Methods for the production of benzoxazole derivatives containing a bicyclic piperazine ring or their salts, and methods for the production of their materials.

Abstract

A method for producing a compound represented by formula (1) or a salt thereof, the method comprising: a step B for producing a compound represented by formula (3) [in formula (3), Boc represents a tert-butoxycarbonyl group] or a salt thereof by using a compound represented by formula (2) [in formula (2), Ra represents a hydrogen atom or an optionally substituted arylmethyl group, Rb represents an optionally substituted alkyl group or a cyclic alkyl group, R3 represents a hydrogen atom, a halogen atom, or a thiazol-2-yl group, and Xa represents a hydrogen atom or a halogen atom] or a salt thereof; and a step C for producing the compound represented by formula (1) or a salt thereof by using the compound represented by formula (3) or a salt thereof.

Description

Method for producing benzoxazole derivatives having bicyclic piperazine rings or salts thereof, and method for producing raw materials thereof

[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 a raw material therefor; more specifically, the present invention relates to a method for producing 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazol-2-yl)benzo[d]oxazol-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol or a salt thereof, and a method for producing a 2-alkoxybenzo[d]oxazole derivative or a salt thereof, which is a raw material therefor.

[0002] 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazol-2-yl)benzo[d]oxazol-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol (a compound represented by formula (1) described below), 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] It is known that 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazol-2-yl)benzo[d]oxazol-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol and salts thereof can be produced, for example, from 4-(benzyloxy)-7-bromobenzo[d]oxazole-2-thiol via an imination reaction, a cross-coupling reaction, and a deprotection reaction (de-O-benzylation) to form an intermediate product: tert-butyl 3-(4-hydroxy-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (a compound represented by formula (3) described below), which is then further subjected to functional group conversion and deprotection reactions (Patent Document 1).

[0004] Furthermore, 4-(benzyloxy)-7-bromobenzo[d]oxazole-2-thiol used in the above production method is known to be produced, for example, from 2-nitroresorcinol through five steps: a di-O-benzyl etherification reaction (protective group formation), 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).

[0005] International Publication No. 2018 / 124060

[0006] In the existing production method using 4-(benzyloxy)-7-bromobenzo[d]oxazole-2-thiol, in the production of the 4-(benzyloxy)-7-bromobenzo[d]oxazole-2-thiol and the production of the intermediate product using the same, there are several steps that need improvement, such as: (i) the use of lachrymatory and toxic benzyl bromide in the formation of a protecting group; (ii) the use of highly toxic boron trichloride in the formation of the protecting group; (iii) the use of carbon disulfide, which is highly toxic and classified as a special flammable material under Japan's Fire Service Act, in the cyclization reaction involving a thiol group, and which generates highly toxic hydrogen sulfide during the reaction; and (iv) the substitution of an imino group for the position of the thiol group in the cyclization reaction involving a thiol group generates highly toxic hydrogen sulfide. These processes have issues such as the use of highly toxic reagents and high-risk operability.

[0007] The present invention has been made in view of the above problems, and an object of the present invention is to provide a novel method for producing 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazol-2-yl)benzo[d]oxazol-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol or a salt thereof, which is excellent in safety and operability and is suitable for industrial production.

[0008] As a result of intensive research aimed at solving the above-mentioned problems, the present inventors 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-(thiazol-2-yl)benzo[d]oxazol-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol or a salt thereof. In other words, the compound represented by formula (2) and a salt thereof can be produced by a method that does not require highly toxic and difficult-to-handle reagents or highly dangerous operations, and further does not generate toxic substances during the reaction.

[0009] Furthermore, highly toxic and difficult-to-handle reagents and highly dangerous procedures are not required for the production of intermediates, such as tert-butyl 3-(4-hydroxy-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate or a salt thereof, and for the production of 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazol-2-yl)benzo[d]oxazol-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol or a salt thereof, using the same. In addition, the present inventors have found that a production method using the compound represented by formula (2) or a salt thereof can reduce the number of steps compared to existing production methods, and can also produce 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazol-2-yl)benzo[d]oxazol-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol or a salt thereof in a high yield equivalent to that of existing production methods.

[0010] Therefore, the present inventors have found that the use of a compound represented by formula (2) or a salt thereof makes it possible to provide a novel industrial production method that is extremely safe and easy to operate, and have completed the present invention. That is, the present invention provides the invention shown below. [1] Formula (2):

[0011]

[0012] [In formula (2), R ａ represents a hydrogen atom or an optionally substituted arylmethyl group, R ｂ represents an optionally substituted alkyl group or a cyclic alkyl group, R ３ represents a hydrogen atom, a halogen atom or a thiazol-2-yl group, ａ represents a hydrogen atom or a halogen atom.] or a salt thereof,

[0013]

[0014] [in formula (3), Boc represents a tert-butoxycarbonyl group] or a salt thereof; and a step B of producing a compound represented by formula (1):

[0015]

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

[0017]

[0018] [In formula (4), R ａ is an optionally substituted arylmethyl group, and R ３ is a halogen atom, and Boc is a tert-butoxycarbonyl group.], and a thiazol-2-yl group is introduced into the compound represented by formula (4) by a cross-coupling reaction in the presence of a metal catalyst to obtain a compound represented by formula (5):

[0019]

[0020] [In formula (5), Rａ is an optionally substituted arylmethyl group, and Boc is a tert-butoxycarbonyl group.], and reacting the compound represented by formula (5) with an organic acid to produce the compound represented by formula (3) or a salt thereof. [3] The method according to [1], wherein step B is a step of reacting the compound represented by formula (2), R ａ is an optionally substituted arylmethyl group, and R ｂ is an optionally substituted alkyl group, and R ３ is a halogen atom, and X ａ is a hydrogen atom, by a cross-coupling reaction in the presence of a metal catalyst to introduce a thiazol-2-yl group into the compound (2-1), ａ is an optionally substituted arylmethyl group, and R ｂ is an optionally substituted alkyl group, and R ３ is a thiazol-2-yl group, and X ａ is a hydrogen atom, and OR of compound (2-11) ｂ is replaced with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate to give the compound of formula (5):

[0021]

[0022] [In formula (5), R ａ is an optionally substituted arylmethyl group, and Boc is a tert-butoxycarbonyl group.], and reacting the compound represented by formula (5) with an organic acid to produce the compound represented by formula (3) or a salt thereof. [4] The method according to [1], wherein step B is a step of reacting the compound represented by formula (2), R ａ is a hydrogen atom, and R ｂ is an optionally substituted alkyl group, and R ３ is a hydrogen atom, and X ａ is a hydrogen atom with a brominating agent, ａ is a hydrogen atom, and R ｂ is an optionally substituted alkyl group, and R３ is a bromine atom, and X ａ is a bromine atom, and OR of compound (2-21) ｂ is replaced with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate to give the compound of formula (8):

[0023]

[0024] [In formula (8), Boc is a tert-butoxycarbonyl group.], and a thiazol-2-yl group is introduced into the compound represented by formula (8) by a cross-coupling reaction in the presence of a metal catalyst to obtain a compound represented by formula (9):

[0025]

[0026] [In formula (9), Boc is a tert-butoxycarbonyl group.], and reacting the compound represented by formula (9) with a metal to produce a compound represented by formula (3) or a salt thereof. [5] The production method according to [1],

[0027]

[0028] [In formula (10), R １ represents a hydroxyl group, a halogen atom, or an arylmethyloxy group; R ２ represents a hydroxyl group or a halogen atom, R ３ represents a hydrogen atom, a halogen atom, or a thiazol-2-yl group.] or a salt thereof. [6] The method according to any one of [1] to [4], wherein the step A is a step of producing a compound represented by formula (2) or a salt thereof using a compound represented by formula (10) or a salt thereof. １ is a halogen atom, and R ２ is a halogen atom and R ３ is a hydrogen atom, and reacting the compound (10-1) with benzyl alcohol to obtain a compound of the formula (10-11):

[0029]

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

[0031]

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

[0033]

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

[0035]

[0036] [In formula (14), Bn is a benzyl group.], and reacting the compound represented by formula (14) with tetraalkoxymethane in the presence of an acid catalyst to produce the compound represented by formula (2) or a salt thereof. [7] The method according to [5], wherein step A is a step of reacting a compound represented by formula (10), R １ is a hydroxyl group, and R ２ is a hydroxyl group, and R ３ [8] The method according to [5], wherein the compound (10-2) is a hydrogen atom, and then the compound (10-2) is reacted with tetraalkoxymethane in the presence of an acid catalyst, followed by reaction with a brominating agent to produce a compound represented by formula (2) or a salt thereof.

[0037]

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

[0039]

[0040] [In formula (6), Bn is a benzyl group, and Et is an ethyl group.]

[10] A compound represented by formula (7):

[0041]

[0042] [In formula (7), Et is an ethyl group.]

[11] A compound represented by formula (8):

[0043]

[0044] A compound represented by the formula (8) or a salt thereof: [in which Boc is a tert-butoxycarbonyl group]

[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-(thiazol-2-yl)benzo[d]oxazol-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol (a compound represented by formula (1)) or a salt thereof, which is safe, easy to operate, 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 a raw material that can be suitably used in the production method, as well as a method for producing the same.

[0046] Hereinafter, the method for producing the compound represented by formula (1) or a salt thereof of the present invention, and the 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) will be described in detail with examples, but the present invention is not limited to the scope of the specific examples presented.

[0047] The method for producing a compound represented by formula (1) of the present invention is a method comprising: step B of producing a compound represented by formula (3) or a salt thereof using a compound represented by formula (2) or a salt thereof; and step C of producing a compound represented by formula (1) or a salt thereof using a compound represented by formula (3) or a salt thereof (hereinafter sometimes simply referred to as the "production method of the present invention").

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

[0049]

[0050] The compound is 1-{[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-7-(thiazol-2-yl)benzo[d]oxazol-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol, represented by the formula (1). This compound has excellent PDE4 (phosphodiesterase type 4) inhibitory activity and also has 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 sometimes referred to as "compound (1)"), and the salt is preferably a pharmacologically acceptable salt. The pharmacologically acceptable salt is preferably in the form of an acid addition salt, and examples of the acid of the acid addition salt include hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid; inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, hydroperoxide, and carbonic acid; organic carboxylic acids 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, and malic acid; acidic amino acids such as aspartic acid and glutamic acid; alkylsulfonic acids such as methanesulfonic acid; and arylsulfonic acids such as p-toluenesulfonic acid.

[0052] Compound (1) and salts thereof are represented by the following formula (3):

[0053]

[0054] [In formula (3), Boc represents a tert-butoxycarbonyl group.] Compound (1) can be obtained using tert-butyl 3-(4-hydroxy-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (hereinafter, sometimes 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 appropriately adopted, and for example, the method described in Patent Document 1 can be used. Salts of compound (3) include the same salts as those of compound (1), including preferred forms thereof.

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

[0056]

[0057] In formula (2), R ａ represents a hydrogen atom or an optionally substituted arylmethyl group, and R ｂ represents an optionally substituted alkyl group or a cyclic alkyl group, and R ３ represents a hydrogen atom, a halogen atom or a thiazol-2-yl group, and X ａ represents a hydrogen atom or a halogen atom.

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

[0059] In the present specification, the term "arylmethyloxy group" refers to 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 a benzyl group being particularly preferred. １ In the arylmethyloxy group represented by the formula: the arylmethyl group may be substituted with one or more substituents which may be the same or different.

[0060] In this specification, the term "alkyl group" refers to a linear or branched alkyl group, preferably having 1 to 6 carbon atoms, more preferably having 1 to 3 carbon atoms. ｂ The alkyl group represented by the formula (I) may be substituted with one or more substituents, which may be the same or different. 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, and an n-hexyl group.

[0061] In this specification, the term "cyclic alkyl group" refers to a cyclic alkyl group, and the number of carbon atoms, i.e., the number of ring members, is preferably 3 to 8, and more preferably 3 to 6. ｂ The cyclic alkyl group represented by the formula (I) may be substituted with one or more substituents, which may be the same or different. Examples of the cyclic alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

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

[0063] In addition, in this specification, the term "optionally 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, carboxy groups, alkyl groups, alkoxy groups, cyclic alkoxy groups, alkylamino groups, cyclic alkylamino groups, and azide groups.

[0064] Examples of the compound (2) according to the present invention include the following compounds: 2-methoxybenzo[d]oxazol-4-ol, 2-ethoxybenzo[d]oxazol-4-ol, 2-propoxybenzo[d]oxazol-4-ol, 2-isopropoxybenzo[d]oxazol-4-ol, 2-butoxybenzo[d]oxazol-4-ol, 2-isobutoxybenzo[d]oxazol-4-ol, 2-(sec-butoxy)benzo[d]oxazol-4-ol, 2-(tert-butoxy)benzo[d]oxazol-4-ol, 2-pentoxybenzo[d]oxazol-4-ol, ol, 2-(pentan-2-yloxy)benzo[d]oxazol-4-ol, 2-[(3-methylbutan-2-yl)oxy]benzo[d]oxazol-4-ol, 2-(tert-pentyloxy)benzo[d]oxazol-4-ol, 2-(hexyloxy)benzo[d]oxazol-4-ol, 2-cyclopropoxybenzo[d]oxazol-4-ol, 2-cyclobutoxybenzo[d]oxazol-4-ol, 2-(cyclopentyloxy)benzo[d]oxazol-4-ol, 2-(cyclohexyloxy)benzo[d]oxazol-4-ol (xyloxy)benzo[d]oxazol-4-ol, 2-benzyloxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-methoxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-ethoxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-propoxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-butoxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-isobutoxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-(se c-butoxy)benzo[d]oxazol-4-ol, 5,7-dibromo-2-(tert-butoxy)benzo[d]oxazol-4-ol, 5,7-dibromo-2-pentoxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-(pentan-2-yloxy)benzo[d]oxazol-4-ol, 5,7-dibromo-2-[(3-methylbutan-2-yl)oxy]benzo[d]oxazol-4-ol, 5,7-dibromo-2-(tert-pentyloxy)benzo[d]oxazol-4-ol, 5,7-Dibromo-2-(hexyloxy)benzo[d]oxazol-4-ol, 5,7-dibromo-2-cyclopropoxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-cyclobutoxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-cyclobutoxybenzo[d]oxazol-4-ol, 5,7-dibromo-2-(cyclopentyloxy)benzo[d]oxazol-4-ol, 5,7-dibromo-2-(cyclohexyloxy)benzo[d]oxazol-4-ol, 5,7-dibromo-2-benzyloxy Benzyloxybenzo[d]oxazol-4-ol, 4-(benzyloxy)-7-bromo-2-methoxybenzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-ethoxybenzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-propoxybenzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-isopropoxybenzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-butoxybenzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-isobutoxybenzo[d]oxazole oxazole, 4-(benzyloxy)-7-bromo-2-(sec-butoxy)benzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-(tert-butoxy)benzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-pentoxybenzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-(pentan-2-yloxy)benzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-[(3-methylbutan-2-yl)oxy]benzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-[(3-methylbutan-2-yl)oxy]benzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-[(3-methylbutan-2-yl)oxy]benzo[d]oxazole, bromo-2-(tert-pentyloxy)benzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-(hexyloxy)benzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-cyclopropoxybenzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-cyclobutoxybenzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-(cyclopentyloxy)benzo[d]oxazole, 4-(benzyloxy)-7-bromo-2-(cyclohexyloxy)benzo[d]oxazole, 2,4-di(benzyloxy)-7-bromobenzo[d]oxazole, 4-(benzyloxy)-2-methoxy-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-ethoxy-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-propoxy-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-isopropoxy-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-bromobenzo[d]oxazole, 4-(benzyloxy)-2-methoxy-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-isobutoxy-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-(sec-butoxy)-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-(tert-butoxy)-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-pentoxy-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-pentoxy-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-(pentan-2-yloxy)-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-[(3-methylbutan-2-yl)oxy]-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-(tert-pentyloxy)-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-(hexyloxy)-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-(hexyloxy)-7-(thiazol-2-yl)benzo[d]oxazole cyclopropoxy-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-cyclobutoxy-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-(cyclopentyloxy)-7-(thiazol-2-yl)benzo[d]oxazole, 4-(benzyloxy)-2-(cyclohexyloxy)-7-(thiazol-2-yl)benzo[d]oxazole, and 2,4-di(benzyloxy)-7-(thiazol-2-yl)benzo[d]oxazole, but the present invention is not limited to these specific examples.

[0065] Among these, preferred examples of the compound (2) according to the present invention include 2-ethoxybenzo[d]oxazol-4-ol and compounds of the following formula (7):

[0066]

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

[0068]

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

[0070]

[0071] [In the formula (6), Bn is a benzyl group, and Et is an ethyl group.]

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

[0073] The compound (2) or a salt thereof according to the present invention is preferably obtained by step A of producing the compound (2) or a salt thereof using a compound represented by the following formula (10) (hereinafter sometimes referred to as “compound (10)”) or a salt thereof:

[0074] The compound (1) or a salt thereof according to the present invention can be produced by a representative method shown in the following scheme 1. Scheme 1:

[0075]

[0076] In each formula of Scheme 1 above, R １ represents a hydroxyl group, a halogen atom, or an arylmethyloxy group, and R ２ represents a hydroxyl group or a halogen atom, and R ａeach independently represents a hydrogen atom or an optionally substituted arylmethyl group, R ｂ represents an optionally substituted alkyl group or a cyclic alkyl group, and R ３ each independently represents a hydrogen atom, a halogen atom, or a thiazol-2-yl group; X ａ each independently represents a hydrogen atom or a halogen atom.

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

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

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

[0080] In the production method of the present invention, in step A, preferably, R １ and R ２ is a halogen atom, and R ３ is a hydrogen atom, more preferably compound (10-1), １ and R ２ is a fluorine atom and R ３is a hydrogen atom, or as compound (10), R １ and R ２ is a hydroxyl group, and R ３ is a hydrogen atom, i.e., 2-nitroresorcinol, to produce compound (2) or a salt thereof.

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

[0082]

[0083] In formula (10-11), Bn is a benzyl group (the same applies hereinafter), and R ２ is a halogen atom, and R ２ Then, the compound (10-11) is reacted with a brominating agent (bromination reaction) to obtain a compound represented by the following formula (10-12):

[0084]

[0085] In formula (10-12), R ２ is a halogen atom, and R ２ Then, the compound (10-12) is reacted with an alkaline aqueous solution (hydration reaction) to form a compound of the following formula (10-13):

[0086]

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

[0088]

[0089] Then, compound (14) is reacted with tetraalkoxymethane (cyclization reaction involving an alkoxy group) to produce compound (2) (for example, a compound represented by formula (15) above) or a salt thereof.

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

[0091] In the production method of the present invention, in step B, preferably, R ａ is an optionally substituted arylmethyl group, and R ｂ is an optionally substituted alkyl group, and R ３ is a halogen atom, and X ａ is a hydrogen atom (more preferably, R ａ is a benzyl group), or as compound (2), R ａ is a hydrogen atom, and R ｂ is an optionally substituted alkyl group, and R ３ is a hydrogen atom, and X ａ is a hydrogen atom (more preferably, R ｂ is an ethyl group) to produce compound (3) or a salt thereof.

[0092] When compound (2-1) is used as compound (2), for example, first, compound (2-1) (more preferably, R ａ is a benzyl group, and R ３ is a bromine atom) ｂis substituted with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (substitution reaction) to obtain the following formula (4):

[0093]

[0094] In formula (4), R ａ is an optionally substituted arylmethyl group, and R ３ is a halogen atom. ａ is preferably a benzyl group, and R ３ 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 a compound of the following formula (5):

[0095]

[0096] In formula (5), R ａ is an optionally substituted arylmethyl group. ａ A benzyl group is preferred as the protecting group. Next, compound (5) is reacted with an organic acid (deprotection reaction) to produce compound (3) or a salt thereof.

[0097] Another method for using compound (2-1) as compound (2) is, for example, first reacting compound (2-1) (more preferably, 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 to introduce a thiazol-2-yl group into the compound (compound) ａ is an optionally substituted arylmethyl group, and R ｂ is an optionally substituted alkyl group, and R ３ is a thiazol-2-yl group, and X ａ is a hydrogen atom. Compound (2-11) is a compound represented by the following formula (6):

[0098]

[0099] In formula (6), Et is an ethyl group (the same applies below). Next, the OR of compound (2-11) is ｂ is substituted with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (substitution reaction) to give compound (5) (R ａ is a benzyl group). Next, compound (5) is reacted with an organic acid (deprotection reaction) to produce compound (3) or a salt thereof.

[0100] When compound (2-2) is used as compound (2), for example, first, compound (2-2) (more preferably, R ｂ is an ethyl group) with a brominating agent, ａ is a hydrogen atom, and R ｂ is an optionally substituted alkyl group, and R ３ is a bromine atom, and X ａ is a bromine atom. Compound (2-21) is a compound represented by the following formula (7):

[0101]

[0102] Next, the compound represented by OR of compound (2-21) is preferred. ｂ is substituted with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (substitution reaction) to give the following formula (8):

[0103]

[0104] Next, a thiazol-2-yl group is introduced into compound (8) by a cross-coupling reaction in the presence of a metal catalyst to obtain a compound represented by the following formula (9):

[0105]

[0106] (Compound (9), Compound B) represented by the formula: Next, Compound (9) is reacted with a metal (conversion reaction) to produce Compound (3) or a salt thereof.

[0107] In the steps shown in Scheme 1 above, each intermediate compound may or may not be isolated. When not isolated, each reaction can be carried out successively.

[0108] Each reaction in Scheme 1 will be described in more detail below. In the following descriptions, the term "equivalent" refers to a chemical equivalent, and one equivalent is defined as the amount of molecules (amount of substance) required for all functional groups of a substrate to react in the same reaction.

[0109] (Partial Substitution Reaction) In the production method of the present invention, compound (10-1) is preferably reacted with benzyl alcohol to obtain compound (10-11) by partial substitution reaction. The partial substitution reaction is preferably carried out by reacting a substrate (here, compound (10-1)) with benzyl alcohol in an appropriate solvent in the presence or absence of a base, and the preferred conditions are as follows.

[0110] Examples of the solvent 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-butyl acetate, and and ester-based organic solvents such as butyl, 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. One of these solvents can be used alone, or two or more of them can be mixed in an appropriate ratio.

[0111] The solvent is preferably 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 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; 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 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. One of these compounds can be used alone, or two or more of them can be mixed in an appropriate ratio.

[0113] The base is preferably 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, preferably 0.1 to 10 equivalents, and more preferably 1 to 5 equivalents, relative to the substrate.

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

[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] (Bromination Reaction) In the production method of the present invention, preferably, compound (2-2) is reacted with a brominating agent to obtain compound (2-21) by bromination reaction. Furthermore, compound (10-11) is reacted with a brominating agent to obtain compound (10-12) by bromination reaction. Furthermore, compound (10-22) is reacted with a brominating agent to obtain compound (2) by bromination reaction. 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 the presence or absence of an acid catalyst, and the preferred conditions are as follows:

[0118] Examples of the solvent 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 acetic acid. 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, and the like. One of these can be used alone, or two or more of them can be mixed in an appropriate ratio and used.

[0119] The solvent is preferably 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 catalyst include organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, succinic acid, citric acid, methanesulfonic acid, trifluoromethanesulfonic acid, 10-camphorsulfonic 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-tungsto(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, stannic 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, tribenzylsilyl chloride, chlorotriphenylsilane, chloromethyldiphenylsilane, and di-tert-butylchloromethylsilane. These may be used alone or in combination of two or more in an appropriate ratio.

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

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

[0123] Examples of the brominating agent 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-undecene hydrogen tribromide, pyridinium bromide perbromide, 4-dimethylaminopyridinium bromide perbromide, N-bromoacetamide, N-bromosuccinimide, N-bromophthalimide, N-bromosaccharin, dibromocyanate, One of 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-dibromoMeldrum's acid, 2,4,4,6-tetrabromo-2,5-cyclohexadienone, boron tribromide, phosphorus tribromide, and the like can be used alone, or two or more of them can be mixed in an appropriate ratio and used.

[0124] The brominating agent is preferably 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, the amount of the brominating agent used is 0.8 to 5 equivalents, preferably 1 to 2 equivalents, relative to the substrate when one bromine atom is introduced per molecule of the substrate, and 1.8 to 5 equivalents, preferably 2 to 3 equivalents, relative to the substrate when two bromine atoms are introduced per molecule of the substrate.

[0126] The reaction temperature of 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 production method of the present invention, compound (10-13) is preferably obtained by hydration reaction of compound (10-12) with an alkaline solution. The hydration reaction is preferably carried out by reacting a substrate (here, compound (10-12)) with an alkaline aqueous solution in a suitable solvent, and the preferred conditions are as follows.

[0129] Examples of the solvent 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-butyl acetate, and and ester-based organic solvents such as butyl, 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. One of these solvents can be used alone, or two or more of them can be mixed in an appropriate ratio.

[0130] The solvent is preferably 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 alkaline aqueous solution, for example, aqueous solutions of sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, etc. can be used alone or in combination of two or more in an appropriate ratio.

[0132] The alkaline aqueous solution is preferably 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 appropriately.

[0133] The reaction temperature of 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 production method of the present invention, preferably, compound (14) is obtained by a reduction reaction by reacting compound (10-13) with a reducing agent. Alternatively, compound (10-2) 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) or compound (10-2)) with a reducing agent in an appropriate solvent, and the preferred conditions are as follows.

[0136] Examples of the solvent 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-based 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. 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, can be used alone or in combination of two or more in an appropriate ratio.

[0137] The solvent is preferably 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. Furthermore, the solvent may contain an acid such as formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, or toluenesulfonic acid, or a base such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, or potassium hydroxide, as appropriate.

[0138] The reducing agent may be, for example, one of metals such as zinc, aluminum, tin, stannous chloride, and iron; hydrogenation catalysts such as palladium, platinum, rhodium, and nickel, which are used together with a hydrogen source and may be used together with a carrier as appropriate; and inorganic salts such as sodium dithionite, which may be used alone or in combination of two or more of them in an appropriate ratio.

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

[0140] In the reduction reaction, when the reducing agent is the metals and / or inorganic salts, they are used in large excess, but when both are contained, the total amount is preferably 20 equivalents or less, more preferably 10 equivalents or less, relative to the substrate. When the reducing agent is the hydrogenation catalyst, it is used in a catalytic amount, and the amount is preferably 10 wt % or less, more preferably 5 wt % or less, relative to the total weight (wt) of the charged 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] (Cyclization Reaction Involving an Alkoxy Group) In the production method of the present invention, preferably, compound (14) is reacted with tetraalkoxymethane to obtain compound (2) by a cyclization reaction involving an alkoxy group. Also, compound (10-21) is reacted with tetraalkoxymethane to obtain compound (10-22) by a cyclization reaction involving an alkoxy group.

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

[0145] Examples of the solvent 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-butyl acetate, and and ester-based organic solvents such as butyl, 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. One of these solvents can be used alone, or two or more of them can be mixed in an appropriate ratio.

[0146] The solvent is preferably 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] Examples of the acid catalyst include organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, succinic acid, citric acid, methanesulfonic acid, trifluoromethanesulfonic acid, 10-camphorsulfonic 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, stannic chloride, ferric chloride, aluminum chloride, titanium tetrachloride, and zirconium tetrachloride. These may be used alone or in combination of two or more in an appropriate ratio.

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

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

[0150] Examples of the tetraalkoxymethane include tetramethoxymethane, tetraethoxymethane, tetrapropoxymethane, tetraisopropoxymethane, tetrabutoxymethane, tetraisobutoxymethane, tetra(sec-butoxy)methane, tetra(tert-butoxy)methane, tetrapentoxymethane, tetra(pentan-2-yloxy)methane, tetra[(3-methylbutan-2-yl)oxy]methane, tetra(tert-pentyloxy)methane, tetra(hexyloxy)methane, tetracyclopropoxymethane, tetracyclobutoxymethane, tetra(cyclopentyloxy)methane, and tetra(cyclohexyloxy)methane. One of these may be used alone, or two or more of these may be used in combination at an appropriate ratio.

[0151] The tetraalkoxymethane is preferably 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 an alkoxy group, the amount of the tetraalkoxymethane used is 0.9 to 5 equivalents, preferably 1 to 2 equivalents, relative to the substrate.

[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, a 2-alkoxy group (OR ｂ) is substituted with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate to obtain compound B (e.g., compound (4), compound (5), or compound (8)) by a substitution reaction. The substitution reaction is preferably carried out by reacting a substrate (here, compound (2)) with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate in an appropriate solvent in the presence or absence of an acid catalyst, and the preferred conditions are as follows.

[0156] The acid catalyst may be one of, for example, organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, succinic acid, citric acid, methanesulfonic acid, trifluoromethanesulfonic acid, 10-camphorsulfonic 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, stannic chloride, ferric chloride, aluminum chloride, titanium tetrachloride, and zirconium tetrachloride, or a mixture of two or more of these acids in an appropriate ratio.

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

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

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

[0160] Examples of the solvent 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-butyl acetate, and and ester-based organic solvents such as butyl, 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. One of these solvents can be used alone, or two or more of them can be mixed in an appropriate ratio.

[0161] The solvent is preferably 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 production method of the present invention, R of compound (2) or compound B ３ is other than a thiazol-2-yl group, a thiazol-2-yl group is introduced thereto by a cross-coupling reaction, if necessary. Preferably, a thiazol-2-yl group is introduced at the 7-position of compound (2) or compound B (e.g., compound (4), compound (2-1), or compound (8)) by a cross-coupling reaction in the presence of a metal catalyst, to form R ３ is a thiazol-2-yl group (for example, compound (5), compound (2-11), compound (9)).

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

[0166] The cross-coupling reaction is preferably carried out by reacting a substrate (here, compound (2) or compound B) with 2-halothiazole (as is, or after reacting with a reactant as necessary) in a suitable solvent in the presence of a metal catalyst, in the presence or absence of a ligand, and in the presence or absence of a base, and the preferred conditions are as follows:

[0167] Examples of the solvent 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 diphenyl ether-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. One of these organic solvents can be used alone, or two or more of them can be mixed in an appropriate ratio.

[0168] The solvent is preferably 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] The term "2-halothiazole" refers to a thiazole in which the second position is substituted with a halogen atom. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, preferably a bromine atom or an iodine atom, and more preferably a bromine atom.

[0170] The reactant is used to replace the halogen atom of 2-halothiazole with another reactive functional group, and examples of the reactant include those that perform a transmetallation reaction, etc. Preferred examples of the reactant include the catalyst and boron compound used in the Miyaura-Ishiyama boronation reaction described below, such as pinacoldiborane, a combination of pinacolborane and diboronic acid, a Grignard reagent, or zinc powder, and more preferred examples include zinc powder.

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

[0172] Examples of the metal catalyst 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, palladium (π-cinnamyl) chloride, and the like. dimer, 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 [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 tert-butyl)(4-trifluoromethylphenyl)phosphine]dichloropalladium(II), [1,1'-bis(di-tert-butylphosphino)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 palladium(II), [2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]dichloropalladium(II), [1,1'-bis(diphenylphosphino)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 tetrakis(acetonitrile)palladium(II) acetate, tetrakis(acetonitrile)palladium(II) tetrafluoroborate, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0) and tris(dibenzylideneacetone)dipalladium(0) chloroform adduct can be used alone or in combination of two or more in an appropriate ratio.

[0173] The metal catalyst is preferably 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(0), tris(dibenzylideneacetone)dipalladium(0) and tris(dibenzylideneacetone)dipalladium(0) 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 ligand 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-trimethylphenyl)phosphine, tris(trimethylphenyl)phosphine, tris(2,4,6-trimethoxyphenyl)phosphine, tris(hydroxymethyl)phosphine, tris(4-fluorophenyl)phosphine, tris(pentafluorophenyl)phosphine, tris(o-methoxyphenyl)phosphine, tris(4-methoxyphenyl)phosphine, triphenylphosphine, triphenylphosphine oxide, tri(o-tolyl)phosphine, tri(o-tolyl)phosphine tetrafluoroborate, tri(m-tolyl)phosphine, tri(p-tolyl)phosphine , 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 phosphine, tris[3,5-bis(trifluoromethyl)phenyl]phosphine, tris(4-chlorophenyl)phosphine, 5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-[1,4']bipyrazole, 5-(di-tert-butylphosphino)-1-(naphthalen-1-yl)-1H-pyrazole, triallylphosphine, triisopropylphosphine, and triisopropylphosphonium tetrafluoroborate can be used alone or in combination of two or more in an appropriate ratio.

[0175] The ligand is preferably 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, and more preferably at least one (preferably any one) selected from the group consisting of tri(p-tolyl)phosphine and 1,1′-bis(diphenylphosphino)ferrocene.

[0176] Examples of the base include those listed above in the (Partial substitution reaction) including their preferred forms.

[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 raw materials charged (excluding the solvent).

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

[0179] The reaction temperature for 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 for 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, the deprotection reaction may be a hydrogenolysis reaction, a deprotection reaction with a Lewis acid, or a deprotection reaction with an organic acid or the like. Preferably, the deprotection reaction with a Lewis acid and / or an organic acid is used, and more preferably, the deprotection reaction with an organic acid is used.

[0182] In the production method of the present invention, R of compound B ａIf R has a protecting group (e.g., a benzyl group), this is removed. Preferably, compound B (e.g., compound (5)) is reacted with an organic acid to convert R ａ The protecting group of is removed to obtain compound (3). Alternatively, Boc is removed by reacting compound C with an organic acid 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 the preferred conditions are as follows.

[0183] Examples of the solvent 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; 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. One of these organic solvents can be used alone, or two or more of them can be mixed in an appropriate ratio.

[0184] The solvent is preferably at least one selected from the group consisting of toluene, xylene, and dichloromethane, and more preferably at least one selected from the group consisting of toluene and dichloromethane.

[0185] The organic acid may be, for example, one of trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, chloroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, 10-camphorsulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, or a mixture of two or more of these acids in an appropriate ratio. A preferred example of the organic acid is trifluoroacetic acid.

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

[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] (Protection Reaction) Note that under the conditions of Scheme 1 above, the deprotection reaction of compound B also removes the N-Boc protecting group of compound B, producing the free base form of compound (3). Therefore, it is preferable to re-protect compound (3 by substitution with Boc). In this case, the free base form of compound (3) can be isolated and then re-protected by a general method known to those skilled in the art. Alternatively, the reaction mixture after completion of the deprotection reaction can be adjusted to a neutral to basic state, and the substrate in the reaction mixture (here, the free base form of compound (3)) can be reacted with di-tert-butyl dicarbonate in the presence or absence of a suitable co-solvent; the latter method is preferred. Preferred conditions for the latter protection reaction are as follows:

[0190] Examples of the auxiliary solvent 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; 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 alone or in combination of two or more in an appropriate ratio.

[0191] The solvent is preferably 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] In order to adjust the reaction mixture to a neutral to basic state, for example, 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; ammonia, methylamine, ethylamine, cyclohexylamine, ethanolamine, aniline, dimethylamine, diethylamine, dibutylamine, dicyclohexylamine, bistrimethylamine, ethylsilylamine, 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-camphorsulfonic acid, acetic ... The following acids may be used alone or in combination of two or more in an appropriate ratio: organic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and perchloric 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, stannic chloride, ferric chloride, aluminum chloride, titanium tetrachloride, and zirconium tetrachloride.

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

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

[0195] The reaction temperature for the protection 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 protection 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 production 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, a reduction reaction, or the like, preferably catalytic hydrogenation or a reduction reaction with a metal, more preferably a reduction reaction with a metal.

[0198] In the production method of the present invention, X of compound B ａ is a halogen atom instead of a hydrogen atom, it is converted to a hydrogen atom. Preferably, compound B (e.g., compound (9)) is reacted with a metal to convert X ａ The halogen atom in the above formula (1) is converted to a hydrogen atom to obtain compound (3). The conversion reaction is preferably carried out by reacting a substrate (here, compound B) with a metal in an appropriate solvent in the presence or absence of an acid or a base, and the preferred conditions are as follows:

[0199] Examples of the solvent 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-based organic solvents such as 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 can be used alone or in combination of two or more in an appropriate ratio.

[0200] The solvent is preferably 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 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. One of these may be used alone or two or more of these may be mixed in an appropriate ratio.

[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; 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-methylpiperidin, Amines such as pyridine, 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 of these can be used alone, or two or more of them can be mixed in an appropriate ratio.

[0203] The base is preferably 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 the 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 metals, for example, one of samarium (II) iodide, ytterbium (III) iodide, aluminum, zinc, iron, tin, samarium, ytterbium, etc. can be used alone or two or more of them can be mixed in an appropriate ratio.

[0206] The metal is preferably at least one selected from the group consisting of zinc and iron (preferably any one), and more preferably zinc.

[0207] The amount of the metal 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.

[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, the hydroxyl group at the 4-position of compound (3) is preferably dialkylated by an O-alkylation reaction to obtain compound C. The O-alkylation reaction is preferably carried out by reacting a substrate (here, compound (3)) with ethyl 2-bromo-2,2-difluoroacetate in an appropriate solvent in the presence or absence of a base, followed by dialkylation with an organometallic reagent, and the preferred conditions are as follows.

[0211] Examples of the solvent 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 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. 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, and the like. One of these can be used alone, or two or more of them can be mixed in an appropriate ratio.

[0212] The solvent is preferably 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 base include salts such as sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, 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 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. One of these compounds can be used alone, or two or more of them can be mixed in an appropriate ratio.

[0214] The base is preferably 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 the base used is 1 to 20 equivalents, preferably 2 to 5 equivalents, relative to the substrate.

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

[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 organomagnesium reagents, organolithium reagents, organozinc reagents, organoboron reagents, organotin reagents, organosilicon reagents, organobismuth reagents, organogermanium reagents, organomercury reagents, etc. can be used alone or two or more of them can be mixed in an appropriate ratio.

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

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

[0222] The reaction temperature for the O-alkylation reaction (reaction with an 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 an 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.

[0224] The present invention will be described in more detail below using examples, but the present invention is not limited to these examples. Various applications, modifications, and alterations can be made to 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 proton nuclear magnetic resonance spectrum of the obtained compound. Pd—C: Palladium catalyst supported on activated carbon. THF: Tetrahydrofuran. DMF: N,N-dimethylformamide. DMSO: Dimethyl sulfoxide. Boc: Tert-butoxycarbonyl group (Boc). ２ O: di-tert-butyl dicarbonate Bn: benzyl group.

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

[0227]

[0228] 2,6-Difluoronitrobenzene (52.75 g, 331.6 mmol) was dissolved in DMSO (158 mL), and benzyl alcohol (35.86 g, 331.6 mmol) and potassium carbonate (91.65 g, 663 mmol) were added thereto, followed by stirring at 90° C. for 24 hours. ２A reaction solution containing a compound in which R is a fluorine atom was obtained. After cooling the reaction solution, it was diluted with ethyl acetate (422 mL) and washed successively with 211 mL each of water and 0.1 M hydrochloric acid. The obtained organic layer was concentrated while being replaced with acetonitrile, to obtain 211 mL of an acetonitrile solution. Acetonitrile (211 mL), N-bromosuccinimide (88.53 g, 497.4 mmol), and acetic acid (4.75 mL, 83.1 mmol) were added to the obtained solution, and the mixture was cooled to 10°C or below. After that, chlorotrimethylsilane (18.02 g, 165.9 mmol) was added, and the mixture was stirred at 10°C or below for 2 hours, and a compound represented by the above formula (10-12), in which R ２ A reaction solution containing a compound in which ⁻ is a fluorine atom was obtained. Water (164 mL) and a 20% aqueous sodium hydrogen sulfite solution (164 mL) were added to the reaction solution and stirred, followed by the addition of toluene (528 mL) and stirring, and the aqueous layer was removed. The resulting organic layer was washed twice with a 2 M aqueous sodium hydroxide solution (249 mL), DMSO (492 mL) was added, the mixture was concentrated, and the toluene was distilled off. A 6.25 M aqueous sodium hydroxide solution (127 mL) was added to the resulting solution, and the mixture was stirred at 70°C for 1 hour. After cooling the reaction solution, toluene (633 mL) and water (1266 mL) were added and stirred, followed by the removal of the organic layer. Toluene (791 mL) and 6 M hydrochloric acid (146 mL) were added to the resulting aqueous layer and stirred, followed by the removal of the aqueous layer. The resulting organic layer was washed with water and concentrated while replacing with 2-propanol, yielding a 2-propanol (370 mL) solution. Water (296 mL) was added to the solution to precipitate a solid, and after cooling and stirring, the solid was separated, washed with a mixed solution of 2-propanol / water=1 / 2, and dried to obtain 84.08 g (yield 78.2%) of the title compound.

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

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

[0231]

[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), added to the aqueous sodium dithionite solution, and stirred at 3 to 10° C. for 1 hour. Water (1200 mL) was added to the reaction solution and stirred, and the resulting solid was collected by filtration, 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]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0235]

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

[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-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0239]

[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 for 1 hour at 60° C. 2-Bromothiazole (6.7 mL, 75.6 mmol) was added to the reaction mixture, and the mixture was stirred for 20 minutes. A toluene (15 mL) solution of tert-butyl 3-(4-benzyloxy-7-bromobenzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (7.5 g, 15.0 mmol) obtained in Synthesis Example 3, 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) were added, and the mixture was stirred for 1 hour at 85° C. 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 insoluble material was removed by filtration. The aqueous layer was removed, and the resulting organic layer was washed with water and then concentrated. 2-Propanol (75 mL) was added to the concentrated residue, and the mixture was stirred. The resulting crystals were collected by filtration, washed with 2-propanol, and dried under reduced pressure to give 6.67 g (yield 88%) of the title compound.

[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-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0243]

[0244] Tert-butyl 3-(4-benzyloxy-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (50.0 g, 99.09 mmol) obtained in Synthesis Example 4 was suspended in toluene (150 mL), trifluoroacetic acid (150 mL, 1960 mmol) was added, and the mixture was stirred at 80°C for 20 hours. The reaction solution was cooled to around room temperature, and methanol (300 mL), water (200 mL), and dichloromethane (480 mL), which had been pre-cooled to around 5°C, were added. Next, 5M aqueous sodium hydroxide solution (400 mL) was added, and the mixture was stirred at room temperature, and the pH was adjusted to around 8.6 with 6M hydrochloric acid. (Boc) ２0 (25.0 mL, 109.0 mmol) was added and the mixture was warmed to 30°C. After 20 minutes, 5% aqueous sodium bicarbonate solution (83.2 mL, 49.50 mmol) was added, and after another 30 minutes, 5% aqueous sodium bicarbonate solution (83.2 mL, 49.50 mmol) was added and 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, and then acetonitrile (300 mL) was added. This process of concentrating under reduced pressure to approximately 250 mL was repeated twice. The mixture was crystallized and aged at room temperature for 30 minutes, stirred at 60°C for 1 hour, cooled to room temperature for aging over 1 hour, and further aged in an ice bath for 1 hour. The resulting solid was collected by filtration, washed with chilled acetonitrile (75 mL), and dried under aeration. Acetonitrile (250 mL) was added to the obtained crude title compound, and the mixture was stirred at 80° C. for 1 hour, cooled to room temperature over 2 hours for aging, and further aged in an ice bath for 1 hour. The solid was collected by filtration, washed with cooled acetonitrile (75 mL), and then dried under reduced pressure at 40° C. to give 42.2 g (yield 93.5%) of the monoacetonitrile solvate of the title compound.

[0245] １ H-NMR (400MHz, CDCl3) δppm: 9.44 (br s, 1H), 7.90 (d, J = 3.2Hz, 1H), 7.81 (d, J = 8.7Hz, 1H), 7.38 (d, J = 3.2Hz, 1H), 6.87 (d, J = 8.7Hz, 1H ), 4.38-4.18 (m, 4H), 3.80-3.68 (m, 2H), 2.75-2.67 (m, 1H), 1.55 (d, J = 8.7Hz, 1H), 1.37 (s, 9H).

[0246] Synthesis Example 6 tert-Butyl 3-(4-(1,1-difluoro-2-hydroxy-2-methylpropoxy)-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0247]

[0248] ​Tert-butyl 3-(4-hydroxy-7-(thiazol-2-yl)benzo[d]oxazol-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, followed by stirring at 30°C for 3 hours. The reaction solution was cooled to around 0°C, and pre-cooled toluene (750 mL) and 0.3 M hydrochloric acid were added and stirred, and the aqueous layer was removed. 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, and toluene (250 mL) was added, followed by further concentration under reduced pressure to 250 mL. The resulting solution was cooled to 5°C, and 1.08 M methylmagnesium bromide THF solution (336 mL, 361.9 mmol) was added and stirred at room temperature for 2 hours. The reaction solution was cooled to around 0°C, and toluene (500 mL) and 1 M hydrochloric acid (500 mL) were added and stirred, and the aqueous layer was removed. The resulting organic layer was washed sequentially with 0.1 M aqueous sodium hydroxide solution (500 mL), 10% aqueous potassium hydrogen sulfate 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 and filtered through Celite. The filtrate was concentrated under reduced pressure to 250 mL, and then ethanol (750 mL) was added, and the mixture was concentrated under reduced pressure to 250 mL. The same procedure was repeated. The resulting solution was stirred at room temperature for 2 hours, then stirred at 0°C for 1 hour to precipitate crystals. The resulting crystals were collected by filtration and washed with ethanol (100 mL). Ethanol (500 mL) was added to the crystals, heated to 70°C, and stirred for 3 hours, then cooled to room temperature over 2 hours and stirred overnight. The solution was cooled to below 0°C and stirred for 1 hour. The resulting crystals were washed with ethanol (2 vol) at below 10°C and dried under reduced pressure to obtain 50.69 g (yield 73.9%) of the monoethanol solvate of the title compound.

[0249] １ ​H-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-thiazol-2-yl)-1,3-benzoxazol-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol

[0251]

[0252] Tert-butyl 3-(4-(1,1-difluoro-2-hydroxy-2-methylpropoxy)-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (10 g, 19.2 mmol) obtained in Synthesis Example 6 was dissolved in dichloromethane (25 mL), and trifluoroacetic acid (18.3 mL, 238.8 mmol) was added, followed by stirring at 40°C for 2 hours. Methanol (30 mL) and dichloromethane (165 mL) were added to the reaction solution, and then a 5N aqueous sodium hydroxide solution (100 mL) was added at 30°C or below, followed by stirring. 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, followed by stirring. The aqueous and organic layers were separated, and the aqueous layer was re-extracted with dichloromethane (10 mL). The combined organic layers were concentrated to 100 mL, and toluene (50 mL) was added, followed by further concentration to 50 mL. Toluene (100 mL) was added to this concentrate, and the mixture was stirred at room temperature for 1 hour, at 55°C for 1 hour, and then at 0°C for 1 hour or more. The resulting solid was then filtered off. The resulting solid was washed with toluene (30 mL) cooled to below 10°C and dried under reduced pressure to obtain 6.76 g (yield 90.9%) of crude crystals of the title compound.

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

[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]

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

[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-(thiazol-2-yl)benzo[d]oxazole

[0260]

[0261] ​Zinc powder (1.57 g, 24.0 mmol) was suspended in DMF (15 mL), and chlorotrimethylsilane (0.25 mL, 2.0 mmol) was added, followed by stirring at 50°C for 1 hour. The reaction solution was heated to 60°C, 2-bromothiazole (1.8 mL, 20.3 mmol) was added, and the mixture was stirred. 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 then added, followed by stirring at 80°C or higher for 1 hour and cooling. Toluene (35 mL), DMF (18 mL), and 20-fold diluted sulfuric acid (18 mL) were added to the reaction solution, followed by stirring for 1 hour, and the aqueous layer was then removed. DMF (18 mL) and 20-fold diluted sulfuric acid (18 mL) were added to the obtained organic layer and stirred, and then 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 replacing with 2-propanol to give a 70 mL solution. This solution was stirred to precipitate a solid, and after cooling, the solid was collected by filtration, washed with 2-propanol, and dried to obtain 6.06 g (yield 86.0%) of the title compound.

[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-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0264]

[0265] ​4-Benzyloxy-2-ethoxy-7-(thiazol-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, followed by heating to reflux for 1 hour. The reaction solution was diluted with toluene and washed sequentially with a 5% aqueous solution of sodium bicarbonate and water. The resulting organic layer was concentrated while replacing with 2-propanol to give a 30 mL solution. This solution was stirred to precipitate a solid. After cooling, the solid was collected by filtration, washed with 2-propanol, and dried to give 3.97 g (yield 92.5%) of the title compound. １ The H-NMR spectrum was consistent with that of the compound obtained in Synthesis Example 4 of Example 1.

[0266] Example 3 Synthesis Example 1 5,7-dibromo-2-ethoxybenzo[d]oxazol-4-ol

[0267]

[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 stirred vigorously 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, and the filter cake 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]oxazol-4-ol. After cooling, the reaction solution was washed sequentially with 5% aqueous sodium bicarbonate solution (50 mL) and water (50 mL), and then concentrated under reduced pressure to 50 mL. Ethyl acetate (50 mL) was added to the resulting solution, and N-bromosuccinimide (12.05 g, 67.770 mmol) was added in portions under ice cooling. The mixture was warmed to room temperature and stirred for 1 hour to obtain a reaction solution containing the title compound. Ethyl acetate (50 mL) was added to the reaction solution, and the mixture was washed sequentially with 20% aqueous sodium hydrogen sulfite solution (50 mL) and twice with 5% brine (50 mL). The resulting organic layer was concentrated under reduced pressure to 50 mL, and ethanol (50 mL) was added and concentrated under reduced pressure to 50 mL twice. Water (100 mL) was added dropwise to the solution to precipitate a solid, which was then aged under ice cooling for 1 hour. The resulting solid was collected by filtration, washed with ethanol / water = 1 / 3 (40 mL divided into several portions), and dried under reduced pressure to obtain 8.73 g of the title compound (yield 80.4%).

[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]heptane-6-carboxylate

[0271]

[0272] ​5,7-Dibromo-2-ethoxybenzo[d]oxazol-4-ol (7.00 g, 20.773 mmol) obtained in Synthesis Example 1 and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (4.94 g, 24.916 mmol) were dissolved in toluene (70 mL), heated to 125°C, and stirred for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure to a 35 mL solution, and n-hexane (175 mL) was added dropwise to precipitate a solid, followed by aging under ice cooling for 1 hour. The resulting solid was collected by filtration, washed with toluene / n-hexane = 1 / 4 (35 mL divided into several portions), and dried under reduced pressure. The resulting solid was dissolved in THF (90 mL) and concentrated under reduced pressure to 48 mL. Ethyl acetate (63 mL) was added, and the mixture was concentrated under reduced pressure to 48 mL, which was repeated three times. The resulting solution was stirred at 60°C for 30 minutes, cooled to room temperature, and then aged on ice for 1 hour. The resulting solid was collected by filtration, washed with cold ethyl acetate (18 mL divided into several portions), and dried under reduced pressure to give 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 = 11.0 Hz, 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-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0275]

[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), and chlorotrimethylsilane (0.45 mL, 3.58 mmol) was added under a nitrogen atmosphere, followed by vigorously stirring at 60° C. for 2 hours. 2-Bromothiazole (4.53 mL, 51.11 mmol) was slowly added dropwise, and a solution of 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 in DMF (15 mL), palladium(II) acetate (0.229 g, 1.022 mmol), and tri(p-tolyl)phosphine (1.24 g, 4.09 mmol) was quickly added using DMF (15 mL), and the mixture was heated to 85°C and stirred for 2.5 hours. The reaction mixture was ice-cooled, and chloroform (50 mL), toluene (25 mL), DMF (50 mL), and 1.8 M aqueous sulfuric acid solution (50 mL) were added, followed by stirring 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 aqueous sulfuric acid (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% aqueous sodium bisulfite (100 mL) were added to the organic layer, and the mixture was stirred at 60°C for 1 hour. After cooling, the mixture was filtered through Celite, the filter cake 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. Toluene (100 mL) was added to the resulting solution, and the mixture was concentrated under reduced pressure to 30 mL twice. Ethanol (100 mL) was then added, and the mixture was concentrated under reduced pressure to 30 mL twice. The resulting solution was cooled with ice to allow it to crystallize and mature, and the crystals were collected by filtration and dried under reduced pressure to give 4.88 g (yield 96.8%) of the title compound.

[0277] １ ​H-NMR (400MHz, CDCl3) δ: 8.10 (s, 1H), 7.92 (d, J = 3.2Hz, 1H), 7.43 (d, J = 3.2Hz, 1H), 4.32 (br m, 4H), 3.78 (br d, J = 11.9Hz, 2H), 2.66-2.83 (m, 1H), 1.57 (d, J = 9.2Hz, 1H), 1.38 (s, 9H).

[0278] Synthesis Example 4 tert-Butyl 3-(4-hydroxy-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0279]

[0280] Tert-butyl 3-(5-bromo-4-hydroxy-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (0.469 g, 0.951 mmol) obtained in Synthesis Example 3, ammonium formate (1.50 g, 23.79 mmol), and zinc powder (1.554 g, 23.77 mmol) were suspended in ethanol (7 mL) and refluxed under a nitrogen atmosphere for 2 hours. After cooling the suspension, ethyl acetate (4.7 mL) was added and the mixture was stirred. The mixture was then filtered through Celite, and the filter cake was washed with ethyl acetate (9.4 mL divided into several portions). The filtrate was washed sequentially with 5% aqueous potassium hydrogen sulfate solution (9.4 mL) and 5% brine (9.4 mL). The resulting organic layer was concentrated under reduced pressure to 4.7 mL, and acetonitrile (9.4 mL) was added. This process was repeated twice. The resulting solution was stirred at room temperature for 2 hours, and then crystallized and aged for 1 hour under ice cooling to give 397 mg (yield 91.7%) of the monoacetonitrile solvate of the title compound. １ The H-NMR spectrum was consistent with that of the compound obtained in Synthesis Example 5 of Example 1.

[0281] 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-(thiazol-2-yl)benzo[d]oxazol-4-yl]oxy}-1,1-difluoro-2-methylpropan-2-ol (compound (1)) or a salt thereof, which is safe, easy to operate, and suitable for industrial production. Furthermore, according to the present invention, it is possible to provide a 2-alkoxybenzo[d]oxazole derivative (compound (2)) or a salt thereof as a raw material that can be used in the production method of compound (1) or a salt thereof, as well as a method for producing the same.

[0282] Compound (2) according to the present invention can be produced by a method that does not require highly toxic and difficult-to-handle reagents or highly dangerous procedures, and does not generate toxic substances during the reaction. Furthermore, the production of compound (1) or a salt thereof using this compound does not require highly toxic and difficult-to-handle reagents or highly dangerous procedures. Additionally, according to the present invention, it is possible to reduce the number of steps compared to existing production methods, and compound (1) or a salt thereof can be obtained in a high yield equivalent to that of existing production methods. Therefore, the production method of compound (1) or a salt thereof according to the present invention, and the production method of compound (2) or a salt thereof used therein, are extremely useful industrially.

Claims

DEPCT6718 / 03 / 25671.Method for the production of compounds represented by formula(1):(chemical formula)(1) or their salts, which include:Step B of the production of compounds represented by formula(3):(chemical formula)(3)[in formula(3),Boc represents the tert-butoxycarbonyl group] or their salts by using compounds represented by formula(2):(chemical formula)(2)[in formula(2),Ra represents the hydrogen atom or selectively substituted arylmethyl group,Rb represents the selectively substituted alkyl or cyclic alkyl group,R3 represents the hydrogen atom, halogen atom, or The thiazole-2-yl group, and Xa represents the hydrogen atom or halogen atom, or their salts; and step C of the production of the compounds represented by formula(1) or their salts by using the compounds represented by formula(3) or their salts.

2. The production method according to claim1, where step B is the step of replacing ORb of the compound(2-1) represented by formula(2), where Ra is the selectively replaced arylmethyl group, Rb is the selectively replaced alkyl group, R3 is the halogen atom, and Xa is the hydrogen atom, with tert-butyl 3,6-diaza bicyclo[3.1.1] Heptane-6-carboxylate, to produce the compound represented by formula(4):(chemical formula)(4)[in formula(4), Ra is the selectively substituted arylmethyl group, R3 is the halogen atom, and Boc is the tert-butoxycarbonyl group], the introduction of the thiazole-2-yl group into the compound represented by formula(4) by cross-coupling reaction in the presence of a metal catalyst, to produce the compound represented by formula(5):(chemical formula)(5)[in formula(5), Ra is the selectively substituted arylmethyl group, and Boc is the tert-butoxycarbonyl group], and reaction of the compound represented by formula(5) with an organic acid, to produce the compound represented by formula(3) or their salts.3.The production method according to claim1, where step B is the step of introducing the thiazole-2-yl group into compound(2-1) represented by formula(2), where Ra is the selectively substituted arylmethyl group, Rb is the selectively substituted alkyl group, R3 is the halogen atom, and Xa is the hydrogen atom, by cross-coupling in the presence of a metal catalyst, to produce compound(2-11) represented by formula(2), where Ra is the selectively substituted arylmethyl group, Rb is the selectively substituted alkyl group. The selectively substituted arylmethyl group, R3 is the thiazole-2-yl group, and Xa is the hydrogen atom, the replacement of ORb of compound(2-11) with tert-butyl3,6-diazabicyclo[3.1.1]heptane-6-carboxylate, to produce the compound represented by formula(5):(chemical formula)(5)[in formula(5), Ra is the selectively substituted arylmethyl group, and Boc is the tert-butoxycarbonyl group], and the reaction of the compound represented by formula(5) with an organic acid, to produce the compound represented by formula(3) or their salts4.The production method according to claim1, where step B is the reaction step of compound(2-2) represented by formula(2), where Ra is the hydrogen atom, Rb is the selectively substituted alkyl group, R3 is the hydrogen atom, and Xa is the hydrogen atom, with a brominating agent, to produce compound(2-21) represented by formula(2), where Ra is the hydrogen atom, Rb is the selectively substituted alkyl group, R3 is the bromine atom, and Xa is the bromine atom, replacing ORb of compound(2-21) with tert-butyl3,6-diazabicyclo[3.1.1]heptane-6-carnitine. Boxylate, to produce the compound represented by formula(8):(chemical formula)(8)[in formula(8),Boc is the tert-butoxycarbonyl group], the introduction of the thiazole-2-yl group into the compound represented by formula(8) by cross-coupling reaction in the presence of a metal catalyst, to produce the compound represented by formula(9):(chemical formula)(9)[in formula(9),Boc is the tert-butoxycarbonyl group], and the reaction of the compound represented by formula(9) with a metal, to produce the compound represented by formula(3) or their salts.5.Any of the production methods under claims 1 through 4, which include step A of the production of the compounds represented by formula (2) or their salts by using the compounds represented by formula (10): (chemical formula) (10) [in formula (10), R1 represents the hydroxyl or halogen atom or aryl-methyloxy group, R2 represents the hydroxyl or halogen atom, R3 represents the hydrogen atom, halogen atom, or thiasol-2-yl group], or their salts.6.The production method according to claim 5, where step A is the reaction of compound (10-1) represented by formula (10), where R1 is the halogen atom, R2 is the halogen atom, and R3 is the hydrogen atom, with benzyl alcohol, to produce the compound represented by formula (10-11): (chemical formula)(10-11)[in formula (10-11), R2 is the halogen atom, and Bn is the benzyl group], reaction of compound represented by formula (10-11) with a brominating agent, to produce the compound represented by formula (10-12): (chemical formula)(10-12)[in formula (10-12), R2 is the halogen atom, and Bn is the benzyl group], a The reaction of the compound represented by formula (10-12) with an alkaline aqueous solution to produce the compound represented by formula (10-13): (chemical formula) (10-13) [in formula (10-13), Bn is the benzyl group], the reaction of the compound represented by formula (10-13) with a reducing agent to produce the compound represented by formula (14): (chemical formula) (14) [in formula (14), Bn is the benzyl group], and the reaction of the compound represented by formula (14) with tetraalcoximethane in the presence of an acid catalyst to produce the compound represented by formula (2) or their salts.7.The production method according to claim 5, where step A is the step of reducing compound (10-2) represented by formula (10), where R1 is a hydroxyl group, R2 is a hydroxyl group, and R3 is a hydrogen atom, followed by reaction with tetraalcoximethane in the presence of an acid catalyst and then by reaction with a brominating agent, to produce the compound represented by formula (2) or their salts.

8. Compound represented by formula (15):(chemical formula)(15) [In formula(15),Bn is the benzyl group, and Et is the ethyl group] or their salts.

9. Compounds represented by formula(6):(chemical formula)(6)[In formula(6),Bn is the benzyl group, and Et is the ethyl group] or their salts.

10. Compounds represented by formula(7):(chemical formula)(7)[In formula(7),Et is the ethyl group] or their salts.

11. Compounds represented by formula(8):(chemical formula)(8)[In formula(8),Boc is the tert-butoxycarbonyl group] or their salts;.