JP2014051492A - Process for producing diamine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a process for industrially producing compounds (1a) which are useful as inhibitors of activated blood coagulation factor X.SOLUTION: Hydrazide derivative compounds (4) are obtained by condensing carboxylic acid derivatives, which are obtained by acid hydrolysis of carboxylic acid ester derivatives using 4 or more N (normality) acid aqueous solutions, with di(methyl) amine or the salt thereof in the presence of a condensation agent. Then compounds (1) are produced by treating the compounds (4) with orthoformic acid esters or orthoacetic acid esters in a polar aprotic solvent in the presence of Lewis acid.

Description

  The present invention relates to an industrial process for producing a compound which exhibits an inhibitory action on activated blood coagulation factor X (FXa) and is useful as a prophylactic / therapeutic agent for thrombotic and / or embolic diseases.

  The following compounds (1 and 1a) are compounds useful for the prevention and treatment of thrombotic and / or embolic diseases, as shown in Patent Document 1 or Patent Document 3, which exhibit FXa inhibitory action. is there.

(Wherein R ¹ represents a hydrogen atom, a halogeno group, a linear or branched C1-C4 alkyl group, a linear or branched C1-C4 alkoxy group, or a nitro group; R ² represents a hydrogen atom, a halogeno group, a linear or branched C1-C4 alkyl group, or a linear or branched C1-C4 alkoxy group; R ³ and R ⁴ are the same or Differently, represents a hydrogen atom or a linear or branched C1-C4 alkyl group; R ⁶ represents a methyl group or an ethyl group; R ⁷ represents a linear or branched C 1 -C 4 group; R ⁸ and R ⁹ are the same or different and each represents a methyl group or an ethyl group; Ring A represents a benzene ring, a thiophene ring or a pyridine ring; Ring B represents 4, 5, 6 , 7-Tetrahydrothiazolo [5,4-c] pyridine ring 4,5,6,7-tetrahydrooxazolo [5,4-c] pyridine ring, 5,6,7,8-tetrahydro-4H-thiazolo [4,5-d] azepine ring, 5,6,7, 8-tetrahydro-4H-thiazolo [4,5-c] azepine ring or 5,6-dihydro-4H-pyrrolo [3,4-d] thiazole ring.
As shown in the following [Scheme A], the conventional production method of compound (1) is to produce compound (11) which is a [1,3,4] oxadiazole derivative from compound (9) which is a carboxylic acid derivative. Then, two types of amide bonds were constructed, and the total yield of compound (1) starting from compound (5) was 41.2%. In this production method, since the [1,3,4] oxadiazole ring is constructed at the initial stage, the step of removing the protecting group of the amino group by acid treatment and the step of constructing the diamide moiety are [1] , 3,4] With the decomposition of the oxadiazole ring, the yield and quality of the reaction process were reduced.

(In the formula, OMs represents a methanesulfonyloxy group; Boc represents a tert-butoxycarbonyl group; Cbz represents a benzyloxycarbonyl group; R ⁴⁰ represents a hydrogen atom, linear or branched C 1 -C 4. Represents an alkyl group or an alkali metal (alkali metal cation); R ⁷⁰ represents a hydrogen atom or an alkali metal (alkali metal cation); R ⁹ represents a linear or branched C1-C4 alkyl group; R ¹ , R ² , R ³ , R ⁴ , R ⁶ , ring A and ring B are the same as above.
In addition, it is reported that the compound (3) which is a carboxylic acid derivative (see Patent Document 2) and the compound (1a) which is a di (alkyl) carbamoyl derivative (see Patent Document 3) exhibit an FXa inhibitory action. Yes. Until now, as shown in [Scheme B], compound (3) has been produced by deprotecting compound (2a) which is a 2,2,2-trichloroethyl ester derivative. The reason why a special ester is used is that, other than the ester that can be deprotected under mild conditions such as 2,2,2-trichloroethyl ester (2a), the two amide sides of compound (2a) during hydrolysis This is because the yield is greatly reduced due to the chain decomposition. However, 2,2,2-trichloroethyl ester was not suitable for mass synthesis of compound (3). Furthermore, a method for producing the compound (3) from the compound (2) which is a linear or branched C1-C4 alkyl ester derivative such as methyl ester or ethyl ester has not been known. Moreover, since it is difficult to produce the carboxylic acid derivative (3), a method for industrially producing the compound (1a) which is a di (alkyl) carbamoyl derivative from the carboxylic acid derivative (3) has not been known.

(Wherein R ⁷ represents a linear or branched C1-C4 alkyl group, and R ¹ , R ² , R ³ , R ⁴ , ring A and ring B are the same as described above. )

International Publication No. 2004/058715 Pamphlet International Publication No. 2003/016302 Pamphlet International Publication No. 2003/000680 Pamphlet

  The object of the present invention is to solve the problems of the production process disclosed in WO 2004/058715, provide an industrial production method of compound (1) useful as an FXa inhibitor, and at the same time provide FXa It is an object to provide an industrial new production method of the inhibitor (1a).

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ , ring A and ring B are the same as described above.)

  As a result of intensive studies by the present inventors, compound (1) is obtained by treating compound (4), which is a hydrazide derivative, with orthoformate or orthoacetate in the presence of a Lewis acid in an aprotic polar solvent. Was found to be obtained in high yield. In addition, the linear or branched C1-C4 alkyl ester (2) is treated in a relatively high concentration hydrochloric acid aqueous solution, sulfuric acid aqueous solution or phosphoric acid aqueous solution, or coexistence with an aprotic polar solvent. The compound (3), which is a carboxylic acid derivative, is obtained by treating with a relatively high concentration sodium hydroxide aqueous solution, potassium hydroxide aqueous solution or lithium hydroxide aqueous solution to avoid decomposition of the amide side chain. I found out that it can be obtained at a rate. Further, the linear or branched C1-C4 alkyl ester (2) is hydrolyzed, and the resulting carboxylic acid-derived compound (3) is condensed with a hydrazide derivative to obtain the compound (4). Can be produced industrially at the same time as it is found that compound (1) can be produced in a high yield by treating with a formic acid ester or orthoacetic acid ester in the presence of a Lewis acid in an aprotic polar solvent. The present invention was completed by finding a new industrial production method of the compound (1a) via the compound (3) which is a carboxylic acid derivative.

That is, the present invention provides the following [1] to [9].
[1] The following formula (2)

(Wherein R ⁷ represents a linear or branched C1-C4 alkyl group;
Partial structure represented by the following formula

Represents a 5-chloro-2-pyridyl group;
Partial structure represented by the following formula

Represents a 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl group. The compound represented by formula (3) is hydrolyzed by the following formula (A) or (B):

(Wherein R ¹ , R ² , R ³ , R ⁴ , ring A and ring B are the same as described above.)
The manufacturing method of the compound represented by these.
(A) Acid hydrolysis using 4N (4N) or more hydrochloric acid aqueous solution, 4N (4N) or more sulfuric acid aqueous solution, or 4N (4N) or more phosphoric acid aqueous solution (B) in the presence of an aprotic polar solvent Alkaline hydrolysis using 5N (5N) or higher sodium hydroxide aqueous solution, 5N (5N) or higher potassium hydroxide aqueous solution or 5N (5N) or higher lithium hydroxide aqueous solution [2] The following formula (2 )

(Wherein R ⁷ represents a linear or branched C1-C4 alkyl group;
Partial structure represented by the following formula

Represents a 5-chloro-2-pyridyl group;
Partial structure represented by the following formula

Represents a 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl group. The compound represented by the following formula (3) is obtained by hydrolyzing the compound represented by (A) or (B) below.

(Wherein R ¹ , R ² , R ³ , R ⁴ , ring A and ring B are the same as described above.)
Wherein the compound represented by formula (1a) is condensed with di (methyl) amine or a salt thereof in the presence of a condensing agent.

(Wherein R ⁸ and R ⁹ represent a methyl group, and R ¹ , R ² , R ³ , R ⁴ , ring A and ring B represent the same as described above.)
The manufacturing method of the compound represented by these.
(A) Acid hydrolysis using 4N (4N) or more hydrochloric acid aqueous solution, 4N (4N) or more sulfuric acid aqueous solution, or 4N (4N) or more phosphoric acid aqueous solution (B) in the presence of an aprotic polar solvent 5N (5N) or higher sodium hydroxide aqueous solution 5N (5N) or higher potassium hydroxide aqueous solution or 5N (5N) or higher lithium hydroxide aqueous solution [3] From compound (2) In the step of producing compound (1a) via compound (3), compound (1a) is produced from compound (2) in the same reaction system (one pot) without isolating compound (3). The production method according to [2], which is characterized.
[4] The production method according to any one of [1] to [3], wherein R ⁷ is a methyl group or an ethyl group.
[5] The production method according to any one of [1] to [4], wherein the acid used in the acid hydrolysis is a 4N (4N) or higher hydrochloric acid aqueous solution.
[6] The production method according to any one of [1] to [4], wherein the acid used in the acid hydrolysis is a 6N (6N) or higher hydrochloric acid aqueous solution.
[7] The production method according to any one of [1] to [4], wherein the alkali used in the alkali hydrolysis is a 5N (5N) or higher aqueous sodium hydroxide solution.
[8] The production method according to any one of [1] to [4], wherein the alkali used in the alkali hydrolysis is an aqueous 8N (8N) or higher sodium hydroxide solution.
[9] The aprotic polar solvent is N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone or dimethyl sulfoxide, [1] to [4], [7] to [7] [8] The production method according to any one of [8].

  According to the present invention, compound (1) useful as an inhibitor of activated blood coagulation factor X (FXa) can be produced from compound (3) which is a carboxylic acid derivative. As a result, compound (1) useful as an inhibitor of activated blood coagulation factor X is solved from compound (5) by solving the problems of the production process disclosed in WO 2004/058715. The yield was 59.6%, and the effect of improving productivity by about 42% was obtained compared to the conventional method (41.2%). Therefore, the production method of the present invention is useful as an industrial production method of the compound (1) which is a diamine derivative. Further, it is useful as a method for producing compound (1a) useful as an FXa inhibitor from compound (3) which is a carboxylic acid derivative.

  The present invention is described in detail below.

  In the present specification, the halogeno group means a fluoro group, a chloro group, a bromo group, or an iodo group.

  The linear or branched C1-C4 alkyl group means a linear or branched alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, An isopropyl group, n-butyl group, sec-butyl group, tert-butyl group and the like can be mentioned.

  The halogeno C1-C4 alkyl group represents a linear or branched C1-C4 alkyl group having the above-mentioned halogeno group as a substituent, and the number of halogeno groups may be two or more even if it is one. The number of each halogeno group in the case of two or more may be the same or different. Specific examples of the halogeno C1-C4 alkyl group include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 1-fluoroethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2-bromoethyl group, (1, 1-difluoro) ethyl group, (1,2-difluoro) ethyl group, (2,2,2-trifluoro) ethyl group, (1,1,2,2-tetrafluoro) ethyl group, (1,1, 2,2,2-pentafluoro) ethyl group, 1-fluoropropyl group, 1,1-difluoropropyl group, 2,2-difluoropropyl group, 3-fluoro-n-propyl group, (3,3,3- (Trifluoro) -n-propyl group, 4-fluoro-n-butyl group and 4,4,4-trifluoro) -n-butyl group.

  The linear or branched C1-C4 alkoxy group means a linear or branched alkoxy group having 1 to 4 carbon atoms, such as a methoxy group, an ethoxy group, an n-propoxy group, An isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group and the like can be mentioned.

  Below, the substituent of this invention is demonstrated.

R ¹ represents a hydrogen atom, a halogeno group, a linear or branched C1-C4 alkyl group, a linear or branched C1-C4 alkoxy group, or a nitro group. R ¹ is preferably a hydrogen atom, a fluoro group, a chloro group, a bromo group, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, or a nitro group;
R ¹ is more preferably a hydrogen atom, a fluoro group, a chloro group, a bromo group, a methyl group, a trifluoromethyl group or a methoxy group.

R ² represents a hydrogen atom, a halogeno group, a linear or branched C1-C4 alkyl group, or a linear or branched C1-C4 alkoxy group. R ² is preferably a hydrogen atom, a fluoro group, a chloro group, a bromo group, a methyl group, an ethyl group, a methoxy group or an ethoxy group;
R ² is more preferably a hydrogen atom, a fluoro group, a chloro group, a bromo group, a methyl group or a methoxy group.

R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a linear or branched C1-C4 alkyl group. R ³ and R ⁴ are the same or different and are preferably a hydrogen atom, a methyl group, an ethyl group or an isopropyl group;
R ³ and R ⁴ are preferably those in which R ³ is a hydrogen atom and R ⁴ is a methyl group, an ethyl group or an isopropyl group.

R ⁵ represents a hydrogen atom or a formyl group. R ⁵ is preferably a hydrogen atom.

R ⁶ represents a hydrogen atom or a methyl group. R ⁶ is preferably a hydrogen atom.

R ⁷ represents a linear or branched C1-C4 alkyl group. R ⁷ is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group or a tert-butyl group;
R ⁷ is more preferably a methyl group or an ethyl group.

R ⁸ and R ⁹ are the same or different and each represents a methyl group or an ethyl group. R ⁸ and R ⁹ are preferably a methyl group.

Partial structure ring A

Represents a benzene ring, a thiophene ring or a pyridine ring. Ring A is preferably a benzene ring and a pyridine ring;
A pyridine ring is more preferable.

Partial structure ring B

Are 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine ring, 4,5,6,7-tetrahydrooxazolo [5,4-c] pyridine ring, 5,6,7, 8-tetrahydro-4H-thiazolo [4,5-d] azepine ring, 5,6,7,8-tetrahydro-4H-thiazolo [4,5-c] azepine ring or 5,6-dihydro-4H-pyrrolo [ 3,4-d] represents a thiazole ring. Ring B is preferably a 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine ring.

  The production process of the present invention will be described below.

  As shown in the following [Scheme 1], the compound (1) of Patent Document 1 is converted from a compound (2) which is a linear or branched C1-C4 alkyl ester derivative to a compound (2) which is a carboxylic acid derivative ( 3), followed by condensation with a hydrazine derivative to produce compound (4), which is treated with orthoformate or orthoacetate in the presence of a Lewis acid in an aprotic polar solvent. be able to.

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , ring A and ring B are the same as described above.)
These [Step a] to [Step c] will be described in detail below.

  [Step a]

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁷ , ring A and ring B are the same as described above.)
In this step, compound (1) is produced by acid hydrolysis or alkali hydrolysis of compound (2).

  (A) In the case of acid hydrolysis, hydrochloric acid aqueous solution, sulfuric acid aqueous solution and phosphoric acid aqueous solution can be used as the acid to be used, and hydrochloric acid aqueous solution is preferable. The concentration of the acid used is preferably an aqueous solution having a concentration of 4N (4N) or higher, and more preferably an aqueous solution having a concentration of 6N (6N) or higher. The amount of the acid used is preferably 20 to 50 times the molar amount relative to the compound (2). As the reaction temperature, the temperature in the reaction system is 10 to 30 ° C, preferably 15 to 25 ° C. The reaction time is usually about 20 hours.

  As a method of purifying the produced compound (3), an organic solvent is added to dilute the solution, while controlling the temperature in the reaction system, the pH is adjusted by adding an alkaline aqueous solution with stirring, and the precipitated crystals are filtered and filtered. The taken crystal may be washed and dried.

As the organic solvent used for dilution, an alcohol solvent is preferable, and methanol, ethanol and the like are preferable. The amount of the solvent is preferably the same amount to 1.5 times the amount of the acid aqueous solution used.
The aqueous alkali solution is preferably added while keeping the temperature in the reaction system at 20 ° C. or lower. The amount of the alkaline aqueous solution to be added is preferably added so that the pH is in the range of 1 to 7, and more preferably added so that the pH is in the range of 3 to 4.

  (B) In the case of alkaline hydrolysis, the hydrolysis reaction is carried out in the presence of an aprotic polar solvent. As the aprotic polar solvent, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide are preferable. As the alkaline aqueous solution, alkali metal, alkaline earth metal hydroxide, carbonate, bicarbonate can be used, and sodium hydroxide, potassium hydroxide and the like are preferable.

  Moreover, as an alkali to be used, a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution and a lithium hydroxide aqueous solution can be used, and a sodium hydroxide acid aqueous solution is preferable. As the concentration of the alkali used, an aqueous solution having a concentration of 5N (5N) or more is preferable, and an aqueous solution having a concentration of 8N (8N) or more is more preferable. The amount of alkali used is preferably 2 to 10 times the molar amount relative to the compound (2). The amount of the aprotic polar solvent used is preferably about 5 to 30 times (% by weight) of the compound (2). As reaction temperature, the temperature in a reaction system is 10-30 degreeC, Preferably it is 20-30 degreeC. The reaction time is usually about 3 hours.

[Step b]

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , ring A and ring B are the same as described above.)
In this step, compound (4) is produced by condensing compound (3) with a hydrazine derivative.

  As the hydrazine derivative, formic acid hydrazide and hydrazine hydrate (hydrazine hydrate) are preferable, and hydrazine hydrate (hydrazine hydrate) is more preferable. The amount of the hydrazine derivative used is in the range of equivalent to 5 times mol, preferably 2 to 3 times mol for the compound (3).

  As the condensing agent, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (water-soluble carbodiimide), N, N-dicyclohexylcarbodiimide, N, N-carbonyldiimidazole, or the like is preferable. -Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (water-soluble carbodiimide) is preferred. The amount of the condensing agent used is stoichiometrically equivalent to 3 times mol, particularly preferably equivalent to 1.2 times mol with respect to the compound (3).

  The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but a halogenated hydrocarbon solvent such as methylene chloride, a hydrocarbon solvent such as toluene, an ether solvent such as tetrahydrofuran, and a nitrile system such as acetonitrile. Examples include aprotic polar solvents such as a solvent, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, and dimethylsulfoxide, and these solvents may be used in combination with water. Among these solvents, nitrile solvents such as acetonitrile, nitrile solvents such as 10-20% water-containing acetonitrile, 10-20% water-containing N, N-dimethylacetamide solvent, 10-20% water-containing dimethylsulfoxide. Hydrous aprotic polar solvents such as solvents are preferred.

  In order to promote the reaction, a base may be added in order to keep the pH in the reaction system in the range of 6.0 to 8.5, preferably 6.4 to 8.3. Examples of the base to be added include organic amine bases such as triethylamine, N-methylmorpholine, 4- (N, N-dimethylamino) pyridine, or alkali metal, alkaline earth metal hydroxide, carbonate, bicarbonate aqueous solution. When using nitrile solvents such as water-containing acetonitrile and 10-20% water-containing N, N-dimethylacetamide, 10-20% water-containing dimethylsulfoxide solvent, aqueous sodium hydroxide solution, aqueous potassium hydroxide solution Is preferred.

  Furthermore, an active esterification reagent such as 1-hydroxybenzotriazole and 1-hydroxy-7-azabenzotriazole may be added, and it is in the range of 0.1 mol to an equivalent amount, particularly 0.1 It is preferable to add in the range of mol to 0.5 mol. The reaction temperature is preferably in the range of 0 ° C. to room temperature. The reaction time is completed in about 4 to 20 hours.

  The above compound (4) is produced by carrying out [Step b] from the compound (2) in the same reaction system (one pot) without isolating and purifying the compound (3) produced in [Step a]. You can also.

[Step b-2]

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁸ , R ⁹ , ring A and ring B are the same as described above.)
In this step, compound (1a) is produced by condensing compound (3) with a di (alkyl) amine derivative.

  As the di (alkyl) amine derivative, dimethylamine and diethylamine are preferable, and dimethylamine is more preferable. As the di (alkyl) amine derivative, a salt such as hydrochloride may be used, or an aqueous solution of di (alkyl) amine may be used. Among these, the di (alkyl) amine derivative used is most preferably a dimethylamine aqueous solution. The amount of the di (alkyl) amine derivative used is in the range of equivalent to 5 times mol, preferably 2 to 3 times mol for the compound (3).

  As the condensing agent, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (water-soluble carbodiimide), N, N-dicyclohexylcarbodiimide, N, N-carbonyldiimidazole, or the like is preferable. -Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (water-soluble carbodiimide) is preferred. The amount of the condensing agent used is preferably in a stoichiometrically equivalent to 10-fold mol range, more preferably 2 to 5-fold mol range relative to the compound (3).

  The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but nitrile solvents such as acetonitrile and aprotic polar solvents such as dimethyl sulfoxide are preferable, and these solvents may be used in combination with water. . Moreover, in order to accelerate | stimulate reaction, you may add active esterification reagents, such as 1-hydroxybenzotriazole and 1-hydroxy-7-azabenzotriazole, 0.1 mol-equivalent with respect to a compound (3). It is preferred to add a range, in particular a range of 0.1 mol to 0.5 mol.

  The reaction temperature is preferably in the range of 0 ° C. to room temperature. The reaction time is completed in about 5 to 20 hours.

  The above compound (1a) is obtained by performing [Step b-2] from the compound (2) in the same reaction system (one pot) without isolating and purifying the compound (3) produced in [Step a]. It can also be manufactured.

[Step c]

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , ring A and ring B are the same as described above.)
In this step, compound (4) is treated with orthoformate or orthoacetate in the presence of a Lewis acid in an aprotic polar solvent to produce compound (1).

  As the aprotic polar solvent, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide are preferable. The amount of the solvent to be used is preferably as small as possible for the reaction to proceed smoothly and industrially, and is about 5 to 10 times the volume (V / W) relative to the weight of the compound (4). preferable.

  As the Lewis acid, a commercially available boron trifluoride-solvent complex is preferable, and a boron trifluoride-tetrahydrofuran complex is particularly preferable. The amount of the Lewis acid to be used is preferably 3 to 5 times mol, more preferably 3 to 3.5 times mol based on the compound (4).

  The orthoformate or orthoacetate may be any of the commercially available orthoformate or orthoacetate, but orthoformic acid trimethyl ester, orthoformic acid triethyl ester, orthoacetic acid trimethyl ester and orthoacetic acid triethyl ester are preferred. The amount of orthoformate or orthoacetate used is preferably about 1 to 5 times (V / W), more preferably about 2 to 3 times (V / W) relative to compound (4).

  As the reaction temperature, the internal temperature may be in the range of 30 to 60 ° C, and preferably 40 to 60 ° C. The reaction time is completed in about 2 hours.

  As the post-treatment, water may be added and neutralized with an aqueous base such as sodium bicarbonate water or triethylamine, and the precipitated crystals may be collected by filtration, washed with water, and dried.

  Compound (2) which is the starting material of the above [Scheme 1] can be synthesized by a known method. A method for producing the compound (2) from the compound (5) which is the starting material of the conventional method shown in the above [Scheme A] is shown in the following [Scheme 2]. Compound (1) can be produced from compound (2) as shown in [Scheme 1].

(In the formula, R ⁴⁰ represents a hydrogen atom, an alkali metal or a C1-C6 alkyl group, R ⁷⁰ represents a hydrogen atom or an alkali metal, and R ¹ , R ² , R ³ , R ⁴ , ring A and ring B shows the same thing as the above.)
[Step d] to [Step j] of [Scheme 2] will be described in detail below.

[Step d] and [Step e]

(In the formula, OMs represents a methanesulfonyloxy group, and Boc represents a tert-butoxycarbonyl group.)
Compound (7) can be produced by producing compound (6) which is an azide form from compound (5) by the method described in International Publication No. 2003/016302 and catalytically reducing compound (6). it can.

  [Step d] is a step of producing an azide isomer (6) by reacting a compound (5) which is a methanesulfonyloxy isomer with an azide.

  Compound (6) is obtained by, for example, treating compound (5) with an alkali metal azide in the presence of a triethylammonium chloride ratio as a phase transfer catalyst in an aprotic polar solvent such as N-methyl-2-pyrrolidone. Can be manufactured. The amount of the aprotic polar solvent to be used is preferably about 1.5 to 5 times (V / W) the amount of the compound (5), and the phase transfer catalyst to be used is about 0.005 to the compound (5). About 2-0.5 times mole is preferable. As an alkali metal azide salt, sodium azide and lithium azide are preferable, and the amount to be used is preferably 1.5 to 2.5 times by mole based on the compound (5). The reaction temperature is preferably 55 to 65 ° C. The reaction time is completed in about 48 to 72 hours.

  [Step e] is a step of producing compound (7) which is an amine body by reducing compound (6) which is an azide body, and the reduction method is a known catalytic reduction reaction using a metal-supported catalyst, or a metal A known method using a supported catalyst and using formic acid or an ammonium salt of formic acid as a hydrogen source can be used.

  For example, compound (7) can be produced by treating compound (6) with ammonium formate as a hydrogen source in an alcohol solvent in the presence of a metal-supported catalyst. As the alcohol solvent, ethanol is preferable, and the amount used is preferably about 10 times the amount of the compound (6). The metal-supported catalyst is preferably palladium / carbon, and the amount used is preferably about 10 to 20% by weight based on the compound (6). The amount of ammonium formate used as the hydrogen source is preferably 4 to 10 moles relative to compound (6). The reaction temperature is preferably 45 to 55 ° C., and the reaction time is completed in 1 to 3 hours.

[Step f]

(In the formula, R ¹ , R ² , R ⁴⁰ , ring A and Boc are the same as described above.)
Compound (18) can be produced by condensing compound (7) and compound (13).

  [Step f] is a step of producing compound (18) by condensing amino compound (7) and compound (13), and includes the following two methods.

(I) When R ⁴⁰ is a hydrogen atom or an alkali metal Compound (17) is a compound (7) that is an amino compound in the presence of a condensing agent (13) that is a carboxylic acid or an alkali metal salt of a carboxylic acid. ) Or a salt thereof.

  The amount of the compound (13) is preferably in the range of equimolar to 1.2 times equivalent with respect to the compound (7). Examples of the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N-dicyclohexylcarbodiimide, N, N-carbonyldiimidazole, or the like, and 1-ethyl- 3- (3-Dimethylaminopropyl) carbodiimide hydrochloride and N, N-dicyclohexylcarbodiimide are preferable, and a stoichiometric range of equimolar to 3-fold mol with respect to the compound (7) is preferable. A range of equimolar to 1.5 times equivalent is more preferable. In this reaction, an organic amine base such as triethylamine, N-methylmorpholine or 4- (N, N-dimethylamino) pyridine is stoichiometrically equimolar to 10 times the compound (7). It may be used in the molar range, preferably in the stoichiometrically equimolar to 5-fold equivalent range. Furthermore, an active esterification reagent such as 1-hydroxybenzotriazole and 1-hydroxy-7-azabenzotriazole is preferably used in an amount of 0.1 to 2 moles compared to compound (7) in order to accelerate the reaction. Is preferably used in a range of 0.1 to 1.5 moles. The reaction solvent is not particularly limited as long as it does not inhibit the reaction. However, a halogenated hydrocarbon solvent such as methylene chloride, a hydrocarbon solvent such as toluene, an ether solvent such as tetrahydrofuran, or N, N- Aprotic polar solvents such as dimethylformamide and N-methyl-2-pyrrolidone are preferred, and N, N-dimethylformamide is more preferred. Reaction temperature can be implemented in the range of -20 degreeC-the boiling point of a solvent, and the range of 0-30 degreeC is preferable. The reaction time is completed in about 1 to 24 hours. The reaction may be carried out in an inert gas atmosphere such as nitrogen or argon.

(Ii) When R ⁴⁰ is a C1-C6 alkyl group Compound (18) can be produced by condensing compound (7), which is an amino form, with compound (13), which is a carboxylic acid ester, or a salt thereof.

R ⁴⁰ is preferably an ethyl group or a methyl group. The amount of the compound (13) is preferably in the range of equimolar to 1.2 times equivalent with respect to the compound (7). The reaction solvent is not particularly limited as long as it does not inhibit the reaction. However, halogenated hydrocarbon solvents such as 1,2-dichloroethane, hydrocarbon solvents such as toluene, ether solvents such as tetrahydrofuran, acetonitrile, etc. Or aprotic polar solvents such as N, N-dimethylformamide and N-methyl-2-pyrrolidone are preferred, and nitrile solvents such as acetonitrile are more preferred. In this reaction, an organic amine base such as triethylamine or N-methylmorpholine is stoichiometrically equimolar to 10-fold equimolar, preferably stoichiometrically equivalent to compound (7). You may use it in the range of a mole-5 times equivalent. Reaction temperature can be implemented in the range of 20 degreeC-the boiling point of a solvent, and the range of 60-75 degreeC is preferable. The reaction time is completed in about 3 to 24 hours. The reaction may be carried out in an inert gas atmosphere such as nitrogen or argon.

[Step g]

(In the formula, R—CO ₂ H represents oxalic acid, malic acid, maleic acid or p-nitrobenzoic acid, and Boc represents the same as described above.)
[Step g] is a step of isolating and purifying compound (7) as a carboxylate crystal by adding carboxylic acid in a solvent to compound (7) which is an amino form.

  Compound (17) can be produced by treating compound (7) and carboxylic acid in a solvent and collecting the precipitated crystals by filtration. As a solvent to be used, a solvent in which the raw material compound (7) and carboxylic acid are dissolved but the product compound (17) is not dissolved is preferable. A preferred solvent is acetonitrile. The total amount of the solvent used is preferably 2 to 20 times the amount (V / W), more preferably about 10 times the amount (V / W), relative to the weight of the compound (7). As the carboxylic acid, oxalic acid, malic acid, maleic acid and p-nitrobenzoic acid are preferable, oxalic acid and malic acid are more preferable, and malic acid is particularly preferable. The amount of carboxylic acid to be added is preferably in the range of 0.9 to 1.2 mol, more preferably in the range of equimolar to 1.05 mol, relative to compound (7).

[Step h]

(In the formula, R ¹ , R ² , R ⁴⁰ , ring A and Boc are the same as described above.)
[Step h] is a step for producing compound (18) by condensing compound (17) which is a carboxylic salt of amine with compound (13). As the condensation method, there are the following two methods (i) and (ii).

(I) In the case where R ⁴⁰ is a hydrogen atom or an alkali metal Compound (18) is compound (13), which is a carboxylic acid or an alkali metal salt of a carboxylic acid in the presence of a base and a condensing agent. It can be produced by treatment with the salt.

  The amount of the compound (13) is preferably in the range of equimolar to 1.2 times equivalent with respect to the compound (17).

  Examples of the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (water-soluble carbodiimide), N, N-dicyclohexylcarbodiimide, N, N-carbonyldiimidazole, or the like, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (water-soluble carbodiimide) and N, N-dicyclohexylcarbodiimide are preferable, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (water-soluble) Carbodiimide) is particularly preferred. The amount of the condensing agent to be added is preferably in the stoichiometric range of equimolar to 1.5-fold molar amount relative to compound (17), and in the stoichiometric range of equimolar to 1.5-fold molar amount. More preferred. As the base, organic amines such as triethylamine or N-methylmorpholine are preferable. The amount of the base to be added is preferably in the stoichiometric range of equimolar to 10-fold molar amount, more preferably in the stoichiometric range of equimolar to 5-fold molar amount relative to the compound (17). Furthermore, an active esterification reagent such as 1-hydroxybenzotriazole and 1-hydroxy-7-azabenzotriazole is preferably used in an amount of 0.1 to 2 times the molar amount of compound (17) in order to accelerate the reaction. Is preferably used in the range of 0.1 to 1.5 moles. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but is a halogenated hydrocarbon solvent such as methylene chloride, a hydrocarbon solvent such as toluene, an ether solvent such as tetrahydrofuran, or N, N-dimethyl. Aprotic polar solvents such as formamide and N-methyl-2-pyrrolidone are preferred, and N, N-dimethylformamide is more preferred. As reaction temperature, the range of 0 degreeC-60 degreeC is preferable, and the range of 0-30 degreeC is more preferable. The reaction time is about 1 to 24 hours. The reaction may be carried out in an inert gas atmosphere such as nitrogen or argon.

(Ii) When R ⁴⁰ is a C1-C6 alkyl group Compound (18) can be produced by condensing compound (17), which is a carboxylate, with compound (13), which is a carboxylic acid ester, or a salt thereof.

R ⁴⁰ is preferably an ethyl group or a methyl group. The amount of the compound (13) is preferably in the range of equimolar to 1.2 times mol with respect to the compound (17). As the base, organic amines such as triethylamine and N-methylmorpholine are preferable. The amount of the base to be added is preferably in the stoichiometric range of equimolar to 10-fold molar amount, more preferably in the stoichiometric range of equimolar to 5-fold molar amount relative to the compound (17). The reaction solvent is not particularly limited as long as it does not inhibit the reaction. However, halogenated hydrocarbon solvents such as 1,2-dichloroethane, hydrocarbon solvents such as toluene, ether solvents such as tetrahydrofuran, acetonitrile, etc. Or aprotic polar solvents such as N, N-dimethylformamide and N-methyl-2-pyrrolidone are preferred, and nitrile solvents such as acetonitrile are more preferred. Reaction temperature can be implemented in the range of 20 degreeC-the boiling point of a solvent, and the range of 60-75 degreeC is preferable. The reaction time is completed in about 3 to 24 hours. The reaction may be carried out in an inert gas atmosphere such as nitrogen or argon.

[Step i]

(Wherein R ¹ , R ² , ring A and Boc are the same as described above.)
[Step i] is a step of producing compound (19) by acid treatment of compound (18).

  As a method for removing the Boc group by acid treatment and converting it to an amino group, for example, the above-mentioned “Protective Groups in Organic Synthesis, eds. By TW Greene and PG Wuts, John Wiley & Sons, Inc. , New York, 1991 "and the like. As the acid to be used, for example, trifluoroacetic acid and methanesulfonic acid are preferable, and methanesulfonic acid is more preferable. The amount of the acid to be added is preferably in a stoichiometrically equimolar to 10-fold molar range, more preferably in a stoichiometrically 2-5 molar range with respect to the compound (18). The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but a halogenated hydrocarbon solvent such as methylene chloride, a hydrocarbon solvent such as toluene, an ether solvent such as tetrahydrofuran, and a nitrile system such as acetonitrile. Solvents are preferred, and nitrile solvents such as acetonitrile are more preferred. As reaction temperature, the range of 0 degreeC-60 degreeC is preferable, and the range of 15-35 degreeC is more preferable. The reaction time is completed in about 2 to 10 hours. The reaction may be carried out in an inert gas atmosphere such as nitrogen or argon. After completion of the reaction, the compound (18) forming an acid addition salt is neutralized by adding an organic amine such as triethylamine. The amount of the organic amine to be added is preferably in the range of equimolar to 1.5 times mol, more preferably in the range of equimolar to 1.1 times mol with respect to the added acid.

[Step j]

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁷⁰ , ring A and ring B are the same as described above.)
[Step j] is a step for producing compound (2) by treating compound (19) with compound (16) in the presence of a condensing agent.

  Examples of the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (water-soluble carbodiimide), N, N-dicyclohexylcarbodiimide, N, N-carbonyldiimidazole, or the like. 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (water-soluble carbodiimide) and N, N-dicyclohexylcarbodiimide are preferable, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (water-soluble) Carbodiimide) is more preferable. The amount of the condensing agent is preferably in the stoichiometric range of equimolar to 1.3 times mol, more preferably in the stoichiometric range of equimolar to 1.1 times mol with respect to the compound (19). . In addition, an active esterification reagent such as 1-hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazole is used in an amount of 0.1 to 2 times mol, preferably 0.1 to 1 with respect to compound (19). It is preferable to use in the range of 5 moles. The reaction solvent is not particularly limited as long as it does not inhibit the reaction. However, a halogenated hydrocarbon solvent such as methylene chloride, a hydrocarbon solvent such as toluene, an ether solvent such as tetrahydrofuran, N, N-dimethyl, etc. Aprotic polar solvents such as formamide and N-methyl-2-pyrrolidone and nitrile solvents such as acetonitrile are preferred, and nitrile solvents such as acetonitrile are more preferred. As reaction temperature, the range of 10 to 60 degreeC is preferable, and the range of 15 to 30 degreeC is more preferable. The reaction time is about 1 to 24 hours. The reaction may be carried out in an inert gas atmosphere such as nitrogen or argon.

  When the condensing agent used is an acid addition salt after completion of the reaction, it is preferable to neutralize by adding a base, and water is added to dissolve the neutralized salt and remove the neutralized salt from the reaction system. May be. The base to be added is preferably an organic amine base such as triethylamine or N-methylmorpholine. The amount of the base to be added is preferably in the range of equimolar to 1.2 times mol with respect to the acid addition salt condensing agent.

  Further, compound (2) is prepared from compound (18) after the production of compound (19) in [Step i], and in the same reaction system (one pot) without isolating and purifying compound (19), etc. The organic amine can be condensed with compound (16) in [Step i].

  The compound of each step of the present invention may exist in any form of free or salt. For example, examples of the addition salt with inorganic acid include hydrochloride, hydrobromide, sulfate, etc. Examples of the salts include acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate, benzenesulfonate, and the like. Examples of the salt of inorganic base or organic base include ammonium salt, sodium salt, potassium salt, lithium salt, calcium salt and the like, and hydrates or solvates of these salts are also included in the present invention.

  In addition, when the compound of the present invention has one or more asymmetric centers in the molecule, it also includes enantiomers, racemates, diastereomers, and mixtures thereof unless otherwise specified. Moreover, when the compound of this invention contains a geometric isomer, a cis compound, a trans compound, and mixtures thereof are included. Furthermore, it includes any tautomers and mixtures thereof when the compound of the present invention includes tautomers.

  Next, although an Example is given and this invention is demonstrated in detail, this invention is not limited to this at all.

  Tetramethylsilane is used as an internal standard substance in the magnetic resonance spectrum (NMR), and abbreviations indicating multiplicity are s = singlet, d = doublelet, t = triplet, q = quartet, m = multiplet, and br. Indicates s = broad singlet.

Examples of synthesis of the compound of formula (13) are shown in the following [Reference Example 1] to [Reference Example 30].
[Reference Example 1] 2- (4-Chloroanilino) -2-oxoacetic acid ethyl ester (13-a)

To a solution of 4-chloroaniline (1.16 g) and methylene chloride (26 ml), triethylamine (1.52 ml) and chlorooxoacetic acid ethyl ester (1.11 ml) were successively added under ice cooling, and the mixture was stirred at room temperature for 14 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was partitioned. The organic layer was washed successively with 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was concentrated under reduced pressure, hexane was added to the residue to precipitate crystals, which were collected by filtration and dried to obtain the title compound (1.89 g).
¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.1 Hz), 4.42 (2H, q, J = 7.1 Hz), 7.34 (2H, d, J = 8.8 Hz), 7.60 (2H, d, J = 8.8 Hz), 8.86 (1 H, br.s).
MS (ESI) m / z: 228 (M + H) ^<+> .

[Reference Example 2] 2- (4-Fluoroanilino) -2-oxoacetic acid methyl ester (13-b)

In the same manner as described in Reference Example 1, the title compound was obtained from 4-fluoroaniline and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 3.98 (3H, s), 7.00-7.14 (2H, m), 7.55-7.68 (2H, m), 8.85 (1H , Br.s).
MS (ESI) m / z: 198 (M + H) ^<+> .

[Reference Example 3] 2- (4-Bromoanilino) -2-oxoacetic acid methyl ester (13-c)

In the same manner as described in Reference Example 1, the title compound was obtained from 4-bromoaniline and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 3.98 (3H, s), 7.49 (2H, d, J = 9.0 Hz), 7.55 (2H, d, J = 9.0 Hz), 8 .85 (1H, br.s).
MS (FAB) m / z: 258 (M) ^<+> .

[Reference Example 4] 2- (4-Chloro-2-methylanilino) -2-oxoacetic acid methyl ester (13-d)

In the same manner as described in Reference Example 1, the title compound was obtained from 4-chloro-2-methylaniline and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 2.31 (3H, s), 3.99 (3H, s), 7.15-7.30 (2H, m), 7.98 (1H, d, J = 8.8 Hz), 8.77 (1H, br).
MS (FAB) m / z: 228 (M + H) ^<+> .

[Reference Example 5] 2-[(4-Chloro-3-methylanilino) -2-oxoacetic acid methyl ester (13-e)

In the same manner as described in Reference Example 1, the title compound was obtained from 4-chloro-3-methylaniline and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 2.39 (3H, s), 3.98 (3H, s), 7.33 (1H, d, J = 12.5 Hz), 7.44 (1H, dd , J = 12.5, 2.5 Hz), 7.53 (1H, d, J = 2.5 Hz), 8.81 (1H, br.s).
MS (ESI) m / z: 228 (M + H) ^<+> .

[Reference Example 6] 2- (4-Chloro-2-fluoroanilino) -2-oxoacetic acid methyl ester (13-f)

In the same manner as described in Reference Example 1, the title compound was obtained from 4-chloro-2-fluoroaniline and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 7.15-7.24 (2H, m), 8.33 (1H, t, J = 8.4 Hz), 9.05 (1H, br.s).
MS (ESI) m / z: 232 (M + H) ^<+> .

Reference Example 7 2- (2,4-Difluoroanilino) -2-oxoacetic acid methyl ester (13-g)

In the same manner as described in Reference Example 1, the title compound was obtained from 2,4-difluoroaniline and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 6.87-7.00 (2H, m), 8.29-8.38 (1H, m), 8.99 (1H , Br.s).
MS (ESI) m / z: 215 (M) ^<+> .

[Reference Example 8] 2- (3,4-Difluoroanilino) -2-oxoacetic acid methyl ester (13-h)

In the same manner as in Reference Example 1, the title compound was obtained from 3,4-difluoroaniline and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 3.98 (3H, s), 7.10-7.28 (2H, m), 7.67-7.78 (1H, m), 8.83 (1H , Br.s).
MS (ESI) m / z: 215 (M) ^<+> .

[Reference Example 9] 2-Oxo-2- (pyridin-4-ylamino) acetic acid methyl ester (13-i)

In the same manner as described in Reference Example 1, the title compound was obtained from 4-aminopyridine and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 7.58 (2H, dd, J = 4.8, 1.6 Hz), 8.60 (2H, dd, J = 4. 8, 1.6 Hz), 9.04 (1H, br.s).
MS (ESI) m / z: 181 (M + H) ^<+> .

[Reference Example 10] 2-[(5-Bromopyridin-2-yl) amino] -2-oxoacetic acid methyl ester

In the same manner as described in Reference Example 1, the title compound was obtained from 2-amino-5-bromopyridine and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 7.87 (1H, dd, J = 8.8, 2.4 Hz), 8.19 (1H, d, J = 8. 8 Hz), 8.41 (1 H, d, J = 2.4 Hz), 9.38 (1 H, br. S).
MS (FAB) m / z: 259 (M) ^<+> .

[Reference Example 11] 2-[(5-Fluoropyridin-2-yl) amino] -2-oxoacetic acid methyl ester (13-k)

In the same manner as described in Reference Example 1, the title compound was obtained from 2-amino-5-fluoropyridine and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 7.48-7.53 (1H, m), 8.21 (1H, d, J = 2.9 Hz), 8.27 -8.31 (1H, m), 9.41 (1H, br.s).
MS (FAB) m / z: 198 (M + H) ⁺ .

[Reference Example 12] 2- [4-Chloro-2- (trifluoromethyl) anilino] -2-oxoacetic acid methyl ester (13-l)

In the same manner as described in Reference Example 1, the title compound was obtained from 4-chloro-2- (trifluoromethyl) aniline and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 4.01 (3H, s), 7.58 (1H, dd, J = 8.8, 2.2 Hz), 7.65 (1H, d, J = 2. 2 Hz), 8.34 (1 H, d, J = 8.8 Hz), 9.30 (1 H, br. S).
MS (EI) m / z: 281 (M + H) ^<+> .

[Reference Example 13] 2- (4-Chloro-2-methoxyanilino) -2-oxoacetic acid methyl ester (13-m)

In the same manner as described in Reference Example 1, the title compound was obtained from 4-chloro-2-methoxyaniline and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 3.92 (3H, s), 3.97 (3H, s), 6.90 (1H, d, J = 2.2 Hz), 6.98 (1H, dd , J = 8.8, 2.2 Hz), 8.35 (1H, d, J = 8.8 Hz), 9.33-9.44 (1H, br).
MS (ESI) m / z: 244 (M + H) ^<+> .

[Reference Example 14] 2- (4-Chloro-3-methoxyanilino) -2-oxoacetic acid methyl ester (13-n)

In the same manner as described in Reference Example 1, the title compound was obtained from 4-chloro-3-methoxyaniline and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 3.93 (3H, s), 3.98 (3H, s), 7.00 (1H, dd, J = 8.5, 2.4 Hz), 7.33 (1H, d, J = 8.5 Hz), 7.57 (1H, d, J = 2.4 Hz), 8.89 (1H, br.s).

[Reference Example 15] 2-[(5-Methylpyridin-2-yl) amino] -2-oxoacetic acid methyl ester (13-o)

In the same manner as described in Reference Example 1, the title compound was obtained from 2-amino-5-methylpyridine and chlorooxoacetic acid methyl ester.
¹ H-NMR (CDCl ₃ ) δ: 2.33 (3H, s), 3.98 (3H, s), 7.57 (1H, dd, J = 8.4, 2.0 Hz), 8.14 (1H, d, J = 8.4 Hz), 8.17 (1H, d, J = 2.0 Hz).
MS (ESI) m / z: 195 (M + H) ^<+> .

[Reference Example 16] 2-Oxo-2- (4-toluidino) acetic acid methyl ester (13-p)

The title compound was obtained from p-toluidine and chlorooxoacetic acid methyl ester in the same manner as described in Reference Example 1.
MS (ESI) m / z: 194 (M + H) ^<+> .

[Reference Example 17] 2-[(5-chloropyridin-2-yl) amino] -2-oxoacetic acid methyl ester (13-q)

2-Amino-5-chloropyridine (1.16 g) and triethylamine (1.51 ml) were dissolved in methylene chloride (26 ml), chlorooxoacetic acid ethyl ester (1.10 ml) was added under ice cooling, and the mixture was stirred at room temperature for 14 hours. Stir. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was partitioned. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1). The obtained solid was dissolved in methanol (20 ml) and stirred at 50 ° C. for 11 hours. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration and dried to give the title compound (0.43 g).
¹ H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 7.73 (1H, dd, J = 8.8, 2.2 Hz), 8.24 (1H, d, J = 8. 8 Hz), 8.31 (1 H, d, J = 2.2 Hz), 9.39 (1 H, br. S).
MS (ESI) m / z: 215 (M + H) ^<+> .

[Reference Example 18] 2-[(6-Chloropyridin-3-yl) amino] -2-oxoacetic acid ethyl ester (13-r)

5-Amino-2-chloropyridine (386 mg) was dissolved in N, N-dimethylformamide (8 ml) to give potassium 2-ethoxy-2-oxoacetate (469 mg), 1- (3-dimethylaminopropyl) -3. -Ethylcarbodiimide hydrochloride (863 mg) and 1-hydroxybenzotriazole monohydrate (203 mg) were added, and the mixture was stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure, and methylene chloride and a saturated aqueous sodium hydrogen carbonate solution were added for liquid separation, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and then purified by silica gel flash column chromatography (hexane: ethyl acetate = 2: 1) to obtain a residue (200 mg) containing the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.2 Hz), 4.44 (2H, q, J = 7.2 Hz), 7.36 (1H, d, J = 8.7 Hz), 8.24 (1H, dd, J = 8.7, 2.7 Hz), 8.55 (1H, d, J = 2.7 Hz), 9.03 (1H, br.s).

[Reference Example 19] 2-[(5-Chlorothiophen-2-yl) amino] -2-oxoacetic acid methyl ester (13-s)

Triethylamine (1.25 ml) and diphenylphosphoryl azide (1.55 ml) were added to a suspension of 5-chlorothiophene-2-carboxylic acid (0.99 g) in toluene (20 ml), and the mixture was stirred at 80 ° C. for 1 hour. . The reaction mixture was cooled to room temperature, tert-butanol (2 ml) was added, and the mixture was heated to reflux for 19 hours. The reaction mixture was concentrated under reduced pressure, methylene chloride (200 ml) was added to the resulting residue, and the mixture was washed successively with distilled water, 10% aqueous citric acid solution, distilled water, saturated aqueous sodium bicarbonate solution and saturated brine, and then anhydrous sodium sulfate. And dried. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain 5-chloro-2-thienylcarbamic acid tert-butyl ester (1.05 g).
¹ H-NMR (CDCl ₃ ) δ: 1.51 (9H, s), 6.21 (1H, d, J = 3.1 Hz), 6.60 (1H, d, J = 3.1 Hz), 6 .91 (1H, br.s).
MS (ESI) m / z: 234 (M + H) ^<+> .
The above product (1.87 g) was added to 4N dioxane hydrochloride solution (40 ml) and stirred at room temperature for 4 hours, and then the solvent was evaporated under reduced pressure. The residue was suspended in tetrahydrofuran (50 ml), sodium hydrogen carbonate (2.02 g) and chlorooxoacetic acid methyl ester (0.883 ml) were added under ice cooling, and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure, and water and methylene chloride were added to the residue for liquid separation. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1), and the solvent was distilled off to obtain the title compound (1.44 g).
¹ H-NMR (CDCl ₃ ) δ: 3.98 (3H, s), 6.61 (1H, d, J = 4.2 Hz), 6.75 (1H, d, J = 4.2 Hz), 9 .42 (1H, br.s).
MS (FAB) m / z: 220 (M + H) ^<+> .

[Reference Example 20] 2- (4-Chloro-3-fluoroanilino) -2-oxoacetic acid methyl ester (13-t)

4-Chloro-3-fluorobenzoic acid was treated in the same manner as described in Reference Example 19 and condensed with chlorooxoacetic acid methyl ester to give the title compound.
¹ H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 7.25-7.27 (1H, m), 7.39 (1H, t, J = 8.5 Hz), 7.72 (1H, dd, J = 10.4, 2.4 Hz), 8.90 (1H, br.s).

[Reference Example 21] 2- [4-Chloro-2- (trifluoromethyl) anilino] -2-oxoacetic acid (13-u)

To a mixed solution of 2- [4-chloro-2- (trifluoromethyl) anilino] -2-oxoacetic acid methyl ester (297 mg) in tetrahydrofuran (7 ml) -water (3 ml) was added lithium hydroxide (28 mg), and room temperature. For 2 hours. 1N hydrochloric acid (8 ml) and methylene chloride (20 ml) were added to the reaction solvent, and a liquid separation operation was performed. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure and dried to obtain the title compound (291 mg).
¹ H-NMR (CDCl ₃ ) δ: 7.61 (1H, dd, J = 8.8, 2.5 Hz), 7.68 (1H, d, J = 2.5 Hz), 8.26 (1H, d, J = 8.8 Hz), 9.36 (1H, br.s).
MS (ESI, anion) m / z: 267 (M−H) ⁻ .

[Reference Example 22] 2- (4-Chloroanilino) -2-oxoacetic acid (13-v)

In the same manner as in Reference Example 21, the title compound was obtained from ethyl 2- (4-chloroanilino) -2-oxoacetate.
¹ H-NMR (DMSO-d ₆ ) δ: 7.37 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.8 Hz), 10.66 (1H, s) .

[Reference Example 23] 2-[(5-Bromopyridin-2-yl) amino] -2-oxoacetic acid (13-w)

In the same manner as described in Reference Example 21, the title compound was obtained from 2-[(5-bromopyridin-2-yl) amino] -2-oxoacetic acid methyl ester.
¹ H-NMR (DMSO-d ₆ ) δ: 7.95-8.00 (1H, m), 8.08 (1H, dd, J = 8.8, 2.0 Hz), 8.50 (1H, d, J = 2.0 Hz), 10.74 (1H, s).

[Reference Example 24] 2- (4-Chloro-3-fluoroanilino) -2-oxoacetic acid (13-x)

In the same manner as described in Reference Example 21, the title compound was obtained from 2- (4-chloro-3-fluoroanilino) -2-oxoacetic acid methyl ester.
¹ H-NMR (DMSO-d ₆ ) δ: 7.52 (1H, t, J = 8.8 Hz), 7.63 (1H, dd, J = 8.8, 2.2 Hz), 7.88 ( 1H, dd, J = 12.0, 2.2 Hz), 10.83 (1H, br.s).

[Reference Example 25] 2- (4-Chloro-3-methoxyanilino) -2-oxoacetic acid (13-y)

In the same manner as described in Reference Example 21, 2- (4-chloro-3-methoxyanilino) -2-oxoacetic acid methyl ester was hydrolyzed to give the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 3.81 (3H, s), 7.36 (1H, d, J = 8.7 Hz), 7.43 (1H, d, J = 8.7 Hz) , 7.65 (1H, d, J = 2.2 Hz), 10.79 (1H, s).
MS (ESI, anion) m / z: 228 (M−H) ⁻ .

[Reference Example 26] 2- (4-Chloro-3-nitroanilino) -2-oxoacetic acid (13-z)

In the same manner as described in Reference Example 1, 4-chloro-3-nitroaniline and chlorooxoacetic acid methyl ester were condensed and then hydrolyzed in the same manner as described in Reference Example 21 to obtain the title compound. .
¹ H-NMR (DMSO-d ₆ ) δ: 7.76 (1H, dd, J = 8.8 Hz), 8.04 (1H, dd, J = 8.8, 2.4 Hz), 8.55 ( 1H, d, J = 2.4 Hz), 11.24 (1H, s). The proton of carboxylic acid is not visible.
MS (EI) m / z: 244 (M) ^<+> .

[Reference Example 27] Lithium salt of 2-[(5-chloropyridin-2-yl) amino] -2-oxoacetic acid (13-aa)

To a solution of 2-[(5-chloropyridin-2-yl) amino] -2-oxoacetic acid methyl ester (1.12 g) in tetrahydrofuran (20 ml) was added water (5.0 ml) and lithium hydroxide (128 mg) at room temperature. And stirred for 5 hours. The solvent was evaporated under reduced pressure, hexane (30 ml) was added to the resulting white solid, and the mixture was stirred for 30 minutes. The solid was collected by filtration and dried to give the title compound (1.02 g).
¹ H-NMR (DMSO-d ₆ ) δ: 7.90 (1H, dd, J = 8.9, 2.6 Hz), 8.12 (1H, d, J = 8.9 Hz), 8.34 ( 1H, d, J = 2.6 Hz), 10.18 (1H, s).

Reference Example 28 2-[(5-Methylpyridin-2-yl) amino] -2-oxoacetic acid lithium salt (13-ab)

In the same manner as in Reference Example 27, the title compound was obtained from 2-[(5-methylpyridin-2-yl) amino] -2-oxoacetic acid methyl ester.
¹ H-NMR (DMSO-d ₆ ) δ: 2.25 (3H, s), 7.63 (1H, d, J = 8.2 Hz), 8.00 (1H, d, J = 8.2 Hz) , 8.15 (1H, s), 10.00 (1H, br. S).
MS (FAB) m / z: 181 (M-Li + 2H) ^<+> .

Reference Example 29 2-[(5-Bromopyridin-2-yl) amino] -2-oxoacetic acid lithium salt (13-ac)

The title compound was obtained from-[(5-bromopyridin-2-yl) amino] -2-oxoacetic acid methyl ester in a manner similar to that described in Reference Example 27.
¹ H-NMR (DMSO-d ₆ ) δ: 8.03 (1H, dd, J = 8.8, 2.4 Hz), 8.09 (1H, d, J = 8.8 Hz), 8.44 ( 1H, d, J = 2.4 Hz), 10.18 (1H, s).

[Reference Example 30] 2- (4-Chloro-2-nitroanilino) -2-oxoacetic acid sodium salt (13-ad)

In the same manner as described in Reference Example 1, 4-chloro-2-nitroaniline and chlorooxoacetic acid methyl ester were condensed and then hydrolyzed according to the method described in Reference Example 27, and the resulting residue was obtained. Was dissolved in methanol, 1N aqueous sodium hydroxide solution was added, and the resulting precipitate was collected by filtration to give the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 7.84 (1H, dd, J = 9.0, 2.5 Hz), 8.20 (1H, d, J = 2.5 Hz), 8.67 ( 1H, d, J = 9.0 Hz), 11.89 (1H, s).
The following [Reference Example 31] to [Reference Example 37] show synthesis examples of the compound represented by the formula (16).

[Reference Example 31] 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt (16-a)
[Step 1] Pyridin-4-ylcarbamic acid tert-butyl ester

4-Aminopyridine (10 g) was dissolved in tetrahydrofuran (500 ml), di-tert-butyl dicarbonate (25.5 g) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, and the precipitated solid was washed with hexane to obtain the title compound (16.9 g).
¹ H-NMR (CDCl ₃ ) δ: 1.53 (9H, s), 6.86 (1H, br. S), 7.30 (2H, dd, J = 1.5, 4.9 Hz), 8 .44 (2H, dd, J = 1.5, 4.9 Hz).
MS (FAB) m / z: 195 (M + H) ^<+> .

[Step 2] 3-sulfanylpyridin-4-ylcarbamic acid tert-butyl ester

Pyridin-4-ylcarbamic acid tert-butyl ester (61.6 g) was dissolved in tetrahydrofuran (2000 ml), and the mixture was stirred at −78 ° C. for 10 minutes. N-Butyllithium (1.59 N hexane solution, 500 ml) was added dropwise to the reaction solution, stirred for 10 minutes, and then stirred for 2 hours under ice cooling. The reaction solution was cooled to −78 ° C., sulfur powder (12.2 g) was added, the temperature was raised to room temperature, and the mixture was stirred for 1 hour. Water (1000 ml) was added to the reaction solution for liquid separation. 3N hydrochloric acid was added to the aqueous layer to adjust the pH to 3 to 4, and methylene chloride was added to separate the layers. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 50: 1) to obtain the title compound (33.2 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.52 (9H, s), 7.89 (1H, d, J = 6.4 Hz), 7.99 (1H, d, J = 6.4 Hz) , 8.20 (1H, s), 9.91 (1H, br. S).
MS (FAB) m / z: 227 (M + H) ^<+> .

[Step 3] Thiazolo [5,4-c] pyridine

3-sulfanylpyridin-4-ylcarbamic acid tert-butyl ester (33.2 g) was dissolved in formic acid (250 ml) and heated to reflux for 3 days. The reaction solution was concentrated under reduced pressure, and 5N aqueous potassium hydroxide solution (100 ml) and diethyl ether were added to the residue to separate the layers. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 25: 1) to obtain the title compound (9.03 g).
¹ H-NMR (CDCl ₃ ) δ: 8.05 (1H, d, J = 5.4 Hz), 8.70 (1H, d, J = 5.4 Hz), 9.23 (1H, s), 9 .34 (1H, s).
MS (FAB) m / z: 137 (M + H) ^<+> .

[Step 4] 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine

Thiazolo [5,4-c] pyridine (1.61 g) was dissolved in N, N-dimethylformamide (50 ml), methyl iodide (1.50 ml) was added, and the mixture was heated and stirred at 80 ° C. for 4 hours. . The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (100 ml), sodium borohydride (1.53 g) was added, and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, and saturated potassium carbonate aqueous solution and diethyl ether were added to the residue to separate the layers. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 25: 1) to obtain the title compound (1.28 g).
¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H, s), 2.83 (2H, t, J = 5.9 Hz), 2.98 (2H, t, J = 5.9 Hz), 3 .70 (2H, s), 8.63 (1H, s).
MS (FAB) m / z: 155 (M + H) ^<+> .

[Step 5] Lithium salt of 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid (16-a)

5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine (6.43 g) was dissolved in anhydrous tetrahydrofuran (200 ml), and n-butyllithium (1.47) was added at −78 ° C. Normal hexane solution, 34.0 ml) was added dropwise and stirred for 40 minutes. Carbon dioxide was introduced into the reaction solution at −78 ° C. for 1 hour, and then the temperature was raised to room temperature. The reaction solution was concentrated under reduced pressure to obtain the title compound (9.42 g).
¹ H-NMR (DMSO-d ₆ ) δ: 2.37 (3H, s), 2.64-2.77 (4H, m), 3.54 (2H, s).
MS (FAB) m / z: 199 (M + H) ^<+> .

[Reference Example 32] 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt (16-b)
[Step 1] 2-Amino-6,7-dihydrothiazolo [5,4-c] pyridine-5 [4H] -carboxylic acid tert-butyl ester

1-tert-Butoxycarbonyl-4-piperidone (40.0 g) is dissolved in cyclohexane (80 ml), p-toluenesulfonic acid monohydrate (191 mg) and pyrrolidine (17.6 ml) are added, and the mixture is added using a Dean Stark apparatus. The mixture was heated to reflux for 2 hours while dehydrating. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol (60 ml), and sulfur powder (6.42 g) was added. A methanol solution (10 ml) of cyanamide (8.44 g) was slowly added dropwise under ice cooling, and the mixture was stirred at room temperature for 5 hours. The precipitated solid was collected by filtration to give the title compound (31.0 g).
¹ H-NMR (DMSO-d ₆ ) δ: 1.41 (9H, s), 2.44 (2H, t, J = 5.6 Hz), 3.57 (2H, t, J = 5.6 Hz) , 4.29 (2H, s), 6.79 (2H, s).
MS (EI) m / z: 255 (M ^<+> ).

[Step 2] 2-Bromo-6,7-dihydrothiazolo [5,4-c] pyridine-5 [4H] -carboxylic acid tert-butyl ester

Cupric bromide (1.05 g) was suspended in N, N-dimethylformamide (20 ml), and tert-butyl nitrite (0.696 ml) and 2-amino-6,7-dihydrothiazolo under ice-cooling. [5,4-c] pyridine-5 [4H] -carboxylic acid tert-butyl ester (1.00 g) was added, and then the reaction solution was heated and stirred at 40 ° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to obtain the title compound (568 mg).
¹ H-NNR (CDCl ₃ ) δ: 1.48 (9H, s), 2.85 (2H, br. S), 3.72 (2H, br. S), 4.56 (2H, br. S) ).
MS (FAB) m / z: 319 (M + H) ^<+> .

[Step 3] 2-Bromo-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine trifluoroacetate

2-Bromo-6,7-dihydrothiazolo [5,4-c] pyridine-5 [4H] -carboxylic acid tert-butyl ester (890 mg) was dissolved in methylene chloride (2 ml) and trifluoroacetic acid (15 ml) was dissolved. The mixture was stirred at room temperature for 30 seconds. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and the precipitated solid was collected by filtration to give the title compound (867 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 2.98 (2H, t, J = 6.1 Hz), 3.45 (2H, t, J = 6.1 Hz), 4.35 (2H, s) , 9.53 (2H, br. S).
MS (FAB) m / z: 219 (M + H) ^<+> .

[Step 4] 2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine

2-Bromo-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine trifluoroacetate (422 mg) was suspended in methylene chloride (10 ml), and dissolved by adding triethylamine (0.356 ml). , Acetic acid (0.216 ml), formaldehyde aqueous solution (35% solution, 0.202 ml) and sodium triacetoxyborohydride (428 mg) were sequentially added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution (100 ml), methylene chloride (100 ml) and a 3N aqueous sodium hydroxide solution (3 ml) were added to the reaction solution to carry out a liquid separation operation. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to obtain the title compound (286 mg).
¹ H-NMR (CDCl ₃ ) δ: 2.49 (3H, s), 2.79 (2H, t, J = 5.7 Hz), 2.85-2.93 (2H, m), 3.58 (2H, t, J = 1.8 Hz).
MS (FAB) m / z: 233 (M + H) ^<+> .

[Step 5] Lithium salt of 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid (16-b)

2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine (531 mg) was dissolved in anhydrous diethyl ether (20 ml), and n-butyllithium ( 1.54N hexane solution, 1.63 ml) was added dropwise, and the mixture was stirred for 30 minutes under ice cooling. Carbon dioxide gas was introduced into the reaction solution at −78 ° C. for 10 minutes, and then the temperature was raised to room temperature. The reaction mixture was concentrated under reduced pressure to obtain the title compound (523 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 2.37 (3H, s), 2.64-2.85 (4H, m), 3.54 (2H, s).

[Reference Example 33] 5-Isopropyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt (16-c)
[Step 1] 2-Bromo-5-isopropyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine

In the same manner as in [Step 4] of [Reference Example 32], the title compound was obtained from 2-bromo-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine trifluoroacetate.
¹ H-NMR (CDCl ₃ ) δ: 1.13 (6H, d, J = 6.5 Hz), 2.86 (4H, s), 2.89-3.00 (1H, m), 3.70 (2H, s).

[Step 2] Lithium salt of 5-isopropyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid (16-c)

In the same manner as in Reference Example 10, the title compound was obtained from the compound obtained in Reference Example 147.
¹ H-NMR (DMSO-d ₆ ) δ: 1.05 (6H, d, J = 6.4 Hz), 2.68-2.70 (2H, m), 2.75-2.77 (2H, m), 2.87-2.93 (1H, m), 3.66 (2H, s).

[Reference Example 34] 5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridine-2-carboxylic acid lithium salt (16-d)
[Step 1] 2-[(E) -2-Phenylethenyl] oxazole-4-carboxylic acid ethyl ester

It was synthesized according to a report by Panek et al. (J. Org. Chem., 1996, 61, 6496). Sodium bicarbonate (22.8 g) and ethyl bromopyruvate (10.5 ml) were added to a solution of cinnamic amide (10.0 g) in tetrahydrofuran (250 ml) at room temperature, and the mixture was heated to reflux for 48 hours. The reaction mixture was allowed to cool to room temperature, filtered through celite, and concentrated under reduced pressure to give a residue. To a solution of this residue in tetrahydrofuran (30 ml) was added trifluoroacetic anhydride (30 ml) at 0 ° C., and the temperature was gradually raised to room temperature. After stirring for 63 hours, a saturated aqueous sodium hydrogen carbonate solution (500 ml) and ethyl acetate (150 ml) were added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted with ethyl acetate (150 ml). The organic layers were combined, washed with saturated brine (150 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 5: 1 → 3: 1). Purification gave the title compound (10.9 g).
¹ H-NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7.0 Hz), 4.42 (2H, q, J = 7.0 Hz), 6.96 (1H, d, J = 16.6 Hz), 7.30-7.40 (3 H, m), 7.53 (2 H, d, J = 6.8 Hz), 7.63 (1 H, d, J = 16.6 Hz), 8. 20 (1H, s).

[Step 2] 2-[(E) -2-Phenylethenyl] oxazole-4-carbaldehyde

To a solution of 2-[(E) -2-phenylethenyl] oxazole-4-carboxylic acid ethyl ester (8.57 g) in methylene chloride (80 ml) at −78 ° C., diisobutylaluminum hydride (1.0 N hexane). Solution, 66 ml) was added dropwise. After stirring for 15 minutes, methanol (11 ml) was added dropwise and the temperature was raised to room temperature in 1 hour. The reaction mixture was filtered through Celite, and the resulting paste-like material was dissolved in ethyl acetate (200 ml) and saturated aqueous ammonium chloride solution (200 ml). After liquid separation, the aqueous layer was extracted with methylene chloride (2 × 100 ml). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (100 ml) and saturated brine (100 ml), combined with the filtrate at the time of celite filtration and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate = 5: 1 → methylene chloride: methanol = 10: 1) to obtain the title compound (5.86 g).
¹ H-NMR (CDCl ₃ ) δ: 6.96 (1H, d, J = 16.6 Hz), 7.35-7.45 (3H, m), 7.56 (2H, d, J = 6. 4 Hz), 7.67 (1H, d, J = 16.6 Hz), 8.26 (1 H, s), 9.98 (1 H, s),
MS (FAB) m / z: 200 (M + H) ^<+> .

[Step 3] 2-[(E) -2-phenylethenyl] -4-vinyloxazole

To a tetrahydrofuran (80 ml) solution of (methyl) triphenylphosphonium bromide (8.16 g), n-butyllithium (1.54 N hexane solution, 14.2 ml) was added dropwise at 0 ° C. and stirred at room temperature for 30 minutes. . The reaction mixture was cooled again to 0 ° C., a solution of 2-[(E) -2-phenylethenyl] oxazole-4-carbaldehyde (3.64 g) in tetrahydrofuran (20 ml) was added, and the temperature was raised to room temperature. After stirring for 2 hours, water (200 ml) and ethyl acetate (100 ml) were added for liquid separation, and the aqueous layer was extracted with ethyl acetate (50 ml). The organic layers were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 1) to obtain the title compound (2.84 g).
¹ H-NMR (CDCl ₃ ) δ: 5.33 (1H, dd, J = 1.5, 10.7 Hz), 5.98 (1H, dd, J = 1.5, 17.6 Hz), 6. 56 (1H, dd, J = 10.7, 17.6 Hz), 6.95 (1H, d, J = 16.6 Hz), 7.31-7.42 (3H, m), 7.49-7 .56 (4H, m).
MS (FAB) m / z: 198 (M + H) ⁺ .

[Step 4] 2- {2-[(E) -2-phenylethenyl] oxazol-4-yl} -1-ethanol

To a solution of 2-[(E) -2-phenylethenyl] -4-vinyloxazole (13.0 g) in tetrahydrofuran (500 ml) at 0 ° C., 9-borabicyclo [3.3.1] nonane (0. 5N tetrahydrofuran solution, 158 ml) was added, and the mixture was stirred at room temperature for 15 hours. Water (10 ml), 3N aqueous sodium hydroxide solution (80 ml) and aqueous hydrogen peroxide (80 ml) were successively added dropwise to the reaction mixture at 0 ° C., and the mixture was stirred at room temperature for 6 hours. Water (600 ml) and ethyl acetate (200 ml) were added to the reaction mixture, and after separation, the aqueous layer was extracted with ethyl acetate (200 ml). The organic layers were combined, washed with saturated brine (200 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → ethyl acetate only) to obtain the title compound (14.1 g).
¹ H-NMR (CDCl ₃ ) δ: 2.69 (1H, br.s), 2.80 (2H, t, J = 5.6 Hz), 3.90-3.97 (2H, m), 6 .91 (1H, d, J = 16.6 Hz), 7.30-7.42 (4H, m), 7.43-7.56 (3H, m).
MS (FAB) m / z: 216 (M + H) ^<+> .

[Step 5] 2- (2- {2-[(E) -2-phenylethenyl] oxazol-4-yl} ethyl) -1H-isoindole-1,3 (2H) -dione

To a solution of 2- {2-[(E) -2-phenylethenyl] oxazol-4-yl} -1-ethanol (292 mg) in tetrahydrofuran (15 ml) in phthalimide (200 mg), triphenylphosphine (357 mg) and azodicarboxylic acid Acid diethyl ester (0.214 ml) was added at room temperature and stirred for 4 hours. The solvent of the reaction mixture was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (447 mg).
¹ H-NMR (CDCl ₃ ) δ: 2.98 (2H, t, J = 7.2 Hz), 4.03 (2H, t, J = 7.2 Hz), 6.88 (1H, d, J = 16.6 Hz), 7.28-7.45 (5 H, m), 7.48 (2 H, d, J = 7.3 Hz), 7.71 (2 H, dd, J = 2.9, 5.4 Hz) ), 7.84 (2H, dd, J = 2.9, 5.4 Hz).
MS (FAB) m / z: 345 (M + H) ^<+> .

[Step 6] 2- {2-[(E) -2-phenylethenyl] oxazol-4-yl} ethylcarbamic acid tert-butyl ester

2- (2- {2-[(E) -2-phenylethenyl] oxazol-4-yl} ethyl) -1H-isoindole-1,3 (2H) -dione (6.40 g) in ethanol (150 ml ) Hydrazine monohydrate (1.50 ml) was added to the solution at room temperature and stirred for 1 hour, and then hydrazine monohydrate (0.500 ml) was added again at room temperature and stirred for 2 hours. To the reaction mixture were added methylene chloride (150 ml), saturated aqueous sodium hydrogen carbonate solution (150 ml) and di-tert-butyl dicarbonate (13.4 g) at room temperature. After stirring for 30 minutes, liquid separation was performed, and the aqueous layer was extracted with methylene chloride (50 ml). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1) to obtain the title compound (5.06 g).
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 2.75 (2H, t, J = 6.6 Hz), 3.46 (2H, dt, J = 5.9, 6. 6 Hz), 4.92 (1 H, br. S), 6.91 (1 H, d, J = 16.6 Hz), 7.29-7.45 (4 H, m), 7.48 (1 H, d, J = 16.6 Hz), 7.52 (2H, d, J = 7.3 Hz).
MS (FAB) m / z: 315 (M + H) ^<+> , 259 (M-isobutene + H) ^<+> , 315 (M-Boc + H) ^<+> .

[Step 7] 2-[(E) -2-phenylethenyl] -6,7-dihydrooxazolo [5,4-c] pyridine-5 (4H) -carboxylic acid tert-butyl ester

2- {2-[(E) -2-phenylethenyl] oxazol-4-yl} ethylcarbamic acid tert-butyl ester (190 mg) in toluene (15 ml) in paraformaldehyde (54.5 mg) and p-toluene Sulfonic acid (7.2 mg) was added at room temperature. After heating to reflux for 1 hour, the mixture was allowed to cool, and ethyl acetate (15 ml) and saturated aqueous sodium hydrogen carbonate solution (15 ml) were added to the reaction mixture to separate the layers. The aqueous layer was extracted with ethyl acetate (10 ml), the organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 → 2: 1) to obtain the title compound (153 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.67 (2H, br. S), 3.73 (2H, br. S), 4.55 (2H, s), 6.90 (1H, d, J = 16.1 Hz), 7.29-7.42 (3H, m), 7.46 (1 H, d, J = 16.1 Hz), 7.52 (2H, d , J = 7.3 Hz).
MS (FAB) m / z: 327 (M + H) ⁺ , 271 (M-isobutene + H) ⁺ , 227 (M-Boc + H) ⁺ .

[Step 8] 2-Formyl-6,7-dihydrooxazolo [5,4-c] pyridine-5 (4H) -carboxylic acid tert-butyl ester

A solution of 2-[(E) -2-phenylethenyl] -6,7-dihydrooxazolo [5,4-c] pyridine-5 (4H) -carboxylic acid tert-butyl ester (803 mg) in tetrahydrofuran (16 ml) Acetone (8.0 ml), water (4.0 ml), N-methylmorpholine N-oxide (577 mg) and 0.039 mol osmium tetroxide aqueous solution (3.20 ml) were added at room temperature and stirred overnight. Ethyl acetate (50 ml) and 10% aqueous sodium thiosulfate solution (50 ml) were added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted with ethyl acetate (30 ml). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Methanol (8.0 ml), water (8.0 ml), and sodium metaperiodate (790 mg) were added to the remaining tetrahydrofuran (16 ml) solution at room temperature. After stirring for 3 hours, ethyl acetate (30 ml) and water (50 ml) were added to the reaction mixture and the phases were separated, and the aqueous layer was extracted with ethyl acetate (20 ml). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (50 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 2: 1) to obtain the title compound (234 mg). Since this aldehyde was unstable, it was immediately used for the next reaction.
¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.77 (2H, br. S), 3.77 (2H, br. S), 4.62 (2H, s), 9.70 (1H, s).

[Step 9] 6,7-Dihydrooxazolo [5,4-c] pyridine-2,5 (4H) -dicarboxylic acid 5- (tert-butyl) 2-methyl ester

To a solution of 2-formyl-6,7-dihydrooxazolo [5,4-c] pyridine-5 (4H) -carboxylic acid tert-butyl ester (225 mg) in methanol (9.0 ml) was added sodium cyanide (220 mg) and Manganese dioxide (780 mg) was added at room temperature, stirred for 30 minutes, and then filtered through celite using ethyl acetate. The filtrate was washed with water (50 ml) and saturated brine (50 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2 → 1: 1) to obtain the title compound (120 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.73 (2H, br. S), 3.74 (2H, br. S), 4.01 (3H, s), 4.59 (2H, s).
MS (FAB) m / z: 283 (M + H) ^<+> .

[Step 10] Lithium salt of 5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridine-2-carboxylic acid (16-d)

Trifluoroacetic acid in a solution of 6,7-dihydrooxazolo [5,4-c] pyridine-2,5 (4H) -dicarboxylic acid 5- (tert-butyl) 2-methyl ester (500 mg) in methylene chloride (15 ml) (15 ml) was added at room temperature and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure, and methylene chloride (20 ml), triethylamine (0.495 ml), acetic acid (205 ml), formalin (0.230 ml) and sodium triacetoxyborohydride (570 mg) were brought to room temperature. Added. After stirring for 15 minutes, methylene chloride (20 ml) and saturated aqueous sodium hydrogen carbonate solution (50 ml) were added to the reaction mixture, and after separation, the aqueous layer was extracted with methylene chloride (3 × 20 ml). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1 → 10: 1) to obtain the title compound (257 mg).
¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H, s), 2.72-2.78 (2H, m), 2.78-2.83 (2H, m), 3.61 (2H , T, J = 1.7 Hz), 4.00 (3H, s).
^{MS (FAB) m / z:} 197 (M + H) +, 165 (M-OCH 3) +.

[Reference Example 35] 5-methyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazole-2-carboxylic acid lithium salt (16-e)
[Step 1] 5- (Phenylsulfonyl) -5,6-dihydro-4H-pyrrolo [3,4-d] thiazole

Under ice cooling, benzenesulfonamide (638 mg) and 4,5-bis (bromomethyl) thiazole (M. Al. Hariri, O. Galley, F. Paulet, H. Filion, Eur. J. Org. Chem. 1998, 593). -594.) (1.10 g) was dissolved in N, N-dimethylformamide (10 ml), sodium hydride (60% oily, 357 mg) was added at once and stirred at room temperature for 3 hours. Water and methylene chloride were added for liquid separation, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate = 9: 1) to give the title compound (137 mg) Got.
¹ H-NMR (CDCl ₃ ) δ: 4.60-4.63 (2H, m), 4.70-4.73 (2H, m), 7.52-7.64 (3H, m), 7 .88-7.92 (2H, m), 8.71 (1H, s).
MS (FAB) m / z: 267 (M + H) ^<+> .

[Step 2] 5,6-dihydro-4H-pyrrolo [3,4-d] thiazole dihydrobromide

A mixture of 5- (phenylsulfonyl) -5,6-dihydro-4H-pyrrolo [3,4-d] thiazole (800 mg), phenol (800 μl) and 47% aqueous hydrobromic acid (5.00 ml) was added for 2 hours. Heated to reflux. After cooling to room temperature, ethyl acetate and water were added for liquid separation, and the aqueous layer was evaporated under reduced pressure. Ethyl acetate was added to the residue, and the precipitate was collected by filtration and dried to give the title compound (521 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 4.42 (2H, br s), 4.56 (2H, br s), 9.14 (1H, s).
MS (FAB) m / z: 127 (M + H) ^<+> .

[Step 3] 5-Methyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazole

In the same manner as in [Step 4] in [Reference Example 32], the title compound was obtained from 5,6-dihydro-4H-pyrrolo [3,4-d] thiazole dihydrobromide.
¹ H-NMR (CDCl ₃ ) δ: 2.67 (3H, s), 3.95-3.99 (2H, m), 4.01-4.05 (2H, m), 8.69 (1H , S).
MS (ESI) m / z: 141 (M + H) ^<+> .

[Step 4] Lithium salt of 5-methyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazole-2-carboxylic acid (16-e)

In the same manner as in [Step 5] of [Reference Example 32], the title compound was obtained from 5-methyl-5,6-dihydro-4H-pyrrolo [3,4-d] thiazole.
¹ H-NMR (DMSO-d ₆ ) δ: 2.52 (3H, s), 3.73 (2H, t, J = 3.2 Hz), 3.87 (2H, t, J = 3.2 Hz) .

[Reference Example 36] 5-methyl-5,6,7,8-tetrahydro-4H-thiazolo [5,4-c] azepine-2-carboxylic acid lithium salt (16-f)
[Step 1] 5-[(4-Methylphenyl) sulfonyl] -5,6,7,8-tetrahydro-4H-thiazolo [5,4-c] azepin-2-ylamine

N, N-dimethyl of 3-bromo-1-[(4-methylphenyl) sulfonyl] -4-azepanone (J. Chem. Soc. Perkin Trans., 1995, 1, 2355) (6.54 g) To a formamide (100 ml) solution, thiourea (1.44 g) was added and stirred at 60 ° C. overnight. After the solvent was distilled off under reduced pressure, methylene chloride (100 ml) and a saturated aqueous sodium hydrogen carbonate solution (100 ml) were added to the residue for liquid separation. The aqueous layer was extracted with methylene chloride (100 ml), combined with the previously obtained organic layer, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and ethyl acetate (100 ml) was added to the resulting residue. The precipitated pale yellow powder was collected by filtration, and the crude product 5-[(4-methylphenyl) sulfonyl] -5,6, 7,8-Tetrahydro-4H-thiazolo [5,4-c] azepin-2-ylformamide (1.86 g) was obtained. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (methanol: methylene chloride = 1: 19) to give 5-[(4-methylphenyl) sulfonyl] -5,6,7,8-tetrahydro. A mixture (4.01 g) of -4H-thiazolo [5,4-c] azepin-2-ylformamide and the title compound was obtained. The mixture and the crude product were combined, suspended in dioxane (50 ml), 3N hydrochloric acid (50 ml) was added, and the mixture was heated to reflux for 1 hour. The solvent was distilled off under reduced pressure, methylene chloride (250 ml) and saturated aqueous sodium carbonate solution (200 ml) were added for liquid separation, the oil layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. Diisopropyl ether (100 ml) was added to the residue and the pale yellow powder precipitated was collected by filtration to obtain the title compound (4.47 g).
¹ H-NMR (CDCl ₃ ) δ: 1.75-1.87 (2H, m), 2.40 (3H, s), 2.62 (2H, t, J = 5.7 Hz), 3.53 (2H, t, J = 5.7 Hz), 4.37 (2H, s), 4.73 (2H, br. S), 7.25 (2H, d, J = 8.5 Hz), 7.61 (2H, d, J = 8.5 Hz).
MS (ESI) m / z: 324 (M + H) ^<+> .

[Step 2] 5,6,7,8-tetrahydro-4H-thiazolo [5,4-c] azepin-2-ylamine hydrobromide

5-[(4-Methylphenyl) sulfonyl] -5,6,7,8-tetrahydro-4H-thiazolo [5,4-c] azepin-2-ylamine and [Step 2] of [Reference Example 35] The title compound was obtained in the same manner.
¹ H-NMR (DMSO-d ₆ ) δ: 1.95 (2H, br.s), 2.70-2.90 (2H, m), 3.38 (2H, br.s), 4.56 (2H, br. S), 9.07 (3H, br. S).
MS (ESI) m / z: 170 (M + H) ^<+> .

[Step 3] 5-Methyl-5,6,7,8-tetrahydro-4H-thiazolo [5,4-c] azepin-2-ylamine

5,6,7,8-Tetrahydro-4H-thiazolo [5,4-c] azepin-2-ylamine Hydrobromide (2.73 g) was suspended in methanol and triethylamine was added to the suspension under ice cooling. (2.30 ml), acetic acid (453 μl), 37% aqueous formaldehyde solution (668 μl) and sodium cyanoborohydride (544 mg) were added. After stirring at room temperature overnight, a saturated aqueous sodium hydrogen carbonate solution (20 ml) was added and concentrated to dryness. The residue was purified by silica gel chromatography (methanol: methylene chloride = 3: 17). Methanol (100 ml) and anhydrous sodium carbonate (20 g) were added to the obtained crude product, and the mixture was stirred at room temperature for 30 minutes, and insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, methylene chloride (250 ml) and methanol (50 ml) were added to the residue, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting pale yellow powder was washed with acetonitrile (100 ml) to give the title compound (1.23 g).
¹ H-NMR (CDCl ₃ ) δ: 1.70-1.85 (2H, s), 2.38 (3H, s), 2.77 (2H, t, J = 5.6 Hz), 2.97 (2H, t, J = 5.6 Hz), 3.65 (2H, s), 4.68 (2H, br. S).
MS (ESI) m / z: 184 (M + H) ^<+> .

[Step 4] 2-Bromo-5-methyl-5,6,7,8-tetrahydro-4H-thiazolo [5,4-c] azepine

5-Methyl-5,6,7,8-tetrahydro-4H-thiazolo [5,4-c] azepin-2-ylamine (1.13 g) was suspended in water (10 ml) and 48% aqueous hydrobromic acid solution (7.0 ml) was added and stirred under ice cooling. An aqueous solution (3.0 ml) containing sodium nitrite (639 mg) was carefully added dropwise to the reaction solution. After completion of the dropwise addition, this suspension was stirred overnight at room temperature. Under ice-cooling, methylene chloride (100 ml) was added to the reaction mixture, and the mixture was stirred and neutralized with a saturated aqueous sodium carbonate solution. After separation, the aqueous layer was extracted with methylene chloride (100 ml), and the organic layers were combined and dried over anhydrous sodium sulfate. Purification by silica gel chromatography (methanol: methylene chloride = 3: 47) gave the title compound (582 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.70-1.85 (2H, s), 2.38 (3H, s), 2.95-3.05 (4H, m), 3.79 (2H , S).
MS (ESI) m / z: 247 (M + H) ^<+> .

[Step 5] 5-methyl-5,6,7,8-tetrahydro-4H-thiazolo [5,4-c] azepine-2-carboxylic acid lithium salt (16-f)

The title compound is obtained from 2-bromo-5-methyl-5,6,7,8-tetrahydro-4H-thiazolo [5,4-c] azepine in the same manner as in [Step 5] of [Reference Example 32]. It was.
¹ H-NMR (DMSO-d ₆ ) δ: 1.65 (2H, br.s), 2.23 (3H, s), 2.80-2.97 (4H, m), 3.75 (2H , S).

[Reference Example 37] 6-methyl-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d] azepine-2-carboxylic acid lithium salt (16-g)
[Step 1] 6-Methyl-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d] azepin-2-ylamine

In the same manner as described in [Step 3] of [Reference Example 32], 5,6,7,8-tetrahydro-4H-thiazolo [4,5-d] azepin-2-ylamine (JP-A-2- No. 45489) gave the title compound.
¹ H-NMR (CDCl ₃ ) δ: 2.44 (3H, s), 2.66-2.69 (2H, m), 2.71 (4H, s), 2.80-2.83 (2H M), 4.66 (2H, s).
MS (ESI) m / z: 184 (M + H) ^<+> .

[Step 2] 2-Bromo-6-methyl-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d] azepine

From 6-methyl-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d] azepin-2-ylamine in the same manner as described in [Step 4] of [Reference Example 32]. The title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H, s), 2.66-2.72 (4H, m), 2.85-2.88 (2H, m), 3.03-3 .06 (2H, m).
MS (ESI) m / z: 247 (M + H) ^<+> .

[Step 3] 6-methyl-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d] azepine-2-carboxylic acid lithium salt (16-g)

The title compound is obtained from 2-bromo-6-methyl-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d] azepine in the same manner as in [Step 5] of [Reference Example 32]. It was.
¹ H-NMR (DMSO-d ₆ ) δ: 2.33 (3H, s), 2.56-2.63 (4H, m), 2.77-2.93 (4H, m).
MS (ESI) m / z: 213 (M + H) ^<+> .

[Example 1] (1S, 3R, 4S) -4-amino-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester 1 oxalate (17a)

Using a 50 ml four-necked flask as a reaction vessel, (1S, 3R, 4R) -4-methanesulfonyl-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester (10 g, 27.4 mmol) (5) , Tetrabutylammonium chloride (2.27 g, 13.7 mmol), sodium azide (3.56 g, 54.9 mol) and N-methyl-2-pyrrolidone (20 ml) were added. This suspension was stirred at an internal temperature of 60 ° C. for 60 hours. The reaction mixture was cooled to room temperature, ethyl acetate (75 ml) and water (75 ml) were added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 ml), combined with the previous organic layer, and washed with 5 wt% aqueous sodium hydrogen carbonate solution (100 ml) and then with water (50 ml) three times. Ethanol (100 ml) was added to the obtained organic layer, and 7.5% -Pd-C (manufactured by Kawaken Chemical: Type PH) (1.5 g) and ammonium formate (3.80 g) were sequentially added under stirring. In addition, the mixture was heated to an internal temperature of 50 ° C. and stirred for 1 hour. The reaction solution was cooled to room temperature (about 25 ° C.), Pd—C was filtered off with a glass filter, and Pd—C removed with ethanol (20 ml) was washed. The filtrate was concentrated to 53.86 g and the concentrated residue was dissolved in ethyl acetate (50 ml). This solution was added dropwise to a solution of oxalic acid (2.63 g, 20.9 mmol) in ethyl acetate (50 ml) at room temperature with stirring. The mixture was stirred for 3 hours, and the precipitated crystals were collected by filtration and washed with ethyl acetate (5 ml). The crystals were dried under reduced pressure to give the title compound (17a) (7.59 g, yield 73.4%) as a mixture with the isomer (20a) (4.5% as HPLC area%).
MS (ESI) m / z: 287 (M-C 2 O 4 H) +;
¹ H-NMR (DMSO-d6) δ: 1.15 to 1.19 (3H, t, J = 7.3 Hz), 1.36 to 1.45 (10H, m), 1.58 to 1.67 (3H, m), 1.85 (2H, m), 2.71-2.77 (1H, m), 3.17-3.20 (1H, m), 4.02 (1H, br) 4 .05 (2H, q, J = 7.3 Hz), 7.06 (1H, d, J = 8.9 Hz).
The following conditions were used for the separation of the title compound (17a) and the isomer (20a) by HPLC.
Apparatus: Agilent 1100 series (DET: G1315A / PUMP: DE 9160762) or SHIMADZU CLASS-VP system (SCL10Avp / SCL-10AVP / SPD-M10AVP);
Column: CAPCELLPAK-CN UG120 (4.6 mm x 250 mm) analytical column;
Flow rate: 1.0 ml / min;
Elution solvent (Isocratic): 30% acetonitrile / 70% -20 mM phosphate buffer (pH 7.0; including 20 mM Sodium Dodecylsulfate);
Detection: UV (210 nm).
Retention time: title compound (17a) 21.0 min; isomer (20a) 23.3 min

Example 2 (1S, 3R, 4S) -4-Amino-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester 1 (DL) -malate (17b)

Using a 1 l four-necked flask as a reaction vessel, (1S, 3R, 4R) -4-methanesulfonyl-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester (5) (250 g, 0.68 mol) , Tetraethylammonium chloride (34.0 g, 0.20 mol), sodium azide (89 g, 1.36 mol) and N-methyl-2-pyrrolidone (0.5 l) were added. This suspension was stirred at an internal temperature of 60 ° C. for 60 hours. The reaction mixture was cooled to room temperature, ethyl acetate (1.88 l) and water (1.88 l) were added, and the organic layer was separated. The aqueous layer was extracted again with ethyl acetate (0.63 l), combined with the previous organic layer, and washed 3 times with 5% aqueous sodium hydrogen carbonate solution (2.5 l) and water (1.25 l).
The obtained ethyl acetate solution was concentrated to 0.75 l, ethanol (1.75 l) was added thereto, and the mixture was concentrated under reduced pressure to 0.75 l (this operation was performed twice). Ethanol was added to the concentrated residue to adjust the total volume to 1.5 l. While stirring, 7.5% -Pd-C (manufactured by Kawaken Chemical: Type PH) (37.5 g) and ammonium formate (95 g) were sequentially added to the solution, and the mixture was heated to an internal temperature of 40 ° C. Stir for hours. The reaction mixture was cooled to room temperature (about 25 ° C.), Pd—C was filtered off with a glass filter, and the filtered Pd—C was washed with ethanol (0.5 l). The filtrate was concentrated to 0.75 l, acetonitrile (1.75 l) was added and concentrated to 0.75 l (this operation was repeated twice). Acetonitrile was added to the concentrated residue to make a total volume of 1.5 l. To this solution, (DL) -malic acid (66 g, 0.71 mol) was added at an internal temperature of about 30 ° C., and the solution was cooled stepwise with an internal temperature of 20 ° C. for 1 hour and an internal temperature of 10 ° C. for 1 hour. Finally, the mixture was stirred at an internal temperature of 0 ° C. or lower for 2 to 4 hours. The precipitated crystals were filtered and washed with 0.25 liters of cooled acetonitrile. The obtained crystals were dried at 40 ° C. under reduced pressure to give the title compound (17b) (223 g, yield 77.6%) as a mixture with the isomer (0.86% in HPL area%). It was.
¹ H-NMR (DMSO-d6) δ: 1.15 to 1.19 (3H, t, J = 7.1 Hz), 1.39 to 1.49 (10H, m), 1.58 to 1.66 (3H, m), 1.84-1.87 (2H, m), 2.29 (dd, J = 15.5, 3.6 Hz) 2.47-2.54 (2H, m) 2.71 -2.77 (1H, m), 3.17-3.20 (1H, m), 3.84-3.91 (1H, m), 4.02 (1H, br) 4.07 (2H, q, J = 7.3 Hz), 7.02 (1H, d, J = 8.9 Hz).

[Example 3] (1S, 3R, 4S) -4-amino-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester 1 (L) -malate (21)

Using a 100 ml four-necked flask as a reaction vessel, (1S, 3R, 4R) -4-methanesulfonyl-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester (5) (20 g, 54.7 mmol), Tetraethylammonium chloride (4,54 g, 27.4 mmol), sodium azide (7.12 g, 109.4 mol) and N-methyl-2-pyrrolidone (40 ml) were added. This suspension was stirred at an internal temperature of 60 ° C. for 66 hours. The reaction mixture was cooled to room temperature, ethyl acetate (150 ml) and water (150 ml) were added, and the organic layer was separated. The aqueous layer was extracted again with ethyl acetate (50 ml), combined with the previous organic layer, and washed 3 times with 5% aqueous sodium hydrogen carbonate solution (200 ml) and then with water (100 ml).
The obtained ethyl acetate solution was concentrated to 30 ml, concentrated residue ethanol (100 ml) was added, and the whole amount was concentrated to 60 ml (this operation was performed twice). Ethanol was added to the concentrated residue to adjust the total volume to 200 ml. To this solution, 7.5% -Pd-C (manufactured by Kawaken Chemical: Type PH) (3.0 g) and ammonium formate (7.59 g) were sequentially added while stirring, and the mixture was heated to an internal temperature of 40 ° C. Stir for 1 hour. The reaction mixture was cooled to room temperature (about 25 ° C.), Pd—C was filtered off with a glass filter, and Pd—C filtered with ethanol (40 ml) was washed. The filtrate was concentrated to 60 ml, acetonitrile (140 ml) was added to the concentrated residue, and the filtrate was concentrated to 60 ml under reduced pressure (this operation was repeated twice).
The concentrated acetonitrile solution was divided into two, and acetonitrile was added to half of the solution to make a total volume of 80 ml. A total amount of 80 ml acetonitrile solution was added to a 100 ml four-necked flask, and (L) -malic acid (3.06 g, 22.8 mmol) was added and stirred. The mixture was stirred at room temperature overnight so as to keep the precipitated crystals uniform, and then stirred at an internal temperature of 3 to 5 ° C. for 2 hours. The precipitated crystals were collected by filtration, washed with acetonitrile (10 ml) and dried under reduced pressure to give the title compound (21) (8.45 g, yield 73.5%) as an isomer (1.1% as HPLC area%). ).
¹ H-NMR (DMSO-d6) δ: 1.15 to 1.19 (3H, t, J = 7.1 Hz), 1.36 to 1.45 (10H, m), 1.58 to 1.67 (3H, m), 1.85 (2H, m), 2.30 (dd, J = 15.8, 4.1 Hz) 2.48-2.55 (2H, m) 2.71-2.77 (1H, m), 3.17-3.22 (1H, m), 3.85-3.89 (1H, m), 4.02 (1H, br) 4.07 (2H, q, J = 7.1 Hz), 7.04 (1H, d, J = 8.7 Hz).

[Example 4] (1S, 3R, 4S) -4-amino-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester 1 (D) -malate (22)

The remaining solution divided into two in [Example 3] above was adjusted to a total volume of 80 ml by adding acetonitrile, and added to a 100 ml four-necked flask. (D) -malic acid (3.06 g, 22.8 mmol) was added to the solution and stirred. The mixture was stirred at room temperature overnight so as to keep the precipitated crystals uniform, and then stirred at 3 to 5 ° C. for 2 hours. The precipitated crystals were collected by filtration, washed with acetonitrile (10 ml), and dried under reduced pressure to give the title compound (22) (8.57 g, yield 74.5%) as its isomer (HPLC area% as 0% by area). 31%).
¹ H-NMR (DMSO-d6) δ: 1.4-1.19 (3H, t, J = 7.3 Hz), 1.39-1.45 (10H, m), 1.58-1.67 (3H, m), 1.85 (2H, m), 2.29 (dd, J = 15.5, 3.6 Hz) 2.48-2.54 (2H, m) 2.71-2.77 (1H, m), 3.17-3.21 (1H, m), 3.84-3.91 (1H, m), 4.02 (1H, br) 4.07 (2H, q, J = 7.3 Hz), 7.02 (1H, d, J = 8.9 Hz).

Example ^5] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (ethoxycarbonyl) cyclohexyl] ethanediamide (2-a)

(1S, 3R, 4S) -4-amino-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester 1 (DL) -malate (17b) (10.0 g, 23.8 mmol), N -(5-Chloropyridin-2-yl) oxalamic acid ethyl ester (6.94 g, 26.2 mmol) and triethylamine (9.63 g, 95.2 mmol) in acetonitrile (40 ml) at an internal temperature of 65-70 ° C. Stir for hours. The reaction mixture was cooled to 40 ° C., water was added, and the mixture was stirred at an internal temperature of 30 to 40 ° C. for 1 hr, and extracted with toluene (70 ml). The extract was washed twice with water (30 ml), and toluene was concentrated under reduced pressure. The operation of adding acetonitrile (100 ml) to the obtained residue and concentrating under reduced pressure was performed twice, and the solvent was replaced with acetonitrile.
Acetonitrile was added to the acetonitrile solution of the obtained residue to prepare a total volume of 100 ml, methanesulfonic acid (11.4 g, 119 mmol) was added, and the mixture was stirred at 30 ° C. for 1 hour. Triethylamine (12.8 g, 126 mmol) was added to the reaction mixture and dissolved, and then 1-hydroxybenzotriazole (364 mg, 2.38 mmol), 5-methyl-4,5,6,7-tetrahydro-thiazolo [5, 4-c] pyridine-2-carboxylic acid hydrochloride (5.87 g, 25.0 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.01 g, 26.2 mmol) were added, Stir overnight at room temperature. Triethylamine (2.89 g, 28.6 mmol) was added to the reaction mixture, water (80 ml) was added, and the mixture was stirred at room temperature for 3 hr and at 3-5 ° C. for 4 hr. The precipitated crystals were filtered, washed successively with acetonitrile / water (1/1) (20 ml), water (20 ml) and acetonitrile / water (1/4) (20 ml), then dried and dried (2-a ) (11.0 g, 84.8% yield) was obtained as a mixture with the isomer (0.1% or less as HPLC area%).
The following conditions were used for separation by HPLC.
Apparatus: Agilent 1100 series (DET: G1315A / PUMP: DE 9160762) or SHIMADZU CLASS-VP system (SCL10Avp / SCL-10AVP / SPD-M10AVP);
Column: CAPCELLPAK-CN UG120 (4.6 mm x 250 mm) analytical column; flow rate: 1.0 ml / min;
Elution solvent (Isocratic): 35% acetonitrile: 65% -20 mM phosphate buffer (pH 7.0);
Detection: UV (220 nm).
Retention time: title compound (2-a) 13.9 min; isomer 14.7 min.
MS (ESI) m / z: 549 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ) δ: 1.26 to 1.29 (3H, t, J = 7.1 Hz), 1.61-1.78 (2H, m), 1.96-2.22 ( 4H, m), 2.45-2.64 (4H, m), 2.79-2.89 (2H, m) 2.94-2.96 (2H, m) 3.68-3.77 ( 2H, m), 4.65-4.68 (1H, m), 4.13-4.19 (2H, q, J = 7.1 Hz), 7.38 (1H, d, J = 8.7 Hz) ), 7.67-7.70 (1H, dd, J = 9.1, 2.4 Hz), 8.07 (1H, dJ = 7.9 Hz), 8.17 (1H, dJ = 8.7 Hz) , 8.31 (1H, dJ = 2.9 Hz), 8.31 (1H, s).

Example ^6] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (ethoxycarbonyl) cyclohexyl] ethanediamide (2-a)

(1S, 3R, 4S) -4-amino-3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid ethyl ester monooxalate (17a) (2.0 g, 5.31 mmol), N- (5- Chloropyridin-2-yl) oxalamic acid ethyl ester (1.48 g, 5.56 mmol) and triethylamine (3.44 ml, 26.55 mmol) were stirred in acetonitrile (10 ml) at an internal temperature of 65 to 70 ° C. for 8 hours. The reaction mixture was cooled to room temperature, ethyl acetate (16 ml) was added, and the organic layer was separated. The organic layer was washed successively with water (8 ml), 5% brine (6 ml) and saturated brine / 4% sodium bicarbonate solution (1/1) (12 ml), and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a residue.
The obtained residue was dissolved in acetonitrile (25 ml), methanesulfonic acid (1.53 g, 15.9 mmol) was added at room temperature, and the mixture was stirred for 4 hours. Triethylamine (1.737 g, 17.5 mmol) was added to the reaction mixture and dissolved, and then 1-hydroxybenzotriazole (72 mg, 0.53 mmol), 5-methyl-4,5,6,7-tetrahydro-thiazolo [ 5,4-c] pyridine-2-carboxylic acid hydrochloride (1.31 g, 5.58 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.12 g, 5.84 mmol). In addition, the mixture was stirred overnight at room temperature. Water (7.5 ml) was added to the reaction solution, triethylamine (0.65 g 6.37 mmol) was added, water (22.5 ml) was further added, and the mixture was stirred for 2 hours. The precipitated crystals were filtered, washed successively with acetonitrile / water (1/2) (7.5 ml), water (2.5 ml) and acetonitrile / water (4/1) (2.5 ml), then dried. The title product (2-a) (2.31 g, 85.3% yield) was obtained as a mixture of isomers (less than 0.1% as HPLC area%). The various spectrum data of this compound was consistent with the data of the compound prepared in [Example 5].

Example ^6a] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (carboxy) cyclohexyl] ethanediamide (3-a)

N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydroisoquinoline [5,4 -C] pyridin-2-yl) carbonyl] amino} -4- (ethoxycarbonyl) cyclohexyl] ethanediamide (2-a) (5.0 g, 9.1 mmol) was added to a 500 ml 4-necked flask and a 6N aqueous hydrochloric acid solution ( 50 ml), and the mixture was stirred at an internal temperature of 18 ° C. for 17 hours. The reaction mixture was cooled, 4N aqueous sodium hydroxide solution (50 ml) was added at an internal temperature of 20 ° C. or lower, and methanol (60 ml) was added to make a homogeneous solution. Further, 4N aqueous sodium hydroxide solution was added to adjust the pH to 3.78 (using 15-25 ml of 4N aqueous sodium hydroxide solution), and the mixture was stirred for 15 hours. The precipitated crystals were filtered, washed with water, washed with a small amount of methanol, and dried under reduced pressure at 40 ° C. to give the title compound (3-a) (3.41 g, yield 71.8%, HPLC area%). 99.3%).

Example ^7] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (hydrazinocarbonyl) cyclohexyl] ethanediamide (4-a)

N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydroisoquinoline [5,4 -C] pyridin-2-yl) carbonyl] amino} -4- (ethoxycarbonyl) cyclohexyl] ethanediamide (2-a) (15.0 g, 27.3 mmol) to dimethyl sulfoxide (150 ml) and 8N (8N) Sodium hydroxide aqueous solution (10.25 ml) was added, and the mixture was stirred at an internal temperature of 30 ° C. for 3 hours. The reaction mixture was cooled to 8 ° C., concentrated hydrochloric acid (9.34 ml) and hydrazine hydrate (3.32 ml, 68.3 mmol) were added, and then adjusted to around pH 9.4 with concentrated hydrochloric acid. To this was added acetonitrile (75 ml), 1-hydroxybenzotriazole monohydrate (2.09 g, 13.6 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (6.81 g, 35 0.5 mmol) was added, and the mixture was stirred at an internal temperature of 20 ° C. (An aqueous 8N sodium hydroxide solution was added to keep the pH of the reaction solution at 7.7 to 8.3 during stirring). The reaction mixture was stirred overnight, then cooled to an internal temperature of 8 ° C., 8N aqueous sodium hydroxide solution (3.4 ml) was added, and the mixture was stirred for 1 hr. Water (75 ml) was added to the reaction mixture, and the mixture was stirred for 2 hours. The precipitated crystals were filtered, washed with water (75 ml), and dried under reduced pressure to give the title compound (4-a) (13.3 g).
MS (ESI) m / z: 535 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ) δ: 1.64-1.70 (3H, m), 1.79-1.88 (1H, m), 2.01-2.13 (4H, m), 2 .36-2.43 (1H, m), 2.52 (3H, s) 2.78-2.90 (2H, m) 2.92-2.95 (2H, m), 3.67-3 .77 (2H, dd, J = 15.5, 10.5 Hz), 4.07-4.12 (1H, m), 4.66-4.69 (1H, m), 6.96 (1H, s), 7.39-7.41 (1H, d, J = 8.3 Hz), 7.67-7.70 (1H, ddJ = 8.9, 2.6 Hz), 8.06 (1H, dJ) = 7.6 Hz), 8.16 (1H, dJ = 8.3 Hz), 8.31 (1H, d, J = 2.6 Hz).

Example ^8] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4- (hydrazinocarbonyl) cyclohexyl] ethanediamide (4-a)

N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydroisoquinoline [5,4 -C] pyridin-2-yl) carbonyl] amino} -4- (ethoxycarbonyl) cyclohexyl] ethanediamide (2-a) (30.0 g, 54.9 mmol) was added with 6N aqueous hydrochloric acid (300 ml), and an internal temperature of 18 Stir at 17 ° C. for 17 hours. The reaction mixture was cooled, 6N aqueous sodium hydroxide solution (150 ml) was added, acetonitrile (600 ml) was added, and 6N aqueous sodium hydroxide solution (70 ml) was further added. Hydrazine hydrate (6.7 ml, 137 mmol) was added to the reaction mixture with stirring, and a 6N aqueous sodium hydroxide solution was added to adjust the pH to 7.0, followed by 1-hydroxybenzotriazole (2.2 g, 16. 3 mM) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (11.6 g, 60.5 mmol) were added. Furthermore, 6N aqueous sodium hydroxide solution was added to the reaction mixture with stirring to adjust the pH to 7.2. During this time, the pH decreased with the precipitation of crystals, so a 6N aqueous sodium hydroxide solution was added to adjust the pH to 6.4 to 7.2, and the mixture was stirred at room temperature for 20 hours. The precipitated crystals were filtered, washed with water (300 ml) and acetonitrile (90 ml), and dried under reduced pressure to obtain the title product (23.6 g). Various spectral data of this compound were consistent with those prepared in [Example 6].

Example ^9] N 1 - (5- ^{chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydrothiazolo Zolo [5,4-c] pyridin-2-yl) carbonyl] amino} -4-([1,3,4] oxadiazol-2-yl) cyclohexyl] ethanediamide (1-a)

N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydroisoquinoline [5,4 -C] pyridin-2-yl) carbonyl] amino} -4- (hydrazinocarbonyl) cyclohexyl] ethanediamide (4-a) (8.0 g, 15.0 mmol) to dimethylacetamide (40 ml) and triethyl orthoformate (16 ml) ) And 47% boron trifluoride-tetrahydrofuran hydrate (6.30 g, 45 mmol) were added, and the mixture was stirred at an internal temperature of 45 to 50 ° C. for 2 hours. Triethylamine (5.31 g, 52.5 mol) and 82 ml of ethanol (16 ml) were added to the reaction solution, and the precipitated crystals were filtered, washed with water (80 ml), and dried under reduced pressure to give the title compound (7.65 g). )

Example ^10] N 1 - ^{(5-chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) 4- dimethylcarbamoyl-2 - {[(5-methyl -4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} -cyclohexyl] ethanediamide (1a-a)

N ¹ - ^{(5-chloropyridin-2-yl) -N 2 - [(1S,} 2R, 4S) -2 - {[(5- methyl-4,5,6,7-tetrahydroisoquinoline [5,4 -C] pyridin-2-yl) carbonyl] amino} -4- (ethoxycarbonyl) cyclohexyl] ethanediamide (2-a) (10.0 g, 18.2 mmol) in dimethyl sulfoxide (100 ml) and 8 N (8N) water. An aqueous sodium oxide solution (6.8 ml) was added, and the mixture was stirred at an internal temperature of 30 ° C. for 4.5 hours. After cooling the reaction mixture to 8 ° C., concentrated hydrochloric acid (6.25 ml) and 40% aqueous dimethylamine solution (5.8 ml, 45.5 mmol) were added, and then concentrated hydrochloric acid was added to bring the pH to around 9.4. It was adjusted. 1-hydroxybenzotriazole monohydrate (1.38 g, 0.91 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (4.54 g, 20.1 mmol) were added to the reaction mixture. And stirred at room temperature for 2 hours under a nitrogen atmosphere. To the reaction mixture, acetonitrile (50 ml), 40% aqueous dimethylamine solution (1.0 ml, 8.0 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.68 g, 20.1 mmol) And stirred overnight. Water (100 ml) and then 8N aqueous sodium hydroxide solution were added to the reaction mixture to adjust to pH = 9.0, and the mixture was stirred at an internal temperature of 8 ° C. for 3 hours. The precipitated crystals were filtered, washed with water (50 ml), and dried under reduced pressure to obtain the title product (9.11 g).
MS (ESI) m / z: 548 (M + H) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 1.62-1.72 (1H, qd, J = 12.8, 4.0 Hz), 1.77-1.87 (1H, m), 1.93- 1.96 (1H, m), 2.02-2.14 (3H, m), 2.52 (3H, s) 2.79-2.90 (5H, m) 2.95 (3H, s) 2.98-3.02 (1H, m), 3.06 (3H, s), 3.72 (2H, q, J = 8.0 Hz), 4.08-4.15 (1H, m) 4.67-4.70 (1 H, m), 7.41 (1 H, d, J = 7.6 Hz), 7.67-7.70 (1 H, dd, J = 8.8, 2.0 Hz) ), 8.05 (1H, d, J = 8.8 Hz), 8.30-8.31 (1H, d, J = 6.4 Hz), 9.7 (1H, s).

  The manufacturing method of this invention can be utilized as a manufacturing method of the compound (1a-a) its salt which is a FXa inhibitor, or those hydrates.

Claims (9)

The following formula (2)
(Wherein R ⁷ represents a linear or branched C1-C4 alkyl group;
Partial structure represented by the following formula
Represents a 5-chloro-2-pyridyl group;
Partial structure represented by the following formula
Represents a 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl group. The compound represented by formula (3) is hydrolyzed by the following formula (A) or (B):
(Wherein R ¹ , R ² , R ³ , R ⁴ , ring A and ring B are the same as described above.)
The manufacturing method of the compound represented by these.
(A) Acid hydrolysis using 4N (4N) or more hydrochloric acid aqueous solution, 4N (4N) or more sulfuric acid aqueous solution, or 4N (4N) or more phosphoric acid aqueous solution (B) in the presence of an aprotic polar solvent Alkaline hydrolysis using 5N (5N) or more sodium hydroxide aqueous solution, 5N (5N) or more potassium hydroxide aqueous solution or 5N (5N) or more lithium hydroxide aqueous solution The following formula (2)
(Wherein R ⁷ represents a linear or branched C1-C4 alkyl group;
Partial structure represented by the following formula
Represents a 5-chloro-2-pyridyl group;
Partial structure represented by the following formula
Represents a 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl group. The compound represented by the following formula (3) is obtained by hydrolyzing the compound represented by (A) or (B) below.
(Wherein R ¹ , R ² , R ³ , R ⁴ , ring A and ring B are the same as described above.)
Wherein the compound represented by formula (1a) is condensed with di (methyl) amine or a salt thereof in the presence of a condensing agent.
(Wherein R ⁸ and R ⁹ represent a methyl group, and R ¹ , R ² , R ³ , R ⁴ , ring A and ring B represent the same as described above.)
The manufacturing method of the compound represented by these.
(A) Acid hydrolysis using 4N (4N) or more hydrochloric acid aqueous solution, 4N (4N) or more sulfuric acid aqueous solution, or 4N (4N) or more phosphoric acid aqueous solution (B) in the presence of an aprotic polar solvent Alkaline hydrolysis using 5N (5N) or more sodium hydroxide aqueous solution, 5N (5N) or more potassium hydroxide aqueous solution or 5N (5N) or more lithium hydroxide aqueous solution In the step of producing compound (1a) from compound (2) via compound (3), compound (3) is isolated from compound (2) in the same reaction system (one pot) without isolating compound (3). The manufacturing method according to claim 2, wherein: R ⁷ is a methyl group or an ethyl group, a manufacturing method according to any one of claims 1 to 3. The manufacturing method of any one of Claims 1-4 whose acid used by acid hydrolysis is 4N (4N) or more hydrochloric acid aqueous solution. The manufacturing method of any one of Claims 1-4 whose acid used by acid hydrolysis is 6 N (6N) or more hydrochloric acid aqueous solution. The manufacturing method of any one of Claims 1-4 whose alkali used by alkali hydrolysis is a 5N (5N) or more sodium hydroxide aqueous solution. The manufacturing method of any one of Claims 1-4 whose alkali used by alkali hydrolysis is 8N (8N) or more sodium hydroxide aqueous solution. The aprotic polar solvent is N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, or dimethyl sulfoxide, according to any one of claims 1 to 4 and 7 to 8. Manufacturing method.