Process for producing a benzoxazole derivative having a bicyclic piperazine ring or a salt thereof and process for producing a raw material thereof

Abstract

The present application provides a method for producing a compound represented by formula (1) or a salt thereof, comprising: a step B of producing a compound represented by formula (3) or a salt thereof using a compound represented by formula (2) or a salt thereof, and a step C of producing a compound represented by formula (1) or a salt thereof using the aforementioned compound represented by formula (3) or a salt thereof, [in formula (2), R a represents a hydrogen atom or an arylmethyl group which can be substituted, R b represents an alkyl group which can be substituted or a cyclic alkyl group, R 3 represents a hydrogen atom, a halogen atom or a thiazol-2-yl group, X a represents a hydrogen atom or a halogen atom] [in formula (3), Boc represents a tert-butyloxy carbonyl group].

Description

Technical Field

[0001] This invention relates to a method for manufacturing benzo[d]oxazole derivatives or salts thereof having a bicyclic piperazine ring, and a method for manufacturing the raw materials thereof. More specifically, it relates to a method for manufacturing 1-{[2-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-7-(thiazol-2-yl)benzo[d]oxazol-4-yl]oxy}-1,1-difluoro-2-methylpropane-2-ol or salts thereof, and a method for manufacturing 2-alkoxybenzo[d]oxazole derivatives or salts thereof of the raw materials thereof. Background Technology

[0002] 1-{[2-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-7-(thiazol-2-yl)benzo[d]oxazol-4-yl]oxy}-1,1-difluoro-2-methylpropane-2-ol (represented by formula (1) below) is a compound with excellent phosphodiesterase type 4 (PDE4) selective inhibition activity (Patent Document 1).

[0003] 1-{[2-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-7-(thiazol-2-yl)benzo[d]oxazol-4-yl]oxy}-1,1-difluoro-2-methylpropane-2-ol and its salts are well known, for example, from 4-(benzyloxy)-7-bromobenzo[d]oxazol-2-thiol through iminolation, cross-coupling and deprotection (de-O-benzylation) to produce the intermediate product: 3-(4-hydroxy-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (represented by formula (3) below), and then through functional group transformation and deprotection reaction (Patent Document 1).

[0004] Furthermore, the 4-(benzyloxy)-7-bromobenzo[d]oxazol-2-thiol used in the above manufacturing method is well known to be manufactured, for example, from 2-nitroresorcinol through a five-stage process involving di-O-benzyl etherification (formation of a protecting group), partial deprotection (partial de-O-benzylation), bromination, reduction, and cyclization with the removal of the detached group (thiol group) (Patent Document 1).

[0005] Existing technical documents

[0006] Patent documents

[0007] Patent Document 1: International Publication No. 2018 / 124060 Summary of the Invention

[0008] The problem to be solved by the present invention

[0009] In the conventional method for manufacturing 4-(benzyloxy)-7-bromobenzo[d]oxazol-2-thiol, there are several drawbacks in the manufacturing process of 4-(benzyloxy)-7-bromobenzo[d]oxazol-2-thiol and the aforementioned intermediates using it. These drawbacks include: (i) the use of benzyl bromide, which is lachrymatory and toxic, in forming the protecting group; (ii) the use of boron trichloride, which is highly toxic, in forming the aforementioned protecting group; (iii) the use of carbon disulfide, which is highly toxic and classified as a special igniter under the Japanese Fire Protection Law, in the cyclization reaction of the thiol group, and which produces highly toxic hydrogen sulfide during the reaction; and (iv) the production of highly toxic hydrogen sulfide if the position of the thiol group is replaced with an imino group in the cyclization reaction of the thiol group. Therefore, there are still issues regarding the use of highly toxic reagents and the high level of operational risk.

[0010] In view of the above-mentioned problems, the present invention aims to provide a new method for manufacturing 1-{[2-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-7-(thiazo-2-yl)benzo[d]oxazol-4-yl]oxy}-1,1-difluoro-2-methylpropane-2-ol or its salts, which has better safety and operability and is suitable for industrial manufacturing.

[0011] Methods for solving problems

[0012] In order to solve the above-mentioned problems, the inventors conducted meticulous research and discovered that the 2-alkoxybenzo[d]oxazole derivative or its salt represented by the following formula (2) can be used as a starting material for 1-{[2-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-7-(thiazol-2-yl)benzo[d]oxazol-4-yl]oxy}-1,1-difluoro-2-methylpropane-2-ol or its salt. That is, the compound represented by formula (2) and its salt can be manufactured in a way that does not require highly toxic and difficult-to-handle reagents or highly dangerous operations, and thus does not produce toxic substances in the reaction.

[0013] Furthermore, the manufacture of its intermediates, tert-butyl 3-(4-hydroxy-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid or its salts, and the manufacture of 1-{[2-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-7-(thiazol-2-yl)benzo[d]oxazol-4-yl]oxy}-1,1-difluoro-2-methylpropane-2-ol or its salts, does not require highly toxic and difficult-to-handle reagents or highly dangerous operations. Furthermore, by using the manufacturing method of the compound represented by the aforementioned formula (2) or its salt, the inventors are able to obtain 1-{[2-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-7-(thiazo-2-yl)benzo[d]oxazol-4-yl]oxy}-1,1-difluoro-2-methylpropane-2-ol or its salt in the same high yield as conventional manufacturing methods.

[0014] Therefore, the inventors have discovered that by using the compound represented by the aforementioned formula (2) or its salt, a new industrial manufacturing method with excellent safety and operability can be provided, thus completing the present invention. That is, the present invention provides the invention shown below.

[0015] [1] A method for producing the compound represented by formula (1) or its salt, comprising the following steps:

[0016] Step B, which involves using the compound represented by formula (2) or a salt thereof, to produce the compound represented by formula (3) or a salt thereof, and

[0017] Step C, which involves using the compound represented by formula (3) or a salt thereof, to produce the compound represented by formula (1) or a salt thereof,

[0018]

[0019] In formula (2),

[0020] R a This represents a hydrogen atom or a substituted aryl methyl group.

[0021] R b Indicates alkyl or cycloalkyl groups that can be substituted.

[0022] R 3 Represents a hydrogen atom, a halogen atom, or a thiazolyl-2- group.

[0023] X a [Represents hydrogen or halogen atoms]

[0024]

[0025] [In formula (3), Boc represents tert-butoxycarbonyl].

[0026] [2] The manufacturing method as described in [1], wherein step B is to use R in the aforementioned formula (2) a For substituted aryl methyl groups, R b For substituted alkyl groups, R 3 For halogen atoms, X a OR in compounds (2-1) containing hydrogen atoms b The compound represented by formula (4) was prepared by substituting 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester.

[0027] In the presence of a metal catalyst, the compound represented by formula (4) is introduced with a thiazol-2- group via a cross-coupling reaction to produce the compound represented by formula (5).

[0028] The step of producing the compound represented by formula (3) or its salt by reacting the compound represented by formula (5) with an organic acid is as follows.

[0029]

[0030] In equation (4), R a For substituted aryl methyl groups, R 3 (The halogen atom is Boc, which is tert-butoxycarbonyl).

[0031]

[0032] In equation (5), R a [The aryl methyl group can be substituted, and Boc is a tert-butoxycarbonyl group].

[0033] [3] The manufacturing method as described in [1], wherein step B is carried out in the presence of a metal catalyst, by a cross-coupling reaction, on R in the aforementioned formula (2). a For substituted aryl methyl groups, R b For substituted alkyl groups, R 3 For halogen atoms, X a Introducing a thiazol-2- group into the compound (2-1) containing hydrogen atoms, to form R in the aforementioned formula (2). a For substituted aryl methyl groups, R b For substituted alkyl groups, R 3 Thiazol-2-yl, X a Compounds containing hydrogen atoms (2-11),

[0034] OR in compound (2-11) bThe compound represented by formula (5) was prepared by substituting 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester.

[0035] The step of producing the compound represented by formula (3) or its salt by reacting the compound represented by formula (5) with an organic acid is as follows.

[0036]

[0037] In equation (5), R a [The aryl methyl group can be substituted, and Boc is a tert-butoxycarbonyl group].

[0038] [4] The manufacturing method as described in [1], wherein step B is to make R in the aforementioned formula (2) a For hydrogen atoms, R b For substituted alkyl groups, R 3 For hydrogen atoms, X a The compound (2-2) containing hydrogen atoms reacts with a brominating agent to produce R in the aforementioned formula (2). a For hydrogen atoms, R b For substituted alkyl groups, R 3 For bromine atoms, X a Compounds containing bromine atoms (2-21),

[0039] OR in compound (2-21) b The compound represented by formula (8) was prepared by substituting 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester.

[0040] In the presence of a metal catalyst, the compound represented by formula (8) is introduced with a thiazol-2- group via a cross-coupling reaction to produce the compound represented by formula (9).

[0041] The step of producing the compound represented by formula (3) or its salt by reacting the compound represented by formula (9) with a metal is described.

[0042]

[0043] [In formula (8), Boc is tert-butoxycarbonyl].

[0044]

[0045] [In formula (9), Boc is tert-butoxycarbonyl].

[0046] [5] The manufacturing method as described in any one of [1] to [4], comprising:

[0047] Step A, which involves using the compound represented by formula (10) or a salt thereof to manufacture the compound represented by formula (2) or a salt thereof,

[0048]

[0049] In formula (10),

[0050] R 1 Indicates a hydroxyl or halogen atom or an aryl methyloxy group.

[0051] R 2 Indicates a hydroxyl or halogen atom.

[0052] R 3 (Represents a hydrogen atom, a halogen atom, or a thiazolyl-2-yl group).

[0053] [6] The manufacturing method as described in [5], wherein step A is to make R in the aforementioned formula (10) 1 For halogen atoms, R 2 For halogen atoms, R 3 The compound (10-1) containing hydrogen atoms reacts with benzyl alcohol to produce the compound represented by formula (10-11).

[0054] The compound represented by formula (10-11) is reacted with a brominating agent to prepare the compound represented by formula (10-12).

[0055] The compound represented by formula (10-12) is reacted with an alkaline aqueous solution to prepare the compound represented by formula (10-13).

[0056] The compounds represented by formulas (10-13) are reacted with a reducing agent to prepare the compound represented by formula (14).

[0057] The process involves reacting the compound represented by formula (14) with tetraalkoxymethane in the presence of an acid catalyst to produce the compound represented by formula (2) or a salt thereof.

[0058]

[0059] In equation (10-11), R 2 [Bn is a halogen atom, and Bn is a benzyl group].

[0060]

[0061] In equation (10-12), R 2 [Bn is a halogen atom, and Bn is a benzyl group].

[0062]

[0063] [In formula (10-13), Bn is benzyl].

[0064]

[0065] [In formula (14), Bn is benzyl].

[0066] [7] The manufacturing method as described in [5], wherein step A is to use R in the aforementioned formula (10) 1 hydroxyl group, R 2 hydroxyl group, R 3 The steps involve reducing a compound (10-2) containing hydrogen atoms, reacting it with tetraalkoxymethane in the presence of an acid catalyst, and then reacting it with a brominating agent to produce the compound represented by the aforementioned formula (2) or a salt thereof.

[0067] [8] Compounds or their salts represented by formula (15):

[0068]

[0069] [In formula (15), Bn is benzyl and Et is ethyl].

[0070] [9] The compound or its salt represented by formula (6),

[0071]

[0072] [In formula (6), Bn is benzyl and Et is ethyl].

[0073]

[10] The compound or its salt represented by formula (7),

[0074]

[0075] [In formula (7), Et is ethyl].

[0076]

[11] The compound or its salt represented by formula (8),

[0077]

[0078] [In formula (8), Boc is tert-butoxycarbonyl].

[0079] Invention Effects

[0080] This invention provides a novel method for manufacturing 1-{[2-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-7-(thiazol-2-yl)benzo[d]oxazol-4-yl]oxy}-1,1-difluoro-2-methylpropane-2-ol (the compound represented by formula (1)) or its salts, which is safe, easy to operate, and suitable for industrial manufacturing. Furthermore, this invention also provides 2-alkoxybenzo[d]oxazole derivatives (the compound represented by formula (2)) or their salts, as raw materials applicable to the aforementioned manufacturing method, and a method for manufacturing them. Detailed Implementation

[0081] The following describes in detail, by way of example, the method for manufacturing the compound represented by formula (1) of the present invention or its salt, and the method for manufacturing the compound represented by formula (2) or its salt used in the method for manufacturing the compound represented by formula (1), but the present invention is not limited to the scope of the specific examples given.

[0082] The method for manufacturing the compound represented by formula (1) of the present invention comprises: step B, using the compound represented by formula (2) or a salt thereof, to manufacture the compound represented by formula (3) or a salt thereof, and step C, using the compound represented by formula (3) or a salt thereof, to manufacture the compound represented by formula (1) or a salt thereof (hereinafter sometimes simply referred to as "the manufacturing method of the present invention").

[0083] The compound obtained by the manufacturing method of the present invention is 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazolyl-2-yl)benzo[d]oxazol-4-yl]oxy}-1,1-difluoro-2-methylpropane-2-ol, represented by the following formula (1).

[0084]

[0085] This compound exhibits excellent PDE4 (phosphodiesterase type 4) inhibitory activity and also demonstrates superior metabolic stability (Patent Document 1).

[0086] The compound obtained by the manufacturing method of the present invention may also be a salt of the compound represented by formula (1) of the present invention (hereinafter, sometimes referred to as "compound (1)"). As such a salt, it is preferably a pharmacologically permissible salt. As such a pharmacologically permissible salt, it is preferably in the form of an acid addition salt. Examples of acids that are such acid addition salts include, for example, hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid; inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, hydrogen peroxide, and carbonic acid; organic carboxylic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, glycolic acid, lactic acid, citric acid, tartaric acid, oxalic acid, benzoic acid, mandelic acid, butyric acid, maleic acid, propionic acid, formic acid, and malic acid; acidic amino acids such as aspartic acid and glutamic acid; alkyl sulfonic acids such as methanesulfonic acid; and aryl sulfonic acids such as p-toluenesulfonic acid.

[0087] Compound (1) and its salts can be obtained using 3-(4-hydroxy-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (hereinafter, sometimes referred to as "compound (3)") or its salts, represented by the following formula (3):

[0088]

[0089] [In formula (3), Boc represents tert-butoxycarbonyl].

[0090] As a method for obtaining compound (1) from such compound (3), appropriate known methods or methods based thereon can be used, such as the method described in Patent Document 1. As a salt of compound (3), it also includes its preferred form, and examples are given as those given as salts of compound (1).

[0091] In the manufacturing method of the present invention, compound (3) or a salt thereof is obtained by using a compound represented by formula (2) of the present invention (hereinafter, sometimes referred to as "compound (2)") or a salt thereof (step B). Compound (2) is a compound represented by the following formula (2).

[0092]

[0093] In equation (2), R a R represents a hydrogen atom or a potentially substituted aryl methyl group. b Indicates a substituted alkyl or cyclic alkyl group, R 3 X represents a hydrogen atom, a halogen atom, or a thiazolyl-2- group. a It represents a hydrogen atom or a halogen atom.

[0094] In this specification, "aryl methyl" can be exemplified by, for example, phenylmethyl (benzyl), diphenylmethyl (diphenylmethyl), and triphenylmethyl (triphenylmethyl), with benzyl being particularly preferred. As the R involved in this invention...a The aryl methyl group shown may also be substituted by one or more identical or different substituents.

[0095] In this specification, "arylmethyloxy" refers to the following formula: -OA, where A represents an arylmethyl group. Examples of the aforementioned arylmethyl groups include those listed above, with benzyl being particularly preferred. As per the R mentioned in this invention... 1 The aryl methyl oxy group shown may also be substituted by one or more identical or different substituents.

[0096] In this specification, "alkyl" refers to a straight-chain or branched alkyl group, preferably having 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms. As the R involved in this invention... b The alkyl group shown may also be substituted with one or more identical or different substituents. Examples of the aforementioned alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and n-hexyl.

[0097] In this specification, "cyclic alkyl" refers to a cyclic alkyl group, preferably with 3 to 8 carbon atoms, i.e., the number of atoms constituting the ring, more preferably 3 to 6. As the R involved in this invention... b The cyclic alkyl groups shown may also be substituted with one or more identical or different substituents. Examples of the aforementioned cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0098] In this specification, "halogen atom" refers to fluorine atom, chlorine atom, bromine atom, and iodine atom.

[0099] Furthermore, in this specification, "may be substituted" means that any one or two or more hydrogen atoms are substituted by other atoms or groups (substituents). When two or more hydrogen atoms are substituted, the aforementioned substituents (atoms, groups) may be the same as or different from each other. Examples of such substituents include halogen atoms, cyano groups, nitro groups, hydroxyl groups, amino groups, carbonyl groups, carboxyl groups, alkyl groups, alkoxy groups, cyclic alkoxy groups, alkylamino groups, cyclic alkylamino groups, and azide groups.

[0100] Examples of compounds (2) involved in this invention include the following:

[0101] 2-Methoxybenzo[d]oxazol-4-ol, 2-ethoxybenzo[d]oxazol-4-ol, 2-propoxybenzo[d]oxazol-4-ol, 2-isopropoxybenzo[d]oxazol-4-ol, 2-butoxybenzo[d]oxazol-4-ol, 2-isobutoxybenzo[d]oxazol-4-ol, 2-(sec-butoxy)benzo[d]oxazol-4-ol, 2-(tert-butoxy)benzo[d]oxazol-4-ol, 2-pentoxybenzo[d]oxazol-4-ol, 2-(pentan-2-yloxy)benzo[d]oxazol-4-ol, 2-[(3-methylbutan-2-yl)oxy]oxazol-4-ol, [Benzo[d]oxazol-4-ol, 2-(tert-pentyloxy)benzo[d]oxazol-4-ol, 2-(hexyloxy)benzo[d]oxazol-4-ol, 2-cyclopropoxybenzo[d]oxazol-4-ol, 2-cyclobutoxybenzo[d]oxazol-4-ol, 2-(cyclopentyloxy)benzo[d]oxazol-4-ol, 2-(cyclohexyloxy)benzo[d]oxazol-4-ol, 2-benzyloxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-methoxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-ethoxybenzo[d]oxazol-4-ol, 5,7 -Dibromo-2-propoxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-butoxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-isobutoxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-(sec-butoxy)benzo[d]oxazol-4-ol, 5,7-dibromo-2-(tert-butoxy)benzo[d]oxazol-4-ol, 5,7-dibromo-2-pentoxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-(pentan-2-yloxy)benzo[d]oxazol-4-ol, 5,7-dibromo-2-[(3-methylbutan-2-yl)oxy]oxazol-4-ol [Benzo[d]oxazol-4-ol, 5,7-dibromo-2-(tert-pentyloxy)benzo[d]oxazol-4-ol, 5,7-dibromo-2-(hexyloxy)benzo[d]oxazol-4-ol, 5,7-dibromo-2-cyclopropoxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-cyclobutoxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-cyclobutoxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-cyclobutoxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-(cyclopentyloxy)benzo[d]oxazol-4-ol, 5,7-Dibromo-2-benzyloxybenzo[d]oxazole-4-ol, 4-(benzyloxy)-7-bromo-2-methoxybenzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-ethoxybenzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-propoxybenzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-isopropoxybenzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-butoxybenzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-isobutoxybenzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-(sec-butoxy)benzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-(tert-butoxy)benzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-(tert-butoxy)benzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-pentoxy Benzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-(pentan-2-yloxy)benzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-[(3-methylbutan-2-yl)oxy]benzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-(tert-pentyloxy)benzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-(hexyloxy)benzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-cyclopropoxybenzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-cyclobutoxybenzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-(cyclopentyloxy)benzo[d]oxazole, 2,4-Di(benzyloxy)-7-bromobenzo[d]oxazole, 4-(benzyloxy)-2-methoxy-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-ethoxy-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-propoxy-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-isopropoxy-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-butoxy 4-(benzyloxy)-2-isobutoxy-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-(sec-butoxy)-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-(tert-butoxy)-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-pentoxy-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)- 2-(pentan-2-yloxy)-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-[(3-methylbutan-2-yl)oxy]-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-(tert-pentyloxy)-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-(hexyloxy)-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-cyclopropoxy-7- The invention comprises (thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-cyclobutoxy-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-(cyclopentyloxy)-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-(cyclohexyloxy)-7-(thiazol-2-yl)benzo[d]oxazole, and 2,4-bis(benzyloxy)-7-(thiazol-2-yl)benzo[d]oxazole, but is not limited to these specific examples.

[0102] Among these, the compound (2) involved in this invention is preferably 2-ethoxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-ethoxybenzo[d]oxazol-4-ol represented by formula (7), 4-(benzyloxy)-7-bromo-2-ethoxybenzo[d]oxazole represented by formula (15), and 4-(benzyloxy)-2-ethoxy-7-(thiazol-2-yl)benzo[d]oxazole represented by formula (6).

[0103]

[0104] [In formula (7), Et is ethyl].

[0105]

[0106] [In formula (15), Bn is benzyl and Et is ethyl].

[0107]

[0108] [In formula (6), Bn is benzyl and Et is ethyl].

[0109] Salts of the compound (2) involved in this invention also include preferred forms thereof, and examples are given as those given as salts of the compound (1).

[0110] The compound (2) or its salt thereof involved in this invention is preferably obtained by step A of manufacturing the compound (2) or its salt by using a compound represented by the following formula (10) (hereinafter, sometimes referred to as "compound (10)") or its salt.

[0111] The compound (1) or its salts involved in this invention can be manufactured by the representative method shown in the following process 1.

[0112] Process 1:

[0113]

[0114] In the various equations of process 1 above, R 1 R represents a hydroxyl group, a halogen atom, or an aryl methyloxy group. 2 R represents a hydroxyl or halogen atom. a Each can independently represent a hydrogen atom or a substituted aryl methyl group, R b Indicates a substituted alkyl or cyclic alkyl group, R 3 Each can be represented independently as a hydrogen atom, a halogen atom, or a thiazolyl-2- group, X a Each can be used independently to represent a hydrogen atom or a halogen atom.

[0115] In the above process 1, firstly, as a preferred option for step A, the nitro group of the compound represented by formula (10) is reduced by a reduction reaction to prepare the compound represented by formula A (hereinafter, sometimes referred to as "compound A"). Then, through the cyclization reaction of compound A, compound (2) is obtained.

[0116] Next, in process 1, as a preferred embodiment of step B, the 2-alkoxy group (OR) of the obtained compound (2) is... b Substitution with 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (substitution reaction) yields the compound represented by formula B (hereinafter, sometimes referred to as "compound B") or compound (3). Alternatively, compound B may be introduced with a thiazol-2- group via a cross-coupling reaction, or with R removed via a deprotection reaction, as needed. a Protecting groups, and X atoms other than hydrogen atoms a It is converted into hydrogen atoms to obtain compound (3).

[0117] Subsequently, as a preferred embodiment of step C, after O-alkylation of compound (3) to prepare a compound represented by formula C (hereinafter, sometimes referred to as "compound C"), the tert-butoxycarbonyl group (hereinafter, sometimes referred to as "Boc") is removed by a deprotection reaction to obtain compound (1).

[0118] As a manufacturing method of the present invention, step A preferably includes: as compound (10), R... 1 and R 2 For halogen atoms, R 3 Compounds containing hydrogen atoms (10⁻¹), more preferably composed of R 1 and R 2 For fluorine atoms, R 3 2,6-Difluoronitrobenzene with hydrogen atoms, or as compound (10), by R 1 and R 2 hydroxyl group, R 3 The steps of preparing compound (2) or its salts, for each of the hydrogen-containing compounds (10-2), namely 2-nitroresorcinol.

[0119] As compound (10), when using compound (10-1), more preferably 2,6-difluoronitrobenzene, for example, firstly, compound (10-1) (preferably 2,6-difluoronitrobenzene) is reacted with benzyl alcohol (partial substitution reaction) to prepare the compound represented by the following formula (10-11) (compound (10-11)).

[0120]

[0121] In formula (10-11), Bn is benzyl (the same applies below), R 2 For halogen atoms, as R 2 More preferably, it is a fluorine atom. Next, the compound (10-11) is reacted with a brominating agent (bromination reaction) to prepare the compound represented by the following formula (10-12) (compound (10-12)).

[0122]

[0123] In equation (10-12), R 2 For halogen atoms, as R 2 More preferably, it is a fluorine atom. Next, the compound (10-12) is reacted with an aqueous alkaline solution (water and reaction) to prepare the compound represented by the following formula (10-13) (compound (10-13)).

[0124]

[0125] Then, the compound (10-13) is reacted with a reducing agent (reduction reaction) to obtain the compound represented by the following formula (14) as compound A (compound (14)).

[0126]

[0127] Next, by reacting compound (14) with tetraalkoxymethane (accompanied by cyclization of alkoxy groups), compound (2) (e.g., the compound represented by the aforementioned formula (15)) or its salt can be produced.

[0128] Alternatively, when using compound (10-2) (2-nitroresorcinol) as compound (10), for example, firstly, compound (10-2) is reacted with a reducing agent (reduction reaction) to prepare compound (10-21) (2-aminoresorcinol), and then compound (10-21) is reacted with tetraalkoxymethane (accompanied by cyclization of alkoxy groups) to prepare compound (10-22) (2-ethoxybenzo[d]oxazol-4-ol). Next, by reacting compound (10-22) with a brominating agent (bromination reaction), compound (2) (for example, the compound represented by the aforementioned formula (7)) or its salt can be produced.

[0129] Furthermore, as a manufacturing method of the present invention, step B preferably includes: as compound (2), R... a For substituted aryl methyl groups, R b For substituted alkyl groups, R 3 For halogen atoms, X a Compounds containing hydrogen atoms (2-1) (more preferably R) a (a benzyl compound), or as compound (2), by R a For hydrogen atoms, R b For substituted alkyl groups, R 3 For hydrogen atoms, X a Compounds containing hydrogen atoms (2-2) (more preferably R) b The steps of producing compound (3) or its salt (for compounds of ethyl groups) are as follows:

[0130] When using compound (2) as compound (2-1), for example, firstly, compound (2-1) (more preferably R) is used. a benzyl, R 3 OR in compounds containing bromine atoms b The compounds represented by the following formula (4) (compound (4), compound B) were prepared by substitution (substitution reaction) with 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester.

[0131]

[0132] In equation (4), R a For substituted aryl methyl groups, R 3 It is a halogen atom. As R in equation (4) a Preferably benzyl, as R 3 Preferably, a bromine atom is introduced. Then, in the presence of a metal catalyst, a thiazol-2- group is introduced into compound (4) by a cross-coupling reaction to prepare the compound represented by the following formula (5) (compound (5), compound B).

[0133]

[0134] In equation (5), R a It is an aryl methyl group that can be substituted. As R in formula (5) a The preferred group is benzyl. Next, by reacting compound (5) with an organic acid (deprotection reaction), compound (3) or its salt can be produced.

[0135] Additionally, as for compound (2), as for other methods of using compound (2-1), for example, firstly, in the presence of a metal catalyst, by cross-coupling reaction, compound (2-1) (more preferably R) is reacted with the compound (2-1) (more preferably R). a benzyl, R b To form R in the aforementioned formula (2), a thiazol-2- group is introduced into a compound that is ethyl. a For substituted aryl methyl groups, R b For substituted alkyl groups, R 3 It is thiazolyl-2-yl, X a The compound (2-11) is a hydrogen atom. As compound (2-11), the preferred compound is the one represented by the following formula (6) (compound (6)).

[0136]

[0137] In formula (6), Et is ethyl (the same applies below). Next, OR in compound (2-11) b By substituting tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid with tert-butyl ester (substitution reaction), compound (5)(R) was prepared. a (For benzyl). Next, by reacting compound (5) with an organic acid (deprotection reaction), compound (3) or its salt can be produced.

[0138] Furthermore, when using compound (2-2) as compound (2), for example, firstly, compound (2-2) (more preferably R) is made. b The ethyl compound reacts with a brominating agent to form R in the aforementioned formula (2). a For hydrogen atoms, Rb For substituted alkyl groups, R 3 For bromine atoms, X a Compounds containing bromine atoms (2-21). As compound (2-21), compounds represented by the following formula (7) are preferred (compound (7)).

[0139]

[0140] Next, the OR in compound (2-21) b The compounds represented by the following formula (8) (compound (8), compound B) were prepared by substitution (substitution reaction) with 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester.

[0141]

[0142] Next, in the presence of a metal catalyst, a thiazol-2- group was introduced into compound (8) via a cross-coupling reaction to prepare the compound represented by the following formula (9) (compound (9), compound B).

[0143]

[0144] Next, by reacting compound (9) with a metal (conversion reaction), compound (3) or its salt can be produced.

[0145] In the steps shown in process 1 above, the compounds that become intermediates can be separated individually or not. If they are not separated, the reactions can proceed continuously.

[0146] The reactions in process 1 are explained in further detail below. It should be noted that in the following descriptions, "equivalent" refers to chemical equivalent. For each functional group in the reaction, the amount of molecules (substance) necessary for all functional groups of the matrix in the reaction to react is expressed as 1 equivalent.

[0147] (Partial substitution reaction)

[0148] In the manufacturing method of the present invention, compound (10-11) is preferably obtained by reacting compound (10-1) with benzyl alcohol via a partial substitution reaction. As the aforementioned partial substitution reaction, it is preferably carried out in a suitable solvent and in the presence or absence of a base, by reacting the matrix (here, compound (10-1)) with benzyl alcohol under the following preferred conditions.

[0149] As the aforementioned solvents, hydrocarbon-based organic solvents such as petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, and xylene can be used; halogenated hydrocarbon-based organic solvents such as carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, and chlorobenzene can be used; ether-based organic solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and diphenyl ether can be used; methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, and acetic acid can be used. The following are ester-based organic solvents: n-butyl acetate, isobutyl acetate, tert-butyl acetate, benzyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, isobutyl propionate, and tert-butyl propionate; and aprotic polar solvents such as acetone, 2-butanone, methyl isobutyl ketone, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, used alone or in combination of two or more in appropriate ratios.

[0150] As the aforementioned solvent, preferably at least one selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and N-methyl-2-pyrrolidone are preferred, and more preferably at least one selected from N,N-dimethylformamide and dimethyl sulfoxide are preferred.

[0151] As the aforementioned base, salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium phosphate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and barium hydroxide can be used; trimethylamine, triethylamine, tributylamine, diisopropylethylamine, 2-(dimethylamino)ethanol, N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine, N,N'-dimethylpiperazine, N,N,N',N'-tetramethylethylenediamine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, and 1,8-diazabicyclo[5.4. [0] Amines such as undecyl-7-ene, pyridine, methylpyridine, 4-(dimethylamino)pyridine, 2,6-dimethylpyridine and 2,4,6-trimethylpyridine; metal hydrides such as lithium hydride, sodium hydride, potassium hydride, barium hydride and calcium hydride; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; metal amides such as lithium amino, sodium amino, potassium amino, diisopropylamino, lithium 2,2,6,6-tetramethylpyridinium, lithium di(trimethylsilyl)amino, sodium di(trimethylsilyl)amino and potassium di(trimethylsilyl)amino; and potassium trimethylsilanolate, etc., used alone or in combination of two or more in appropriate proportions.

[0152] As the aforementioned base, preferably at least one selected from sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, sodium tert-butoxide, and potassium tert-butoxide is preferred; more preferably at least one selected from potassium carbonate and sodium tert-butoxide is preferred. The amount of the aforementioned base used in the aforementioned partial substitution reaction is 0.01 to 20 equivalents relative to the aforementioned matrix, preferably 0.1 to 10 equivalents, and even more preferably 1 to 5 equivalents.

[0153] The amount of benzyl alcohol used in the aforementioned partial substitution reaction is 0.8 to 5 equivalents relative to the aforementioned matrix, preferably 0.9 to 2 equivalents.

[0154] The reaction temperature for the aforementioned partial substitution reaction is in the range of 0 to 200°C, preferably in the range of 50 to 150°C, and more preferably in the range of 80 to 120°C.

[0155] The reaction time for the aforementioned partial substitution reaction is in the range of 1 to 100 hours, preferably in the range of 5 to 50 hours, and more preferably in the range of 10 to 30 hours.

[0156] (bromination reaction)

[0157] In the manufacturing method of the present invention, compound (2-21) is preferably obtained by reacting compound (2-2) with a brominating agent to obtain compound (10-12) by reacting compound (10-11) with a brominating agent to obtain compound (10-12) by reacting compound (10-22) with a brominating agent to obtain compound (2) by reacting compound (10-22) with a brominating agent. As for the aforementioned bromination reaction, it is preferable to carry out the reaction between the matrix (here, compound (2-2), compound (10-11), or compound (10-22)) and the brominating agent in a suitable solvent, in the presence or absence of an acid catalyst, and the preferred conditions are as follows.

[0158] As the aforementioned solvents, protic solvents such as water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, and tert-butanol can be used; hydrocarbon organic solvents such as petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, and xylene can be used; halogenated hydrocarbon organic solvents such as carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, and chlorobenzene can be used; ether organic solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and diphenyl ether can be used; methyl acetate, ethyl acetate, etc. Ester-based organic solvents such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, benzyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, isobutyl propionate, and tert-butyl propionate; and nonprotic polar solvents such as acetone, 2-butanone, methyl isobutyl ketone, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, can be used alone or in combination of two or more in appropriate ratios.

[0159] Preferably, the solvent is selected from at least one of ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide and N-methyl-2-pyrrolidone, and more preferably, at least one of acetonitrile and ethyl acetate.

[0160] Examples of acid catalysts include organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, succinic acid, citric acid, methanesulfonic acid, trifluoromethanesulfonic acid, 10-camphor-sulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, 12-molybdenum(VI) phosphate hydrate, and 12-tungsten(VI) phosphate hydrate; and Lewis acids such as tetrafluoroborate diethyl ether complex, boron trifluoride diethyl ether complex, boron trichloride, boron tribromide, magnesium chloride, magnesium bromide diethyl ether complex, zinc chloride, tin(IV) chloride, ferric chloride(III), aluminum chloride, titanium tetrachloride, and zirconium tetrachloride. In addition, examples include chlorosilanes such as trichlorotrimethylsilane, trichlorotriethylsilane, trichlorotriisopropylsilane, chloroisopropyldimethylsilane, dichlorodiethylisopropylsilane, tert-butylchlorodimethylsilane, tert-butylchlorodiphenylsilane, tribenzylsilane, trichlorotriphenylsilane, chloromethyldiphenylsilane, and di-tert-butylchloromethylsilane. These can be used alone or in combination of two or more in appropriate proportions.

[0161] Among these, at least one (preferably any one) selected from acetic acid, diethyl tetrafluoroborate complex and trichlorosilane is preferred as the aforementioned acid catalyst from the viewpoint of low toxicity. More preferably, at least one (preferably any one) selected from acetic acid and trichlorosilane is preferred.

[0162] In the aforementioned bromination reaction, the amount of the aforementioned acid catalyst used relative to the aforementioned matrix is ​​0 to 1 equivalent, preferably 0 to 0.7 equivalent.

[0163] As the aforementioned brominating agent, bromine, 1,4-dioxane bromine complex, tetrabutylammonium tribromide, benzyltrimethylammonium tribromide, trimethylphenylammonium tribromide, 1-butyl-3-methylimidazolium tribromide, 1,8-diazabicyclo[5.4.0]-7-undecene tribromide, pyridinium tribromide, 4-dimethylaminopyridinium tribromide, N-bromoacetamide, N-bromosuccinimide, N-bromophthalimide, N-bromosaccharin, dibromocyanuric acid, and bromocyanurate can be used. Sodium tribromide, 1,3-dibromo-5,5-dimethylhydantoin, dimethyl sulfonium bromide, bis(2,4,6-trimethylpyridine)bromonium hexafluorophosphate, trimethylsilane, carbon tetrabromide, chloroform, 1,2-dibromo-1,1,2,2-tetrachloroethane, 5,5-dibromomelinic acid, 2,4,4,6-tetrabromo-2,5-cyclohexadienone, boron tribromide, and phosphorus tribromide, etc., are used alone or in combination of two or more in appropriate proportions.

[0164] As the aforementioned brominating agent, preferably at least one (preferably any one) selected from bromine, tetrabutylammonium tribromide, benzyltrimethylammonium tribromide, N-bromosuccinimide, N-bromosaccharin and 1,3-dibromo-5,5-dimethylhydantoin is preferred, and more preferably at least one (preferably any one) selected from N-bromosuccinimide is preferred.

[0165] In the aforementioned bromination reaction, the amount of brominating agent used, when introducing one bromine atom into one molecule of the aforementioned matrix, is 0.8 to 5 equivalents, preferably 1 to 2 equivalents, relative to the aforementioned matrix. Furthermore, when introducing two bromine atoms into one molecule of the aforementioned matrix, the amount is 1.8 to 5 equivalents, preferably 2 to 3 equivalents, relative to the aforementioned matrix.

[0166] The reaction temperature of the aforementioned bromination reaction is in the range of -50 to 100°C, preferably in the range of -25 to 50°C, and more preferably in the range of -10 to 30°C.

[0167] The reaction time for the aforementioned bromination reaction is in the range of 10 minutes to 12 hours, preferably in the range of 20 minutes to 6 hours, and more preferably in the range of 30 minutes to 4 hours.

[0168] (Water and reaction)

[0169] In the manufacturing method of the present invention, it is preferable to obtain compound (10-13) by reacting compound (10-12) with an alkaline solution and reacting with water. As for the aforementioned water reaction, it is preferable to carry out the reaction by reacting the matrix (here, compound (10-12)) with an aqueous alkaline solution in a suitable solvent, and the preferred conditions are as follows.

[0170] As the aforementioned solvents, hydrocarbon-based organic solvents such as petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, and xylene can be used; halogenated hydrocarbon-based organic solvents such as carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, and chlorobenzene can be used; ether-based organic solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and diphenyl ether can be used; methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, and acetic acid can be used. The following are ester-based organic solvents: n-butyl acetate, isobutyl acetate, tert-butyl acetate, benzyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, isobutyl propionate, and tert-butyl propionate; and aprotic polar solvents such as acetone, 2-butanone, methyl isobutyl ketone, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, used alone or in combination of two or more in appropriate ratios.

[0171] As the aforementioned solvent, preferably, at least one selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and N-methyl-2-pyrrolidone is preferred, and more preferably, at least one selected from N,N-dimethylacetamide and dimethyl sulfoxide is preferred.

[0172] As the aforementioned alkaline aqueous solution, one or more of the following aqueous solutions may be used alone or in appropriate proportions: sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and barium hydroxide.

[0173] As the aforementioned alkaline aqueous solution, preferably an aqueous solution selected from at least one of sodium bicarbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide (preferably any one of them) is preferred; more preferably, an aqueous solution selected from at least one of sodium hydroxide and potassium hydroxide (preferably any one of them) is preferred. In the aforementioned water and reaction, the concentration of the aforementioned alkaline aqueous solution is not particularly limited and can be appropriately adjusted.

[0174] The reaction temperature of the aforementioned water and reaction is in the range of 0 to 200°C, preferably in the range of 25 to 150°C, and more preferably in the range of 50 to 100°C.

[0175] The reaction time of the aforementioned water and reaction is in the range of 10 minutes to 20 hours, preferably in the range of 20 minutes to 10 hours, and more preferably in the range of 30 minutes to 5 hours.

[0176] (Reduction reaction)

[0177] In the manufacturing method of the present invention, it is preferable to obtain compound (14) by reacting compound (10-13) with a reducing agent to obtain compound (14) by a reduction reaction. Alternatively, compound (10-21) is obtained by reacting compound (10-2) with a reducing agent to obtain compound (10-21) by a reduction reaction. As for the aforementioned reduction reaction, it is preferable to carry out the reaction between the matrix (here, compound (10-13) and compound (10-2)) and the reducing agent in a suitable solvent, and the preferred conditions are as follows.

[0178] As the aforementioned solvents, protic solvents such as water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, and tert-butanol can be used; hydrocarbon solvents such as petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, and xylene can be used; halogen solvents such as carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, and chlorobenzene can be used; ether-based organic solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and diphenyl ether can be used; methyl acetate and ethyl acetate can also be used. The following are ester-based organic solvents: n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, benzyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, isobutyl propionate, and tert-butyl propionate; and aprotic polar solvents such as acetone, 2-butanone, methyl isobutyl ketone, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, used alone or in combination of two or more in appropriate ratios.

[0179] Preferably, at least one solvent selected from water, methanol, ethanol, ethyl acetate, and n-butyl acetate is preferred; more preferably, at least one solvent selected from water, ethanol, and ethyl acetate is preferred. Additionally, acids such as formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, and toluenesulfonic acid, or bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, and potassium hydroxide may be appropriately added to the aforementioned solvent.

[0180] As the aforementioned reducing agent, one or more of the following can be used alone or in appropriate proportions: metals such as zinc, aluminum, tin, tin(II) chloride and iron; hydrogenation catalysts such as palladium, platinum, rhodium and nickel that can be used with a hydrogen source and also with a suitable support; and inorganic salts such as sodium dithionite.

[0181] As the aforementioned reducing agent, preferably at least one selected from zinc, iron, palladium supported on activated carbon and sodium dithionite (preferably any one) is preferred, and more preferably at least one selected from palladium supported on activated carbon and sodium dithionite (preferably any one) is preferred.

[0182] In the aforementioned reduction reaction, when the reducing agent is one of the aforementioned metals and / or inorganic salts, they may be used in extremely excess amounts. However, when both are present, the total amount, relative to the aforementioned matrix, is preferably 20 equivalents or less, more preferably 10 equivalents or less. When the reducing agent is one of the aforementioned hydrogenation catalysts, the amount of catalyst used, relative to the total weight (wt) of the added raw materials, is preferably 10 wt% or less, more preferably 5 wt% or less.

[0183] The reaction temperature of the aforementioned reduction reaction is in the range of -10 to 100°C, preferably in the range of -5 to 80°C, and more preferably in the range of 0 to 50°C.

[0184] The reaction time of the aforementioned reduction reaction is in the range of 10 minutes to 24 hours, preferably in the range of 20 minutes to 12 hours, and more preferably in the range of 30 minutes to 6 hours.

[0185] (accompanied by alkoxy cyclization)

[0186] In the manufacturing method of the present invention, compound (2) is preferably obtained by reacting compound (14) with tetraalkoxymethane to induce a cyclization reaction of the alkoxy group. Alternatively, compound (10-22) is obtained by reacting compound (10-21) with tetraalkoxymethane to induce a cyclization reaction of the alkoxy group.

[0187] As for the aforementioned cyclization reaction with alkoxy groups, it is preferred to carry out the reaction of the matrix (here, compound (14) or compound (10-21)) with tetraalkoxymethane in a suitable solvent and in the presence of an acid catalyst, with the preferred conditions shown below.

[0188] As the aforementioned solvents, hydrocarbon-based organic solvents such as petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, and xylene can be used; halogenated hydrocarbon-based organic solvents such as carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, and chlorobenzene can be used; ether-based organic solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and diphenyl ether can be used; methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, and acetic acid can be used. The following are ester-based organic solvents: n-butyl acetate, isobutyl acetate, tert-butyl acetate, benzyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, isobutyl propionate, and tert-butyl propionate; and aprotic polar solvents such as acetone, 2-butanone, methyl isobutyl ketone, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, used alone or in combination of two or more in appropriate ratios.

[0189] Preferably, the solvent is selected from at least one of n-hexane, n-heptane, toluene, xylene, methyl tert-butyl ether, 2-methyltetrahydrofuran, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, and tert-butyl acetate; more preferably, the solvent is selected from at least one of toluene and ethyl acetate.

[0190] As the aforementioned acid catalysts, one or more of the following can be used alone or in appropriate proportions: organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, succinic acid, citric acid, methanesulfonic acid, trifluoromethanesulfonic acid, 10-camphor-sulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and perchloric acid; and Lewis acids such as boron trifluoride diethyl ether complex, boron trichloride, boron tribromide, magnesium chloride, magnesium bromide diethyl ether complex, zinc chloride, tin(IV) chloride, ferric chloride(III) chloride, aluminum chloride, titanium tetrachloride, and zirconium tetrachloride.

[0191] From the viewpoint of low toxicity, at least one of acetic acid and hydrochloric acid (preferably either one) is preferred as the aforementioned acid catalyst, and acetic acid is more preferred.

[0192] In the aforementioned cyclization reaction accompanied by alkoxy groups, the amount of the aforementioned acid catalyst used relative to the aforementioned matrix is ​​0.01 to 1 equivalent, preferably 0.1 to 0.6 equivalents.

[0193] As the aforementioned tetraalkoxymethane, one of the following can be used alone or in combination with two or more in appropriate proportions: tetramethoxymethane, tetraethoxymethane, tetrapropoxymethane, tetraisopropoxymethane, tetrabutoxymethane, tetraisobutoxymethane, tetra(sec-butoxy)methane, tetra(tert-butoxy)methane, tetrapentoxymethane, tetra(pentan-2-yloxy)methane, tetra[(3-methylbutan-2-yl)oxy]methane, tetra(tert-pentyloxy)methane, tetra(hexyloxy)methane, tetracyclopropoxymethane, tetracyclobutoxymethane, tetra(cyclopentyloxy)methane, and tetra(cyclohexyloxy)methane.

[0194] As for the aforementioned tetraalkoxymethane, preferably at least one (preferably any one) selected from tetramethoxymethane, tetraethoxymethane and tetrabenzyloxymethane is preferred, and more preferably tetraethoxymethane is preferred.

[0195] In the aforementioned cyclization reaction accompanied by alkoxy groups, the amount of the aforementioned tetraalkoxymethane used relative to the aforementioned matrix is ​​0.9 to 5 equivalents, preferably 1 to 2 equivalents.

[0196] The reaction temperature for the aforementioned cyclization reaction accompanied by alkoxy groups is in the range of 0 to 200°C, preferably in the range of 50 to 150°C, and more preferably in the range of 70 to 120°C.

[0197] The reaction time for the aforementioned cyclization reaction accompanied by alkoxy groups is in the range of 5 minutes to 10 hours, preferably in the range of 10 minutes to 5 hours, and more preferably in the range of 20 minutes to 3 hours.

[0198] (Substitution reaction)

[0199] In the manufacturing method of the present invention, it is preferable to use the 2-alkoxy group (OR) of compound (2) (e.g., compound (2-1), compound (2-11), or compound (2-21)). b The matrix (2) was substituted with 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester to give compound B (e.g., compound (4), compound (5), compound (8)). As the aforementioned substitution reaction, it is preferred to carry out the reaction of the matrix (here, compound (2)) with 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester in a suitable solvent, in the presence or absence of an acid catalyst, under the preferred conditions shown below.

[0200] As the aforementioned acid catalysts, one or more of the following can be used alone or in appropriate proportions: organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, succinic acid, citric acid, methanesulfonic acid, trifluoromethanesulfonic acid, 10-camphor-sulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and perchloric acid; and Lewis acids such as boron trifluoride diethyl ether complex, boron trichloride, boron tribromide, zinc chloride, tin(IV) chloride, ferric chloride(III) chloride, aluminum chloride, titanium tetrachloride, and zirconium tetrachloride.

[0201] From the viewpoint of low toxicity, at least one of acetic acid and hydrochloric acid (preferably either one) is preferred as the aforementioned acid catalyst, and acetic acid is more preferred.

[0202] In the aforementioned substitution reaction, the amount of the aforementioned acid catalyst used relative to the aforementioned matrix is ​​0.01 to 1 equivalent, preferably 0.1 to 0.6 equivalent.

[0203] In the aforementioned substitution reaction, the amount of tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid used relative to the aforementioned matrix is ​​0.9 to 3 equivalents, preferably 1 to 1.5 equivalents.

[0204] As the aforementioned solvents, hydrocarbon-based organic solvents such as petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, and xylene can be used; halogenated hydrocarbon-based organic solvents such as carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, and chlorobenzene can be used; ether-based organic solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and diphenyl ether can be used; methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, and acetic acid can be used. The following are ester-based organic solvents: n-butyl acetate, isobutyl acetate, tert-butyl acetate, benzyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, isobutyl propionate, and tert-butyl propionate; and aprotic polar solvents such as acetone, 2-butanone, methyl isobutyl ketone, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, used alone or in combination of two or more in appropriate ratios.

[0205] Preferably, the solvent is selected from at least one of n-hexane, n-heptane, toluene, xylene, methyl tert-butyl ether, 2-methyltetrahydrofuran, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, and tert-butyl acetate; more preferably, the solvent is selected from at least one of toluene and ethyl acetate.

[0206] The reaction temperature of the aforementioned substitution reaction is in the range of 0 to 200°C, preferably in the range of 30 to 150°C, and more preferably in the range of 60 to 130°C.

[0207] The reaction time of the aforementioned substitution reaction is in the range of 10 minutes to 10 hours, preferably in the range of 20 minutes to 5 hours, and more preferably in the range of 30 minutes to 3 hours.

[0208] (Cross-coupling reaction)

[0209] In the manufacturing method of the present invention, the R of compound (2) or compound B 3 If the group is not thiazol-2-yl, a thiazol-2-yl group may be introduced via a cross-coupling reaction as needed. Preferably, a thiazol-2-yl group is introduced at the 7th position of compound (2) or compound B (e.g., compound (4), compound (2-1), compound (8)) via a cross-coupling reaction in the presence of a metal catalyst to obtain R. 3 Compound B is a thiazol-2-yl compound (e.g., compound (5), compounds (2-11), compound (9)).

[0210] As for the aforementioned cross-coupling reaction, the Kumada-Tamao-Corriu coupling reaction, the Yuda-Kosugi-Stille coupling reaction, the Suzuki-Miyaura coupling reaction, the Negishi coupling reaction, the Buchwald-Hartwig coupling reaction, or the Hiyama coupling reaction can be used, with the Kumada-Tamao-Corriu coupling reaction, the Suzuki-Miyaura coupling reaction, or the Negishi coupling reaction being preferred, and the Negishi coupling reaction being even more preferred.

[0211] As described above, the cross-coupling reaction is preferably carried out in a suitable solvent, in the presence of a metal catalyst, in the presence or absence of a ligand, and in the presence or absence of a base, by reacting the matrix (here, compound (2) or compound B) with 2-halothiazole (as needed, the substance that has been reacted with the reactant or directly), the preferred conditions of which are shown below.

[0212] As the aforementioned solvents, protic solvents such as water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, and tert-butanol can be used; hydrocarbon solvents such as petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, and xylene can be used; aromatic hydrocarbon solvents such as benzene, toluene, and xylene can be used; halogen solvents such as carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, and trifluoromethylbenzene can be used; and ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and diphenyl ether can be used. Organic solvents include methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, benzyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, isobutyl propionate, and tert-butyl propionate, etc.; and nonprotic polar solvents such as acetone, 2-butanone, methyl isobutyl ketone, cyclohexanone, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, etc., used alone or in combination of two or more in appropriate ratios.

[0213] As the aforementioned solvent, preferably, at least one selected from water, ethanol, toluene, tetrahydrofuran, 1,4-dioxane and N,N-dimethylformamide is preferred, and more preferably, at least one selected from toluene, tetrahydrofuran and N,N-dimethylformamide is preferred.

[0214] "2-Haloxythiazole" refers to a substance in which the second position of a thiazole is substituted with a halogen atom. Examples of such halogen atoms include fluorine, chlorine, bromine, or iodine, with bromine or iodine being preferred, and bromine being more preferred.

[0215] The aforementioned reactant refers to a substance used to replace the halogen atom of 2-halothiazole with other reactive functional groups, and examples include substances that perform metal exchange reactions. Preferably, the catalyst and boron compound used in the Miyauchi-Ishiyama boration reaction are examples such as pinacol diborane, combinations of pinacol borane and diboric acid, Grignard reagent, or zinc powder, and more preferably, zinc powder.

[0216] In the aforementioned cross-coupling reaction, the amount of 2-halothiazole used relative to the aforementioned matrix is ​​1 to 20 equivalents, preferably 1 to 10 equivalents.

[0217] As the aforementioned metal catalysts, palladium metal, palladium(II) chloride, palladium(II) bromide, palladium(II) iodide, palladium(II) acetate, palladium(II) trifluoroacetate, palladium(II) propionate, palladium(II) tert-valerate, palladium(II) acetylacetone, palladium(II) hexafluoroacetylacetone, palladium(II) cyanide, palladium(II) sulfate, palladium(II) nitrate, palladium(II) oxide, palladium(II) chloride (π-cinnamyl) dimer, [1,3-bis(diphenylphosphino)propane]bis(benzylnitrile)bis(tetrafluoroborate)palladium(II), trans-bis(acetate)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II), bis(acetonitrile)dichloropalladium(II), trans-bis(dicyclohexylamino)palladium(II) acetate, etc. [(dicyclohexyl)(4-dimethylaminophenyl)phosphine]dichloropalladium(II), [1,1'-bis(dicyclohexylphosphino)ferrocene]dichloropalladium(II), [1,2-bis(diphenylphosphino)ethane]dichloropalladium(II), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct, [1,4-bis(diphenylphosphino)butane]dichloropalladium(II), [1,3-bis(diphenylphosphino)propane]dichloropalladium(II), bis[di-(tert-butyl)(4-trifluoromethylphenyl)phosphine]dichloropalladium(II), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), bis(dibenzylene) Palladium (0) of acetone, bis(tricyclohexylphosphine)palladium (0), bis[tri-(2-methylphenyl)phosphine]palladium (0), bis(triphenylphosphine)dichloropalladium (II), bis(tri-tert-butylphosphine)palladium (0), bis[1,2-bis(diphenylphosphine)ethane]palladium (0), bis(benzylnitrile)dichloropalladium (II), bis(benzylnitrile)dibromopalladium (II), (2,2'-bispyridine)dichloropalladium (II), (2-butenyl)chloropalladium dimer, [1,3-bis(diphenylphosphine)propane]palladium (II) trifluoromethane sulfonate, [1,2-bis(phenylsulfinyl)ethane]palladium (II) acetate, diacetylbis(tricyclohexylphosphine)palladium (II), [2,2'-bis(diphenylphosphine)-1,1'-binaphthyl]dibromo Palladium(II), [1,1'-bis(diphenylphosphino)ferrocene]dibromopalladium(II), (1,5-cyclooctadiene)dibromopalladium(II), [2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]dichloropalladium(II), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) acetone adduct, bis(methyldiphenylphosphino)dichloropalladium(II), bis(triphenylphosphino)dichloropalladium(II), (1,10-phenanthroline)dichloropalladium(II), (N,N,N',N'-tetramethylethylenediamine)dichloropalladium(II), bis[di-tert-butyl(4-dimethylaminophenyl)phosphino]dichloropalladium(II), allyl palladium(II) chloride dimer, ethylenediamine (ethylenediamine)palladium(II), chloro(1,One of the following, 5-cyclooctadiene)methylpalladium(II), (1,5-cyclooctadiene)dichloropalladium(II), bis(tricyclohexylphosphine)dichloropalladium(II), bis(tri-o-tolylphosphine)dichloropalladium(II), 2-(2'-di-tert-butylphosphine)bisphenylpalladium(II) acetate, tetra(acetonitrile)tetrafluoroborate palladium(II), tetra(triphenylphosphine)palladium(O), tris(dibenzylacetone)dipalladium(O) and tris(dibenzylacetone)dipalladium(O) chloroform adduct, may be used alone or in combination of two or more in appropriate proportions.

[0218] As the aforementioned metal catalyst, preferably at least one (preferably any one) selected from palladium(II) acetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct, bis(triphenylphosphino)dichloropalladium(II), tetra(triphenylphosphino)palladium(O), tris(dibenzylideneacetone)dipalladium(O) and tris(dibenzylideneacetone)dipalladium(O) chloroform adduct is preferred, and more preferably at least one (preferably any one) selected from palladium(II) acetate and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct is preferred.

[0219] As the aforementioned ligand, for example, trimethylphosphine, triethylphosphine, tributylphosphine, tri-tert-butylphosphine, tri-tert-butylphosphonium tetrafluoroborate, trioctylphosphine, tricyclohexylphosphine, tricyclohexylphosphine tetrafluoroborate, tris(dimethylamino)phosphine, tris(diethylamino)phosphine, tris(3,5-dimethylphenyl)phosphine, tris(4-trifluoromethylphenyl)phosphine, tris(2,4,6-trimethylphenyl)phosphine, tris(2,4,6-trimethoxyphenyl)phosphine, tris(hydroxymethyl)phosphine, tris(4-fluorophenyl)phosphine, tris(pentafluorophenyl)phosphine, tris(o-methoxyphenyl)phosphine, tris(4-methoxyphenyl)phosphine, triphenylphosphine, triphenylphosphine oxide, tris(o-tolyl)phosphine, tris(o-tolyl)phosphine tetrafluoroborate, tris(m-tolyl)phosphine, tris(p-tolyl)phosphine, tris(2-furanyl)phosphine, bis(dicyclohexylphosphinophenyl) ether, 1, 1'-bis(diphenylphosphino)ferrocene, 1,1'-bis(di-tert-butylphosphino)ferrocene, bis[3,5-bis(trifluoromethyl)phenyl][2',6'-bis(isopropoxy)-3,6-dimethoxybisphenyl-2-yl]phosphine, 2,2'-bis(diphenylphosphino)-1,1'-biphenyl, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, tri-1-naphthylphosphine, tri[3, One of the following, 5-bis(trifluoromethyl)phenyl]phosphine, tris(4-chlorophenyl)phosphine, 5-(di-tert-butylphosphine)-1',3',5'-triphenyl-1'H-[1,4']bispyrazole, 5-(di-tert-butylphosphine)-1-(naphth-1-yl)-1H-pyrazole, triallylphosphine, triisopropylphosphine and triisopropylphosphonium tetrafluoroborate, may be used alone or in combination of two or more in appropriate proportions.

[0220] As the aforementioned ligand, preferably, at least one (preferably any one) selected from triphenylphosphine, tris(o-tolyl)phosphine, tris(m-tolyl)phosphine, tris(p-tolyl)phosphine, tris(2-furanyl)phosphine and 1,1'-bis(diphenylphosphino)ferrocene is preferred, and more preferably, at least one (preferably any one) selected from tris(p-tolyl)phosphine and 1,1'-bis(diphenylphosphino)ferrocene is preferred.

[0221] As the aforementioned base, it also includes its preferred form, as exemplified by the examples given above (partial substitution reaction).

[0222] The amount of the aforementioned metal catalyst used in the aforementioned cross-coupling reaction is 0.01 to 20 mol% relative to the total moles of the added raw materials (excluding solvent), preferably 0.1 to 15 mol%.

[0223] When using the aforementioned ligand and / or the aforementioned base, the ratio of the aforementioned metal catalyst to the aforementioned ligand (metal catalyst: ligand) and the ratio of the aforementioned metal catalyst to the aforementioned base (metal catalyst: base) are each independently 1:0.25 to 20 in molar ratio, preferably 1:1 to 5.

[0224] The reaction temperature of the aforementioned cross-coupling reaction is in the range of 0 to 200°C, preferably in the range of 30 to 150°C, and more preferably in the range of 60 to 120°C.

[0225] The reaction time of the aforementioned cross-coupling reaction is in the range of 1 minute to 48 hours, preferably in the range of 15 minutes to 12 hours, and more preferably in the range of 30 minutes to 6 hours.

[0226] (Deprotection reaction)

[0227] In the manufacturing method of the present invention, as the deprotection reaction, a hydrodecomposition reaction, a Lewis acid-based deprotection reaction, or an organic acid-based deprotection reaction can be used. Preferably, a Lewis acid-based and / or organic acid-based deprotection reaction can be used, and more preferably, an organic acid-based deprotection reaction can be used.

[0228] In the manufacturing method of the present invention, the R of compound B a If a protecting group (e.g., benzyl) is present, it is removed. R is preferably removed by reacting compound B (e.g., compound (5)) with an organic acid. a The protecting group was removed to obtain compound (3). Alternatively, compound (1) was obtained by reacting compound C with an organic acid to remove Boc. As the aforementioned deprotection reaction, it is preferred to carry out the reaction of the matrix (here, compound (5) or compound C) with an organic acid in a suitable solvent, and the preferred conditions are shown below.

[0229] As the aforementioned solvents, one or more of the following can be used alone or in appropriate proportions: hydrocarbon organic solvents such as petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, and xylene; halogenated hydrocarbon organic solvents such as carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, and chlorobenzene; and ether organic solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and diphenyl ether.

[0230] As the aforementioned solvent, preferably at least one selected from toluene, xylene, and dichloromethane is preferred, and more preferably at least one selected from toluene and dichloromethane is preferred.

[0231] As the aforementioned organic acid, one or more of the following can be used alone or in appropriate proportions: trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, chloroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, 10-camphor-sulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Trifluoroacetic acid is preferably one of the aforementioned organic acids.

[0232] In the aforementioned deprotection reaction, the amount of the aforementioned organic acid used relative to the aforementioned matrix is ​​1 to 50 equivalents, preferably 5 to 20 equivalents.

[0233] The reaction temperature for the aforementioned deprotection reaction is in the range of 0 to 200°C, preferably in the range of 20 to 150°C.

[0234] The reaction time for the aforementioned deprotection reaction is in the range of 5 minutes to 48 hours, preferably in the range of 20 minutes to 24 hours.

[0235] (Protective response)

[0236] It should be noted that in the conditions of process 1 above, by performing the aforementioned deprotection reaction on compound B, the N-Boc group of compound B, which serves as the protecting group, is also removed, generating the free base of compound (3). Therefore, it is preferable to add Boc again (to replace it with Boc for protection). In this case, after separating the free base of compound (3), Boc can be added again using a general method known to those skilled in the art, or the reaction mixture after the above deprotection reaction can be adjusted to neutral to basic, and the matrix in the aforementioned reaction mixture (here, the free base of compound (3)) can be reacted with di-tert-butyl dicarbonate in the presence or absence of a suitable auxiliary solvent, preferably the method described later. The preferred conditions for the protection reaction described later are as follows.

[0237] As auxiliary solvents, protic solvents such as water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, and tert-butanol; hydrocarbon organic solvents such as petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, and xylene; halogenated hydrocarbon organic solvents such as carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, and chlorobenzene; ether organic solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and diphenyl ether; and methyl acetate, etc. Ester-based organic solvents such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, benzyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, isobutyl propionate, and tert-butyl propionate; and nonprotic polar solvents such as acetone, 2-butanone, methyl isobutyl ketone, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, can be used alone or in combination of two or more in appropriate ratios.

[0238] As the aforementioned solvent, preferably at least one selected from water, methanol, ethanol, n-propanol, 2-propanol, dichloromethane, chloroform and ethyl acetate is preferred, and more preferably at least one selected from water, methanol and dichloromethane is preferred.

[0239] To adjust the aforementioned reaction mixture to a neutral to alkaline state, salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium phosphate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and barium hydroxide; ammonia, methylamine, ethylamine, cyclohexylamine, ethanolamine, aniline, dimethylamine, diethylamine, dibutylamine, dicyclohexylamine, bis(trimethylsilylamine), pyrrolidine, piperidine, piperazine, morpholine, trimethylamine, triethylamine, tributylamine, diisopropylethylamine, 2-(dimethylamino)ethanol, N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine, N,N'-dimethylpiperazine, N,N,N',N'-tetramethylethylenediamine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8 -Amines such as diazabicyclo[5.4.0]undec-7-ene, pyridine, methylpyridine, 4-(dimethylamino)pyridine, 2,6-dimethylpyridine and 2,4,6-trimethylpyridine; alkane oxides such as lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, succinic acid, citric acid, methanesulfonic acid, trifluoromethanesulfonic acid, 10-camphor-sulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and perchloric acid; and Lewis acids such as boron trifluoride diethyl ether complex, boron trichloride, boron tribromide, magnesium chloride, magnesium bromide diethyl ether complex, zinc chloride, tin(IV) chloride, ferric chloride(III) chloride, aluminum chloride, titanium tetrachloride and zirconium tetrachloride, etc., used alone or in appropriate proportions in combination of two or more.

[0240] From the viewpoint of low toxicity, at least one of the following is preferably selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, acetic acid, trifluoroacetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, and nitric acid (preferably any one); more preferably, at least one of the following is selected from sodium bicarbonate, sodium hydroxide, hydrochloric acid, and sulfuric acid (preferably any one). In this case, the pH of the aforementioned reaction mixture is adjusted to approximately 6.8 to 12.0, preferably to approximately 7.0 to 9.5.

[0241] Di-tert-butyl dicarbonate is used in an amount of 0.9 to 5 equivalents relative to the aforementioned matrix, preferably in an amount of 1 to 2 equivalents.

[0242] The reaction temperature of the aforementioned protective reaction is in the range of 0 to 100°C, preferably in the range of 10 to 80°C, and more preferably in the range of 20 to 60°C.

[0243] The reaction time of the aforementioned protective reaction is in the range of 10 minutes to 24 hours, preferably in the range of 20 minutes to 12 hours, and more preferably in the range of 30 minutes to 6 hours.

[0244] (Transformation reaction)

[0245] In the manufacturing method of the present invention, as a conversion reaction of halogen atoms to hydrogen atoms, a method for removing halogen atoms by means of metal exchange reaction or reduction reaction can be used. Preferably, a reduction reaction based on catalytic hydrogenation or metal can be used, and more preferably, a reduction reaction based on metal can be used.

[0246] In the manufacturing method of the present invention, compound B's X a In the case where it is not a hydrogen atom but a halogen atom, it is converted into a hydrogen atom. Preferably, this is achieved by reacting compound B (e.g., compound (9)) with a metal, thereby converting X into a hydrogen atom. a The halogen atoms are converted into hydrogen atoms to obtain compound (3). As for the aforementioned conversion reaction, it is preferred to carry out the reaction between the matrix (here, compound B) and the metal in a suitable solvent, in the presence or absence of an acid or base, and the preferred conditions are as follows.

[0247] As the aforementioned solvents, protic solvents such as water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, and tert-butanol can be used; hydrocarbon solvents such as petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, and xylene can be used; aromatic hydrocarbon solvents such as benzene, toluene, and xylene can be used; ether-based organic solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and diphenyl ether can be used; methyl acetate, ethyl acetate, acetic acid, etc. The following are ester-based organic solvents: n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, benzyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, isobutyl propionate, and tert-butyl propionate; and a variety of nonprotic polar solvents such as acetone, 2-butanone, methyl isobutyl ketone, cyclohexanone, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, used alone or in appropriate proportions.

[0248] As the aforementioned solvent, preferably, at least one selected from water, methanol, ethanol, n-propanol, 2-propanol, tetrahydrofuran, and 1,4-dioxane is preferred, and more preferably, at least one selected from water, 1,4-dioxane, and ethanol is preferred.

[0249] As the aforementioned acid, one or more of the following can be used alone or in appropriate proportions: inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and nitric acid; carboxylic acids such as formic acid, acetic acid, propionic acid, and trifluoroacetic acid; and ammonium salts of carboxylic acids such as ammonium carbonate, ammonium formate, and ammonium acetate.

[0250] As the aforementioned base, salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium phosphate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and barium hydroxide; ammonia, methylamine, ethylamine, cyclohexylamine, ethanolamine, aniline, dimethylamine, diethylamine, dibutylamine, dicyclohexylamine, bis(trimethylsilylamine), pyrrolidine, piperidine, piperazine, morpholine, trimethylamine, triethylamine, tributylamine, diisopropylethylamine, 2-(dimethylamino)ethanol, N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine, N,N'- Amines such as dimethylpiperazine, N,N,N',N'-tetramethylethylenediamine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, methylpyridine, 4-(dimethylamino)pyridine, 2,6-dimethylpyridine, and 2,4,6-trimethylpyridine; and alkane oxides such as lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide, etc., are used alone or in combination of two or more in appropriate proportions.

[0251] As the aforementioned base, preferably, at least one selected from sodium hydroxide, potassium hydroxide, ammonium formate and ammonium acetate is preferred, and more preferably, at least one selected from sodium hydroxide and ammonium formate is preferred.

[0252] The amount of acid or base used in the aforementioned conversion reaction is 10 to 50 equivalents relative to the aforementioned matrix, preferably 20 to 40 equivalents, and more preferably 20 to 30 equivalents.

[0253] As for the aforementioned metals, one of samarium (II) iodide, ytterbium (III) iodide, aluminum, zinc, iron, tin, samarium and ytterbium can be used alone or in combination of two or more in appropriate proportions.

[0254] As for the aforementioned metals, at least one selected from zinc and iron (preferably either one) is preferred, and zinc is more preferred.

[0255] The amount of the aforementioned metal used in the aforementioned conversion reaction is 10 to 50 equivalents relative to the aforementioned matrix, preferably 20 to 40 equivalents, and more preferably 20 to 30 equivalents.

[0256] The reaction temperature of the aforementioned conversion reaction is in the range of 0 to 200°C, preferably in the range of 30 to 150°C, and more preferably in the range of 60 to 120°C.

[0257] The reaction time of the aforementioned conversion reaction is in the range of 30 minutes to 24 hours, preferably in the range of 1 hour to 12 hours, and more preferably in the range of 2 hours to 6 hours.

[0258] (O-alkylation reaction)

[0259] In the manufacturing method of the present invention, compound C is preferably obtained by dialkylating the 4th hydroxyl group of compound (3) via an O-alkylation reaction. As the aforementioned O-alkylation reaction, it is preferred to react the matrix (here, compound (3)) with ethyl 2-bromo-2,2-difluoroacetate in a suitable solvent, in the presence or absence of a base, followed by dialkylation with an organometallic reagent, with the preferred conditions as shown below.

[0260] As the aforementioned solvents, protic solvents such as water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, and tert-butanol can be used; hydrocarbon solvents such as petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, and xylene can be used; ether-based organic solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and diphenyl ether can be used; methyl acetate, ethyl acetate, n-propyl acetate, and isopropyl acetate can be used. The following are ester-based organic solvents: n-butyl acetate, isobutyl acetate, tert-butyl acetate, benzyl acetate, methyl propionate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, isobutyl propionate, and tert-butyl propionate; and aprotic polar solvents such as acetone, 2-butanone, methyl isobutyl ketone, cyclohexanone, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, used alone or in combination of two or more in appropriate ratios.

[0261] As the aforementioned solvent, preferably at least one selected from methanol, ethanol, toluene, tetrahydrofuran, ethyl acetate, acetonitrile, and N,N-dimethylformamide is preferred, and more preferably at least one selected from acetonitrile and N,N-dimethylformamide is preferred.

[0262] As the aforementioned base, salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium phosphate, phosphorus, potassium, lithium hydroxide, sodium hydroxide, potassium hydroxide, and barium hydroxide can be used; trimethylamine, triethylamine, tributylamine, diisopropylethylamine, 2-(dimethylamino)ethanol, N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine, N,N'-dimethylpiperazine, N,N,N',N'-tetramethylethylenediamine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4]octane, etc. [0] Amines such as undecyl-7-ene, pyridine, methylpyridine, 4-(dimethylamino)pyridine, 2,6-dimethylpyridine and 2,4,6-trimethylpyridine; metal hydrides such as lithium hydride, sodium hydride, potassium hydride, barium hydride and calcium hydride; alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; metal amides such as lithium amino, sodium amino, potassium amino, diisopropylamino, lithium 2,2,6,6-tetramethylpyridinium, lithium di(trimethylsilyl)amino, sodium di(trimethylsilyl)amino and potassium di(trimethylsilyl)amino; and potassium trimethylsilanolate, etc., used alone or in combination of two or more in appropriate proportions.

[0263] As the aforementioned base, preferably, at least one selected from sodium carbonate, potassium carbonate, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydride and sodium tert-butoxide is preferred, and more preferably, at least one selected from 1,8-diazabicyclo[5.4.0]undec-7-ene and sodium tert-butoxide is preferred.

[0264] In the aforementioned O-alkylation reaction (reaction with ethyl 2-bromo-2,2-difluoroacetate), the amount of the aforementioned base used relative to the aforementioned matrix is ​​1 to 20 equivalents, preferably 2 to 5 equivalents.

[0265] In the aforementioned O-alkylation reaction, the amount of ethyl 2-bromo-2,2-difluoroacetate used relative to the aforementioned matrix is ​​1 to 10 equivalents, preferably 2 to 6 equivalents.

[0266] The reaction temperature of the aforementioned O-alkylation reaction (reaction with ethyl 2-bromo-2,2-difluoroacetate) is in the range of 0 to 100°C, preferably in the range of 10 to 60°C, and more preferably in the range of 15 to 40°C.

[0267] The reaction time for the aforementioned O-alkylation reaction (reaction with ethyl 2-bromo-2,2-difluoroacetate) is in the range of 5 minutes to 24 hours, preferably in the range of 10 minutes to 12 hours, and more preferably in the range of 20 minutes to 6 hours.

[0268] As the aforementioned organometallic reagents, one of the following can be used alone or in combination in appropriate ratios: organomagnesium reagents, organolithium reagents, organozinc reagents, organoboron reagents, organtin reagents, organosilicon reagents, organobisman reagents, organgermanium reagents, organmercury reagents, etc.

[0269] As the aforementioned organometallic reagent, at least one (preferably any one) selected from organomagnesium reagent, organolithium reagent, and organozinc reagent is preferred, and organomagnesium reagent is more preferred.

[0270] In the aforementioned O-alkylation reaction, the amount of the aforementioned organometallic reagent used relative to the aforementioned matrix is ​​2 to 10 equivalents, preferably 2.5 to 5 equivalents.

[0271] The reaction temperature of the aforementioned O-alkylation reaction (reaction with organometallic reagent) is in the range of 0 to 100°C, preferably in the range of 10 to 60°C, and more preferably in the range of 15 to 40°C.

[0272] The reaction time for the aforementioned O-alkylation reaction (reaction with organometallic reagent) is in the range of 5 minutes to 24 hours, preferably in the range of 10 minutes to 12 hours, and more preferably in the range of 20 minutes to 6 hours.

[0273] Example

[0274] The present invention will be described in more detail below using embodiments, but the invention is not limited to these embodiments. Various applications, modifications, and alterations can be made to the embodiments described below without departing from the scope of the invention.

[0275] In the following examples, the ellipsis has the following meaning.

[0276] M: mol / L

[0277] 1 H-NMR: Results of the proton nuclear magnetic resonance spectrum of the obtained compound.

[0278] Pd-C: Palladium catalyst supported on activated carbon

[0279] THF: Tetrahydrofuran

[0280] DMF: N,N-Dimethylformamide

[0281] DMSO: Dimethyl sulfoxide

[0282] Boc: tert-butoxycarbonyl

[0283] (Boc)2O: Di-tert-butyl dicarbonate

[0284] Bn: Benzyl.

[0285] (Example 1)

[0286] [Synthetic Example 1] 3-Benzyloxy-6-bromo-2-nitrophenol

[0287]

[0288] 2,6-Difluoronitrobenzene (52.75 g, 331.6 mmol) was dissolved in DMSO (158 mL), and benzyl alcohol (35.86 g, 331.6 mmol) and potassium carbonate (91.65 g, 663 mmol) were added. The mixture was stirred at 90 °C for 24 hours to obtain a product containing the aforementioned formula (10-11), wherein R in the formula... 2 The reaction solution was a compound containing a fluorine atom. After cooling, the reaction solution was diluted with ethyl acetate (422 mL), and washed sequentially with 211 mL each of water and 0.1 M hydrochloric acid. The resulting organic layer was replaced with acetonitrile while the solution was concentrated to obtain a 211 mL acetonitrile solution. Acetonitrile (211 mL), N-bromosuccinimide (88.53 g, 497.4 mmol), and acetic acid (4.75 mL, 83.1 mmol) were added to the obtained solution. After cooling to below 10 °C, trichlorosilane (18.02 g, 165.9 mmol) was added, and the mixture was stirred at below 10 °C for 2 hours to obtain a compound containing the aforementioned formula (10-12), where R... 2 The reaction solution contained in the fluorine atom was prepared. Water (164 mL) and a 20% sodium bisulfite aqueous solution (164 mL) were added to the aforementioned reaction solution. After stirring, toluene (528 mL) was added and stirred, and the aqueous layer was removed. The resulting organic layer was washed twice with a 2M sodium hydroxide aqueous solution (249 mL), DMSO (492 mL) was added and the solution was concentrated, with the toluene distilled off. A 6.25M sodium hydroxide aqueous solution (127 mL) was added to the resulting solution, and the mixture was stirred at 70°C for 1 hour. After cooling the reaction solution, toluene (633 mL) and water (1266 mL) were added, and the solution was stirred, with the organic layer removed. Toluene (791 mL) and 6M hydrochloric acid (146 mL) were added to the resulting aqueous layer, and the solution was stirred, with the aqueous layer removed. The resulting organic layer was washed with water, and the solution was concentrated while simultaneously replacing it with 2-propanol to obtain a 2-propanol (370 mL) solution. Water (296 mL) was added to the solution to precipitate the solid. After cooling and stirring, the solid was separated, washed with a mixture of 2-propanol / water = 1 / 2, and dried to give 84.08 g of the title compound (yield 78.2%).

[0289] 1H-NMR (400MHz, CDCl3) δppm: 9.81 (s, 1H), 7.61 (d, J = 9.1Hz, 1H), 7.45-7.32 (m, 5H), 6.55 (d, J = 9.1Hz, 1H), 5.20 (s, 2H).

[0290] [Synthetic Example 2] 2-Amino-3-benzyloxy-6-bromophenol

[0291]

[0292] Sodium dithionite (purity 90.6%) (118.58 g, 617 mmol) was dissolved in water (480 mL) and cooled to 10 °C. 3-Benzyloxy-6-bromo-2-nitrophenol (40.0 g, 123.4 mmol) obtained in Synthetic Example 1 was dissolved in ethanol (560 mL) and added to the sodium dithionite aqueous solution. The mixture was stirred at 3–10 °C for 1 hour. Water (1200 mL) was added to the reaction mixture, and after stirring, the resulting solid was filtered off, washed with water, and dried to give 29.9 g of the title compound (yield 82.4%).

[0293] 1 H-NMR (400MHz, CDCl3) δppm: 7.45-7.33 (m, 5H), 6.80 (d, J = 8.7Hz, 1H), 6.44 (d, J = 8.7Hz, 1H), 5.37 (br s, 1H), 5.07 (s, 2H), 3.91 (br s, 2H).

[0294] [Synthetic Example 3] 3-(4-benzyloxy-7-bromobenzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

[0295]

[0296] The 2-amino-3-benzyloxy-6-bromophenol (10.0 g, 33.99 mmol) obtained in Synthesis Example 2 was suspended in toluene (20 mL), and acetic acid (0.98 mL, 17.1 mmol) and tetraethoxymethane (7.84 mL, 37.3 mmol) were added. The mixture was heated under reflux for 30 minutes to obtain a reaction solution containing the compound represented by the aforementioned formula (15). 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (8.79 g, 44.3 mmol) and toluene (6 mL) were added to the aforementioned reaction solution, and the mixture was heated under reflux for 2 hours. After cooling, the reaction solution was diluted with toluene (40 mL), washed sequentially with 5% sodium bicarbonate aqueous solution (40 mL) and water (40 mL), and concentrated to 24 mL. Add 180 mL of n-heptane to the resulting solution to precipitate the solid. After cooling and stirring, filter the solid, wash it with n-heptane, and dry it to obtain 15.93 g of the title compound (yield 93.7%).

[0297] 1 H-NMR (400MHz, CDCl3) δppm: 7.44 (d, J=6.9Hz, 2H), 7.37-7.25 (m, 3H), 6.97 (d, J=8.4Hz, 1H), 6.59 (d, J=8.4Hz, 1H ),5.35(s,2H),4.35-4.20(m,4H),3.76(d,J=11.0Hz,2H),2.75-2.67(m,1H),1.55(d,J=9.2Hz,1H),1.41(s,9H).

[0298] [Synthetic Example 4] 3-(4-benzyloxy-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

[0299]

[0300] Zinc powder (6.47 g, 98.9 mmol) was suspended in DMF (22.5 mL), and trichloromethylsilane (0.6 mL, 4.7 mmol) was added. The mixture was stirred at 60 °C for 1 hour. 2-Bromothiazole (6.7 mL, 75.6 mmol) was added to the reaction mixture, and the mixture was stirred for 20 minutes. A toluene (15 mL) solution of 3-(4-benzyloxy-7-bromobenzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (7.5 g, 15.0 mmol) obtained in Synthesis Example 3, copper chloride (I) (0.15 g, 1.5 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.61 g, 0.75 mmol) were added, and the mixture was stirred at 85 °C for 1 hour. After cooling the reaction solution, toluene (225 mL) and 1 M hydrochloric acid (225 mL) were added, and the mixture was stirred for 30 minutes. The insoluble matter was then removed by filtration. The organic layer obtained after removing the aqueous layer was washed with water and concentrated. 2-Propanol (75 mL) was added to the concentrated residue and stirred. The resulting crystals were filtered off, washed with 2-propanol, and dried under reduced pressure to give 6.67 g of the title compound (88% yield).

[0301] 1 H-NMR (400MHz, CDCl3) δppm: 7.88 (d, J = 3.2Hz, 1H), 7.75 (d, J = 8.7Hz, 1H), 7.48 (d, J = 7.4Hz, 2H), 7.38-7.25 (m, 4H), 6.80 (d, J=8.7Hz,1H),5.44(s,2H),4.45-4.25(m,4H),3.83(d,J=10.6Hz,2H),2.75-2.68(m,1H),1.58(d,J=8.7Hz,1H),1.42(s,9H).

[0302] [Synthetic Example 5] 3-(4-hydroxy-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

[0303]

[0304] The tert-butyl 3-(4-benzyloxy-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid obtained in Synthesis Example 4 (50.0 g, 99.09 mmol) was suspended in toluene (150 mL), and trifluoroacetic acid (150 mL, 1960 mmol) was added. The mixture was stirred at 80 °C for 20 hours. The reaction solution was cooled to near room temperature, and methanol (300 mL), water (200 mL), and dichloromethane (480 mL), which had been pre-cooled to near 5 °C, were added. Then, 5 M sodium hydroxide aqueous solution (400 mL) was added, and the mixture was stirred at room temperature. The pH was adjusted to near 8.6 with 6 M hydrochloric acid. Add (Boc)₂O (25.0 mL, 109.0 mmol), heat to 30 °C, and after 20 minutes, add 5% sodium bicarbonate aqueous solution (83.2 mL, 49.50 mmol), followed by another 5% sodium bicarbonate aqueous solution (83.2 mL, 49.50 mmol) after 30 minutes, and stir for 1 hour. Separate the aqueous and organic layers of the reaction solution, and extract the aqueous layer again with dichloromethane (100 mL). Concentrate the combined organic layer under reduced pressure to approximately 250 mL, add acetonitrile (300 mL), and concentrate under reduced pressure to approximately 250 mL, repeating twice. Allow to crystallize and mature at room temperature for 30 minutes, stir at 60 °C for 1 hour, cool to room temperature for 1 hour, and then mature on an ice bath for 1 hour. Filter the resulting solid, wash with cooled acetonitrile (75 mL), and then dry under aeration. Acetonitrile (250 mL) was added to the obtained crude title compound, and the mixture was stirred at 80 °C for 1 hour. After cooling to room temperature for 2 hours, it was allowed to mature, and then matured in an ice bath for 1 hour. The solid was filtered off, washed with cooled acetonitrile (75 mL), and dried under reduced pressure at 40 °C to obtain 42.2 g of the title compound 1-acetonitrile compound (yield 93.5%).

[0305] 1 H-NMR (400MHz, CDCl3) δppm: 9.44 (br s,1H),7.90(d,J=3.2Hz,1H),7.81(d,J=8.7Hz,1H),7.38(d,J=3.2Hz,1H),6.87(d,J=8.7Hz,1H ),4.38-4.18(m,4H),3.80-3.68(m,2H),2.75-2.67(m,1H),1.55(d,J=8.7Hz,1H),1.37(s,9H).

[0306] [Synthetic Example 6] 3-(4-(1,1-difluoro-2-hydroxy-2-methylpropoxy)-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

[0307]

[0308] The tert-butyl 3-(4-hydroxy-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid ester (50.0 g, 120.6 mmol) obtained in Synthetic Example 5 was dissolved in acetonitrile (225 mL), and ethyl 2-bromo-2,2-difluoroacetate (46.7 mL, 361.9 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (54.0 mL, 361.9 mmol) were added. The mixture was stirred at 30 °C for 3 hours. The reaction solution was cooled to near 0 °C, and pre-cooled toluene (750 mL) and 0.3 M hydrochloric acid were added and stirred to remove the aqueous layer. The resulting organic layer was washed twice with water (250 mL), and magnesium sulfate (5 g) was added before filtration. The filtrate was concentrated to 250 mL under reduced pressure. Toluene (250 mL) was added, and the solution was concentrated again to 250 mL under reduced pressure. The resulting solution was cooled to 5°C, and 336 mL (361.9 mmol) of 1.08 M methyl magnesium bromide THF solution was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was cooled to near 0°C, and 500 mL of toluene and 500 mL of 1 M hydrochloric acid were added and stirred to remove the aqueous layer. The resulting organic layer was washed sequentially with 500 mL of 0.1 M sodium hydroxide aqueous solution, 500 mL of 10% potassium hydrogen sulfate aqueous solution, and 500 mL of water, and then concentrated to 250 mL under reduced pressure. Activated carbon (5 g) was added to the resulting solution, and the mixture was stirred at 60°C for 1 hour and filtered through diatomaceous earth. The filtrate was concentrated to 250 mL under reduced pressure, and 750 mL of ethanol was added. The concentration was repeated. The resulting solution was stirred at room temperature for 2 hours, and then stirred at 0°C for 1 hour to allow crystallization. The resulting crystals were filtered and washed with ethanol (100 mL). Ethanol (500 mL) was added to the crystals, and the mixture was heated to 70 °C and stirred for 3 hours. After cooling to room temperature for 2 hours, the mixture was stirred overnight. The solution was cooled to below 0 °C and stirred for 1 hour. The resulting crystals were washed with ethanol (2 vol) at below 10 °C and dried under reduced pressure to give 50.69 g of the monoethanolate of the title compound (yield 73.9%).

[0309] 1H-NMR (400MHz, DMSO-d6) δppm: 8.05(s,J=4.0Hz,1H),7.97(s,J=4.0Hz,1H),7.79(s,J=10.0Hz,1H),7.21(s,J=1 0.0Hz,1H),5.59(s,1H),4.38-3.70(m,6H),2.70-2.55(m,1H),1.61(d,J=8.0Hz,1H),1.41(s,6H),1.27(S,9H).

[0310] [Synthetic Example 7] 1-{[2-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-7-(1,3-thiazo-2-yl)-1,3-benzoxazol-4-yl]oxy}-1,1-difluoro-2-methylpropane-2-ol

[0311]

[0312] 10 g (19.2 mmol) of 3-(4-(1,1-difluoro-2-hydroxy-2-methylpropoxy)-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester obtained from Synthesis Example 6 was dissolved in dichloromethane (25 mL), and trifluoroacetic acid (18.3 mL, 238.8 mmol) was added. The mixture was stirred at 40 °C for 2 hours. Methanol (30 mL) and dichloromethane (165 mL) were added to the reaction mixture, followed by the addition of 5N sodium hydroxide aqueous solution (100 mL) at below 30 °C and stirring. The aqueous and organic layers were separated, and the aqueous layer was extracted again with dichloromethane (10 mL). Methanol (30 mL) and water (100 mL) were added to the combined organic layer and stirred. The aqueous and organic layers were separated, and the aqueous layer was extracted again with dichloromethane (10 mL). The combined organic layer was concentrated to 100 mL, and after adding toluene (50 mL), it was concentrated to 50 mL. Toluene (100 mL) was added to this concentrate, and the mixture was stirred at room temperature for 1 hour, then at 55 °C for 1 hour, and finally at 0 °C for at least 1 hour. The resulting solid was filtered off. The solid was washed with toluene (30 mL) cooled to below 10 °C, dried under reduced pressure, and 6.76 g of crude crystals of the title compound were obtained (yield 90.9%).

[0313] [Synthesis example 8]

[0314] The crude crystals (20 g) of 1-{[2-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-7-(1,3-thiazo-2-yl)-1,3-benzoxazol-4-yl]oxy}-1,1-difluoro-2-methylpropane-2-ol obtained in Synthesis Example 7 were dissolved in 300 mL of 85% aqueous ethanol solution. This solution was heated to 70 °C, and after confirming the dissolution of the crude crystals, it was cooled to 40 °C and filtered. The filtrate was concentrated to 100 mL under reduced pressure, and 100 mL of ethanol was added. The concentration was then reduced to 100 mL under reduced pressure, and this process was repeated twice. The concentrate was stirred overnight at 0 °C to allow the solid to precipitate. The resulting solid was filtered off, washed with pre-cooled ethanol (40 mL), and dried under reduced pressure to give 17.8 g (89.0% yield) of recrystallized 1-{[2-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-7-(1,3-thiazo-2-yl)-1,3-benzoxazol-4-yl]oxy}-1,1-difluoro-2-methylpropane-2-ol.

[0315] 1 H-NMR (400MHz, DMSO-d6) δppm: 8.02 (d, J = 3.2Hz, 1H), 7.92 (d, J = 3.2Hz, 1H), 7.76 (d, J = 8.7Hz, 1H), 7.20 (d, J = 8.7Hz, 1H), 5.48(s,1H),3.93-3.80(m,4H),3.69(d,J=6.0Hz,2H),2.61-2.54(m,1H),1.89(s,1H),1.60(d,J=9.2Hz,1H),1.41(s,6H).

[0316] (Example 2)

[0317] [Synthetic Example 1] 4-Benzyloxy-7-bromo-2-ethoxybenzo[d]oxazole

[0318]

[0319] 2-Amino-3-benzyloxy-6-bromophenol (8.83 g, 30.0 mmol) obtained in Synthesis Example 2 of Example 1 was dissolved in toluene (27 mL), and acetic acid (0.86 mL, 15.0 mmol) and tetraethoxymethane (6.34 g, 33.0 mmol) were added. The mixture was heated under reflux for 30 minutes. The reaction solution was diluted with ethyl acetate and washed sequentially with 5% sodium bicarbonate aqueous solution and water. The resulting organic layer was concentrated while replacing it with 2-propanol to prepare a 72 mL solution. The solution was stirred and allowed to precipitate a solid. After cooling, the solid was filtered off, washed with 2-propanol, and dried to give 9.84 g of the title compound (yield 94.3%).

[0320] 1 H-NMR (400MHz, CDCl3) δppm: 7.45 (d, J = 7.4Hz, 2H), 7.39-7.27 (m, 3H), 7.12 (d, J = 8.7Hz ,1H),6.65(d,J=8.7Hz,1H),5.37(s,2H),4.68(q,J=7.3Hz,2H),1.51(t,J=7.3Hz,3H).

[0321] [Synthetic Example 2] 4-Benzyloxy-2-ethoxy-7-(thiazolyl-2-yl)benzo[d]oxazole

[0322]

[0323] Zinc powder (1.57 g, 24.0 mmol) was suspended in DMF (15 mL), and trichloromethylsilane (0.25 mL, 2.0 mmol) was added. The mixture was stirred at 50 °C for 1 hour. The reaction solution was heated to 60 °C, and 2-bromothiazole (1.8 mL, 20.3 mmol) was added and stirred. Then, 4-benzyloxy-7-bromo-2-ethoxybenzo[d]oxazole (3.48 g, 10.0 mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II)dichloromethane adduct (0.24 g, 0.29 mmol), and DMF (10 mL) obtained from Synthesis Example 1 were added, and the mixture was stirred at above 80 °C for 1 hour and then cooled. Toluene (35 mL), DMF (18 mL), and sulfuric acid diluted 20 times (18 mL) were added to the reaction solution, and the mixture was stirred for 1 hour. The aqueous layer was then removed. DMF (18 mL) and sulfuric acid diluted 20 times (18 mL) were added to the obtained organic layer, and the mixture was stirred. The aqueous layer was then removed. The resulting organic layer was washed with water. The same operation was repeated to obtain the same amount of organic layer. The resulting organic layers were mixed and concentrated while being replaced with 2-propanol to prepare a 70 mL solution. This solution was stirred to precipitate a solid. After cooling, the solid was filtered off, washed with 2-propanol, and dried to give 6.06 g of the title compound (yield 86.0%).

[0324] 1 H-NMR (400MHz, CDCl3) δppm: 7.91 (d, J = 3.2Hz, 1H), 7.84 (d, J = 9.2Hz, 1H), 7.49 (d, J = 7.4Hz, 2H), 7 .40-7.30(m,4H),6.86(d,J=9.2Hz,1H),5.45(s,2H),4.72(q,J=6.8Hz,2H),1.55(t,J=6.8Hz,3H).

[0325] [Synthetic Example 3] 3-(4-benzyloxy-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

[0326]

[0327] 4-Benzyloxy-2-ethoxy-7-(thiazol-2-yl)benzo[d]oxazole (3.0 g, 8.5 mmol) obtained in Synthetic Example 2 was dissolved in toluene (12 mL), and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid (1.86 g, 9.4 mmol) and acetic acid (0.25 mL, 4.4 mmol) were added. The mixture was heated under reflux for 1 hour. The reaction solution was diluted with toluene and washed sequentially with 5% sodium bicarbonate aqueous solution and water. The resulting organic layer was concentrated while replacing it with 2-propanol to prepare a 30 mL solution. This solution was stirred to precipitate a solid. After cooling, the solid was filtered off, washed with 2-propanol, and dried to give 3.97 g of the title compound (yield 92.5%). 1 The H-NMR values ​​were consistent with those of the compound obtained in Synthesis Example 4 of Example 1.

[0328] (Example 3)

[0329] [Synthetic Example 1] 5,7-Dibromo-2-ethoxybenzo[d]oxazol-4-ol

[0330]

[0331] 2-Nitroresorcinol (5.0 g, 32.235 mmol) was dissolved in ethyl acetate (50 mL), and 10% Pd-C (PE type) (0.25 g) was added. The mixture was stirred vigorously at room temperature under hydrogen conditions for 1.5 hours to obtain a reaction solution containing 2-aminoresorcinol. The reaction solution was filtered through diatomaceous earth, and the residue was washed with ethyl acetate (30 mL divided into several portions). The filtrate was concentrated under reduced pressure to 50 mL. Ethyl acetate (25 mL), acetic acid (0.92 mL, 16.060 mmol), and tetraethoxymethane (10.1 mL, 48.330 mmol) were added to this solution under nitrogen conditions, and the mixture was stirred at 85 °C for 1 hour to obtain a reaction solution containing 2-ethoxybenzo[d]oxazol-4-ol. The reaction solution was cooled and washed sequentially with 5% sodium bicarbonate aqueous solution (50 mL) and water (50 mL), and concentrated under reduced pressure to 50 mL. Ethyl acetate (50 mL) was added to the resulting solution, and N-bromosuccinimide (12.05 g, 67.770 mmol) was added in portions under ice-cold conditions. The mixture was heated to room temperature and stirred for 1 hour to obtain a reaction solution containing the title compound. Ethyl acetate (50 mL) was added to the aforementioned reaction solution, and the mixture was washed sequentially with 20% sodium bisulfite aqueous solution (50 mL) and then washed twice with 5% saline solution (50 mL). The resulting organic layer was concentrated to 50 mL under reduced pressure, and ethanol (50 mL) was added. The concentration was repeated twice under reduced pressure. Water (100 mL) was added dropwise to the solution to precipitate the solid, which was then matured under ice-cold conditions for 1 hour. The resulting solid was filtered off, washed with ethanol / water = 1 / 3 (40 mL divided into several portions), and dried under reduced pressure to obtain 8.73 g of the title compound (yield 80.4%).

[0332] 1 H-NMR (400MHz, CDCl3) δppm: 7.45 (s, 1H), 4.65 (q, J = 6.9Hz, 2H), 1.52 (t, J = 6.9Hz, 3H).

[0333] [Synthetic Example 2] 3-(5,7-dibromo-4-hydroxybenzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

[0334]

[0335] 5,7-Dibromo-2-ethoxybenzo[d]oxazol-4-ol (7.00 g, 20.773 mmol) obtained from Synthetic Example 1 and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid (4.94 g, 24.916 mmol) were dissolved in toluene (70 mL), heated to 125 °C, and stirred for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure to 35 mL, and n-hexane (175 mL) was added dropwise to precipitate the solid. The solution was then matured under ice for 1 hour. The obtained solid was filtered off, washed with toluene / n-hexane = 1 / 4 (dividing the 35 mL solution into several portions), and dried under reduced pressure. The obtained solid was dissolved in THF (90 mL) and concentrated under reduced pressure to 48 mL. Ethyl acetate (63 mL) was added, and the solution was concentrated under reduced pressure to 48 mL. This process was repeated 3 times. The resulting solution was stirred at 60 °C for 30 minutes, cooled to room temperature, and matured under ice for 1 hour. The obtained solid was filtered off, washed with cold ethyl acetate (divided into several portions of 18 mL), and dried under reduced pressure to give 7.77 g of the title compound (yield 84.8%).

[0336] 1 H-NMR (400MHz, DMSO-d6) δ: 10.65 (s, 1H), 7.34 (s, 1H), 4.02-4.26 (m, 4H), 3.66 (br d,J=11.0Hz,2H),2.53-2.63(m,1H),1.57(d,J=9.2Hz,1H),1.29(s,9H).

[0337] [Synthetic Example 3] 3-(5-bromo-4-hydroxy-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

[0338]

[0339] Anhydrous lithium chloride (2.22 g, 51.11 mmol) and zinc powder (5.01 g, 76.65 mmol) were suspended in THF (10 mL), and chlorotrimethylsilane (0.45 mL, 3.58 mmol) was added under nitrogen. The mixture was stirred vigorously at 60 °C for 2 hours. 2-Bromothiazole (4.53 mL, 51.11 mmol) was slowly added dropwise using DMF (15 mL). Then, a DMF (15 mL) solution of 3-(5,7-dibromo-4-hydroxybenzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (5.00 g, 10.22 mmol) obtained in Synthetic Example 2, palladium(II) acetate (0.229 g, 1.022 mmol), and tris(p-tolyl)phosphine (1.24 g, 4.09 mmol) were rapidly added. The mixture was heated to 85 °C and stirred for 2.5 hours. The reaction solution was then chilled, and chloroform (50 mL), toluene (25 mL), DMF (50 mL), and 1.8 M sulfuric acid aqueous solution (50 mL) were added. The mixture was stirred for 30 minutes. After settling, the aqueous layer was separated, and the resulting organic layer was washed with a mixed solution of DMF (50 mL) and 1.8 M sulfuric acid aqueous solution (50 mL). The resulting aqueous layer was combined with the previous aqueous layer and extracted again with a mixed solution of chloroform (40 mL) and toluene (20 mL). The resulting organic layer was combined with the previous organic layer and washed twice with water (100 mL). Activated carbon (0.5 g) and 20% sodium bisulfite aqueous solution (100 mL) were added to the organic layer, and the mixture was stirred at 60 °C for 1 hour. After cooling, the mixture was filtered through diatomaceous earth, and the filter residue was washed with chloroform. The filtrate was separated. The resulting organic layer was washed twice with water (100 mL) and then concentrated under reduced pressure to 30 mL. Toluene (100 mL) was added to the resulting solution, and the mixture was concentrated under reduced pressure to 30 mL, repeated twice. Then, ethanol (100 mL) was added, and the mixture was concentrated under reduced pressure to 30 mL, repeated twice. The resulting solution was cooled to allow crystallization to mature. After filtration, the solution was dried under reduced pressure to obtain 4.88 g of the title compound (yield 96.8%).

[0340] 1 H-NMR (400MHz, CDCl3) δ: 8.10 (s, 1H), 7.92 (d, J = 3.2Hz, 1H), 7.43 (d, J = 3.2Hz, 1H), 4.32 (br m, 4H), 3.78 (br d,J=11.9Hz,2H),2.66-2.83(m,1H),1.57(d,J=9.2Hz,1H),1.38(s,9H).

[0341] [Synthetic Example 4] 3-(4-hydroxy-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

[0342]

[0343] The tert-butyl 3-(5-bromo-4-hydroxy-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid obtained in Synthesis Example 3 (0.469 g, 0.951 mmol), ammonium formate (1.50 g, 23.79 mmol), and zinc powder (1.554 g, 23.77 mmol) were suspended in ethanol (7 mL) and refluxed under nitrogen for 2 hours. After cooling the suspension, ethyl acetate (4.7 mL) was added and stirred, followed by diatomaceous earth filtration. The residue was washed with ethyl acetate (9.4 mL divided into several portions). The filtrate was washed sequentially with 5% potassium hydrogen sulfate aqueous solution (9.4 mL) and 5% saline solution (9.4 mL). The resulting organic layer was concentrated under reduced pressure to 4.7 mL, acetonitrile (9.4 mL) was added, and the concentration was repeated twice under reduced pressure to 4.7 mL. The resulting solution was stirred at room temperature for 2 hours, and then allowed to crystallize and mature under ice for 1 hour to obtain 397 mg of the title compound acetonitrile compound (yield 91.7%). 1 The H-NMR values ​​were consistent with those of the compound obtained in Synthesis Example 5 of Example 1.

[0344] [Industry Availability]

[0345] This invention provides a novel method for manufacturing 1-{[2-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-7-(thiazol-2-yl)benzo[d]oxazol-4-yl]oxy}-1,1-difluoro-2-methylpropane-2-ol (compound (1)) or its salts, which is safe, easy to operate, and suitable for industrial manufacturing. Furthermore, this invention also provides a 2-alkoxybenzo[d]oxazole derivative (compound (2)) or its salts, which can be used as raw materials in the method for manufacturing compound (1) or its salts, and a method for manufacturing them.

[0346] The compound (2) of this invention can be manufactured by a method that does not require highly toxic and difficult-to-handle reagents or highly hazardous operations, and thus does not produce toxic substances during the reaction. Furthermore, the manufacture of the compound (1) or its salt using the compound does not require highly toxic and difficult-to-handle reagents or highly hazardous operations. In addition, this invention allows for fewer steps than conventional manufacturing methods, while achieving the same high yield as conventional methods. Therefore, the method for manufacturing the compound (1) or its salt of this invention, and the method for manufacturing the compound (2) or its salt used therein, are industrially quite useful.

Claims

1. A method for producing the compound represented by formula (1) or a salt thereof, comprising the following steps: Step A, which produces the compound represented by formula (2) or a salt thereof, Step B, which involves using the compound represented by formula (2) or a salt thereof, to produce the compound represented by formula (3) or a salt thereof, and Step C, which involves using the compound represented by formula (3) or a salt thereof, to produce the compound represented by formula (1) or a salt thereof, In step A, the compound represented by formula (10) is reacted with benzyl alcohol to prepare the compound represented by formula (10-11). The compound represented by formula (10-11) is reacted with a brominating agent to prepare the compound represented by formula (10-12). The compound represented by formula (10-12) is reacted with an alkaline aqueous solution to prepare the compound represented by formula (10-13). The compounds represented by formulas (10-13) are reacted with a reducing agent to prepare the compound represented by formula (14). The compound represented by the aforementioned formula (14) or its salt is produced by reacting the compound represented by the aforementioned formula (2) with tetraalkoxymethane in the presence of an acid catalyst. Step B above involves removing the OR from the compound represented by formula (2) above. b The compound represented by formula (4) was prepared by substituting 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester. In the presence of a metal catalyst, the compound represented by formula (4) is introduced with a thiazol-2- group via a cross-coupling reaction to prepare the compound represented by formula (5). The step of producing the compound represented by formula (3) or its salt by reacting the compound represented by formula (5) with an organic acid, or Step B above involves introducing a thiazol-2- group into the compound represented by formula (2) via a cross-coupling reaction in the presence of a metal catalyst, to produce R in formula (2). 3 It is a thiazol-2-yl compound (2-11). OR in compound (2-11) b The compound represented by formula (5) was prepared by substituting 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester. The step of producing the compound represented by formula (3) or its salt by reacting the compound represented by formula (5) with an organic acid is as follows. In equation (2), R a Indicates benzyl, R b Indicates substituted or unsubstituted alkyl groups. R 3 This represents the bromine atom, Br. X a Represents a hydrogen atom. In formula (3), Boc represents tert-butoxycarbonyl. In equation (10), R 1 Represents halogen atoms, R 2 Represents halogen atoms, R 3 Represents a hydrogen atom. In equation (10-11), R 2 Bn is a halogen atom, and Bn is a benzyl group. In equation (10-12), R 2 Bn is a halogen atom, and Bn is a benzyl group. In formula (10-13), Bn is benzyl. In formula (14), Bn is benzyl. In equation (4), R a It is benzyl, R 3 The atom is bromine (Br), and Boc is tert-butoxycarbonyl. In equation (5), R a It is benzyl, and Boc is tert-butoxycarbonyl.

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