Method for producing a benzoxazole derivative having a bicyclic piperazine ring or a salt thereof, and method for producing the raw material thereof.

Abstract

To provide a production method of a benzoxazole derivative having a bicyclic piperazine ring or a salt thereof, which is excellent in safety and operability and is suited for industrial production.SOLUTION: A production method of a compound represented by formula (1) includes: a step B to produce a compound represented by formula (3) by using a compound represented by formula (2); and a step C to produce a compound represented by formula (1) by using a compound represented by formula (3).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing a benzoxazole derivative having a bicyclic piperazine ring or a salt thereof, and a method for producing the raw material thereof, and more specifically, to a method for producing 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazole-2-yl)benzo[d]xazole-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol or a salt thereof, and a method for producing the 2-alkoxybenzo[d]xazole derivative or a salt thereof, which is the raw material thereof. [Background technology]

[0002] 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazole-2-yl)benzo[d]oxazole-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol (a compound represented by formula (1) described later), which is a benzoxazole derivative having a bicyclic piperazine ring, is a compound that has excellent phosphodiesterase type 4 (PDE4) selective inhibitory activity (Patent Document 1).

[0003] 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazole-2-yl)benzo[d]oxazole-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol and its salts are known to be produced, for example, from 4-(benzyloxy)-7-bromobenzo[d]oxazole-2-thiol via iminoization, cross-coupling, and deprotection reactions (de-O-benzylation) to an intermediate product: tert-butyl 3-(4-hydroxy-7-(thiazole-2-yl)benzo[d]oxazole-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-carboxylate (a compound represented by formula (3) described later), and further produced via functional group conversion and deprotection reactions (Patent Document 1).

[0004] Furthermore, 4-(benzyloxy)-7-bromobenzo[d]oxazole-2-thiol, used in the above-mentioned manufacturing method, is known to be produced, for example, from 2-nitroresorcinol through a five-step process consisting of a di-O-benzyl etherification reaction (formation of a protecting group), a partial deprotection reaction (partial de-O-benzylation), a bromination reaction, a reduction reaction, and a cyclization reaction involving a leaving group (thiol group) (Patent Document 1). [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. 2018 / 124060 [Overview of the project] [Problems that the invention aims to solve]

[0006] In existing manufacturing methods using 4-(benzyloxy)-7-bromobenzo[d]oxazole-2-thiol, the production of 4-(benzyloxy)-7-bromobenzo[d]oxazole-2-thiol and the production of the aforementioned intermediate product using it have several steps that could be improved, including: (i) the use of tear-inducing and toxic benzyl bromide in the formation of the protecting group; (ii) the use of highly toxic boron trichloride in the formation of the protecting group; (iii) the use of highly toxic carbon disulfide, which is classified as a special flammable substance under Japanese fire safety laws, in the cyclization reaction involving the thiol group, and the generation of highly toxic hydrogen sulfide during the reaction; and (iv) the generation of highly toxic hydrogen sulfide when the position of the thiol group is replaced with an imino group in the cyclization reaction involving the thiol group. These steps have several issues, including the use of highly toxic reagents and hazardous handling.

[0007] The present invention has been made in view of the above problems, and aims to provide a novel method for producing 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazole-2-yl)benzo[d]oxazole-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol or a salt thereof that is superior in safety and operability and suitable for industrial production. [Means for solving the problem]

[0008] The present inventors have conducted diligent research to solve the above problems and have found that a 2-alkoxybenzo[d]oxazole derivative represented by the following formula (2) or a salt thereof can be used as a raw material for 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazole-2-yl)benzo[d]oxazole-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol or a salt thereof. In other words, the compound represented by formula (2) and its salt can be produced by a method that does not require highly toxic and difficult-to-handle reagents or highly dangerous operations, and furthermore, does not generate toxic substances during the reaction.

[0009] Furthermore, the production of the intermediate tert-butyl 3-(4-hydroxy-7-(thiazole-2-yl)benzo[d]oxazole-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-carboxylate or its salts using this compound, as well as the production of 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazole-2-yl)benzo[d]oxazole-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol or its salts using this compound, does not require highly toxic or difficult-to-handle reagents or highly dangerous procedures. In addition, the present inventors have found that a manufacturing method using the compound represented by formula (2) or a salt thereof can reduce the number of steps compared to existing manufacturing methods, and that 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazole-2-yl)benzo[d]oxazole-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol or a salt thereof can be obtained in a yield as high as that of existing manufacturing methods.

[0010] Therefore, the inventors have discovered that by using the compound represented by formula (2) or a salt thereof, it is possible to provide a novel industrial manufacturing method that is extremely safe and easy to operate, and have completed the present invention. That is, the present invention provides the following invention. [1] Formula (2):

[0011] [ka]

[0012] [In formula (2), R a This represents a hydrogen atom or an optionally substituted arylmethyl group. R b This represents an optionally substituted alkyl group or cyclic alkyl group. R 3 This represents a hydrogen atom, a halogen atom, or a thiazole-2-yl group. Xa represents a hydrogen atom or a halogen atom. Using the compound represented by the formula (3) or a salt thereof, formula (3):

[0013] [Chemical formula]

[0014] [In formula (3), Boc represents a tert-butoxycarbonyl group. Step B for producing the compound represented by the formula (3) or a salt thereof, and Using the compound represented by the formula (3) or a salt thereof, formula (1):

[0015] [Chemical formula]

[0016] Step C for producing the compound represented by the formula (1) or a salt thereof, and A method for producing the compound represented by the formula (1) or a salt thereof, comprising the above steps. [2] In step B, In the formula (2), R a is an optionally substituted arylmethyl group, R b is an optionally substituted alkyl group, R 3 is a halogen atom, X a is a hydrogen atom, and OR b of the compound (2-1) is substituted with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate to obtain formula (4):

[0017] [Chemical formula]

[0018] <​​​​​​Let the compound be represented by the following: The compound represented by formula (4) above is modified by introducing a thiazole-2-yl group via a cross-coupling reaction in the presence of a metal catalyst to obtain formula (5):

[0019] [ka]

[0020] [In formula (5), R a [wherein B is an arylmethyl group that may be substituted, and Boc is a tert-butoxycarbonyl group.] Let the compound be represented by the following: The manufacturing method according to [1], which involves reacting a compound represented by formula (5) with an organic acid to produce a compound represented by formula (3) or a salt thereof. [3] The aforementioned step B is In equation (2) above, R a It is an arylmethyl group which may be substituted, R b It is an alkyl group which may be substituted, and R 3 X is a halogen atom, a A thiazole-2-yl group is introduced to compound (2-1), in which R is a hydrogen atom, by a cross-coupling reaction in the presence of a metal catalyst, so that in formula (2), R a It is an arylmethyl group which may be substituted, R b It is an alkyl group which may be substituted, and R 3 is a thiazole-2-yl group, X a Let (2-11) be a compound in which the atom is a hydrogen atom. OR of compounds (2-11) b Substituting this with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate gives formula (5):

[0021] [ka]

[0022] [In formula (5), Ra [wherein B is an arylmethyl group that may be substituted, and Boc is a tert-butoxycarbonyl group.] Let the compound be represented by the following: The manufacturing method according to [1], which involves reacting a compound represented by formula (5) with an organic acid to produce a compound represented by formula (3) or a salt thereof. [4] The aforementioned step B is In equation (2) above, R a is a hydrogen atom, and R b It is an alkyl group which may be substituted, and R 3 X is a hydrogen atom, a A compound (2-2) in which is a hydrogen atom is reacted with a brominating agent, and in formula (2), R a is a hydrogen atom, and R b It is an alkyl group which may be substituted, and R 3 X is a bromine atom, a Let (2-21) be a compound in which the atom is bromine. OR of compound (2-21) b Substitute with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate to obtain formula (8):

[0023] [ka]

[0024] [In formula (8), Boc is a tert-butoxycarbonyl group.] Let the compound be represented by the following: The compound represented by formula (8) above is subjected to a cross-coupling reaction in the presence of a metal catalyst to introduce a thiazole-2-yl group, resulting in formula (9):

[0025] [ka]

[0026] [In formula (9), Boc is a tert-butoxycarbonyl group.] Let the compound be represented by the following: The manufacturing method according to [1], which involves reacting a compound represented by formula (9) with metals to produce a compound represented by formula (3) or a salt thereof. [5] Equation (10):

[0027] [ka]

[0028] [In formula (10), R 1 This represents a hydroxyl group, a halogen atom, or an arylmethyloxy group. R 2 This indicates a hydroxyl group or a halogen atom. R 3 This represents a hydrogen atom, a halogen atom, or a thiazole-2-yl group. A manufacturing method according to any one of [1] to [4], comprising step A of producing a compound represented by formula (2) or a salt thereof using a compound represented by or a salt thereof. [6] The aforementioned step A is In the above equation (10), R 1 is a halogen atom, R 2 is a halogen atom and R 3 A compound (10-1) in which the atom is a hydrogen atom is reacted with benzyl alcohol to produce formula (10-11):

[0029] [ka]

[0030] [In formula (10-11), R 2 [Bn is a halogen atom, and Bn is a benzyl group.] Let the compound be represented by the following: The compound represented by formula (10-11) is reacted with a brominating agent to produce formula (10-12):

[0031] [ka]

[0032] [In formula (10-12), R 2 [Bn is a halogen atom, and Bn is a benzyl group.] Let the compound be represented by the following: The compound represented by formula (10-12) is reacted with an alkaline aqueous solution to produce formula (10-13):

[0033] [ka]

[0034] [In formula (10-13), Bn is a benzyl group.] Let the compound be represented by the following: The compound represented by formula (10-13) is reacted with a reducing agent to obtain formula (14):

[0035] [ka]

[0036] [In formula (14), Bn is a benzyl group.] Let the compound be represented by the following: The manufacturing method according to [5], which involves reacting a compound represented by formula (14) with tetraalkoxymethane in the presence of an acid catalyst to produce a compound represented by formula (2) or a salt thereof. [7] The aforementioned step A is In the above equation (10), R 1 is a hydroxyl group, R 2 is a hydroxyl group, R 3 The manufacturing method according to [5], which involves reducing a compound (10-2) in which is a hydrogen atom, reacting it with tetraalkoxymethane in the presence of an acid catalyst, and then reacting it with a brominating agent to produce a compound represented by formula (2) or a salt thereof. [8] Formula (15):

[0037] [ka]

[0038] [In formula (15), Bn is a benzyl group and Et is an ethyl group.] A compound represented by or a salt thereof. [9] Formula (6):

[0039] [ka]

[0040] [In formula (6), Bn is a benzyl group and Et is an ethyl group.] A compound represented by or a salt thereof.

[10] Formula (7):

[0041] [ka]

[0042] [In formula (7), Et is an ethyl group.] A compound represented by or a salt thereof.

[11] Formula (8):

[0043] [ka]

[0044] [In formula (8), Boc is a tert-butoxycarbonyl group.] A compound represented by or a salt thereof. [Effects of the Invention]

[0045] According to the present invention, it is possible to provide a novel method for producing 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazole-2-yl)benzo[d]oxazole-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol (a compound represented by formula (1)) or a salt thereof, which is excellent in safety and operability and suitable for industrial production. Furthermore, according to the present invention, it is also possible to provide a 2-alkoxybenzo[d]oxazole derivative (a compound represented by formula (2)) or a salt thereof, as well as a method for producing the same, as a raw material that can be suitably used in the above production method. [Modes for carrying out the invention]

[0046] The following describes in detail, with examples, a method for producing the compound represented by formula (1) or a salt thereof, and a method for producing the compound represented by formula (2) or a salt thereof used in the method for producing the compound represented by formula (1). However, the present invention is not limited to the scope of the specific examples presented.

[0047] The present invention provides a method for producing the compound represented by formula (1), comprising: 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 (hereinafter, may be simply referred to as the "present invention method").

[0048] The compound obtained by the production method of the present invention is given by the following formula (1):

[0049] [ka]

[0050] This compound is represented as 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazole-2-yl)benzo[d]oxazole-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol. This compound has excellent PDE4 (phosphodiesterase type 4) inhibitory activity and also exhibits excellent metabolic stability (Patent Document 1).

[0051] The compound obtained by the production method of the present invention may be a salt of the compound represented by formula (1) according to the present invention (hereinafter optionally referred to as "compound (1)"), and the salt is preferably a pharmaceutically acceptable salt. The pharmaceutically acceptable salt is preferably in the form of an acid addition salt, and the acid of the acid addition salt can be, for example, a hydrohalogen acid such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, or hydroiodic acid; an inorganic acid such as sulfuric acid, nitric acid, phosphoric acid, hydrogen peroxide, or carbonic acid; an organic carboxylic acid such as acetic acid, trichloroacetic acid, trifluoroacetic acid, hydroxyacetic acid, lactic acid, citric acid, tartaric acid, oxalic acid, benzoic acid, mandelic acid, butyric acid, maleic acid, propionic acid, formic acid, or malic acid; an acidic amino acid such as aspartic acid or glutamic acid; an alkyl sulfonic acid such as methanesulfonic acid; or an aryl sulfonic acid such as p-toluenesulfonic acid.

[0052] Compound (1) and its salt are given by the following formula (3):

[0053] [ka]

[0054] [In formula (3), Boc represents a tert-butoxycarbonyl group.] It can be obtained using tert-butyl 3-(4-hydroxy-7-(thiazole-2-yl)benzo[d]oxazole-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-carboxylate (hereinafter, optionally referred to as "compound (3)") or a salt thereof. As a method for obtaining compound (1) from such compound (3), a known method or a method similar thereto can be used as appropriate, for example, the method described in Patent Document 1 can be used. As salts of compound (3), including their preferred forms, the same salts as those listed as salts of compound (1) can be used.

[0055] In the manufacturing method of the present invention, compound (3) or a salt thereof is obtained using the compound represented by formula (2) according to the present invention (hereinafter optionally referred to as "compound (2)") or a salt thereof (step B). Compound (2) is given by the following formula (2):

[0056] [ka]

[0057] It is a compound represented by formula (2). In formula (2), R a R represents a hydrogen atom or an optionally substituted arylmethyl group. b R represents an optionally substituted alkyl group or cyclic alkyl group. 3 X represents a hydrogen atom, a halogen atom, or a thiazole-2-yl group. a This represents a hydrogen atom or a halogen atom.

[0058] In this specification, examples of "arylmethyl group" include phenylmethyl group (benzyl group), diphenylmethyl group (benzhydryl group), and triphenylmethyl group (trityl group), with the benzyl group being particularly preferred. a The arylmethyl group represented by may be substituted with one or more substituents that may be identical or different from each other.

[0059] In this specification, "arylmethyloxy group" is a group represented by the following formula: -OA, where A represents an arylmethyl group. Examples of the arylmethyl group include the groups listed above, with the benzyl group being particularly preferred. The following R according to the present invention 1 The arylmethyloxy group represented by may be substituted with one or more substituents that are identical or different from each other.

[0060] In this specification, "alkyl group" refers to a linear or branched alkyl group, preferably having 1 to 6 carbon atoms, and more preferably having 1 to 3 carbon atoms. b The alkyl group represented by may be substituted with one or more substituents that are the same or different from each other. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group, and the like.

[0061] In this specification, "cyclic alkyl group" refers to a cyclic alkyl group, and preferably has 3 to 8 carbon atoms, i.e., 3 to 6 ring members. b The cyclic alkyl group represented by may be substituted with one or more substituents that may be the same or different from each other. Examples of the cyclic alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like.

[0062] In this specification, "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0063] Furthermore, in this specification, "may be substituted" means that any one or more hydrogen atoms may be substituted with other atoms or groups (substituents), and when two or more hydrogen atoms are substituted, the substituents (atoms, groups) may be the same 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.

[0064] Examples of compound (2) according to the present invention include the following compounds: 2-Methoxybenzo[d]oxazole-4-ol, 2-Ethoxybenzo[d]oxazole-4-ol, 2-Propoxybenzo[d]oxazole-4-ol, 2-Isopropoxybenzo[d]oxazole-4-ol, 2-Butoxybenzo[d]oxazole-4-ol, 2-Isobutoxybenzo[d]oxazole-4-ol, 2-(sec-butoxy)benzo[d]oxazole-4-ol, 2-(tert-butoxy)benzo[d]oxazole-4-ol, 2-Pentoxybenzo[d]oxazole-4- ol, 2-(pentan-2-yloxy)benzo[d]oxazole-4-ol, 2-[(3-methylbutan-2-yl)oxy]benzo[d]oxazole-4-ol, 2-(tert-pentyloxy)benzo[d]oxazole-4-ol, 2-(hexyloxy)benzo[d]oxazole-4-ol, 2-cyclopropoxybenzo[d]oxazole-4-ol, 2-cyclobutoxybenzo[d]oxazole-4-ol, 2-(cyclopentyloxy)benzo[d]oxazole-4-ol, 2-(cyclo Xyloxy)benzo[d]oxazole-4-ol, 2-benzyloxybenzo[d]oxazole-4-ol, 5,7-dibromo-2-methoxybenzo[d]oxazole-4-ol, 5,7-dibromo-2-ethoxybenzo[d]oxazole-4-ol, 5,7-dibromo-2-propoxybenzo[d]oxazole-4-ol, 5,7-dibromo-2-butoxybenzo[d]oxazole-4-ol, 5,7-dibromo-2-isobutoxybenzo[d]oxazole-4-ol, 5,7-dibromo-2-(se c-butoxy)benzo[d]oxazole-4-ol, 5,7-dibromo-2-(tert-butoxy)benzo[d]oxazole-4-ol, 5,7-dibromo-2-pentoxybenzo[d]oxazole-4-ol, 5,7-dibromo-2-(pentan-2-yloxy)benzo[d]oxazole-4-ol, 5,7-dibromo-2-[(3-methylbutan-2-yl)oxy]benzo[d]oxazole-4-ol, 5,7-dibromo-2-(tert-pentyloxy)benzo[d]oxazole-4-ol, 5,7-Dibromo-2-(hexyloxy)benzo[d]oxazole-4-ol, 5,7-Dibromo-2-cyclopropoxybenzo[d]oxazole-4-ol, 5,7-Dibromo-2-cyclobutoxybenzo[d]oxazole-4-ol, 5,7-Dibromo-2-cyclobutoxybenzo[d]oxazole-4-ol, 5,7-Dibromo-2-(cyclopentyloxy)benzo[d]oxazole-4-ol, 5,7-Dibromo-2-(cyclohexyloxy)benzo[d]oxazole-4-ol, 5,7-Dibromo-2-ben Dyloxybenzo[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]ol Xazol, 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-(pentan-2-yloxy)benzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-[(3-methylbutan-2-yl)oxy]benzo[d]oxazole, 4-(benzyloxy)-7- Romo-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, 4-(benzyloxy)-7-bromo-2-(cyclohexyloxy)benzo[d]oxazole, 2,4-di(benzyloxy)-7-bromobenzo[d]oxazole, 4-(benzyloxy)-2-methoxy-7-(thiazole-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-ethoxy-7-(thiazole-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-propoxy-7-(thiazole-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-isopropoxy-7-(thiazole-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-but Xy-7-(thiazole-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-isobutoxy-7-(thiazole-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-(sec-butoxy)-7-(thiazole-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-(tert-butoxy)-7-(thiazole-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-pentoxy-7-(thiazole-2-yl)benzo[d]oxazole, 4-(benzyloxy) (Benzyloxy)-2-(pentan-2-yloxy)-7-(thiazole-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-[(3-methylbutan-2-yl)oxy]-7-(thiazole-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-(tert-pentyloxy)-7-(thiazole-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-(hexyloxy)-7-(thiazole-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-cy Clopropoxy-7-(thiazole-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-cyclobutoxy-7-(thiazole-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-(cyclopentyloxy)-7-(thiazole-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-(cyclohexyloxy)-7-(thiazole-2-yl)benzo[d]oxazole and 2,4-di(benzyloxy)-7-(thiazole-2-yl)benzo[d]oxazole, While these are some examples, the present invention is not limited to these specific examples.

[0065] Among these, the compound (2) according to the present invention is preferably 2-ethoxybenzo[d]oxazole-4-ol, with the following formula (7):

[0066] [ka]

[0067] [In formula (7), Et is an ethyl group.] 5,7-dibromo-2-ethoxybenzo[d]oxazole-4-ol, represented by the following formula (15):

[0068] [ka]

[0069] [In formula (15), Bn is a benzyl group and Et is an ethyl group.] 4-(benzyloxy)-7-bromo-2-ethoxybenzo[d]oxazole, represented by the following formula (6):

[0070] [ka]

[0071] [In formula (6), Bn is a benzyl group and Et is an ethyl group.] This is a 4-(benzyloxy)-2-ethoxy-7-(thiazole-2-yl)benzo[d]oxazole represented by .

[0072] Examples of salts of compound (2) according to the present invention include those similar to those listed as salts of compound (1), including their preferred forms.

[0073] The compound (2) or salt thereof according to the present invention is preferably obtained by step A of manufacturing compound (2) or salt thereof using a compound represented by the following formula (10) (hereinafter optionally referred to as "compound (10)") or salt thereof.

[0074] Compound (1) or a salt thereof according to the present invention can be produced by a typical method shown in Scheme 1 below. Scheme 1:

[0075] [ka]

[0076] In each of the equations in Scheme 1 above, R 1 R represents a hydroxyl group, a halogen atom, or an arylmethyloxy group. 2 R represents a hydroxyl group or halogen atom. a Each independently represents a hydrogen atom or an optionally substituted arylmethyl group, R b R represents an optionally substituted alkyl group or cyclic alkyl group. 3 Each of these independently represents a hydrogen atom, a halogen atom, or a thiazole-2-yl group, and X a Each of these independently represents either a hydrogen atom or a halogen atom.

[0077] In the above scheme 1, first, as a preferred embodiment of step A, the nitro group of the compound represented by formula (10) is reduced by a reduction reaction to obtain the compound represented by formula A (hereinafter, possibly referred to as "compound A"), and then compound (2) is obtained by a cyclization reaction of compound A.

[0078] Next, in Scheme 1, as a preferred embodiment of step B, the 2-alkoxy group (OR) of the obtained compound (2) b ) is substituted with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (substitution reaction) to obtain the compound represented by formula B (hereinafter, sometimes referred to as "compound B") or compound (3). Compound B can also be subjected to the introduction of a thiazole-2-yl group by cross-coupling reaction, or, if necessary, R by deprotection reaction. a Removal of the protecting group, X other than the hydrogen atom a Compound (3) is obtained by converting to hydrogen atoms.

[0079] Subsequently, in a preferred embodiment of step C, compound (3) is subjected to O-alkylation to obtain a compound represented by formula C (hereinafter, optionally referred to as "compound C"), and then the tert-butoxycarbonyl group (hereinafter, optionally referred to as "Boc") is removed by a deprotection reaction to obtain compound (1).

[0080] In the manufacturing method of the present invention, step A is preferably compound (10) is R 1 and R 2 is a halogen atom, R 3 A compound in which is a hydrogen atom (10-1), more preferably R 1 and R 2 is a fluorine atom and R 3 From 2,6-difluoronitrobenzene, where R is a hydrogen atom, or as compound (10), 1 and R 2 is a hydroxyl group, R 3 Preferably, the process includes a step of producing compound (2) or a salt thereof from compound (10-2), which is a hydrogen atom, i.e., 2-nitroresorcinol.

[0081] When compound (10) is compound (10-1), more preferably 2,6-difluoronitrobenzene, for example, first, compound (10-1) (preferably 2,6-difluoronitrobenzene) is reacted with benzyl alcohol (partial substitution reaction) to obtain the following formula (10-11):

[0082] [ka]

[0083] Let the compound be represented by (compound (10-11)). In formula (10-11), Bn is a benzyl group (the same applies below), R 2 is a halogen atom, R 2 As such, a fluorine atom is more preferred. Next, the compound (10-11) is reacted with a brominating agent (bromination reaction), resulting in the following equation (10-12):

[0084] [ka]

[0085] Let the compound be represented by (compound (10-12)). In formula (10-12), R 2 is a halogen atom, R 2 Fluorine atoms are more preferable. Next, the compound (10-12) is reacted with an alkaline aqueous solution (hydration reaction), resulting in the following equation (10-13):

[0086] [ka]

[0087] Let the compound be represented by (compound (10-13)). Furthermore, compound (10-13) is reacted with a reducing agent (reduction reaction) to obtain compound A, which is given by the following equation (14):

[0088] [ka]

[0089] A compound represented by (compound (14)) is obtained. Then, compound (2) (for example, the compound represented by formula (15)) or a salt thereof can be produced by reacting compound (14) with tetraalkoxymethane (cyclization reaction involving an alkoxy group).

[0090] Furthermore, when compound (10) is used as compound (10), for example, first, compound (10) is reacted with a reducing agent (reduction reaction) to obtain compound (10-21) (2-aminoresorcinol), and then compound (10-21) is reacted with tetraalkoxymethane (cyclization reaction with an alkoxy group) to obtain compound (10-22) (2-ethoxybenzo[d]oxazole-4-ol). Subsequently, compound (10-22) is reacted with a brominating agent (bromination reaction) to produce compound (2) (for example, the compound represented by formula (7) above) or a salt thereof.

[0091] Furthermore, in the manufacturing method of the present invention, step B is preferably compound (2) is R a It is an arylmethyl group which may be substituted, R b It is an alkyl group which may be substituted, and R 3 X is a halogen atom, a Compounds in which (2-1) is a hydrogen atom (more preferably, R a From a compound in which the group is a benzyl group, or as compound (2), R a is a hydrogen atom, and R b It is an alkyl group which may be substituted, and R 3 X is a hydrogen atom, a Compounds in which (2-2) is a hydrogen atom (more preferably, R b Preferably, the process includes a step of producing compound (3) or a salt thereof from a compound in which the group is an ethyl group.

[0092] When compound (2) is used as compound (2-1), for example, first compound (2-1) (more preferably R a The benzyl group is R 3 OR (compounds in which the atom is bromine) b Substitution with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (substitution reaction) is performed as follows (4):

[0093] [ka]

[0094] Let the compound be the one represented by (Compound (4), Compound B). In Formula (4), R a is an optionally substituted arylmethyl group, and R 3 is a halogen atom. As R a in Formula (4), a benzyl group is preferred, and as R 3 a bromine atom is preferred. Next, a thiazol-2-yl group is introduced into Compound (4) by a cross-coupling reaction in the presence of a metal catalyst to obtain the following Formula (5):

[0095]

Chemical formula

[0096] Let the compound be the one represented by (Compound (5), Compound B). In Formula (5), R a is an optionally substituted arylmethyl group. As R a in Formula (5), a benzyl group is preferred. Next, Compound (3) or a salt thereof can be produced by reacting Compound (5) with an organic acid (deprotection reaction).

[0097] Also, as another method when using Compound (2-1) as Compound (2), for example, first, a thiazol-2-yl group is introduced into Compound (2-1) (more preferably, a compound in which R a is a benzyl group and R b is an ethyl group) by a cross-coupling reaction in the presence of a metal catalyst, and in the above Formula (2), R a is an optionally substituted arylmethyl group, R b is an optionally substituted alkyl group, R 3 is a thiazol-2-yl group, and X a is a hydrogen atom to obtain Compound (2-11). As Compound (2-11), the following Formula (6):

[0098]

Chemical formula

[0099] A compound represented by (compound (6)) is preferred. In formula (6), Et is an ethyl group (the same applies hereafter). Next, the OR of compounds (2-11) b This is replaced with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (substitution reaction), and compound (5)(R a (wherein this is a benzyl group). Then, compound (3) or a salt thereof can be produced by reacting compound (5) with an organic acid (deprotection reaction).

[0100] Furthermore, when compound (2-2) is used as compound (2), for example, first compound (2-2) (more preferably R b A compound in which R is an ethyl group is reacted with a brominating agent, and in formula (2), R a is a hydrogen atom, and R b It is an alkyl group which may be substituted, and R 3 X is a bromine atom, a Let (2-21) be a compound in which the atom is bromine. Compound (2-21) is given by the following formula (7):

[0101] [ka]

[0102] A compound represented by (compound (7)) is preferred. Next, the OR of compound (2-21) b By substituting with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (substitution reaction), the following equation (8):

[0103] [ka]

[0104] Let the compounds be represented by (compound (8), compound B). Next, a thiazole-2-yl group is introduced into compound (8) by a cross-coupling reaction in the presence of a metal catalyst, resulting in the following equation (9):

[0105] [ka]

[0106] Let the compounds be represented by (compound (9), compound B). Then, compound (3) or its salt can be produced by reacting compound (9) with metals (conversion reaction).

[0107] In the process shown in Scheme 1 above, each intermediate compound may or may not be isolated, and if not isolated, each reaction can be carried out sequentially.

[0108] The following describes each reaction in Scheme 1 in more detail. In the following descriptions, "equivalent" refers to a chemical equivalent, where 1 equivalent is defined as the amount of molecules (amount of substance) required for all the functional groups of the substrate to react in the reaction.

[0109] (Partial substitution reaction) In the manufacturing method of the present invention, compound (10-11) is preferably obtained by a partial substitution reaction by reacting compound (10-1) with benzyl alcohol. The partial substitution reaction is preferably carried out by reacting the substrate (in this case, compound (10-1)) with benzyl alcohol in a suitable solvent, in or without a base, and the preferred conditions are as follows.

[0110] Examples of the aforementioned solvents include 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, methylcyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and diphenyl ether; methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-propyl acetate Ester-based organic solvents such as ethyl 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 can be used individually or in combination of two or more in appropriate proportions.

[0111] Preferably, the solvent is at least one selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, and more preferably, at least one selected from the group consisting of N,N-dimethylformamide and dimethyl sulfoxide.

[0112] Examples of the aforementioned bases include 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; 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[5.4.0]undec-7-ene, pyridine, picoline, 4 One of the following can be used alone or in appropriate proportions: amines such as -(dimethylamino)pyridine, 2,6-lutidine, and 2,4,6-collidine; 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 amide, sodium amide, potassium amide, lithium diisopropylamide, lithium-2,2,6,6-tetramethylpiperidide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, and potassium bistrimethylsilylamide; and potassium trimethylsiloxide.

[0113] Preferably, the base is at least one selected from the group consisting of sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, sodium tert-butoxide, and potassium tert-butoxide, and more preferably at least one selected from the group consisting of potassium carbonate and sodium tert-butoxide. The amount of the base used in the partial substitution reaction is 0.01 to 20 equivalents relative to the substrate, preferably 0.1 to 10 equivalents, and more preferably 1 to 5 equivalents.

[0114] The amount of benzyl alcohol used in the partial substitution reaction is 0.8 to 5 equivalents relative to the substrate, preferably 0.9 to 2 equivalents.

[0115] The reaction temperature for the 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.

[0116] The reaction time for the 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.

[0117] (Bromization reaction) In the manufacturing method of the present invention, compound (2-21) is preferably obtained by a bromination reaction by reacting compound (2-2) with a brominating agent. Compound (10-12) is also obtained by a bromination reaction by reacting compound (10-11) with a brominating agent. Furthermore, compound (2) is obtained by a bromination reaction by reacting compound (10-22) with a brominating agent. The bromination reaction is preferably carried out by reacting a substrate (here, compound (2-2), compound (10-11), or compound (10-22)) with a brominating agent in a suitable solvent, in or without an acid catalyst, and the preferred conditions are as follows.

[0118] Examples of the aforementioned solvents include 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, methylcyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and diphenyl ether; and vinegar. Ester-based organic solvents such as methyl acid, 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 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 may be used individually or in combination of two or more in appropriate proportions.

[0119] Preferably, the solvent is at least one selected from the group consisting 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 selected from the group consisting of acetonitrile and ethyl acetate.

[0120] Examples of the 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-molybdo(VI) phosphate hydrate, and 12-tungst(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 chloride, ferric chloride, aluminum chloride, titanium tetrachloride, and zirconium tetrachloride. Other examples include chlorosilanes such as chlorotrimethylsilane, chlorotriethylsilane, chlorotriisopropylsilane, chloroisopropyldimethylsilane, chlorodiethylisopropylsilane, tert-butylchlorodimethylsilane, tert-butylchlorodiphenylsilane, trimenzylsilyl chloride, chlorotriphenylsilane, chloromethyldiphenylsilane, and di-tert-butylchloromethylsilane. These may be used individually or in combination of two or more in appropriate proportions.

[0121] Among these, from the viewpoint of low toxicity, the acid catalyst is preferably at least one selected from the group consisting of acetic acid, diethyl ether tetrafluoroborate complex, and chlorotrimethylsilane (preferably any one of these), and more preferably at least one selected from the group consisting of acetic acid and chlorotrimethylsilane (preferably any one of these).

[0122] In the bromination reaction described above, the amount of the acid catalyst used is 0 to 1 equivalent relative to the substrate, preferably 0 to 0.7 equivalents.

[0123] Examples of the brominating agents include bromine, bromine 1,4-dioxane complex, tetrabutylammonium tribromide, benzyltrimethylammonium tribromide, trimethylphenylammonium tribromide, 1-butyl-3-methylimidazolium tribromide, 1,8-diazabicyclo[5.4.0]-7-undecenehydrogen tribromide, pyridinium bromide perbromide, 4-dimethylaminopyridinium bromide perbromide, N-bromoacetamide, N-bromosuccinimide, N-bromophthalimide, N-bromosaccharin, and dibromosia. One of the following can be used individually or in appropriate proportions: nuric acid, monosodium bromocyanurate, 1,3-dibromo-5,5-dimethylhydantoin, bromodimethylsulfonium bromide, bis(2,4,6-trimethylpyridine)bromonium hexafluorophosphate, bromotrimethylsilane, carbon tetrabromide, bromotrichloromethane, 1,2-dibromo-1,1,2,2-tetrachloroethane, 5,5-dibromomeldrumic acid, 2,4,4,6-tetrabromo-2,5-cyclohexadienone, boron tribromide, and phosphorus tribromide.

[0124] Preferably, the brominating agent is at least one (preferably any one) selected from the group consisting of bromine, tetrabutylammonium tribromide, benzyltrimethylammonium tribromide, N-bromosuccinimide, N-bromosaccharin, and 1,3-dibromo-5,5-dimethylhydantoin, and more preferably at least one (preferably any one) selected from the group consisting of N-bromosuccinimide.

[0125] In the bromination reaction described above, the amount of brominating agent used is 0.8 to 5 equivalents relative to the substrate when introducing one bromine atom into one molecule of the substrate, preferably 1 to 2 equivalents. When introducing two bromine atoms into one molecule of the substrate, the amount is 1.8 to 5 equivalents relative to the substrate, preferably 2 to 3 equivalents.

[0126] The reaction temperature for the 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.

[0127] The reaction time for the 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.

[0128] (Hydration reaction) In the manufacturing method of the present invention, compound (10-13) is preferably obtained by a hydration reaction by reacting compound (10-12) with an alkaline solution. The hydration reaction is preferably carried out by reacting the substrate (in this case, compound (10-12)) with an alkaline aqueous solution in a suitable solvent, and the preferred conditions are as follows.

[0129] Examples of the aforementioned solvents include 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, methylcyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and diphenyl ether; methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-propyl acetate Ester-based organic solvents such as ethyl 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 can be used individually or in combination of two or more in appropriate proportions.

[0130] Preferably, the solvent is at least one selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, and more preferably at least one selected from the group consisting of N,N-dimethylacetamide and dimethyl sulfoxide.

[0131] As the aforementioned alkaline aqueous solution, for example, one of the aqueous solutions of 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 can be used alone or by mixing two or more of them in appropriate proportions.

[0132] Preferably, the alkaline aqueous solution is an aqueous solution of at least one (preferably any one) selected from the group consisting of sodium bicarbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide, and more preferably, an aqueous solution of at least one (preferably any one) selected from the group consisting of sodium hydroxide and potassium hydroxide. In the hydration reaction, the concentration of the alkaline aqueous solution is not particularly limited and can be adjusted as appropriate.

[0133] The reaction temperature for the hydration 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.

[0134] The reaction time for the hydration 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.

[0135] (Reduction reaction) In the manufacturing method of the present invention, compound (14) is preferably obtained by a reduction reaction by reacting compound (10-13) with a reducing agent. Also, compound (10-21) is obtained by a reduction reaction by reacting compound (10-2) with a reducing agent. The reduction reaction is preferably carried out by reacting a substrate (here, compound (10-13) and compound (10-2)) with a reducing agent in a suitable solvent, and the preferred conditions are as follows.

[0136] Examples of the aforementioned solvents include protic solvents such as water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, and tert-butanol; hydrocarbon solvents such as petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, and xylene; halogenated 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, methylcyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and diphenyl ether; and methyl acetate. One of the following can be used alone or in appropriate proportions: 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 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.

[0137] Preferably, the solvent is at least one selected from the group consisting of water, methanol, ethanol, ethyl acetate, and n-butyl acetate, and more preferably, at least one selected from the group consisting of water, ethanol, and ethyl acetate. In addition, 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 added to the solvent as appropriate.

[0138] The reducing agent can be one of the following, for example: metals such as zinc, aluminum, tin, stannous chloride, and iron; hydrogenation catalysts such as palladium, platinum, rhodium, and nickel, which may be used with a hydrogen source and, as appropriate, with a carrier; and inorganic salts such as sodium dithionite. One of these can be used alone or two or more can be mixed in appropriate proportions.

[0139] The reducing agent is preferably at least one (preferably any one) selected from the group consisting of zinc, iron, activated carbon-supported palladium, and sodium dithionite, and more preferably at least one (preferably any one) selected from the group consisting of activated carbon-supported palladium and sodium dithionite.

[0140] In the reduction reaction described above, if the reducing agent is the metals and / or the inorganic salts, these are used in excess, but the amount is preferably 20 equivalents or less in total, and more preferably 10 equivalents or less, relative to the substrate, if both are included. If the reducing agent is the hydrogenation catalysts, these are used in catalytic amounts, and the amount is preferably 10 wt% or less, and more preferably 5 wt% or less, relative to the total weight (wt) of the raw materials.

[0141] The reaction temperature for the 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.

[0142] The reaction time for the 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.

[0143] (Cyclation reaction involving alkoxy groups) In the production method of the present invention, compound (2) is preferably obtained by reacting compound (14) with tetraalkoxymethane through a cyclization reaction involving an alkoxy group. Alternatively, compound (10-21) is obtained by reacting compound (10-21) with tetraalkoxymethane through a cyclization reaction involving an alkoxy group.

[0144] The cyclization reaction involving the aforementioned alkoxy group is preferably carried out by reacting a substrate (here, compound (14) or compound (10-21)) with tetraalkoxymethane in a suitable solvent in the presence of an acid catalyst, and the preferred conditions are as follows.

[0145] Examples of the aforementioned solvents include 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, methylcyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and diphenyl ether; methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-propyl acetate Ester-based organic solvents such as ethyl 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 can be used individually or in combination of two or more in appropriate proportions.

[0146] Preferably, the solvent is at least one selected from the group consisting 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, and more preferably at least one selected from the group consisting of toluene and ethyl acetate.

[0147] As the acid catalyst, one 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 chloride, ferric chloride, aluminum chloride, titanium tetrachloride, and zirconium tetrachloride.

[0148] From the viewpoint of low toxicity, the acid catalyst is preferably at least one (preferably either one) selected from the group consisting of acetic acid and hydrochloric acid, and more preferably acetic acid.

[0149] In the cyclization reaction involving the alkoxy group, the amount of the acid catalyst used is 0.01 to 1 equivalent relative to the substrate, preferably 0.1 to 0.6 equivalents.

[0150] As the tetraalkoxymethane, for example, one of the following can be used alone or by mixing 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, tetra(cyclohexyloxy)methane, etc.

[0151] Preferably, the tetraalkoxymethane is at least one (preferably any one) selected from the group consisting of tetramethoxymethane, tetraethoxymethane, and tetrabenzyloxymethane, and more preferably tetraethoxymethane.

[0152] In the cyclization reaction involving the alkoxy group, the amount of tetraalkoxymethane used is 0.9 to 5 equivalents relative to the substrate, preferably 1 to 2 equivalents.

[0153] The reaction temperature for the cyclization reaction involving the alkoxy group 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.

[0154] The reaction time for the cyclization reaction involving the alkoxy group 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.

[0155] (Substitution reaction) In the production method of the present invention, preferably, the 2-alkoxy group (OR) of compound (2) (for example, compound (2-1), compound (2-11), or compound (2-21)) is used. b Compound B (e.g., compound (4), compound (5), compound (8)) is obtained by substitution reaction by replacing ) with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate. The substitution reaction is preferably carried out by reacting the substrate (here, compound (2)) with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate in a suitable solvent, in or without an acid catalyst, and the preferred conditions are as follows.

[0156] As the acid catalyst, one 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, stannous chloride, ferric chloride, aluminum chloride, titanium tetrachloride, and zirconium tetrachloride.

[0157] From the viewpoint of low toxicity, the acid catalyst is preferably at least one (preferably either one) selected from the group consisting of acetic acid and hydrochloric acid, and more preferably acetic acid.

[0158] In the substitution reaction described above, the amount of the acid catalyst used is 0.01 to 1 equivalent relative to the substrate, preferably 0.1 to 0.6 equivalents.

[0159] In the substitution reaction described above, the amount of tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate used is 0.9 to 3 equivalents relative to the substrate, preferably 1 to 1.5 equivalents.

[0160] Examples of the aforementioned solvents include 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, methylcyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and diphenyl ether; methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-propyl acetate Ester-based organic solvents such as ethyl 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 can be used individually or in combination of two or more in appropriate proportions.

[0161] Preferably, the solvent is at least one selected from the group consisting 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, and more preferably at least one selected from the group consisting of toluene and ethyl acetate.

[0162] The reaction temperature for the 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.

[0163] The reaction time for the 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.

[0164] (Cross-coupling reaction) In the manufacturing method of the present invention, compound (2) or compound B R 3 If the group is not a thiazole-2-yl group, a thiazole-2-yl group is introduced there by a cross-coupling reaction as needed. Preferably, a thiazole-2-yl group is introduced at the 7th position of compound (2) or compound B (e.g., compound (4), compound (2-1), compound (8)) by a cross-coupling reaction in the presence of a metal catalyst, R 3 Compound B (e.g., compound (5), compound (2-11), compound (9)) is obtained, in which the group is a thiazole-2-yl group.

[0165] As the aforementioned cross-coupling reaction, the Kumada-Tamao-Coliu coupling reaction, the Migita-Kosugi-Still coupling reaction, the Suzuki-Miyaura coupling reaction, the Negishi coupling reaction, the Buchwald-Hartwig coupling reaction, or the Hiyama coupling reaction can be used. Preferably, the Kumada-Tamao-Coliu coupling reaction, the Suzuki-Miyaura coupling reaction, or the Negishi coupling reaction can be used, and more preferably, the Negishi coupling reaction can be used.

[0166] The aforementioned cross-coupling reaction is preferably carried out by reacting a substrate (here, compound (2) or compound B) with 2-halothiazole (either reacted with a reagent as needed or used as is) in a suitable solvent, in the presence or absence of a metal catalyst, a ligand, or a base, under the following preferred conditions.

[0167] Examples of the aforementioned solvents include protic solvents such as water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, and tert-butanol; hydrocarbon solvents such as petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, and xylene; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; halogenated solvents such as carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, and trifluoromethylbenzene; diethyl ether, diisopropyl ether, methyl tert-butyl ether, methylcyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and dimethyl ether. One of the following can be used alone or in appropriate proportions: ether-based organic solvents such as nyl ethers; ester-based organic solvents such as 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; 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.

[0168] Preferably, the solvent is at least one selected from the group consisting of water, ethanol, toluene, tetrahydrofuran, 1,4-dioxane, and N,N-dimethylformamide, and more preferably, at least one selected from the group consisting of toluene, tetrahydrofuran, and N,N-dimethylformamide.

[0169] "2-halothiazole" refers to a thiazole in which the 2nd position is substituted with a halogen atom. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a bromine atom or an iodine atom, and more preferably a bromine atom.

[0170] The aforementioned reagent is used to substitute the halogen atom of 2-halothiazole with another reactive functional group, and includes those used in transmetallation reactions. Preferably, the aforementioned reagent is a combination of the catalyst and boron compound used in the Miyaura-Ishiyama boration reaction described later, such as pinacol diborane, pinacol borane and diboronic acid, Grignard reagent, or zinc powder, and more preferably zinc powder.

[0171] In the aforementioned cross-coupling reaction, the amount of 2-halothiazole used is 1 to 20 equivalents relative to the substrate, preferably 1 to 10 equivalents.

[0172] Examples of the aforementioned metal catalysts include palladium metal, palladium(II) chloride, palladium(II) bromide, palladium(II) iodide, palladium(II) acetate, palladium(II) trifluoroacetate, palladium(II) propionate, palladium(II) pivalate, palladium(II) acetylacetonate, palladium(II) hexafluoroacetylacetonate, palladium(II) cyanide, palladium(II) sulfate, palladium(II) nitrate, palladium(II) oxide, and palladium(π-cinnamyl) chloride. Immer, palladium(II)[1,3-bis(diphenylphosphino)propane]bis(benzonitrile)bistetrafluoroborate, trans-bis(acetate)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II), bis(acetonitrile)dichloropalladium(II), trans-bis(dicyclohexylamino)palladium(II)acetate, bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]dichloropalladium(II), [1,1'-bis(dicyclohexyl [di(diphenylphosphino)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-(t [1,1'-bis(di-tert-butylphosphine)(4-trifluoromethylphenyl)phosphine]dichloropalladium(II), [1,1'-bis(di-tert-butylphosphineno)ferrocene]dichloropalladium(II), bis(dibenzylideneacetone)palladium(0), bis(tricyclohexylphosphine)palladium(0), bis[tris-(2-methylphenyl)phosphine]palladium(0), bis(triphenylphosphine)dichloropalladium(II), bis(tri-tert-butylphosphine)palladium(0), bis[1,2-Bis(diphenylphosphino)ethane]palladium(0), bis(benzonitrile)dichloropalladium(II), bis(benzonitrile)dibromopalladium(II), (2,2'-bipyridine)dichloropalladium(II), (2-butenyl)chloropalladium dimer, [1,3-bis(diphenylphosphino)propane]palladium(II) trifluoromethanesulfonate, [1,2-bis(phenylsulfinyl)ethane]palladium(II) acetate, diacetobis(tricyclohexylphosphine)palladium(II), [2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]dibromopalladium(II), [1,1'-bis(diphenylphosphino)ferrocene]dibromopalladium(II), (1,5-cyclooctadiene)dibromopalladium ¹(II), [2,2'-bis(diphenylphosphin)-1,1'-binaphthyl]dichloropalladium(II), [1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium(II)acetone adduct, bis(methyldiphenylphosphine)dichloropalladium(II), bis(triphenylphosphine)dichloropalladium(II), (1,10-phenanthroline)dichloropalladium(II), (N,N,N',N'-tetramethylethylenediamine)dichloropalladium(II), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II), allylpalladium(II) chloride dimer, (ethylenediamine)palladium(II) chloride, chloro(1,5-cyclooctadiene)methylpalladium(II), (1,One of the following can be used individually or in appropriate proportions: 5-cyclooctadiene)dichloropalladium(II), bis(tricyclohexylphosphine)dichloropalladium(II), bis(tri-o-tolylphosphine)dichloropalladium(II), 2-(2'-di-tert-butylphosphine)biphenylpalladium(II) acetate, tetrakis(acetonitrile)palladium(II) tetrafluoroborate, tetrakis(triphenylphosphine)palladium(O), tris(dibenzylideneacetone)dipalladium(O), and tris(dibenzylideneacetone)dipalladium(O) chloroform adduct.

[0173] Preferably, the metal catalyst is at least one (preferably any one) selected from the group consisting of palladium(II) acetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct, bis(triphenylphosphine)dichloropalladium(II), tetrakis(triphenylphosphine)palladium(O), tris(dibenzylideneacetone)dipalladium(O) and tris(dibenzylideneacetone)dipalladium(O) chloroform adduct, and more preferably at least one (preferably any one) selected from the group consisting of palladium(II) acetate and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct.

[0174] Examples of the ligands include 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-) (Methylphenyl)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, tri(o-tolyl)phosphine, tri(o-tolyl)phosphine tetrafluoroborate, tri(m-tolyl)phosphine, tri(p-tolyl)phosphine N, tri(2-furyl)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-dimethoxybiphenyl-2-yl]phosphine, 2,2'-bis(diphenylphosphino)-1,1'-biphenyl, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, tri-1-naphthylphosphine One of the following can be used individually or in appropriate proportions: tris[3,5-bis(trifluoromethyl)phenyl]phosphine, tris(4-chlorophenyl)phosphine, 5-(di-tert-butylphosphine)-1',3',5'-triphenyl-1'H-[1,4']bipyrazole, 5-(di-tert-butylphosphine)-1-(naphthalene-1-yl)-1H-pyrazole, triallylphosphine, triisopropylphosphine, and triisopropylphosphonium tetrafluoroborate.

[0175] Preferably, as the ligand, at least one (preferably any one) selected from the group consisting of triphenylphosphine, tri(o-tolyl)phosphine, tri(m-tolyl)phosphine, tri(p-tolyl)phosphine, tri(2-furyl)phosphine, and 1,1'-bis(diphenylphosphino)ferrocene is mentioned. More preferably, at least one (preferably any one) selected from the group consisting of tri(p-tolyl)phosphine and 1,1'-bis(diphenylphosphino)ferrocene is mentioned.

[0176] As the base, those mentioned in the above (partial substitution reaction) including its preferred forms are mentioned.

[0177] The amount of the metal catalyst used in the cross-coupling reaction is 0.01 to 20 mol%, preferably 0.1 to 15 mol%, based on the total number of moles of the charged raw materials (excluding the solvent).

[0178] When using the ligand and / or the base, the ratios of the metal catalyst to the ligand (metal catalyst:ligand) and the metal catalyst to the base (metal catalyst:base) are each independently 1:0.25 to 20 in molar ratio, preferably 1:1 to 5.

[0179] The reaction temperature of the 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.

[0180] The reaction time of the 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.

[0181] (Deprotection reaction) In the production method of the present invention, as the deprotection reaction, a hydrogenolysis reaction, a deprotection reaction using a Lewis acid, or a deprotection reaction using an organic acid or the like can be used. Preferably, a deprotection reaction using a Lewis acid and / or an organic acid can be used, and more preferably, a deprotection reaction using an organic acid can be used.

[0182] In the production method of the present invention, when R of compound B a has a protecting group (for example, a benzyl group), this is removed. Preferably, by reacting compound B (for example, compound (5)) with an organic acid, the protecting group of R a is removed to obtain compound (3). Also, by reacting compound C with an organic acid, Boc is removed to obtain compound (1). The deprotection reaction is preferably carried out by reacting a substrate (here, compound (5) or compound C) with an organic acid in an appropriate solvent, and its preferred conditions are as follows.

[0183] Examples of the solvent include hydrocarbon-based organic solvents such as petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, and xylene; halogenated hydrocarbon-based organic solvents such as carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, and chlorobenzene; and ether-based organic solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methylcyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and diphenyl ether. One of them can be used alone or two or more of them can be mixed in an appropriate ratio.

[0184] Preferably, at least one selected from the group consisting of toluene, xylene, and dichloromethane can be mentioned as the solvent, and more preferably, at least one selected from the group consisting of toluene and dichloromethane can be mentioned.

[0185] As the organic acid, for example, one of the following can be used alone or in a mixture of two or more 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 a preferred example of the organic acid.

[0186] In the deprotection reaction described above, the amount of organic acid used is 1 to 50 equivalents relative to the substrate, preferably 5 to 20 equivalents.

[0187] The reaction temperature for the deprotection reaction is in the range of 0 to 200°C, preferably in the range of 20 to 150°C.

[0188] The reaction time for the deprotection reaction is in the range of 5 minutes to 48 hours, preferably in the range of 20 minutes to 24 hours.

[0189] (Protective reaction) Furthermore, under the conditions of Scheme 1 described above, the deprotection reaction on compound B also removes the protecting group N-Boc of compound B, generating the free base of compound (3). Therefore, it is preferable to re-add Boc (protect by substitution with Boc). In this case, after isolating the free base of compound (3), Boc can be added again by a general method known to those skilled in the art. Alternatively, the reaction mixture after the deprotection reaction can be adjusted to neutral to basic, and then the substrate (in this case, the free base of compound (3)) in the reaction mixture can be reacted with di-tert-butyl dicarbonate, either in the presence or absence of a suitable auxiliary solvent. The latter method is preferred. The preferred conditions for the latter protection reaction are as follows.

[0190] Examples of the auxiliary solvents include 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; and ether organic solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methylcyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and diphenyl ether. Ester-based organic solvents such as 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; 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 can be used individually or in combination of two or more in appropriate proportions.

[0191] Preferably, the solvent is at least one selected from the group consisting of water, methanol, ethanol, n-propanol, 2-propanol, dichloromethane, chloroform, and ethyl acetate, and more preferably, at least one selected from the group consisting of water, methanol, and dichloromethane.

[0192] To adjust the reaction reaction to be neutral to basic, 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, bistrime Cylsilylamine, 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, Amines such as 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, picoline, 4-(dimethylamino)pyridine, 2,6-lutidine, and 2,4,6-collidine; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide; formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, succinic acid, citric acid, methanesulfonic acid, trifluoromethanesulfonic acid, 10-camphor-sulfonic acid Organic acids such as folic 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 chloride, ferric chloride, aluminum chloride, titanium tetrachloride, and zirconium tetrachloride may be used individually or in combination of two or more in appropriate proportions.

[0193] From the viewpoint of low toxicity, among these, at least one (preferably any one) selected from the group consisting of 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 is preferred, and more preferably at least one (preferably any one) selected from the group consisting of sodium bicarbonate, sodium hydroxide, hydrochloric acid, and sulfuric acid is preferred. At this time, the pH of the reaction mixture is adjusted to about 6.8 to 12.0, preferably to about 7.0 to 9.5.

[0194] Di-tert-butyl dicarbonate is used in an amount of 0.9 to 5 equivalents relative to the substrate, preferably 1 to 2 equivalents.

[0195] The reaction temperature of the 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.

[0196] The reaction time for the 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.

[0197] (Conversion reaction) In the manufacturing method of the present invention, the conversion reaction of halogen atoms to hydrogen atoms can be a method of removing halogen atoms by a transmetallation reaction or a reduction reaction, preferably a catalytic hydrogenation reaction or a reduction reaction with metals, and more preferably a reduction reaction with metals.

[0198] In the manufacturing method of the present invention, the X of compound B a If it is a halogen atom instead of a hydrogen atom, it is converted to a hydrogen atom. Preferably, by reacting compound B (for example, compound (9)) with metals, X aCompound (3) is obtained by converting the halogen atoms to hydrogen atoms. The conversion reaction is preferably carried out by reacting the substrate (here, compound B) with metals in a suitable solvent, in or without the presence of an acid or base, and the preferred conditions are as follows.

[0199] Examples of the aforementioned solvents include protic solvents such as water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, and tert-butanol; hydrocarbon solvents such as petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, and xylene; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; ether organic solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methylcyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and diphenyl ether; methyl acetate, ethyl acetate, acetic acid Ester organic solvents such as n-propyl, 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, cyclohexanone, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone may be used alone or in combination of two or more in appropriate proportions.

[0200] Preferably, the solvent is at least one selected from the group consisting of water, methanol, ethanol, n-propanol, 2-propanol, tetrahydrofuran, and 1,4-dioxane, and more preferably, at least one selected from the group consisting of water, 1,4-dioxane, and ethanol.

[0201] Examples of the acid include one kind alone or a mixture of two or more kinds in an appropriate ratio selected from mineral 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.

[0202] Examples of the base include salts such as sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium phosphate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and barium hydroxide; amines such as ammonia, methylamine, ethylamine, cyclohexylamine, ethanolamine, aniline, dimethylamine, diethylamine, dibutylamine, dicyclohexylamine, bistrimethylsilylamine, 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-diazabicyclo[5.4.0]undec-7-ene, pyridine, picoline, 4-(dimethylamino)pyridine, 2,6-lutidine, and 2,4,6-collidine; and metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide. One kind alone or a mixture of two or more kinds in an appropriate ratio can be used.

[0203] Preferably, the base includes at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonium formate, or ammonium acetate, and more preferably, at least one selected from the group consisting of sodium hydroxide or ammonium formate.

[0204] The amount of acid or base used in the conversion reaction is 10 to 50 equivalents, preferably 20 to 40 equivalents, and more preferably 20 to 30 equivalents, relative to the substrate.

[0205] As the aforementioned metals, for example, one of the following can be used alone or a mixture of two or more in appropriate proportions: samarium(II) iodide, ytterbium(III) iodide, aluminum, zinc, iron, tin, samarium, or ytterbium.

[0206] Preferably, the aforementioned metals include at least one (preferably either one) selected from the group consisting of zinc and iron, and more preferably zinc.

[0207] The amount of metals used in the conversion reaction is 10 to 50 equivalents relative to the substrate, preferably 20 to 40 equivalents, and more preferably 20 to 30 equivalents.

[0208] The reaction temperature of the 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.

[0209] The reaction time for the 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.

[0210] (O-alkylation reaction) In the production method of the present invention, compound C is preferably obtained by dialkylating the hydroxyl group at position 4 of compound (3) by an O-alkylation reaction. The O-alkylation reaction is preferably carried out by reacting the substrate (in this case, compound (3)) with ethyl 2-bromo-2,2-difluoroacetate in a suitable solvent, in or without a base, and then dialkylating with an organometallic reagent, and the preferred conditions are as follows.

[0211] Examples of the aforementioned solvents include protic solvents such as water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, and tert-butanol; hydrocarbon solvents such as petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, and xylene; ether-based organic solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methylcyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and diphenyl ether; methyl acetate, ethyl acetate, n-propyl acetate, and isopropyl acetate One of the following can be used alone or in appropriate proportions: ester-based organic solvents such as 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.

[0212] Preferably, the solvent is at least one selected from the group consisting of methanol, ethanol, toluene, tetrahydrofuran, ethyl acetate, acetonitrile, and N,N-dimethylformamide, and more preferably, at least one selected from the group consisting of acetonitrile and N,N-dimethylformamide.

[0213] Examples of the aforementioned bases include 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; 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[5.4.0]undec-7-ene, pyridine, picoline, 4 One of the following can be used alone or in appropriate proportions: amines such as -(dimethylamino)pyridine, 2,6-lutidine, and 2,4,6-collidine; 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 amide, sodium amide, potassium amide, lithium diisopropylamide, lithium-2,2,6,6-tetramethylpiperidide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, and potassium bistrimethylsilylamide; and potassium trimethylsiloxide.

[0214] Preferably, the base is at least one selected from the group consisting of sodium carbonate, potassium carbonate, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydride, and sodium tert-butoxide, and more preferably, at least one selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene and sodium tert-butoxide.

[0215] In the O-alkylation reaction (reaction with ethyl 2-bromo-2,2-difluoroacetate), the amount of base used is 1 to 20 equivalents relative to the substrate, preferably 2 to 5 equivalents.

[0216] In the O-alkylation reaction described above, the amount of ethyl 2-bromo-2,2-difluoroacetate used is 1 to 10 equivalents relative to the substrate, preferably 2 to 6 equivalents.

[0217] The reaction temperature for the 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.

[0218] The reaction time for the 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.

[0219] As the organometallic reagent, for example, one of the following can be used alone or by mixing two or more in appropriate proportions: organomagnesium reagent, organolithium reagent, organozinc reagent, organoboron reagent, organotin reagent, organosilicon reagent, organobismuth reagent, organegermanium reagent, organomercury reagent, etc.

[0220] Preferably, the organometallic reagent is at least one (preferably any one) selected from the group consisting of organomagnesium reagents, organolithium reagents, and organozinc reagents, and more preferably an organomagnesium reagent.

[0221] In the O-alkylation reaction described above, the amount of organometallic reagent used is 2 to 10 equivalents relative to the substrate, preferably 2.5 to 5 equivalents.

[0222] The reaction temperature for the 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.

[0223] The reaction time for the 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. [Examples]

[0224] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. Various applications, modifications, and alterations are possible in the following examples without departing from the scope of the present invention.

[0225] The abbreviations used in the following examples have the following meanings. M: mol / L 1 H-NMR: Results of the proton nuclear magnetic resonance spectrum of the obtained compound. Pd-C: Activated carbon-supported palladium catalyst THF: Tetrahydrofuran DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide Boc:tert-butoxycarbonyl group (Boc)2O: Ditert-butyl dicarbonate Bn: Benzyl group.

[0226] (Example 1) [Synthesis Example 1] 3-benzyloxy-6-bromo-2-nitrophenol

[0227] [ka]

[0228] 2,6-Difluoronitrobenzene (52.75 g, 331.6 mmol) is dissolved in DMSO (158 mL), benzyl alcohol (35.86 g, 331.6 mmol) and potassium carbonate (91.65 g, 663 mmol) are added, and the mixture is stirred at 90°C for 24 hours to obtain the compound represented by the above formula (10-11), where R is located. 2 A reaction solution containing a compound in which is a fluorine atom was obtained. After cooling the reaction solution, it was diluted with ethyl acetate (422 mL) and washed sequentially with water and 0.1 M hydrochloric acid (211 mL each). The obtained organic layer was concentrated while substituting with acetonitrile to obtain 211 mL of acetonitrile solution. To the obtained solution, acetonitrile (211 mL), N-bromosuccinimide (88.53 g, 497.4 mmol) and acetic acid (4.75 mL, 83.1 mmol) were added, and after cooling to below 10°C, chlorotrimethylsilane (18.02 g, 165.9 mmol) was added, and the mixture was stirred at below 10°C for 2 hours to obtain the compound represented by the above formula (10-12), in which R 2 A reaction solution containing a compound whose atom is a fluorine atom was obtained. Water (164 mL) and 20% sodium bisulfite aqueous solution (164 mL) were added to the reaction solution and stirred, then toluene (528 mL) was added and stirred, and the aqueous layer was removed. The obtained organic layer was washed twice with 2 M sodium hydroxide aqueous solution (249 mL), concentrated with DMSO (492 mL), and the toluene was removed by distillation. 6.25 M sodium hydroxide aqueous solution (127 mL) was added to the obtained solution and stirred at 70°C for 1 hour. After cooling the reaction solution, toluene (633 mL) and water (1266 mL) were added and stirred, and the organic layer was removed. To the obtained aqueous layer, toluene (791 mL) and 6 M hydrochloric acid (146 mL) were added and stirred, and the aqueous layer was removed. The obtained organic layer was washed with water and concentrated while substituting 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 obtain 84.08 g (yield 78.2%) of the compound described in the title.

[0229] 1H-NMR (400MHz, CDCl3) δppm: 9.81 (s, 1H), 7.61 (d, J = 9.1 Hz, 1 H), 7.45-7.32 (m, 5 H), 6.55 (d, J = 9.1 Hz, 1 H), 5.20 (s, 2 H).

[0230] [Synthesis Example 2] 2-amino-3-benzyloxy-6-bromophenol

[0231] [ka]

[0232] 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 Synthesis Example 1 was dissolved in ethanol (560 mL) and added to the aqueous sodium dithionite solution. The mixture was stirred at 3-10°C for 1 hour. After adding water (1200 mL) to the reaction mixture and stirring, the resulting solid was filtered, washed with water, and dried to obtain 29.9 g of the title compound (yield 82.4%).

[0233] 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).

[0234] [Synthesis Example 3] tert-butyl 3-(4-benzyloxy-7-bromobenzo[d]oxazole-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0235] [ka]

[0236] 2-amino-3-benzyloxy-6-bromophenol (10.0 g, 33.99 mmol) obtained in Synthesis Example 2 was suspended in toluene (20 mL), acetic acid (0.98 mL, 17.1 mmol) and tetraethoxymethane (7.84 mL, 37.3 mmol) were added, and the mixture was heated under reflux for 30 minutes to obtain a reaction solution containing the compound represented by formula (15). To the reaction solution, tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (8.79 g, 44.3 mmol) and toluene (6 mL) were added, and the mixture was heated under reflux for 2 hours. After cooling the reaction solution, it was diluted with toluene (40 mL), washed sequentially with 5% sodium bicarbonate aqueous solution (40 mL) and water (40 mL), and then concentrated to 24 mL. 180 mL of n-heptane was added to the resulting solution to precipitate a solid. After cooling and stirring, the solid was filtered, washed with n-heptane, and dried to obtain 15.93 g of the title compound (yield 93.7%).

[0237] 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).

[0238] [Synthesis Example 4] tert-butyl 3-(4-benzyloxy-7-(thiazole-2-yl)benzo[d]oxazole-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-carboxylate

[0239] [ka]

[0240] Zinc powder (6.47 g, 98.9 mmol) was suspended in DMF (22.5 mL), chlorotrimethylsilane (0.6 mL, 4.7 mmol) was added, and 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 solution of tert-butyl 3-(4-benzyloxy-7-bromobenzo[d]oxazole-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (7.5 g, 15.0 mmol) obtained in Synthesis Example 3 was added in toluene (15 mL), copper(I) chloride (0.15 g, 1.5 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.61 g, 0.75 mmol), and the mixture was stirred at 85°C for 1 hour. After cooling the reaction mixture, toluene (225 mL) and 1 M hydrochloric acid (225 mL) were added and the mixture was stirred for 30 minutes, after which the insoluble material was filtered off. The aqueous layer was removed, and the resulting organic 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 obtain 6.67 g of the title compound (yield 88%).

[0241] 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).

[0242] [Synthesis Example 5] tert-butyl 3-(4-hydroxy-7-(thiazole-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-carboxylate

[0243] [ka]

[0244] 50.0 g, 99.09 mmol of tert-butyl 3-(4-benzyloxy-7-(thiazole-2-yl)benzo[d]oxazole-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate obtained in Synthesis Example 4 was suspended in toluene (150 mL), trifluoroacetic acid (150 mL, 1960 mL) was added, and the mixture was stirred at 80°C for 20 hours. The reaction mixture was cooled to near room temperature, and methanol (300 mL), water (200 mL), and dichloromethane (480 mL), which had been cooled to around 5°C beforehand, were added. Then, 400 mL of 5 M aqueous sodium hydroxide solution was added, the mixture was stirred at room temperature, and the pH was adjusted to around 8.6 with 6 M hydrochloric acid. (Boc)2O (25.0 mL, 109.0 mmol) was added, the mixture was heated to 30°C, and after 20 minutes, 5% sodium bicarbonate aqueous solution (83.2 mL, 49.50 mmol) was added. After another 30 minutes, 5% sodium bicarbonate aqueous solution (83.2 mL, 49.50 mmol) was added, and the mixture was stirred for 1 hour. The aqueous and organic layers of the reaction solution were separated, and the aqueous layer was re-extracted with dichloromethane (100 mL). The combined organic layer was concentrated under reduced pressure to approximately 250 mL, then acetonitrile (300 mL) was added, and the concentration under reduced pressure to approximately 250 mL was repeated twice. The mixture was allowed to crystallize and mature at room temperature for 30 minutes, stirred at 60°C for 1 hour, then cooled to room temperature over 1 hour and matured, and further matured on an ice bath for 1 hour. The resulting solid was filtered, washed with cooled acetonitrile (75 mL), and then air-dried. The crude title compound obtained was mixed with acetonitrile (250 mL), stirred at 80°C for 1 hour, cooled to room temperature over 2 hours for aging, and then aged for another hour on an ice bath. The solid was filtered off, washed with cooled acetonitrile (75 mL), and then dried under reduced pressure at 40°C to obtain 42.2 g of the title compound as monoacetonitrile (93.5% yield).

[0245] 1H-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).

[0246] [Synthesis Example 6] tert-butyl 3-(4-(1,1-difluoro-2-hydroxy-2-methylpropoxy)-7-(thiazole-2-yl)benzo[d]oxazole-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-carboxylate

[0247] [ka]

[0248] 50.0 g, 120.6 mmol of tert-butyl 3-(4-hydroxy-7-(thiazole-2-yl)benzo[d]oxazole-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (50.0 g, 120.6 mmol) obtained in Synthesis 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, and the mixture was stirred at 30°C for 3 hours. The reaction mixture was cooled to around 0°C, and pre-cooled toluene (750 mL) and 0.3 M hydrochloric acid were added and the mixture was stirred to remove the aqueous layer. The resulting organic layer was washed twice with water (250 mL), magnesium sulfate (5 g) was added, and the mixture was filtered. The filtrate was concentrated under reduced pressure to 250 mL, toluene (250 mL) was added, and then concentrated under reduced pressure again to 250 mL. The resulting solution was cooled to 5°C, 1.08 M methylmagnesium bromide THF solution (336 mL, 361.9 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to around 0°C, toluene (500 mL) and 1 M hydrochloric acid (500 mL) were added, and the mixture was stirred to remove the aqueous layer. The resulting organic layer was sequentially washed with 0.1 M sodium hydroxide aqueous solution (500 mL), 10% potassium bisulfate aqueous solution (500 mL), and water (500 mL), and then concentrated under reduced pressure to 250 mL. Activated carbon (5 g) was added to the resulting solution and the mixture was stirred at 60°C for 1 hour, followed by Celite filtration. The filtrate was concentrated under reduced pressure to 250 mL, ethanol (750 mL) was added, and the mixture was concentrated under reduced pressure again to 250 mL, and the same procedure was repeated. The obtained solution was stirred at room temperature for 2 hours, then stirred at 0°C for 1 hour to precipitate crystals. The resulting crystals were filtered and washed with ethanol (100 mL). Ethanol (500 mL) was added to the crystals, the mixture was heated to 70°C and stirred for 3 hours, then cooled to room temperature over 2 hours and stirred overnight. After cooling the solution to below 0°C, it was stirred for 1 hour. The obtained crystals were washed with ethanol (2 vol) below 10°C and dried under reduced pressure to obtain 50.69 g (yield 73.9%) of the monoethanolized compound of the title compound.

[0249] 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).

[0250] [Synthesis Example 7] 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(1,3-thiazole-2-yl)-1,3-benzoxazole-4-yl]oxy}-1,1-difluoro-2-methylpropane-2-ol

[0251] [ka]

[0252] 10 g, 19.2 mmol of tert-butyl 3-(4-(1,1-difluoro-2-hydroxy-2-methylpropoxy)-7-(thiazole-2-yl)benzo[d]oxazole-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (10 g, 19.2 mmol) obtained in Synthesis Example 6 was dissolved in dichloromethane (25 mL), trifluoroacetic acid (18.3 mL, 238.8 mmol) was added, and the mixture was stirred at 40°C for 2 hours. Methanol (30 mL) and dichloromethane (165 mL) were added to the reaction mixture, and then 100 mL of 5N sodium hydroxide aqueous solution was added and the mixture was stirred at a temperature below 30°C. The aqueous and organic layers were separated, and the aqueous layer was re-extracted with dichloromethane (10 mL). Methanol (30 mL) and water (100 mL) were added to the combined organic layers and the mixture was stirred. The aqueous and organic layers were separated, and the aqueous layer was re-extracted with dichloromethane (10 mL). The combined organic layer was concentrated to 100 mL, toluene (50 mL) was added, and then concentrated to 50 mL. To this concentrate, toluene (100 mL) was added and the mixture was stirred at room temperature for 1 hour, then at 55°C for 1 hour, and then at 0°C for more than 1 hour. The resulting solid was then filtered. The obtained 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%).

[0253] [Synthesis Example 8] Crude crystals (20 g) of 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(1,3-thiazole-2-yl)-1,3-benzoxazole-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol obtained in Synthesis Example 7 were dissolved in 85% ethanol aqueous solution (300 mL). 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 under reduced pressure to 100 mL, ethanol (100 mL) was added, and then concentrated under reduced pressure to 100 mL, and this procedure was repeated twice. The concentrated solution was stirred overnight at 0°C to precipitate the solid. The resulting solid was filtered, washed with pre-cooled ethanol (40 mL), and dried under reduced pressure to obtain 17.8 g (89.0% yield) of 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(1,3-thiazole-2-yl)-1,3-benzoxazole-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol recrystallized product.

[0254] 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).

[0255] (Example 2) [Synthesis Example 1] 4-benzyloxy-7-bromo-2-ethoxybenzo[d]oxazole

[0256] [ka]

[0257] 8.83 g, 30.0 mmol of 2-amino-3-benzyloxy-6-bromophenol obtained in Synthesis Example 2 of Example 1 was dissolved in toluene (27 mL), 0.86 mL, 15.0 mmol of acetic acid and tetraethoxymethane (6.34 g, 33.0 mmol) were added, and the mixture was heated under reflux for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed sequentially with 5% aqueous sodium bicarbonate solution and water. The resulting organic layer was concentrated while substituting with 2-propanol to a 72 mL solution, which was stirred to precipitate the solid. After cooling, the resulting solid was filtered, washed with 2-propanol, and dried to obtain 9.84 g (yield 94.3%) of the title compound.

[0258] 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).

[0259] [Synthesis Example 2] 4-benzyloxy-2-ethoxy-7-(thiazole-2-yl)benzo[d]oxazole

[0260] [ka]

[0261] Zinc powder (1.57 g, 24.0 mmol) was suspended in DMF (15 mL), chlorotrimethylsilane (0.25 mL, 2.0 mmol) was added, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was heated to 60°C, 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) obtained in Synthesis Example 1, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.24 g, 0.29 mmol) and DMF (10 mL) were added, and the mixture was stirred at 80°C or higher for 1 hour and then cooled. Toluene (35 mL), DMF (18 mL), and 20-fold diluted sulfuric acid (18 mL) were added to the reaction mixture, and the mixture was stirred for 1 hour, after which the aqueous layer was removed. To the obtained organic layer, 18 mL of DMF and 18 mL of 20-fold diluted sulfuric acid were added and stirred, and the aqueous layer was removed. The obtained organic layer was washed with water. The same procedure was repeated to obtain the same amount of organic layer. The obtained organic layers were mixed and concentrated while substituting with 2-propanol to a 70 mL solution. This solution was stirred to precipitate the solid, and after cooling, the solid was filtered, washed with 2-propanol, and dried to obtain 6.06 g of the title compound (yield 86.0%).

[0262] 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).

[0263] [Synthesis Example 3] tert-butyl 3-(4-benzyloxy-7-(thiazole-2-yl)benzo[d]oxazole-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-carboxylate

[0264] [ka]

[0265] 4-benzyloxy-2-ethoxy-7-(thiazole-2-yl)benzo[d]oxazole (3.0 g, 8.5 mmol) obtained in Synthesis Example 2 was dissolved in toluene (12 mL), and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (1.86 g, 9.4 mmol) and acetic acid (0.25 mL, 4.4 mmol) were added, and the mixture was heated under reflux for 1 hour. The reaction mixture was diluted with toluene and washed sequentially with 5% aqueous sodium bicarbonate solution and water. The resulting organic layer was concentrated while substituting with 2-propanol to prepare a 30 mL solution. This solution was stirred to precipitate the solid, and after cooling, the solid was filtered, washed with 2-propanol, and dried to obtain 3.97 g (yield 92.5%) of the title compound. 1 The 1H-NMR spectrum matched that of the compound obtained in Synthesis Example 4 of Example 1.

[0266] (Example 3) [Synthesis Example 1] 5,7-Dibromo-2-ethoxybenzo[d]oxazole-4-ol

[0267] [ka]

[0268] 2-nitroresorcinol (5.0 g, 32.235 mmol) was dissolved in ethyl acetate (50 mL), 10% Pd-C (PE type) (0.25 g) was added, and the mixture was vigorously stirred at room temperature under a hydrogen atmosphere for 1.5 hours to obtain a reaction solution containing 2-aminoresorcinol. The reaction solution was filtered through Celite, the residue was washed with ethyl acetate (30 mL divided into several portions), and the filtrate was concentrated under reduced pressure to 50 mL. To this solution, ethyl acetate (25 mL), acetic acid (0.92 mL, 16.060 mmol), and tetraethoxymethane (10.1 mL, 48.330 mmol) were added under a nitrogen atmosphere, and the mixture was stirred at 85°C for 1 hour to obtain a reaction solution containing 2-ethoxybenzo[d]oxazole-4-ol. After cooling the reaction solution, it was sequentially washed with 5% sodium bicarbonate aqueous solution (50 mL) and water (50 mL), and concentrated under reduced pressure to 50 mL. To the obtained solution, ethyl acetate (50 mL) was added, and under ice cooling, N-bromosuccinimide (12.05 g, 67.770 mmol) was added in portions. The mixture was heated to room temperature and stirred for 1 hour to obtain a reaction solution containing the title compound. To the reaction solution, ethyl acetate (50 mL) was added, and the mixture was sequentially washed with 20% sodium bisulfite aqueous solution (50 mL), followed by two washes with 5% saline solution (50 mL). The obtained organic layer was concentrated under reduced pressure to 50 mL, and the process of adding ethanol (50 mL) and concentrating under reduced pressure to 50 mL was repeated twice. Water (100 mL) was added dropwise to the solution to precipitate the solid, and the mixture was aged under ice cooling for 1 hour. The obtained solid was filtered, washed with ethanol / water = 1 / 3 (in several portions of 40 mL), and dried under reduced pressure to obtain 8.73 g of the title compound (yield 80.4%).

[0269] 1 H-NMR (400MHz, CDCl3) δppm: 7.45 (s, 1H), 4.65 (q, J = 6.9Hz, 2H), 1.52 (t, J = 6.9Hz, 3H).

[0270] [Synthesis Example 2] tert-butyl 3-(5,7-dibromo-4-hydroxybenzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-carboxylate

[0271] [ka]

[0272] 5,7-dibromo-2-ethoxybenzo[d]oxazole-4-ol (7.00 g, 20.773 mmol) and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (4.94 g, 24.916 mmol) obtained in Synthesis Example 1 were dissolved in toluene (70 mL), heated to 125 °C, and stirred for 2 hours. After cooling the reaction mixture, it was concentrated under reduced pressure to a 35 mL solution, and n-hexane (175 mL) was added dropwise to precipitate the solid. The mixture was then aged on ice for 1 hour. The obtained solid was filtered, 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. The addition of ethyl acetate (63 mL) and concentration under reduced pressure to 48 mL was repeated three times. The resulting solution was stirred at 60°C for 30 minutes, then cooled to room temperature and aged on ice for 1 hour. The resulting solid was filtered, washed with cold ethyl acetate (18 mL divided into several portions), and dried under reduced pressure to obtain 7.77 g of the title compound (yield 84.8%).

[0273] 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).

[0274] [Synthesis Example 3] tert-butyl 3-(5-bromo-4-hydroxy-7-(thiazole-2-yl)benzo[d]oxazole-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-carboxylate

[0275] [ka]

[0276] Anhydrous lithium chloride (2.22 g, 51.11 mmol) and zinc powder (5.01 g, 76.65 mmol) were suspended in THF (10 mL), chlorotrimethylsilane (0.45 mL, 3.58 mmol) was added under a nitrogen atmosphere, and the mixture was stirred at 60°C for slightly more than 2 hours. 2-bromothiazole (4.53 mL, 51.11 mmol) was slowly added dropwise, and tert-butyl 3-(5,7-dibromo-4-hydroxybenzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (5.00 g, 10.22 mmol) obtained in Synthesis Example 2 was rapidly added in DMF (15 mL) solution, palladium(II) acetate (0.229 g, 1.022 mmol), and tri(p-tolyl)phosphine (1.24 g, 4.09 mmol) were added using DMF (15 mL), and the mixture was heated to 85°C and stirred for 2.5 hours. The reaction mixture was cooled on ice, and chloroform (50 mL), toluene (25 mL), DMF (50 mL), and 1.8 M aqueous sulfuric acid (50 mL) were added and stirred for 30 minutes. After standing, 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 re-extracted 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 by Celite, the residue was washed with chloroform, and the filtrate was separated. The resulting organic layer was washed twice with water (100 mL), and then concentrated under reduced pressure to 30 mL. To the resulting solution, toluene (100 mL) was added, and the concentration under reduced pressure to 30 mL was repeated twice. Then, ethanol (100 mL) was added, and the concentration under reduced pressure to 30 mL was repeated twice. The resulting solution was cooled on ice and allowed to crystallize and mature. After filtration and reduced-pressure drying, 4.88 g of the title compound (yield 96.8%) was obtained.

[0277] 1H-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).

[0278] [Synthesis Example 4] tert-butyl 3-(4-hydroxy-7-(thiazole-2-yl)benzo[d]oxazole-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-carboxylate

[0279] [ka]

[0280] The tert-butyl 3-(5-bromo-4-hydroxy-7-(thiazole-2-yl)benzo[d]oxazole-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (0.469 g, 0.951 mmol), ammonium formate (1.50 g, 23.79 mmol), and zinc powder (1.554 g, 23.77 mmol) obtained in Synthesis Example 3 were suspended in ethanol (7 mL) and refluxed under a nitrogen atmosphere for 2 hours. After cooling the suspension, ethyl acetate (4.7 mL) was added and stirred, then filtered by Celite filtration, and the filtrate was washed with ethyl acetate (9.4 mL divided into several portions). The filtrate was sequentially washed with 5% potassium bisulfate 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 process was repeated twice to 4.7 mL. The resulting solution was stirred at room temperature for 2 hours, then crystallized and aged on ice for 1 hour to obtain 397 mg (91.7% yield) of the title compound as monoacetonitrile. 1 The 1H-NMR spectrum matched that of the compound obtained in Synthesis Example 5 of Example 1. [Industrial applicability]

[0281] The present invention makes it possible to provide a novel method for producing 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazole-2-yl)benzo[d]oxazole-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol (compound (1)) or a salt thereof, which is excellent in safety and operability and suitable for industrial production. Furthermore, the present invention makes it possible to provide a 2-alkoxybenzo[d]oxazole derivative (compound (2)) or a salt thereof, as well as a method for producing the same, as a raw material that can be used in the method for producing compound (1) or a salt thereof.

[0282] Compound (2) according to the present invention can be produced without requiring highly toxic and difficult-to-handle reagents or highly dangerous operations, and furthermore, without generating any toxic substances during the reaction. Moreover, the production of compound (1) or its salt using this compound also does not require highly toxic and difficult-to-handle reagents or highly dangerous operations. In addition, according to the present invention, it is possible to reduce the number of steps compared to existing production methods, and compound (1) or its salt can be obtained with a high yield equivalent to that of existing production methods. Therefore, the method for producing compound (1) or its salt, and the method for producing compound (2) or its salt used therein, according to the present invention are extremely useful industrially.

Claims

1. Formula (2): 【Chemistry 1】 [In formula (2), R ａ This represents a hydrogen atom or an optionally substituted arylmethyl group. R ｂ This represents an optionally substituted alkyl group or cyclic alkyl group. R ３ This indicates a hydrogen atom or a halogen atom. X ａ This represents a hydrogen atom or a halogen atom. A compound represented by is reacted with a brominating agent to obtain compound (2-21) in which, in formula (2), Ra is a hydrogen atom, R b is an optionally substituted alkyl group, R 3 is a bromine atom, and X a is a bromine atom. By substituting OR b of compound (2-21) with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate, we obtain formula (8): 【Chemistry 2】 [In formula (8), Boc represents a tert-butoxycarbonyl group.] Let the compound be represented by the following: The compound represented by formula (8) above is subjected to a cross-coupling reaction in the presence of a metal catalyst to introduce a thiazole-2-yl group, resulting in formula (9): 【Transformation 3】 [In formula (9), Boc represents a tert-butoxycarbonyl group.] Let the compound be represented by the following: By reacting the compound represented by formula (9) with metals, formula (3): 【Chemistry 4】 [In formula (3), Boc represents a tert-butoxycarbonyl group.] Step B for producing a compound represented by or a salt thereof, Using the compound represented by formula (3) or a salt thereof, formula (1): 【Transformation 5】 Step C for producing a compound represented by or a salt thereof, A method for producing a compound represented by formula (1) or a salt thereof, including the above.

2. Formula (10): 【Transformation 6】 [In formula (10), R １ This represents a hydroxyl group, a halogen atom, or an arylmethyloxy group. R ２ This indicates a hydroxyl group or a halogen atom. R ３ This represents a hydrogen atom or a halogen atom. The manufacturing method according to claim 1, comprising step A, which involves using a compound represented by formula (2) or a salt thereof to produce a compound represented by formula (2) or a salt thereof.

3. The above step A is, In the above formula (10), R １ is a hydroxyl group, R ２ is a hydroxyl group, R ３ is a hydrogen atom. After reducing the compound (10-2), it is reacted with tetraalkoxymethane in the presence of an acid catalyst to produce the compound represented by the above formula (2) or a salt thereof. This is the step of The manufacturing method according to claim 2.

4. Formula (7): 【Transformation 7】 [In formula (7), Et is an ethyl group.] A compound represented by or a salt thereof.

5. Formula (8): 【Transformation 8】 [In formula (8), Boc is a tert-butoxycarbonyl group.] A compound represented by or a salt thereof.

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