropwise at an internal temperature not exceeding 50 °C, followed by heating to 65-75 °C and stirring for 17 hours. Thionyl chloride (1.24 mL) was then added at this temperature, and the mixture was stirred for 6 days at an internal temperature of 95-105 °C. The reaction mixture was cooled to room temperature and added dropwise (at an internal temperature not exceeding 30 °C) dropwise to an ice-cold solution of 11.9 g of dipotassium hydrogen phosphate in 10 mL of water. The resulting mixture was filtered while being washed with toluene. The filtrate was separated, and the organic layer was washed with an aqueous sodium bicarbonate solution to obtain a toluene solution of 6-bromo-2,4,7-trichloro-8-fluoroquinazoline. To this toluene solution, DIPEA (875 μL) and (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.71 g) were added at room temperature, and the mixture was stirred for 2.5 hours. After adding water, the mixture was separated, and the organic layer was washed with water and concentrated under reduced pressure. EtOH was added to the residue, and the mixture was concentrated again under reduced pressure. After azeotropic treatment of the toluene, EtOH (4 mL) was added to the residue to dissolve it. After stirring at 50°C, the mixture was cooled to room temperature, and the precipitated solid was filtered off. The solid was then dried at 60°C under reduced pressure to obtain (1S,4S)-5-(6-bromo-2,7-dichloro-8-fluoroquinazoline-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.27 g) in solid form.

[0447] Example 17

[0448] (1S,4S)-5-(6-bromo-2,7-dichloro-8-fluoroquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylic acid tert-butyl ester (5 g) and tetrahydro-2H-pyran-4-ol (1.24 g) were dissolved in DMF (15 mL) at room temperature, cesium carbonate (9.93 g) was added and stirred. To this, DABCO (228 mg) was added at room temperature and stirred for 20 minutes, then stirred at 55°C for 1.5 hours. After cooling to room temperature, toluene and water were added to separate the layers, and the organic layer was washed with water twice. The organic layer was concentrated, to the residue, EtOH (50 mL) and water (10 mL) were added, the precipitate was filtered, washed with EtOH / water (1 / 1), and dried under reduced pressure at 60°C to obtain (1S,4S)-5-{6-bromo-7-chloro-8-fluoro-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5- diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a solid (4.13 g).

[0449] Example 18

[0450] tBuONa (620 mg) was dissolved in DMF (5 mL) under nitrogen atmosphere and stirred, a solution of (1S)-1-phenylethan-1-ol (821 mg) and (1S,4S)-5-{6-bromo-7-chloro-8-fluoro-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (3 g) in DMF (10 mL) was added at room temperature and stirred for 2 hours. Toluene (15 mL) was added, after 10 minutes, (1S)-1-phenylethan-1-ol (82.1 mg) and tBuONa (62 mg) were added and stirred for 45 minutes, then tBuONa (103 mg) was added. After stirring at room temperature for 45 minutes, toluene and water were added to separate the layers. The organic layer was washed with water twice, dried with sodium sulfate, the insoluble matter was filtered, concentrated under reduced pressure. To the residue, EtOH was added and stirred, the precipitated solid was filtered, washed with EtOH, dried under reduced pressure at 50°C to obtain (1S,4S)-5-{6-bromo-7-chloro-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a solid (3.07 g).

[0451] Example 19

[0452] A mixture of (1S,4S)-5-{6-bromo-7-chloro-2-[(oxan-4-yl)oxy]-8-[(1S)-1- phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1 g), toluene (7 mL), water (2 mL), potassium phosphate tribasic (964 mg), cyclopropylboronic acid (221 mg) was degassed at room temperature under reduced pressure. After addition of PdCl2(dppf)CH2Cl2(55.4 mg) and degassing under reduced pressure, it was stirred at 80°C for 16 hours. After cooling to room temperature, activated carbon was added to the reaction liquid and stirred at room temperature for 30 minutes. The insolubles were filtered off while washing with toluene and water, and the filtrate was partitioned. The resulting organic layer was dried with sodium sulfate, filtered, concentrated under reduced pressure, and (1S,4S)-5-{7-chloro-6-cyclopropyl-2-[(oxan-4-yl)oxy]-8-[(1S)-1- phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.95 g) was obtained as a solid.

[0453] Example 20

[0454] A mixture of 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- (triphenylmethyl)-2H-indazole (100 mg), (1S,4S)-5-{7-chloro-6-cyclopropyl-2-[(oxan-4- yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2- carboxylic acid tert-butyl ester (100 mg), barium hydroxide octahydrate (152 mg), RuPhos (4 mg), 2-methyl-2-butanol (0.8 mL), and water (0.2 mL) was mixed and degassed under reduced pressure. After adding RuPhos Pd G3 (7 mg) thereto and degassing under reduced pressure, it was stirred at 65°C for 1.5 hours. After cooling to room temperature, water (0.6 mL), activated carbon (10 mg) were added, and stirred for 30 minutes.

[0455] The filtrate was separated while washing the insoluble with toluene. The obtained organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure to obtain a solid. To the obtained solid was added MeOH / water (4 / 1), and the precipitated solid was filtered and washed with MeOH / water (4 / 1) (ratio of isomers derived from the axial chirality M:P = 4.5:1). The obtained solid was suspended in MeOH, filtered while washing with MeOH, and the obtained solid was again suspended in MeOH, filtered while washing with MeOH, and dried under reduced pressure to obtain (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a solid (53.9 mg, ratio of isomers derived from the axial chirality M:P = 58:1).

[0456] Example 21

[0457] (3S)-3-[{7-bromo-6-cyclopropyl-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-(naphthalen-1- yl)ethoxy]quinazolin-4-yl}(methyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (1.40 g), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (1.50 g), SPhos (85 mg), SPhos Pd G3 (155 mg), tripotassium phosphate (1.70 g), DOX (30 mL), and water (6 mL) were mixed, stirred at 80°C for 3 hours under an argon atmosphere after several degassing-argon replacement. To the reaction suspension after natural cooling was added ethyl acetate, filtered with Celite (registered trademark) while washing with ethyl acetate, and the filtrate was washed with water and saturated aqueous sodium chloride solution. The organic layer was dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (hexane / ethyl acetate) to obtain (3S)-3-[{6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-(naphthalen-1-yl)ethoxy]quinazolin-4-yl}(methyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester as a foamy solid (1.47 g).

[0458] Example 22

[0459] Under an argon atmosphere, to a solution of 7-bromo-4-tert-butoxy-6-cyclopropyl-2- (ethylthio)-8-[(lS)-l-(naphthalen-l-yl)ethoxy]quinazoline (1.5 g) in DOX (30 mL), water (6 mL) was added 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- (triphenylmethyl)-2H-indazole (1.17 g), SPhos (81 mg), SPhos Pd G3 (153 mg) and potassium phosphate tribasic (1.66 g) at room temperature and stirred at 80°C for 3 hours under an argon atmosphere. After natural cooling to room temperature, water and ethyl acetate were added to the reaction solution and partitioned, and the organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 4-tert-butoxy-6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-2- (triphenylmethyl)-2H-indazol-4-yl]-8-[(lS)-l-(naphthalen-l-yl)ethoxy]quinazoline (1.00 g) as a foamy solid.

[0460] Example 23

[0461] Under an argon atmosphere, (3S)-3-[{6-cyclopropyl-7-(5,5-dimethyl-1,3,2- dioxaborinan-2-yl)-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-(naphthalen-1- yl)ethoxy]quinazolin-4-yl}(methyl)amino]pyrrolidine-1-carboxylate (1.00 g, about 83% purity), 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (630 mg), SPhos (90.0 mg), barium hydroxide octahydrate (1.06 g), 2-methyl-2-butanol (4.15 mL), water (4.15 mL) were degassed under reduced pressure. To the reaction solution was added SPhos Pd G3 (170 mg), and degassed again under reduced pressure, followed by stirring at 60°C for 3 hours. After cooling to room temperature, activated carbon (80 mg) was added and stirred for 68 hours. The insolubles were filtered using Celite (registered trademark), and washed with toluene (33 mL), water (17 mL). The filtrate was partitioned, and the organic layer was washed with water (4.1 mL) twice, and concentrated under reduced pressure. To the residue (ratio of atropisomeric isomers M:P = 8.2:1) was added toluene (4 mL), heptane (6 mL), further added amino-modified silica gel (3.3 g), neutral silica gel (1.6 g), heptane (40 mL), and stirred for 2 hours and 40 minutes. The mixture was filtered, washed with heptane, ethyl acetate, and the filtrate was concentrated. After adding MeOH to the residue and stirring, it was concentrated, and half of the residue was purified twice by silica gel column chromatography (hexane / ethyl acetate), and purified by silica gel column chromatography (amino-modified silica gel, hexane / ethyl acetate) to obtain (3S)-3-[{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-(naphthalen-1-yl)ethoxy]quinazolin-4-yl}(methyl)amino]pyrrolidine-1-carboxylate (105 mg) as a foamy solid.

[0462] The starting material used in Example 23 was prepared by the following method.

[0463] Under an argon atmosphere, (3S)-3-[{7-chloro-6-cyclopropyl-2-[(2S)-2- methoxypropoxy]-8-[(1S)-1-(naphthalen-1-yl)ethoxy]quinazolin-4-yl}(methyl)amino] pyrrolidine-1-carboxylic acid tert-butyl ester (2.21 g), 5,5,5',5'-tetramethyl-2,2'-bi-1,3,2-dioxaborolane (1.51 g), potassium propionate (1.12 g), 2-(2,6-dimethoxyphenyl)-3-(diphenylphosphino)-1-methyl-1H-indole (0.15 g) and toluene (17.7 mL) were mixed at room temperature and degassed under reduced pressure. Di-μ-chlorobis(2'-amino-1,1'-biphenyl-2-yl-C,N)palladium(II) (0.05 g) was added to the reaction solution, degassed under reduced pressure and stirred at 70°C for 24 hours. The reaction solution was cooled to room temperature, the insoluble matter was filtered through Celite (registered trademark), washed with toluene and the filtrate was concentrated under reduced pressure. After adding MeOH to the residue and co-evaporating 3 times, MeOH (6 mL) was added to dissolve it, which was added dropwise to water (80 mL) while rinsing with MeOH (2 mL). The precipitated solid was filtered and dried under reduced pressure to obtain (3S)-3-[{6-cyclopropyl-7-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-(naphthalen-1-yl)ethoxy]quinazolin-4-yl}(methyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (2.99 g, about 83% purity) as a solid.

[0464] Example 34

[0465] At room temperature, 4-tert-butoxy-7-chloro-6-cyclopropyl-2-[(2S)-2-methoxypropoxy]-8- [(1S)-1-(naphthalen-1-yl)ethoxy]quinazoline (0.7 g), DOX (5.6 mL), water (1.4 mL), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H- indazole (814 mg), barium hydroxide octahydrate (1.24 g), and SPhos (53.7 mg) were mixed and degassed under reduced pressure. Then SPhos Pd G3 (102 mg) was added and degassed under reduced pressure, and stirred at 65°C for 6 hours. After cooling to room temperature, activated carbon (70 mg) was added and stirred for 10 minutes, and then filtered and washed with toluene. The filtrate was partitioned, and the organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. To the residue was added iPrOH (14 mL) to dissolve it, and water (4.9 mL) was added little by little. The resulting solid was filtered off, washed with iPrOH / water (3 / 1), and dried under reduced pressure to obtain 4-tert-butoxy-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-(naphthalen-1-yl)ethoxy]quinazoline (0.74 g) as a solid.

[0466] Example 35

[0467] At room temperature, 4-{7-bromo-4-tert-butoxy-6-cyclopropyl-8-[(1S)-1-phenylethoxy]quinazolin-2-yl}piperazine-1-carboxylic acid 2-(trimethylsilyl)ethyl ester (200 mg), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (220 mg), SPhos Pd G3 (47 mg), SPhos (25 mg), barium hydroxide anhydrous (73 mg), toluene (6 mL), and water (6 mL) were mixed, and after performing degassing-argon replacement several times, stirred at 60°C for 3 hours under an argon atmosphere. The reaction mixture was allowed to cool naturally, ethyl acetate was added, and Celite (registered trademark) filtration was performed, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 4-{4-tert-butoxy-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazolin-2-yl}piperazine-1-carboxylic acid 2-(trimethylsilyl)ethyl ester (237 mg) as a foamy solid.

[0468] Example 36

[0469] To a mixture of 7-bromo-4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (21.0 g), molecular sieves 4A (21.0 g), DIPEA (10.35 mL) and THF (210 mL) was added piperazine-1-carboxylic acid 2-(trimethylsilyl)ethyl ester (8.9 g) and stirred at 40 °C for 12 h. To the mixture was added water (400 mL) and extracted with ethyl acetate 3 times. The combined organic layers were washed with saturated aqueous sodium chloride solution 2 times, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. To the resulting residue was added MeOH (100 mL) to powder, filtered, dried under reduced pressure to give 4-(7-bromo-4-tert-butoxy-8-fluoro-6-iodoquinazolin-2-yl)piperazine-1-carboxylic acid 2-(trimethylsilyl)ethyl ester (12.2 g) as a solid.

[0470] Example 37

[0471] To a mixture of 4-(7-bromo-4-tert-butoxy-8-fluoro-6-iodoquinazolin-2-yl)piperazine-1-carboxylic acid 2-(trimethylsilyl)ethyl ester (2.00 g), (1S)-1-phenylethan-1-ol (0.42 g) and THF (20 mL) was added tBuOK (0.72 g) while stirring at room temperature under argon atmosphere, and stirred at room temperature for 40 min. To the reaction mixture was added ice and saturated aqueous ammonium chloride solution, and extracted with ethyl acetate 2 times. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate. Filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (amino modified silica gel, hexane / ethyl acetate) to give 4-{7-bromo-4-tert-butoxy-6-iodo-8-[(1S)-1-phenylethoxy]quinazolin-2-yl}piperazine-1-carboxylic acid 2-(trimethylsilyl)ethyl ester (2.13 g) as a foamy solid.

[0472] Example 38

[0473] A mixture of 4-{7-bromo-4-tert-butoxy-6-iodo-8-[(lS)-l-phenylethoxy]quinazolin-2- yl}piperazine-l-carboxylic acid 2-(trimethylsilyl)ethyl ester (2.02 g), cyclopropylboronic acid (400 mg), potassium phosphate tribasic (2.00 g), PdCl2(dppf)-CH2Cl2(230 mg), MeCN (50 mL), and water (10 mL) was mixed at room temperature, stirred under an argon atmosphere at 90°C for 6 hours. The reaction mixture was allowed to cool naturally, ethyl acetate was added and filtered through Celite (registered trademark). Water was added to the filtrate, the two layers were separated, and the organic layer was dried over anhydrous magnesium sulfate. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 4-{7-bromo-4-tert-butoxy-6-cyclopropyl-8-[(lS)-l-phenylethoxy]quinazolin-2-yl}piperazine-l-carboxylic acid 2-(trimethylsilyl)ethyl ester (1.41 g) as a foamy solid.

[0474]

[0475] Industrial applicability

[0476] According to the method of the present application, by using a chiral auxiliary group to control the axial chirality in the production of the compound of the formula (I) or its salt having axial chirality, an axial chirality compound or its salt can be selectively obtained. If the method of the present application is used, the yield can be increased compared to the conventional method, and the fractionation step can be reduced, and thus it is very useful.

Claims

1. A method for producing a compound of formula (I) or a salt thereof, In the formula, A is N or CH. Y represents a bond, -CH2-, -O-, -S-, or -NR. Y -, R Y H or C that can be substituted 1-3 alkyl, R 1 For example, (IV) or (V) below. Ring A is a substituted 7- to 9-membered bridged heterocyclic alkane containing 1 to 2 nitrogen atoms, or a substituted 4- to 6-membered heterocyclic alkane containing 1 to 2 nitrogen atoms. Z represents a bond, -CH2-, -O-, -S-, or -N(R). Z1 )-, R Z1 H or C that can be substituted 1-3 alkyl, PG 1 It is a protecting group for NH contained in ring A. PG 2 It is a protecting group for OH. R 2 C can be replaced 1-15 Alkyl or substituted heterocyclic alkyl groups, R 3 Halogen, C 3-6 cycloalkyl, vinyl, or substituted C 1-3 alkyl, R 4 For example, (VI) or (VII) below. R 4A C 1-3 alkyl, R 4B It can be naphthyl, phenanthrene, or a substituted phenyl group. R 5 For example, (VIII) or (IX) below. PG 3 It is a protecting group for NH. R 5A It can be H, methyl, F or Cl. R 5B It is Cl, methyl, ethyl or vinyl, Indicates the chiral axis, in, The method includes the following steps: reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof, or reacting a compound of formula (IIB) or a salt thereof with a compound of formula (IIIB) or a salt thereof, to obtain a compound of formula (I) or a salt thereof. In the formula, A, Y, R Y R 1 Rings A, Z, R Z1 PG 1 PG 2 R 2 R 3 R 4 R 4A R 4B R 5 PG 3 R 5A R 5B and As stipulated above, X is Cl, Br, I, methanesulfonyloxy, or p-toluenesulfonyloxy. BLG can be borate, borate ester, trifluoroborate, or triol borate. Here, one of the axially chiral compounds of formula (I) or salts thereof, having axial chirality, is selectively produced.

2. The method according to claim 1, wherein, This includes reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof. Here, X is Cl or Br. Y is either -O- or -S-. R 1 The groups selected are those from the group consisting of the following formulas (IV-1), (IV-2), (IV-3), and (V). R 2 It is a tetrahydropyranyl group or a C group that can be substituted with -OCH3. 1-3 alkyl, R 3 It is cyclopropyl. R 4 The groups selected are those from the group consisting of the following formulas (VI-1), (VI-2), and (VI-3). R 5 The groups selected are those from the group consisting of the following formulas (VIII-1) and (IX-1). 。 3. The method according to claim 2, wherein, This includes reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof. Here, A is N, R 1 The groups selected are those from the group consisting of the following formulas (IV-1), (IV-2), and (V). R 5 The group is represented by the following formula (VIII-1). 。 4. The method according to claim 3, wherein, The compounds of formula (IIA) or their salts are compounds represented by formula (IIA-1) below. The compounds of formula (IIIA) or their salts are compounds represented by formula (IIIA-1) below. The method includes the step of obtaining the compound represented by formula (I-1) through the following steps. 。 5. The method according to claim 4, wherein, This includes obtaining compound (1) or its salt through the following steps. 。 6. The method according to claim 5, wherein, Compound (14) is obtained by the following steps from the following compounds (16) and (17) described below. 。 7. The method according to claim 5, wherein, This includes compounds of formula (IIA-1) obtained from the following compound (2) through the following steps. 。 8. The method according to claim 6, wherein, Compound (20) is obtained by the following steps from the following compounds (24) and (25), 。 9. The method according to any one of claims 4 to 8, wherein, This includes compounds of formula (IIIA-1) obtained from the following compounds (27) through the following steps. 。 10. The method according to claim 3, wherein, The compounds of formula (IIA) or their salts are compounds represented by formula (IIA-2) below. The compounds of formula (IIIA) or their salts are compounds represented by formula (IIIA-1) below. The method includes the step of obtaining the compound represented by formula (I-1) through the following steps. 。 11. The method according to claim 10, wherein, This includes obtaining compound (1) or its salt through the following steps. 。 12. The method according to claim 10 or 11, wherein, This includes compounds of formula (IIA-2) obtained through the following steps. 。 13. Any of the following compounds or their salts, 。

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