TW200909437A - Process for the preparation of diamine-derivatives - Google Patents

Abstract

The present invention provides an industrial process for preparing the compound (1) and (1a), which is useful as a inhibitor of activated blood clotting X factor. The industrial process for preparing the compound (1) and (1a) useful as a inhibitor of activated blood clotting X factor, the process is characterized by the following [process a] to [process c] [wherein, R1 represents a hydrogen atom or a halogeno group etc., R2 represents a hydrogen atom or a halogeno group etc., R3 and R4 maybe the same or different, each represents a hydrogen atom or a C1-C4alkyl group, R5 represents a hydrogen atom or a formyl group, R6 represents a hydrogen atom or a methyl group, R8 and R9 maybe the same or different, each represents a methyl group or an ethyl group, Ring A represents pyridine ring etc., Ring B represents 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine etc.].

Description

200909437 IX. Description of the Invention: [Technical Field] The present invention relates to a compound which exhibits an inhibitory effect on activated blood coagulation factor X (FXa) and is useful as a prophylactic or therapeutic drug for thrombotic and/or embolic diseases. Industrial production method. [Prior Art] The following compounds (1 and 1 a) are compounds which are useful as a prophylactic/therapeutic agent for thrombotic and/or embolic diseases, as shown in Patent Document 1 or Patent Document 3, which exhibits an inhibitory action against FXa.

(wherein R1 is a hydrogen atom, a halogen group, a linear or branched chain C1 to C4 alkyl group, a linear or branched chain C1-C4 alkoxy group or a nitro group; and R2 is a hydrogen atom; a halogenated, linear or branched chain C1~C4 alkyl group or a linear or branched chain C1-C4 alkoxy group; R3 and R4 may be the same or different as a hydrogen atom or a linear chain or a minute Branched C1~C4 alkyl; R6 is methyl or ethyl; R7 is linear or branched chain C 1~C4 alkyl; R8 and R9 may be the same or different methyl or ethyl; Ring A is a benzene ring, a thiophene ring or a pyridine ring; the ring ^ is 4.5.6.7-tetrahydrothiazolo[5,4-c]pyridine ring, 4,5,6,7-tetrahydrocarbazo[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] Anthraquinone ring or 5,6-dihydro-4H-pyrrolo[3,4-d]thiazole ring). In the conventional method of the compound (1), a compound of the [1,3,4] anthracene derivative (ln) is produced from the carboxylic acid derivative, that is, the compound (9), as shown in the following [Scheme A]. The latter two kinds of guanamine bonds, the total yield of the compound (1) based on the compound (5) is 4 1.2 %. The method of the present invention builds the [1,3,4 ] oxadiazole ring at the initial stage. The engineering of removing the protecting group of the amine group by acid treatment, and the engineering of constructing the diamine moiety, accompanied by the decomposition of the [丨, 3, 4] azeotropic ring, and the yield reduction and quality reduction of the reaction engineering Problem [Process A]

200909437

Oxycarbonyl; R4° is a hydrogen atom, a linear or branched chain of a Cl~C4 alkyl group or an alkali metal (alkali metal cation); R7° is a hydrogen atom or an alkali metal (alkali metal cation); R9 is a linear chain C1~C4 alkyl group in the form of a branched or branched chain: R1, R2, R3, R4, R6, ring A and ring B are as defined above). Further, the carboxylic acid derivative, that is, the compound (3) (see Patent Document 2) and the di(alkyl)aminocarbazinyl derivative (the compound Ua) (see Patent Document 3) have a report showing the FXa inhibitory action. Conventionally, the compound (3) is produced by deprotecting a compound (2a) which is a 2,2,2-trichloroethyl ester derivative as shown in [Scheme B]. The reason for the use of a special ester is that in addition to the ester which can be deprotected under mild conditions such as 2,2,2-trichloroethyl ester (2a), the hydrolysis is accompanied by the decomposition of the 2 amide side chain of the compound (2a), and the yield Greatly reduced. However, the synthesis of 2,2,2-trichloroethyl ester in compound (3) is not suitable. Further, a method of producing the compound (3) from a compound (2) which is a linear or branched chain C1 to C4 alkyl ester derivative such as a methyl ester or an ethyl ester is more unknown. Further, since the production of the carboxylic acid derivative (3) is difficult, it is not known that the carboxylic acid derivative (3) is a compound of the compound (1 a) which is a di(alkyl)aminocarbamyl derivative, which is industrially produced. 200909437 [Scheme B]

, R4, ring A and ring B are the same as above). [Patent Document 1] International Publication No. 2004/0587 No. 5 Booklet [Patent Document 2] International Publication No. 2003/01 6302 Booklet [Patent Document 3] International Publication No. 2003/000680 Booklet [Invention Content]. (Problem to be Solved by the Invention) The object of the present invention is to solve the problem of the manufacturing process shown in International Publication No. 2004/05 87 15 5, and to provide the compound (1) useful as an FXa inhibitor. The manufacturing method and the industrial new method of providing FXa inhibitor (la) are the subject.

(In the formula, R1, R2, R3, R4, R7, R8, and R9, and the ring A and the ring B are the same as the above) 200909437 (Means for Solving the Problem) The inventors of the present invention have conducted a review of the results and found that the compound of the anthracene derivative (4) In the aprotic polar solvent, in the presence of Lewis acid, 'treated with orthoformate or n-acetate, compound U) is obtained in high yield. It has also been found that the linear or branched chain C1~C4 alkyl ester body (2) is treated in a relatively high concentration aqueous hydrochloric acid solution, an aqueous sulfuric acid solution or an aqueous phosphoric acid solution, or in the coexistence of an aprotic polar solvent. When the treatment is carried out in comparison with a high concentration aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution or an aqueous lithium hydroxide solution, the decomposition of the side chain of the indoleamine is avoided, and the compound (3) of the carboxylic acid derivative is obtained in high yield. Further, it was found that the linear or branched chain C1 to C4 alkyl ester body (2) is hydrolyzed, and the compound (3) of the obtained carboxylic acid derivative is condensed with an anthracene derivative, and the obtained compound (4) is aprotic. In a polar solvent, in the presence of a Lewis acid, treatment with n-formic acid vinegar or n-acetate can produce a compound (丨) in high yield, and at the same time, find a compound (3) which is a possible carboxylic acid derivative by industrial production. The present invention has been accomplished by a new industrial process for the compound (la). That is, the present invention provides: [1] a compound of the following formula (4)

(wherein R1 is a hydrogen atom, a halogen group, a linear chain or a branched chain; alkane-10-200909437 group, halogenated Cl~C4 alkyl group, linear or branched chain Cl~C4 alkane Oxygen or nitro; R2 is a hydrogen atom, a halogen group, a linear or branched chain C1 to C4 alkyl group or a linear or branched chain C1-C4 alkoxy group; R3 and R4 may be the same Or a hydrogen atom or a linear or branched chain C1 to C4 alkyl; R5 is a hydrogen atom or a fluorenyl group;

Partially constructed ring A

a benzene ring, a thiophene ring or a pyridine ring; a partially constructed ring B

Is 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), treated with orthoformate or n-acetate in the presence of a Lewis acid in an aprotic polar solvent The following is a method for preparing a compound of the following formula (1)?

200909437 (wherein 116 is a hydrogen atom or a methyl group, 1^, 1^2, 113, 114, ring VIII and ring 8 are the same as described above). Further, the present invention provides the following methods of [2] to [32]. [2] A compound of the following formula (2)

(wherein R1 is a hydrogen atom, a halogen group, a linear or branched chain C1-C4 alkyl group, a halogen C1-C4 alkyl group, a linear or branched chain C1 to C4 alkoxy group or a nitrate Base: R2 is a hydrogen atom, a crypto group, a linear or branched chain C1~C4 courtyard group or a linear or branched chain CbC4 alkoxy group; R3 and R4 may be the same or different hydrogen a C1~C4 alkyl group having an atomic or linear or branched bond; R7 is a linear or branched chain C1 to C4 alkyl group;

Partially constructed ring A

a benzene ring, a thiophene ring or a pyridine ring; a partially constructed ring B

Is 4,5,6,7-tetrachloroindeno[5,4-cmt, 4,5,6,7•tetrahydroindeno[5,4-c]pyridine ring, 5,6, 7,8-tetrahydro-4H-thiazolo[4,5_d]n丫gyne ring, -12- 200909437 5,6,7,8-tetrahydro-4H-salzolo[4,5-c]吖Method for producing a compound of the following formula (3) by hydrolysis of a heptane ring or a 5,6-dihydro-4H-pyrrolo[3,4-d]thiazole ring)

(wherein R1, R2, R3, R4, ring A and ring B are the same as defined above). [3] The compound of the following formula (2) CCXR7

(wherein R1 is a hydrogen atom, a halogen group, a linear or branched chain C C4 alkyl group, a halogen C1 to C4 alkyl group, a linear or branched chain C1 to C4 alkoxy group or a nitrate R2 is a hydrogen atom, a halogen group, a linear or branched chain C1~C4 courtyard group or a linear or branched chain C1~C4 alkoxy group; R3 and R4 may be the same or different hydrogen An atomic or linear or branched chain C1 to C4 alkyl; R7 is a linear or branched chain C1 to C4 alkyl;

Partially constructed ring A

a benzene ring, a thiophene ring or a pyridine ring; -13- 200909437

Partially constructed ring B© is 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine ring, 4,5,6,7-tetrahydroindeno[5,4-c]pyridine Cyclo, 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine ring, 5,6,7,8-tetrazole-411-reservo[4,5- a compound of the following formula (3) obtained by hydrolysis of €]^' (/heptane ring or 5,6-dihydro_4^^-diazolo[3,4-d]thiazole ring)

υ (wherein R1, R2, R3, R4, cyclic oxime and cyclic oxime are as defined above) are condensed with an anthracene derivative in the presence of a condensing agent to give a compound of the following formula (4)

XJ

(wherein R5 is a hydrogen atom or a carbenyl group, R1, R2, R3, R4, ring A and ring B are the same as defined above)' in an aprotic polar solvent, in the presence of a Lewis acid, orthoformate Or a positive acetate treatment is a method of preparing a compound of the following formula (1). -14- 200909437

(wherein R6 is a hydrogen atom or a methyl group; R1, R2, R3, R4, ring A and ring B are the same as defined above). [4] In the process of producing the compound (4) from the compound (2) by the compound (3), the compound (3) is not isolated from the same reaction system (one-pot) (one p〇t) from the compound ( 2) The method for producing the compound (4) is described in [3]; [5] The method described in [1] or [3] wherein R5 in the compound (4) is a hydrogen atom; [6] The hydrazine derivative is hydrated. The method described in [1] or [3]; [7] The condensing agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (water-soluble carbodiimide) Or N,N-dicyclohexylcarbodiimide according to the method described in [1] or [3]; [8] The condensing agent is 1-ethyl-3-(3-dimethylaminopropyl)carbamate The imine hydrochloride (water-soluble carbodiimide) is prepared by [1] or [3]; [9] Lewis acid is boron trifluoride-solvent complex [1] or [3] [Method] [10] The boron trifluoride-solvent complex is a boron trifluoride-tetrahydrofuran complex compound according to the method described in [1] or [3]; [1 1] the aprotic polar solvent is ruthenium, Ν-dimethylformamide, hydrazine, hydrazine-dimethylacetamide, hydrazine-methyl-2-pyrrolidone or dimethyl hydrazine ρ] or [3] Method -15- 200909437 [12] Orthoformate or n-acetate is trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate or triethyl orthoacetate [1] or [3] [13] The method described in [1] or [3] wherein orthoformate or orthoacetate is trimethyl orthoformate or triethyl orthoformate; [1 4] a compound of the following formula (2)

(wherein R1 is a hydrogen atom, a halogen group, a linear or branched chain C1 to C4 alkyl group, a halogen C1 to C4 alkyl group, a linear or branched chain C1 to C4 alkoxy group or a nitrate R2 is a hydrogen atom, a halogen group, a linear or branched chain C1 to C4 alkyl group or a linear or branched chain C1 to C4 alkoxy group; R3 and R4 may be the same or different hydrogen Aromatic or linear or branched chain C1~C4 alkyl; R7 is a linear or branched chain C1~C4 alkyl;

Partially constructed ring A

a benzene ring, a thiophene ring or a pyridine ring; a partially constructed ring B

Is 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine ring, 4,5,6,7-tetrahydrocarbazol-16 - 200909437 [5,4-c]pyridinium Ring, 5,6,7,8-tetrahydro-4H-thiazino[4,5-d]azepinidine, 5,6,7,8-tetrahydro-4H-thiazolium [4, 5-c] anthracene ring or 5,6-dihydro·4Η-pyrrolo[3,4-d]thiazole ring), hydrolyzed, resulting in a compound of the following formula (3)

(Formula wherein R1, R2, R3, R4, Ring A and Ring B are the same as defined above), and a compound of the following formula (la) wherein a compound is condensed with a dialkylamine in the presence of a condensing agent

(wherein R8 and R9 may be the same or different from a methyl group or an ethyl group, rI, r2, r3, R4, ring A and ring B are the same as defined above). [1 5] In the process of producing the compound (1 a) from the compound (2) via the compound (3), the compound (3) is produced in the same reaction system (single pot) from the compound (2) (la) is a method described in [14]; [16] R7 is a methyl or ethyl group according to any one of [2], [3], and [14]. [17] R8 and R9 are Process for the preparation of methyl [14]; -17- 200909437 [18] The hydrolysis of the compound (3) produced by the compound (2) is acid hydrolysis of any of [2], [3] and [14] The method for preparing the method; [1] The acid used in the acid hydrolysis is a method described in [18] of an aqueous hydrochloric acid solution, an aqueous sulfuric acid solution or an aqueous phosphoric acid solution; [20] the acid is an aqueous solution of 4 equivalents (4N) or more of hydrochloric acid [18]. [21] The method described in [18] wherein the acid is 6 equivalents (6N) or more of aqueous hydrochloric acid; [22] The hydrolysis of the compound (3) produced by the compound (2) is coexistence with an aprotic polar solvent. The method described in any one of [2], [3], and [14]. [23] The base used in the alkali hydrolysis is a method described in [2 2] of an aqueous solution of sodium hydroxide, potassium hydroxide or lithium hydroxide; [24] a method described in [22] wherein the base is an aqueous solution of sodium hydroxide; 25] a method described in [22] wherein the base is a sodium hydroxide aqueous solution of 5 equivalents (5N) or more; [26] a method described in [22] wherein the base is an aqueous solution of 8 equivalents (8N) or more; [27] The aprotic polar solvent is N,N-dimethylformamide, hydrazine, hydrazine-dimethylacetamide, hydrazine-methyl-2-pyrrolidone or dimethyl hydrazine [22]~[26 The method of making any of the records. [28] Partial construction of equations (1), (ia), (2), (3) and (4)

Is 4-phenylphenyl, 4-diphenyl, 4-chlorophenyl, 4-chloro-3-tolyl, 4-chloro-2-fluorophenyl, 4-chloro-2-tolyl, 4-chloro 3-nitrophenyl, 4-chloro-2-nitrophenyl, 3,4-difluorophenyl, 4-chloro-3-fluorophenyl, 4-chloro-3-methoxyphenyl, -18- 200909437 4-Chloro-2-trifluoromethylphenyl, 4-chloro-2-methoxyphenyl, 5-bromo-2-pyridyl, 5-chloro-2-pyridyl, 5-methyl-2-pyridyl Or the method described in any one of [1], [2], [3], and [14] of 5-chloro-2-thiophenyl; [29] formula (1), (la), (2), Partial construction of 3) and (4)

The method described in any one of [1], [2], [3], and [14] of 5-chloro-2-pyridyl; [30] formula (1), (la), (2), Partial construction of 3) and (4)

Is 5-(Cl~C4 alkyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl, 5-(C1-C4 alkyl)-4,5, 6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl, 6-(C1~C4 alkyl)-5,6,7,8-tetrahydro-411-thiazolo[4, 5-(1)azepin-2-yl, 5-(Cl~C4 alkyl)-5,6,7,8-tetrahydro-41 thiazolo[4,5-(;]azepine-2 -yl or 5-(Cl~C4 alkyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl], [2], [3] and [14 a method of making any of the descriptions; [31] part of the structures of equations (1), (U), (2), (3), and (4)

Is 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl, 5-ethyl-4,5,6,7-tetrahydrothiazolo[5 , 4<]pyridin-2-yl, 5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl, 5-methyl-4,5, 6,7-tetrahydrocarbazolo[5,4-(:]lath-2-yl,6-methyl-5,6,7,8-tetrahydro-4^1-thiazepine [4, 5-(1]11丫heptan-2-yl, 5-methyl-5,6,7,8-tetrahydro-411-thiazolo[4,5-(:]azepin-2-yl or 5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl [1], -19- 200909437 [2], [3] and [14] a documented method; and part of the structure of [32] (1), (la), (2), (3), and (4)

Is 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl, any of [1], [2], [3], and [14] The method of recording the items. (Effect of the Invention) According to the present invention, the compound (1) which is useful as an inhibitor of activated blood coagulation factor X (FXa) can be produced from the compound (3) of a carboxylic acid derivative. As a result, the problem of the manufacturing process of the publication of the International Publication No. 2004/05 87 15 is solved, and the compound (1) which is useful as an inhibitor of the activated blood coagulation factor X can be solved by the compound (5). The yield was 59.6%, and the effect of improving productivity of about 42% was obtained in comparison with the conventional method (41.2%). Therefore, the process of the present invention is useful as an industrial process for the compound (1) of a diamine derivative. Further, a compound (la) which is useful as an FXa inhibitor is useful for a method of producing a compound (3) of a carboxylic acid derivative. [Embodiment] (Best Mode for Carrying Out the Invention) The present invention will be described in detail below. The halogen group in the present specification is a fluorine group, a chlorine group, a bromine group or an iodine group. A linear or branched chain C1 to C4 alkyl group is a linear or branched chain alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, or Butyl, second butyl, tert-butyl, and the like. The halogen C1 to C4 alkyl group is a linear or branched chain C1-C4 alkyl group having a substituent of the above halogen group, and the number of the halogen group may be one or two or more ' -20- 200909437 2 The types of the respective halogen groups may be the same or different. Specific examples of the halogen C1 to C4 alkyl group are fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, (1) ,1-difluoro)ethyl, (1,2-fluoro)ethyl, (2,2,2·trifluoro)ethyl, (1,1,2,2-tetrafluoro)ethyl, (1 , 1,2,2,2-pentafluoro)ethyl, 1-fluoropropyl, 1,1-difluoropropyl, 2,2-difluoropropyl, 3-fluoro-n-propyl, (3, 3,3-Difluoro)-n-propyl, 4-fluoro-n-butyl and 4,4,4-difluoro)-n-butyl. The linear or branched chain C1-C4 alkoxy group is a linear or branched chain alkoxy group having a carbon number of 1 to 4, such as a methoxy group, an ethoxy group or a n-propoxy group. Isopropoxy, n-butoxy, second butoxy, tert-butoxy and the like. The substituent of the present invention is explained below. R1 is a hydrogen atom, a halogen group, a linear or branched chain C1-C4 alkyl group, a linear or branched chain C1 to C4 alkoxy group or a nitro group. R1 is preferably a hydrogen atom, a fluorine 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; and R1 is a hydrogen atom, a fluorine group, a chlorine group or a bromine group; The group, methyl group, trifluoromethyl group and methoxy group are more preferred. R2 is a hydrogen atom, a halogen group, a linear or branched chain C1 to C4 alkyl group or a linear or branched chain C1 to C4 alkoxy group. R2 is preferably a hydrogen atom, a fluorine group, a chloro group, a bromo group, a methyl group, an ethyl group, a methoxy group or an ethoxy group; and R2 is a hydrogen atom, a fluorine group, a chlorine group, a bromine group, a methyl group and a methoxy group. Better. R3 and R4 may be the same or different in a hydrogen atom or a linear or branched chain C1-C4 alkyl group. R3 and R4 are preferably the same or different hydrogen atom, methyl group, ethyl group and isopropyl group; -21 - 200909437 R3 and R4 are preferably R3 as a hydrogen atom and R4 is a methyl group, an ethyl group or an isopropyl group. 〇R5 is a hydrogen atom or a fluorenyl group. R5 is preferably a hydrogen atom. R6 is a hydrogen atom or a methyl group. R6 is preferably a hydrogen atom. R7 is a linear or branched chain C1 to C4 alkyl group. R7 is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or t-butyl; R7 is more preferably methyl or ethyl. R8 and R9 may be the same or different as a methyl group or an ethyl group. R8 and R9 are more methyl.

Partially constructed ring A

It is a benzene ring, a thiophene ring or a pyridine ring. Ring A is preferably a benzene ring or a pyridine ring; a pyridine ring is more preferred.

Partially constructed ring B

Is 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-4-thiazolo[4,5-(:]azepine Ring or 5,6-dihydro-411-laloco[3,4-d]thiazole ring. Ring B is preferably 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine ring The production process of the present invention is described below. The compound (1) of Patent Document 1 can be produced from the compound (2) of a linear or branched chain C1 to C4 alkyl ester derivative as shown in the following [Scheme 1]. Carboxylic acid derivative-22- 200909437 Biological compound (3), which is condensed with an anthracene derivative to produce compound (4), in the presence of a Lewis acid in an aprotic polar solvent, orthoformate Or a positive acetate treatment to make.

Same as above). The details of [Engineering a]~[Engineering c] are as follows. [Engineering a]

This is a process for producing a compound (1) by subjecting the compound (2) to acid hydrolysis or base hydrolysis. (A) In the case of acid hydrolysis, the acid may be an aqueous hydrochloric acid solution, a sulfuric acid aqueous solution -23-200909437 or an aqueous phosphoric acid solution. The concentration of the acid to be used is preferably 4 or more (4N) or more, and more preferably 6 equivalents (6N) or more. The amount of the acid used is preferably 20 to 50 times the molar amount of the compound (2). The reaction temperature is 10 to 30 ° C in the reaction system, preferably 15 to 25 ° C. The reaction time is usually 20 hours. The method for purifying the produced compound (3) is to dilute with an organic solvent, and while controlling the temperature in the reaction system, the pH is adjusted by adding an aqueous alkali solution while stirring, and the crystals are collected by filtration to wash the crystals which are filtered, and dried. can. The organic solvent used for the dilution is preferably an alcohol solvent, particularly preferably methanol, ethanol or the like. 5倍量优选。 The amount of the solvent is preferably in the same amount as the aqueous acid solution used. The aqueous alkali solution is preferably added while maintaining the temperature in the reaction system at 20 ° C or lower. The amount of the aqueous alkali solution to be added is preferably in the range of pH 1 to 7, and more preferably in the range of pH 3 to 4. (B) In the case of alkaline hydrolysis, a hydrolysis reaction is carried out in the presence of an aprotic polar solvent. The aprotic polar solvent is preferably N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or dimethyl hydrazine. The aqueous alkali solution is preferably a hydroxide, a carbonate or a bicarbonate of an alkali metal or an alkaline earth metal, and sodium hydroxide, potassium hydroxide or the like is preferred. Further, a base can be used as an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide or an aqueous solution of lithium hydroxide, and an aqueous solution of sodium hydroxide is preferred. The concentration of the base to be used is preferably 5 equivalents (5N) or more, more preferably an aqueous solution having a concentration of 8 equivalents (8N) or more. The amount of the base to be used is preferably 2 to 10 moles per mole of the compound (2). The amount of the aprotic polar solvent to be used is preferably from 5 to 30 times by weight (% by weight) based on the compound (2). The reaction temperature is the temperature in the reaction system -24-200909437 10~30 °C, preferably 20~30 °C. The reaction time is usually about 3 hours. [Engineering b]

(wherein R1, R2, R3, R4, R5, ring A and ring B are the same as defined above). This project produces a compound (4) by condensing the compound (3) with an anthracene derivative. The hydrazine derivative is preferably hydrazine hydrate or hydrazine hydrate (hydrazine hydrate), and more preferably hydrated hydrazine (hydrazine hydrate). The amount of the anthracene derivative used is preferably in the range of -5 times the molar amount of the compound (3), and is preferably 2 to 3 times by mole. The condensing agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (water-soluble carbodiimide), hydrazine, hydrazine-dicyclohexylcarbodiimide, N, N-carbonyldiimidazole, or the like, is preferred, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (water-soluble carbodiimide) is preferred. . The amount of the condensing agent to be used is preferably in the range of -3 times the molar amount of the compound (3) by a stoichiometric amount of -3 times the molar amount. The reaction solvent is not limited, and may be a halogenated hydrocarbon solvent such as dichloromethane, a hydrocarbon solvent such as toluene, an ether solvent such as tetrahydrofuran or a nitrile solvent such as acetonitrile or N,N-dimethylformamide. An aprotic polar solvent such as N,N-dimethylacetamide, N-methyl-2-pyrrolidone or dimethyl arsenate, or a solvent may be used in combination with water. The solvent is a nitrile solvent such as acetonitrile, a nitrile solvent such as 10 to 20% aqueous acetonitrile, and 10 to 20% aqueous N,N-dimethylacetamide solvent, and 10 to 20% aqueous dimethyl hydrazine solvent. Iso-aqueous aprotic-25-200909437 A polar solvent is preferred. Further, in order to promote the reaction, the pH in the reaction system is maintained at 6.0 to 8.5, preferably in the range of 6 to 4 to 8.3, and a base may be added. The base to be added is an organic amine base such as triethylamine, N-methylmorpholine or 4-(N,N-dimethylamino)pyridine or an alkali metal or an alkali earth metal hydroxide, carbonate or heavy An aqueous solution of a carbonate, a nitrile solvent such as acetonitrile containing water, and 10 to 20% of aqueous N,N-dimethylacetamide. If a solvent of 10 to 20% aqueous dimethyl hydrazine is used, the aqueous solution of hydrogen hydroxide is hydrogen. An aqueous potassium oxide solution is preferred.

/ 'V can also be added with 1-hydroxybenzotriazole, 1-hydroxy-7-indole benzotriazole and other active esterification reagents, adding 0.1 mole to the equivalent amount of compound (3), especially A range of 0.1 mole to 0.5 mole is preferably added. The reaction temperature is preferably in the range of 0 ° C to room temperature. The reaction time is completed in 4 to 20 hours. The above compound (4) can also be produced by subjecting the compound (3) produced in [Engineering a] not to be refined, and the compound (2) is subjected to [engine b] in the same reaction system (single pot).

(wherein R1, R2, R3, R4, R8, R9, ring A and ring B are the same as defined above). This work is to produce a compound (la) by condensing the compound (3) with a di(alkyl)amine derivative. The di(alkyl)amine derivative is preferably dimethylamine or diethylamine, more preferably dimethylamine -26-200909437. The di(alkyl)amine derivative may also be a salt such as a hydrochloride or an aqueous solution of a di(alkyl)amine. Among them, the di(alkyl)amine derivative used is most preferably a solution of dimethylamine in water. The di(alkyl)amine derivative is used in an amount equivalent to ～5 times the molar amount of the compound (3), preferably 2 to 3 times the molar. The condensing agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (water-soluble carbodiimide), N,N-dicyclohexylcarbodiimide, N, N-carbonyldiimidazole, or the like, is preferred, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (water-soluble carbodiimide) is preferred. . The amount of the condensing agent used is preferably in the range of -10 times the molar amount of the chemical amount of the compound (3), and more preferably in the range of 2 to 5 times the molar amount. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, and a nitrile-based solvent such as acetonitrile or an aprotic polar solvent such as dimethyl hydrazine is preferred, and these solvents may be used in combination with water. Further, in order to promote the reaction, an active esterification reagent such as 1-hydroxybenzotriazole or i-hydroxy-7-indole benzotriazole may be added, and a range of 〇1 molars to the equivalent amount of the compound (3) may be added. It is preferably in the 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 was completed at 5 to 20 hours < K ' degree. The above compound (la) can also be produced by subjecting the compound (3) produced in [Engineering a] to "precision" from the compound (2) in the same reaction system (single pot) [Engineering b_2]. [Engineering c] -27- 200909437

This project is to make compound (1) in the presence of Lewis acid in an aprotic polar solvent, orthoformate or n-acetate to produce compound (1) 〇 aprotic polar solvent. Preferably, hydrazine-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl hydrazine are preferred. The amount of the solvent to be used is such that the reaction proceeds smoothly, and industrially, it is preferably as small as possible, and the weight of the compound (4) is preferably 5 to 10 times by volume (V/W). Lewis acid is preferably a commercially available boron trifluoride-solvent complex, and a boron trifluoride-tetrahydrofuran complex is preferred. The amount of Lewis acid used is preferably 3 to 5 times the molar amount of the compound (4), and more preferably 3 to 3.5 times the molar amount. The orthoformate or n-acetate may be a commercially available orthoester or n-acetate, preferably trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate and triethyl orthoacetate. . The amount of orthoformate or n-acetate used is preferably from 1 to 5 times (V/W) to the compound (4), and more preferably from 2 to 3 times (V/W). The reaction temperature can be in the range of 30 to 60 ° C, preferably 40 to 60 ° C. The reaction time is completed in 2 hours. The post-treatment is to neutralize with an organic base such as water, sodium hydrogencarbonate or triethylamine, and the precipitated crystals are collected by filtration, washed with water, and dried. The starting material compound (2) of the above [Scheme 1] can be obtained by a known method in the form of -28-200909437. The method of producing the compound (2) from the starting material compound (5) by the conventional method is shown in the following [Scheme 2]. Further, the compound (1) can be produced from the compound (2) shown in [Scheme 1]. [Process 2]

(2) (1) (wherein R4° is a hydrogen atom, an alkali metal or a C1 to C6 alkyl group, and is a hydrogen atom or an alkali metal; the ruler 1, 1^2, 1^, 114, ring 8 and ring 8 are the same as defined above). The [Engineering d] to [Engineering] of [Flow 2] above will be described in detail below. [Engineering d] and [X-course e] -29- 200909437 C〇2Et [Engineering d]

Boc 丫L OMs C(XEt Boc

[Engineering e]

Boc 丫I CO,Et

Nh2 (5) (6) (7) (wherein OMs is methylsulfonyloxy and Boc is third butoxycarbonyl). The compound (7) is produced according to the method described in the pamphlet of International Publication No. 2003/016302. The azide compound (6) is produced from the compound (5), and the compound (6) is contact-reduced. [Engineering d] is a process for producing azide (6) by reacting a methanesulfonate compound (5) with an azo compound. 1 The compound (6) can, for example, be a compound (5) in an aprotic polar solvent such as N-methyl-2-pyrrolidone, in the presence of triethylammonium chloride as a phase-shifting catalyst, and an azo Manufactured by alkali metal salt treatment. The amount of the aprotic polar solvent to be used is preferably 1.5 to 5 times (V/W) to the compound (5), and the relevant mobile catalyst used is preferably 0.2 to 0.5 times the molar amount of the compound (5). . The azo alkali metal salt is preferably sodium azohydride or lithium azohydride in an amount of from 1.5 to 2.5 moles per mole of the compound (5). The reaction temperature is 55 to 65. (: Preferably, the reaction time is completed in the range of 48 to 72 hours. [Engineering e] is an engineering process for reducing the azide compound (6) to produce an amine compound (7). The reduction method can utilize a metal-carrying catalyst. A known method such as a contact reduction reaction or a metal-carrying catalyst, a hydrogen source, or an ammonium salt of formic acid is known. For example, the compound (7) can be used in an alcohol solvent, and the metal is supported by a catalyst. In the presence of 'the hydrogen source is treated with ammonium formate. The alcohol solvent -30-200909437 is preferably ethanol, and the amount used is preferably 10 times the amount of the compound (6). The metal-supporting catalyst is palladium/ The carbon is preferably used in an amount of from 10 to 20% by weight based on the compound (6). The amount of ammonium formate used as the hydrogen source is preferably from 4 to 10 moles per mole of the compound (6). It is preferably 45 to 55 ° C, and the reaction time is completed in 1 to 3 hours. [Engineering f]

(wherein R1, R2, R4°, ring A and Boc are the same as above). The compound (18) can be produced by condensing the compound (7) with the compound (13). [Engineering f] is a process for producing a compound (18) by condensing an amine matrix compound (7) with a compound (13), and has the following two methods. (i) When R4 is a hydrogen atom or an alkali metal, the compound (17) can be treated with an amine base compound (7) in the presence of a condensing agent, a carboxylic acid or an alkali metal salt compound of a carboxylic acid (13) or a salt thereof. To manufacture. The amount of the compound (13) is preferably in the range of an equivalent amount of the compound (7) by a molar amount of 1.2 times. The condensing agent may be 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, hydrazine, hydrazine-dicyclohexylcarbodiimide, N,N-carbonyldiimidazole, or Such congeners are preferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, hydrazine, hydrazine-dicyclohexylcarbodiimide, and compound (7). It is preferable to use a chemical quantity theory such as a molar range of ~3 times the molar amount, and a range of a molar amount of 1.5 times the equivalent amount of the chemical quantity theory. Further, in this reaction, an organic amine base such as triethylamine-31 - 200909437, N-methylmorpholine or 4-(N,N-dimethylamino)pyridine is used, and a chemical quantity is used for the compound (7). Moer ~1〇 times the range of Mo, etc., should be used in the range of the equivalent amount of Mohr. More effective in promoting the reaction of hydroxybenzotriazine, 1-transyl-7-indole benzotriazole and other active esterification reagents, the compound (7) with 〇_1~2 times the range of moles, should be on. Use 5 times the range of Moule. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, and a halogenated hydrocarbon solvent such as dichloromethane, a hydrocarbon solvent such as toluene or an ether solvent such as tetrahydrofuran, or N,N-dimethylformamide or N-methyl- An aprotic polar solvent such as 2-pyrrolidone is preferred, and ruthenium, osmium-dimethylformamide is more preferred. The reaction temperature can be carried out in the range of _2 (TC~ solvent boiling point, 〇~3 (the range of TC is preferred. The reaction time is completed in the range of 1-4 hours. The reaction can also be carried out under an inert atmosphere such as nitrogen or stupidity. (ii) When R4° is a C1-C6 alkyl group, the compound (18) can be produced by condensing an amine matrix compound (7) with a carboxylate compound (13) or a salt thereof. R4° is ethyl or A. Preferably, the amount of the compound (13) is preferably in the range of the chemical amount of the compound (7) by a molar amount of 1 to 2 times. The reaction solvent has no limitation as long as it does not inhibit the reaction, and the ratio is 1, 2 - Halogenated hydrocarbon solvent such as ethyl chloride, hydrocarbon solvent such as toluene, ether solvent such as tetrahydrofuran, nitrile solvent such as acetonitrile or N,N-dimethylformamide or N-methyl-2-pyrrolidone The protic polar solvent is preferred, and a nitrile solvent such as acetonitrile is more preferred. In this reaction, an organic amine such as triethylamine or N-methylmorpholine may be used, and the chemical amount of the compound (7) may be used. Ear ~ 10 times and other molar range ' should be used in the range of the molar amount of the molar amount of ~ 5 times. The reaction temperature can be in the range of 20 ° C ~ the boiling point of the solvent , -32-200909437 in the range of 6 0~7 5 ° C preferred. The reaction time of 3 hours to 24 hours the degree of completion of the junction. The reaction may be implemented under a nitrogen or argon inert atmosphere. [Engineering g]

[工程g] r-co2h

R*co2 (wherein R-CChH is oxalic acid, malic acid, maleic acid or p-nitrobenzoic acid,

Boc is the same as above). [Engineering g] is an engineering in which the amine base compound (7) is added with a carboxylic acid as a crystal of the carboxylate salt to separate the purified compound (17).

The compound (17) can be produced by treating the compound (7) and a carboxylic acid in a solvent and collecting and crystallizing the precipitate. The solvent to be used is preferably one which is capable of dissolving the starting compound (7) and the carboxylic acid without dissolving the resulting compound (17). A preferred solvent is acetonitrile. The total amount of the solvent to be used is preferably in the range of 2 to 20 times the weight of the compound (7) (V/W), more preferably in an amount of 1 〇 (V/W). The carboxylic acid is preferably oxalic acid, malic acid, maleic acid or p-nitrobenzoic acid, oxalic acid and malic acid are preferred, and malic acid is particularly preferred. The amount of the carboxylic acid to be added is preferably in the range of 0.9 to 1.2 mol per mol of the compound (7), and particularly preferably in the range of from 0 to 1.05 mol.

-33- 200909437 (wherein R1, R2, R4, ring A and Boc are the same as above). [Engineering h] is a process for producing a compound (18) by condensing an amine carboxylate compound (17) with a compound (13). The condensation method is as follows in the following two methods (1) and (ii). (i) When R4 is a hydrogen atom or an alkali metal, the compound (18) can be treated with the carboxylic acid or an alkali metal salt compound of the carboxylic acid (13) or a salt thereof in the presence of a base and a condensing agent. To manufacture. The amount of the compound (13) is preferably in the range of the equivalent amount of the compound (17) by a molar amount of -1.2 times. The condensing agent may be 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (water-soluble carbodiimide), N,N-dicyclohexylcarbodiimide, N , N-carbonyldiimidazole or the like, with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (water-soluble carbodiimide), N, N- Dicyclohexylcarbodiimide is preferred, and ethylethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (water-soluble carbodiimide) is preferred. The amount of the condensing agent to be added is preferably in the range of the molar amount of the compound (17) by a molar amount of 1.5 to 1.5 moles, more preferably in the range of the molar amount of the molar amount of 1.5 to 1.5 moles. The base is preferably an organic amine such as triethylamine or N-methylmorpholine. The amount of the base to be added is preferably in the range of the molar amount of the compound (1 7), such as the molar amount of the molar amount, and the range of the molar amount of the molar amount to the molar ratio of the molar amount of the molar amount to the molar ratio of the molar amount of the molar amount to the molar ratio of the molar amount of the molar amount to the molar ratio of the molar amount of the molar amount to the molar ratio of the molar amount of the molar amount to the molar ratio of the molar amount of the molar amount to the molar ratio of the molar amount of the molar amount to the molar ratio of the molar amount of the molar amount to the molar ratio of the molar amount of the molar amount to the molar ratio of the molar amount of the molar amount to the molar ratio of the molar amount of the molar amount to the molar ratio of the molar amount of the molar amount to the molar ratio of the molar amount of the molar amount to the molar ratio of the molar amount of the molar amount to the molar ratio of the molar amount of the Further promoting the reaction may be an active esterification reagent such as 1-hydroxybenzotriazole or 1-hydroxy-7-indole benzotriazole, and the compound (17) is used in a range of 0.1 times Mo, preferably 0.1 to 1.5. The range of the use of the mole is preferred. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, and a halogenated hydrocarbon solvent such as dichloromethane, a hydrocarbon solvent such as toluene, or an ether such as tetrahydrofuran-34-200909437 solvent or N,N-dimethylformamide, N_ An aprotic polar solvent such as methyl-2-pyrrolidone is preferred, and N,N-dimethylformamide is more preferred. The reaction temperature is preferably in the range of 0 ° C to 60 ° C, especially in the range of 〇 3 (the range of TC is better. The reaction time is completed in the range of 1 to 24 hours. The reaction can be carried out under an inert atmosphere such as nitrogen or argon. Ii) In the case where R is a C1 to C6 building group, the compound (18) can be produced by condensing a carboxylate compound (17) with a carboxylate compound (13) or a salt thereof. R4° is ethyl or methyl. Preferably, the amount of the compound (13) is preferably in the range of a molar amount of the compound (17) to the molar amount of 1.2 mol%, and the base is preferably an organic amine such as triethylamine or N-methylmorpholine. The amount of the base to be added is preferably in the range of the molar amount of the compound (17) by a molar amount of 10 to 10 moles, more preferably in the range of the molar amount of the molar amount of 5 to 5 moles. The reaction is not limited, and a halogenated hydrocarbon solvent such as 1,2-dichloroethane, a hydrocarbon solvent such as toluene, an ether solvent such as tetrahydrofuran, a nitrile solvent such as acetonitrile or N,N-dimethylformamidine. An aprotic polar solvent such as an amine or N-methyl-2-pyridinone is preferred, and a nitrile solvent such as acetonitrile is more preferred. The reaction temperature can be carried out at a temperature ranging from 20 ° C to the boiling point of the solvent. The reaction time at the end of the preferred range of 60~75 ° C to the extent of 3 hours ~ 24 hours. The reaction may also be under a nitrogen or argon inert atmosphere embodiments. [Engineering 1] -35-200909437

(wherein R1, R2, ring A and Boc are the same as above). [Engineering i] is a process for producing a compound (19) by subjecting the compound (18) to acid treatment. For the method of converting the Boc group to an amine group by acid treatment, for example, "Protective Groups in Organic Synthesis, eds. by TW Greene and PGWuts, John Wiley & Sons, Inc., New York, 1991". The document is implemented in the literature. The acid to be used is, for example, trifluoroacetic acid or methanesulfonic acid, and more preferably methanesulfonic acid. The amount of the acid to be added is preferably in the range of 10 to 10 moles of the chemical amount of the compound (18), and more preferably 2 to 5 times the molar amount of the chemical quantity. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, and a halogenated hydrocarbon solvent such as dichloromethane, a hydrocarbon solvent such as toluene, an ether solvent such as tetrahydrofuran or a nitrile solvent such as acetonitrile is preferred, and a nitrile solvent such as acetonitrile is more preferred. . The reaction temperature is preferably in the range of 0 ° C to 60 ° C, more preferably in the range of 15 to 35 ° C. The reaction time is completed in the range of 2 to 10 hours. The reaction can also be carried out under an inert atmosphere such as nitrogen or argon. After the completion of the reaction, the compound (18) which forms an acid addition salt is neutralized with an organic amine such as triethylamine. The amount of the organic amine to be added is preferably in the range of from 1 to 5 moles per mole of the acid to be added, and more preferably in the range of from 0 to 1.1 moles. [Engineering j] -36- 200909437

Π 9) (2) (where R1, R2, R3, R4, R7°, ring Α and ring Β are the same as above). [Engineering_j] is a process for producing the compound (2) by treating the compound (19) with the compound (16) in the presence of a condensing agent. The condensing agent may be 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (water-soluble carbodiimide), N,N-dicyclohexylcarbodiimide, N , N-carbonyldiimidazole, or the like, with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (water-soluble carbodiimide), N, N The dicyclohexylcarbodiimide is preferably a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (water-soluble carbodiimide). The amount of the condensing agent is preferably in the range of the chemical amount of the chemical compound (19), and the range of the molar amount is 1.3 times the molar amount, and the range of the molar amount of the molar amount is preferably better. Further, the active esterification reagent such as 1-hydroxybenzotriazole or 1-hydroxy-7-indole benzotriazole is used in the range of 0.1 to 2 times the molar amount of the compound (19), preferably from 1 to 1.5 times. The range of Moh is preferred. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, and a halogenated hydrocarbon solvent such as dichloromethane, a hydrocarbon solvent such as toluene or an ether solvent such as tetrahydrofuran, hydrazine, hydrazine-dimethylformamide or hydrazine-methyl-2. An aprotic polar solvent such as pyrrolidone or a nitrile solvent such as acetonitrile is preferred, and a nitrile solvent such as acetonitrile is more preferred. The reaction temperature is preferably in the range of 丨0 °C to 60 °C, and particularly preferably in the range of 1 5 to 30 °. The reaction time is completed in 1 to 24 hours. The reaction can also be carried out under an inert atmosphere such as nitrogen or argon. -37- 200909437 After the end of the reaction, when the condensing agent used is an acid addition salt, it is preferable to neutralize with a base, and the neutralized salt may be dissolved, and water may be added in addition to the neutralization salt exclusion reaction system. 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 from 1.2 ppm to the molar amount of the condensing agent for the acid addition salt. Further, the compound (2) can be produced from the compound (18) according to [Engineering i]. After the compound (19) is produced, the compound (19) can be purified without isolation, but in the same reaction system (single pot), after adding an organic amine such as triethylamine. The compound obtained by the condensation of [Engineering i] with the compound (丨6) can also be present in the form of a free or arbitrary salt. For example, the addition salt with an inorganic acid can be a hydrochloride or a hydrobromic acid. An example of a salt such as a salt or a sulfate and an organic acid may be an acetate, a fumarate, a maleate, a benzoate, a citrate, a malate, a methanesulfonate or a benzenesulfonic acid. Salt and so on. Further, the salt of the inorganic base or the organic base may be an ammonium salt, a sodium salt, a potassium salt, a lithium salt, a calcium salt or the like, and a hydrate or a solvate of such a salt is also included in the present invention. When the compound of the present invention has one or more asymmetric centers in the molecule, the image, the racemate, the diastereomer and a mixture thereof are also included unless otherwise specified. Further, if the compound of the present invention contains a geometric isomer, it comprises a cis compound, a trans compound, and a mixture thereof. Further encompassing any tautomers and mixtures thereof when the compounds of the invention contain tautomers. EXAMPLES The present invention will be described in detail by way of the following examples, but the present invention is not limited thereto. In the nuclear magnetic resonance spectrum (NMR), the internal standard substance uses tetramethyl decane, and the abbreviation of multiplicity is s=single line. , d = double line, t = three lines, q = four lines, multi-line 'and br · S = 单 line single line. In the following [Reference Example] to [Reference Example 3], a synthesis example of the compound of the formula (13) is shown. [Reference Example 1] 2-(4-Chloroanilino)_2-oxyacetic acid ethyl ester (13-a)

A solution of 4-chloroaniline (1.16 g) and methylene chloride (26 ml), EtOAc (EtOAc) After the liquid was added to a saturated aqueous solution of sodium hydrogencarbonate and the mixture was partitioned, the organic layer was washed successively with 10% aqueous citric acid and brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. 'H-NMRCCDCh)^ : 1.43 (3H, t, J = 7.1Hz), 4.4 2 (2H, q, J = 7.1 Η z), 7.34(2H,d,J = 8.8Hz), 7.60 (2H, d , J = 8.8 Hz), 8.86 (lH, br.s). MS (ESI) m/z: 228 (M + H) + .

[Reference Example 2] 2-(4-Fluoroanilino)-2-oxoacetic acid methyl ester (13-b) The title compound 〇1H-NMR was obtained from 4-fluoroaniline and methyl chloroacetate. (CDCl3) (5: 3.98 (3H, s), 7.00-7.14 (2H, m), 7.55--39-200909437 7.68 (2H, m), 8.85 (1 H, br.s). MS (ESI) m /z: 198(M + H) + .

[Reference Example 3] 2-(4-bromobenzenefeeyl)-2.oxyacetic acid methyl ester (i3_c)

(13-c) /° </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Hz), 7.55 (2H, d, J = 9.0 Hz), 8.85 (lH, br.s). MS (FAB) m/z: 258 (M) + .

[Reference Example 4] 2-(4-chloro-2-toluidine)-2-oxyacetic acid methyl ester (13-d)

The title compound was obtained from the title compound of Example 1 from 4-chloro-2-toluamine and methyl chloroacetate. 'H-NMR (CDCl3) &lt;5: 2.31 (3H, s), 3.99 (3H, s), 7.1 5-7.30 (2H, m), 7.98 (lH, d, J = 8.8 Hz), 8.77 (lH) , br). MS (FAB) m / z: 228 (M + H) + .

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

The title compound was obtained from the title compound of Example 1 from 4-chloro-3-toluidine and methyl chloroacetate. -40- 200909437 丨 H-NMR (CDCh) 5 : 2.39 (3H, s), 3.98 (3H, s), 7.3 3 (1 Η, d, J = 1 2.5

Hz), 7.44 (lH, dd, J = 12.5, 2.5 Hz), 7.53 (lH, d, J = 2.5 Hz), 8.8 l (lH, br.s). MS (ESI) m/z: 228 (M + H) + .

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

The title compound was obtained from the title compound (1). 'H-NMR (CDCl3) (5: 3.99 (3H, s), 7. 1 5-7.24 (2H, m), 8.33 (lH, t, J = 8.4 Hz), 9.05 (lH, br.s). MS (ESI) m/z: 232 (M + H) + .

[Reference Example 7] 2-(2,4-difluoroanilino)-2-oxoacetic acid methyl ketone U3-g)

The title compound was obtained from 2,4-difluoroaniline and methyl chloroacetate as a reference. 'H-NMR (CDCl3) &lt;5: 3.99 (3H, s), 6.87 - 7.00 (2H, m) ' 8.29-8.38 (lH, m), 8.99 (lH, br.s). MS (ESI) m /z:215(M) + .

[Reference Example 8] Methyl 2-(3,4-difluoroanilino)-2-oxyacetate (l3_h)

-41 - 200909437 The title compound was obtained from the title compound 1 from 3,4-difluoroaniline and methyl chloroacetate. 'H-NMR CCD Ch) &lt;5: 3.98 (3H, s), 7.1 0-7.28 (2H, m), 7.67- 7.78 (lH, m), 8.8 3 (1 H, br. s). MS (ESI) m/z: 215 (M) + .

[Reference Example 9] 2-oxo-2·(pyridin-4-amino)acetic acid methyl ester (13-i) (13.〇0 f ' imitative reference example 1, from 4-aminopyridine and chlorooxyacetate The title compound was obtained as the title compound. 'H-NMR (CDCh) &lt;5: 3.99 (3H, s), 7.58 (2H, dd, J = 4.8, 1.6 Hz), 8.60 (2H, dd, J = 4., 8 , 1.6Hz), 9.04 (lH, br.s). MS (ESI) m/z: 1 8 1 (M + H) + .

[Reference Example 10] Methyl 2-[(5-bromopyridin-2-yl)amino]-2-oxyacetate

The title compound was obtained from 2-amino-5-bromopyridine and methyl chloroacetate. 'H-NMRCCDCh' δ : 3.99 (3H, s), 7 · 8 7 (1 Η, dd, J = 8 · 8, 2.4H z), 8.19 (lH, d, J = 8.8 Hz), 8.4 1 ( 1 H,d,J = 2.4 Hz), 9.3 8 (1 H , br. s). MS (FAB) m/z: 259 (M) + .

[Reference Example 1 l] 2-[(5-Fluoropyridin-2-yl)amino]-2-oxoacetic acid methyl ester (13-k) -42- 200909437 ο imitative reference example 1, from 2-amino-5- The title compound was obtained from fluoropyridine and methyl chloroacetate. 'H-NMR (CDCh) (5: 3.99 (3H, s), 7.4 8 - 7.5 3 ( 1 Η, m), 8.21 (lH, d, J = 2.9 Hz), 8.27 - 8.3 1 (1 H, m ), 9.4 1 (1 H, br. s). MS(FAB)m/z: 1 98(M + H)+.

[Reference Example 12] 2-[4-Chloro-2-(trifluoromethyl)anilino]-2-oxoacetic acid methyl vinegar (丨3- 1)

C1 (13-1) The title compound was obtained from the title compound (1), 4-chloro-2-(trifluoromethyl)aniline and methyl chloroacetate. 'H-NMRCCDCh) (5: 4.01 (3H, s), 7.5 8 (1 Η, dd, J = 8.8, 2.2H z), 7.65 (lH, d, J-2.2Hz), 8.34 (lH, d, J = 8.8 Hz), 9.3 0 ( 1 H , b r. s). MS (EI) m/z: 28 1 (M + H) + .

[Reference Example 13] Methyl 2-(4-chloro-2-methoxyanilino)-2-oxyacetate (13-m)

The title compound was obtained from the title compound, m. 'H-NMR (CDCh) (5: 3.92 (3H, s), 3.97 (3H, s), 6.9 0 (1 Η, d, J - 2.2

Hz), 6.98 (lH, dd, J = 8.8, 2.2 Hz), 8.3 5 (1 H, d , J = 8.8 H z), 9.33- -43- 200909437 9.44 (lH, br). MS (ESI) m /z:244(M + H) + .

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

The title compound was obtained from the title compound, m. H-NMR (CDCh) (5: 3.93 (3H, s), 3.9 8 (3H, s), 7.00 (1H, dd, J = 8.5, 2.4 Hz), 7.33 (lH, d, J = 8.5 Hz) ), 7.5 7 (lH, d, J = 2.4 Hz), 8.8 9 (lH, br.s) [Reference Example 15] 2-[(5-methylpyridin-2-yl)amino]-2-oxo Methyl acetate (13-0)

The title compound was obtained from the title compound 1 '2-amino-5-methylpyridine and methyl chloroacetate. 'H-NMR CCD Ch) &lt;5: 2.33 (3H, s), 3.98 (3H, s), 7.57 (lH, dd, J = 8.4, 2.0 Hz), 8.14 (lH, d, J = 8.4 Hz), 8.1 7 (1H, d, I = 2. OH z). MS (ESI) m/z: 195 (M + H) + .

[Reference Example 16] 2-Oxygen. - (Shame toluidine acetoacetate methyl ester 彳 ^-...

The title compound -44 - 200909437 MS (ESI) m/z: 194 (M + H) + was obtained from the title compound.

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

2-Amino-5-chloropyridine (1.16g) and triethylamine (1.51ml) were dissolved in dichloromethane (26ml). 1 4 hours. After a liquid separation operation was carried out by adding a saturated aqueous solution of sodium hydrogencarbonate, the organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3:1). The obtained solid was dissolved in methanol (20 ml) and stirred at 50 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure. 'H-NMR CCDCh) 5 : 3.99 (3H, s), 7.73 ( lH, dd, J = 8.8, 2.2 Hz), 8.24 (lH, d, J = 8.8 Hz), 8.3 1 (1 H, d, J = 2.2 Hz), 9.39 (lH, br. s). MS (ESI) m/z: 215 (M + H) + .

[Reference Example 18] Ethyl 2-[(6-chloropyridin-3-yl)amino]-2-oxoacetate (13-r)

5-Amino-2·chloropyridine (3 86 mg) was dissolved in hydrazine, hydrazine-dimethylformamide (8 ml), potassium 2-ethoxy-2-oxoacetate (469 mg), 1-( 3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (863 mg), 1-hydroxybenzotriazole.1 hydrate (203 mg), stirred at room temperature for 2 days. The solvent was evaporated under reduced pressure, and the mixture was evaporated and evaporated. The solvent was concentrated under reduced pressure. EtOAcjjjjjjjj -45- 200909437 'H-NMRCCDCh) (5 : 1.4 3 (3 Η, t, J = 7.2H z), 4.44 (2H, q , J = 7.2Hz), 7.36 (lH,d,J = 8.7Hz) , 8.24 (1 H, dd, J = 8.7, 2.7 Hz), 8.55 (lH, d, J = 2.7 Hz), 9.03 (1 H, br. s).

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

To a suspension of toluene (20 ml) of 5-chlorothiophene-2-carboxylic acid (0.99 g) was added triethylamine (1.25 ml) and diphenylphosphonium azo (1.55 ml), and stirred at 80 ° C for 1 hour. After the reaction mixture was cooled to room temperature, tributyl alcohol (2 ml) was added and the mixture was refluxed for 19 hr. The reaction mixture was concentrated under reduced pressure. methylene chloride (dichloromethane) (dichloromethane) (dichloroacetic acid), distilled water, saturated aqueous sodium hydrogen carbonate and saturated brine were washed successively. The solvent was evaporated under reduced pressure, and the residue was applied to silica gel column (hexane: ethyl acetate = 4:1) to give the titled butyl 5-chloro-2-thiopheneamine (1.05 g). 'H-NMR (CDCh) ά : 1.51 (9H, s), 6.2 1 (1H, d, J = 3.1 Hz), 6.60 (1H, d, J = 3.1 Hz), 6.9 1 (1 H , b r. s). MS (ESI) m/z: 234 (M + H) +. The product (1.87 g) was added to 4 eq. of dioxane hydrochloride (40 ml) and stirred at room temperature for 4 hours. The solvent was distilled off. The residue was suspended in tetrahydrofuran (50 ml), EtOAc (EtOAc) The solvent was evaporated under reduced pressure, and the residue was evaporated. The residue was purified by silica gel chromatography chromatography eluting -46 - 200909437 1H-NMR (CDCl3) 5 : 3.98 (3H, s), 6.6 1 (1 H, d, J = 4.2 Hz), 6.75 (1H, d, J = 4.2 Hz), 9.42 (1 H, Br. s). MS(FAB)m/z: 220(M + H) + .

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

4-Chloro-3-fluorobenzoic acid was treated in the same manner as in Example 19 and condensed with methyl chloroacetate to give the title compound. 'H-NMR (CDC13) (5: 3.99 (3H, s), 7.2 5 - 7.2 7 ( 1 Η, m), 7.39 (lH, t, J = 8.5 Hz), 7.72 (lH, dd, J = 10.4) , 2.4Hz), 8.90 (1 H, b r. s).

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

(13-u) a mixture of tetrahydrofuran (7 m 1 )-water (3 m 1 ) in methyl 2-[4-chloro-2-(trifluoromethyl)anilino]-2-oxoacetate (297 mg) Lithium hydroxide (28 mg) was added and stirred at room temperature for 2 hours. 1 part of hydrochloric acid (8 ml) and dichloromethane (20 ml) were added to the reaction solvent, and the liquid separation operation was carried out. The obtained organic layer was dried over anhydrous sodium sulfate. 'H-NMR(CDCl3) 5 : 7.61 (lH, dd, J = 8.8, 2.5 Hz), 7.68 (lH, d, J = 2.5 Hz), 8.26 (1Η, d, J = 8.8 Hz), 9.3 6 ( 1 H, br. s). MS (ESI, anion) m/z: 267 (MH).

[Reference Example 22] 2-(4-chloroanilino)-2-oxyacetic acid (13-v) -47- 200909437

(13-v) The title compound was obtained from m. 'H-NMIU DMSO-cM^ : 7.37 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.8 Hz), 10.66 (lH, s).

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

The title compound was obtained from the title compound (m.). 'H-NMR (DMSO-d6) &lt;5: 7.95 - 8.00 ( 1 H, m), 8.0 8 (1 H, dd, J = 8.8, 2.0 Hz), 8.50 (lH, d, J = 2.0 Hz) , 10.74 (lH, s).

[Reference Example 24] 2-(4-Chloro-3-fluoroanilino)-2-oxyacetic acid (13-x). Reference Example 21, from 2-(4-chloro-3-fluoroanilinyl)-2- Methyl oxyacetate gave the title compound. 'H-NMR (DMSO-d6) (5: 7.52 (lH, t, J = 8.8 Hz), 7.6 3 (1 H, dd, J = 8. 8 , 2.2 Hz), 7.88 (lH, dd, J = 12.0, 2.2 Hz), 1 0.8 3 (1 H, br. s).

[Reference Example 25] 2-(4-chloro-3-methoxyanilino)-2-oxyacetic acid (13-y) -48- 200909437

Methyl 2-(4-chloro-3-methoxyanilino)-2-oxoacetate was hydrolyzed to give the title compound. 'H-NMR (DMSO-d6) &lt;5: 3.81 (3H, s), 7.3 6 (1 Η, d, J = 8.7 Hz), 7.43 (lH, d, J = 8.7 Hz), 7.65 (lH, d, J = 2.2 Hz), 10.79 (lH, s). MS (ESI, anion) m/z: 228 (MH).

[Reference Example 26] 2-(4-chloro-3-nitroanilino)-2-oxyacetic acid (13-z)

After the condensation of 4-chloro-3-nitroaniline with methyl chlorooxyacetate was carried out in the same manner as in Reference Example 1, the title compound was obtained. 'H-NMR (DMSO-d6) 5: 7.76 (lH, dd, J = 8.8 Hz), 8.04 (lH, dd, J = 8.8, 2.4 Hz), 8.55 (lH, d, J = 2.4 Hz), 11.24 (lH, s). No protons of carboxylic acid. MS (EI) m / z: 244 (M) + .

[Reference Example 27] 2-[(5-Chloropyridin-2-yl)amino]-2-oxyacetic acid lithium salt (13-aa)

A solution of methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate (1.12 g) in tetrahydrofuran (20 ml) was added water (5.0 ml) and lithium hydroxide (128 mg) 5 hours. The solvent was evaporated under reduced pressure. EtOAc (EtOAc m. -49- 200909437 'H-NMRCDMSO-de) 5 : 7.9 0 (1 Η, dd, J = 8.9, 2.6H z), 8.12 (lH,d, J = 8.9Hz), 8.34(lH,d,J = 2.6 Hz), 10.18 (lH, s).

[Reference Example 2 8 ] 2 - [(5-Methylpyridin-2-yl)amino]-2-ethoxyacetic acid lithium salt (1 3 -ab)

The title compound was obtained from the title compound (m.). 'H-NMR (DMSO-d6) 5 : 2.25 (3H, s), 7.6 3 (1 Η, d, J = 8.2 Η z), 8.00 (lH, d, J = 8.2 Hz), 8.15 (lH, s ), 1 0.00( 1 H, 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 m.p. 1 Η - NMR (DMS 0 - cU) 5 : 8 · 0 3 (1 Η, dd, J = 8.8, 2.4 Η z), 8.0 9 (1 Η, d, J = 8.8 Hz), 8.44 (lH, d , J = 2.4Hz), 10.18(lH, s).

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

Referring to Example 1, after condensing 4-chloro-2-nitroaniline with methyl chlorooxyacetate, it was hydrolyzed in the same manner as in Reference Example 27, and the obtained residue was dissolved in methanol, and an aqueous solution of 1N sodium hydroxide-50-200909437 was added thereto, and the mixture was filtered. Precipitation gave the title compound. 'H-NMIU DMSO-cMd : 7.84 (lH, dd, J = 9.0, 2.5 Hz), 8.20 (1H, d, J = 2.5 Hz), 8.67 (lH, d, J = 9.0 Hz), 11.89 (lH, s In the following [Reference Example 31] to [Reference Example 37], a synthesis example of the compound of the formula (16) is shown. [Reference Example 31] 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid lithium salt (16-a) [Engineering 1] Pyridine-4- Tert-butyl carbamic acid

4-Aminopyridine (10 g) was dissolved in tetrahydrofuran (500 ml), dibutyl succinate (25.5 g) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure. 'H-NMR (CDCl3) (5: 1.53 (9H, s), 6.8 6 (1 Η, b r. s), 7.30 (2H, dd, I = 1.5, 4.9 Hz), 8.44 (2H, dd, J = 1.5, 4.9 Hz). MS (FAB) m/z: 195 (M + H) + .

[Engineering 2] 3-Butyl pyridylpyridin-4-ylaminecarboxylic acid

The tert-butyl pyridin-4-ylaminecarboxylate (61.6 g) was dissolved in tetrahydrofuran (2000 ml), and stirred at -78 °C for 10 minutes. After n-butyllithium (1.59 equivalents of a hexane solution, 500 ml) was added to the reaction liquid for 10 minutes, the mixture was stirred for 2 hours under ice cooling. After the reaction mixture was cooled to -78 ° C, a sulfur powder (12.2 g) was added, and the mixture was warmed to room temperature and stirred for 1 hour. Water (1000 ml) was added to the reaction mixture for liquid separation. After adding -3 hydrochloric acid to the water layer at -51- 200909437, adjust to pH 3~4, then add dichloromethane to separate the liquid. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography chromatography chromatography chromatography 'H-NMR (DMSO-d6) (5: 1.52 (9H, s), 7.8 9 (1 Η, d, J = 6.4 Hz), 7.99 (lH, d, J = 6.4 Hz), 8.20 (lH, s ), 9.9 1 (1 H, br. s). MS (FAB) m/z: 227 (M + H) + . , [Engineering 3] Thiazolo[5,4-c]pyridine

The third butyl 3-sulfanylpyridin-4-ylcarbamate (33.2 g) was dissolved in formic acid (250 m 1) and heated to reflux for 3 days. The reaction mixture was concentrated under reduced pressure. After the organic layer was dried over anhydrous sodium sulfate, solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography chromatography chromatography 1H-NMR (CDCh) (5: 8.05 (lH, dJ = 5.4 Hz), 8.70 (1 Η, d, J = 5.4 Hz), 9.23 (lH, s), 9.34 (lH, s). i MS (FAB) m/z: 1 37 (M + H) + .

[Engineering 4] 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-(:]pyridine

The thiazolo[5,4-c]pyridine (1.61 g) was dissolved in N,N-dimethylformamide (50 ml), and methyl iodide (1.50 ml) was added, and the mixture was stirred under heating at 80 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure. EtOAc m. The reaction mixture was concentrated under reduced pressure, and the residue was evaporated and evaporated. The organic layer was dried over anhydrous sodium sulfate-EtOAc-EtOAc (EtOAc) 'H-NMRCCDCh) (5:2.52 (3H, s), 2.8 3 (2H, t, J = 5.9 Hz), 2.98 (2H, t, J = 5.9 Hz), 3.70 (2H, s), 8.63 (lH , s). MS (FAB) m / z: 155 (M + H) + .

[Engineering 5] 5-Methyl-4,5,6,7-dihydrothiazolo[5,4-c]pyridine-2-carboxylic acid lithium salt (16-a)

Let 5-methyl-4,5,6,7-tetrahydrothiazide sit and [5,4-c] oxime D (6.43g) dissolved in anhydrous tetrahydrofuran (200ml), drip at -78 °C Butyllithium (1.47 equivalents of hexane solution, 34.0 ml) was stirred for 40 minutes. After introducing a carbon dioxide gas at -78 °C for 1 hour, the mixture was heated to room temperature. 'H-NMR (DMSO-d6) (5: 2.37 (3H, s), 2.64-2.77 (4H, m), 3.54 (2H, s). i MS (FAB) m/z: 199 (M + H) + .

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

1-Dicoxybutyryl-4-consinone (40.0g) was dissolved in Huanjiyuan (8〇mi), -53- 200909437 plus p-toluenesulfonic acid monohydrate (191mg), pyrrolidine (17.6 Ml), heated to reflux with a Dean-Stark apparatus for 2 hours while dehydrating. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (60 ml). A methanol solution (10 ml) of cinnamylamine (8.4 4 g) was slowly added dropwise under ice cooling, and stirred at room temperature for 5 hours. The precipitated solid was filtered to give the title compound (31.0 g). 1H-NMR (DMSO-d6) 5: 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: 25 5 (M + ).

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

The second copper bromide (1.05 g) was suspended in N,N-dimethylformamide (20 ml), and butyl nitrite (0.696 ml) and 2-amino-6,7- After dihydrothiazolo[5,4-c]pyridine-5[4H]-carboxylic acid tert-butyl ester (1.0 g), the reaction solution was heated and stirred at 40 ° C for 30 minutes. The reaction mixture was concentrated under reduced pressure. 'H-NNR(CDCl3) (5: 1.48(9H,s), 2.85(2H,br.s), 3.72(2H,br.s), 4.56(2H,br.s). MS(FAB)m/ z: 3 1 9 (M + H) + .

[Engineering 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-54- 200909437 (890 mg) dissolved in dichloromethane (2 ml) Trifluoroacetic acid (15 ml) was stirred at room temperature for 30 sec. The reaction mixture was concentrated under reduced vacuo. 'H-NMR (DMSO-d6) 5 : 2.9 8 (2H, t, J = 6.1 Η z), 3.45 (2H, t, J = 6.1 Hz), 4.35 (2H, s), 9.5 3 (2H fb r s). MS(FAB)m/z: 219(M + H) + .

[Engineering 4] 2-Bromo-5-methyl-4,5,6,7-tetraoxathiazide [5,4-(:]卩 ratio 1]

2-Bromo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine trifluoroacetate (422 mg) was suspended in dichloromethane (10 ml), and triethylamine was added. 35 6ml), after dissolution, add acetic acid (0.2 1 6 m 1), aqueous formaldehyde solution (3 5 % solution, 0.2 0 2 m 1), sodium triethoxy hydride hydride (428 mg), stir at room temperature 1 hour. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (100 ml), dichloromethane (1 ml) and 3N aqueous sodium hydroxide (3 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography chromatography chromatography 'H-NMR (CDCh) 5 : 2.49 (3H, s), 2.7 9 (2 Η , t, J = 5.7 Η z), 2.85-2.93 (2H, m), 3.5 8 (2H, t, J = 1 8Hz). MS(FAB)m/z: 233 (M + H) + .

[Engineering 5] 5-Methyl-4,5,6,7-tetrahydrothiazino[5,4-anthracene][]-thirty-residue lithium salt (16-b)

Dissolve 2-bromo-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (5 3 1 mg)-55-200909437 in anhydrous diethyl ether (20 ml) at - n-Butyllithium (1.54 equivalent of a house solution, 1.63 ml) was added dropwise at 78 ° C, and stirred under ice cooling for 30 minutes. After introducing a carbon dioxide gas into the reaction solution at 78 °C for 1 minute, the temperature was raised to room temperature. The reaction mixture was concentrated under reduced pressure to give the title compound ( 523 mg). 'H-NMR (DMSO-d6) 5 : 2.37 (3H, s), 2.64 - 2.8 5 (4H, m), 3.54 (2H, s).

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

The title compound was obtained from 2-bromo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine trifluoroacetate as described in [Comp. 4]. 'H-NMR (CDCl3) (5: 1.13 (6H, d, J = 6.5 Hz), 2.86 (4H, s), 2.89- 3.00 (lH, m), 3.70 (2H, s).

[Engineering 2] 5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid lithium salt (16-c)

The title compound was obtained from the compound obtained in the title compound. H-NMR (DMSO-d6) 5 : 1.05 (6H, d, J = 6.4 Hz), 2.68-2.70 (2H, m), 2.75-2.77 (2H, m), 2.87 - 2.9 3 ( 1 Η, m) , 3.66(2H, s).

[Reference Example 34] 5-Methyl-4,5,6,7-tetrahydrooxazolo[5,4-fluorene]pyridine-2-carboxylic acid lithium salt (16-d) -56- 200909437 [Engineering 1 ]2-[(Ε)-2-styryl]oxazole-4-carboxylic acid ethyl ester

Synthesized according to the report of Panek et al. (J. 〇rg. Chem., 1996, vol. 61, p. 6496). To a solution of cinnamic acid citrate (10. Og) in tetrahydrofuran (250 ml), sodium hydrogencarbonate (22.8 g) and ethyl bromopyruvate (1. 5 ml) were added at room temperature and refluxed for 48 hours. The reaction mixture was allowed to cool to room temperature, and the mixture was filtered and evaporated. A solution of this residue in tetrahydrofuran (30 ml) was added EtOAc (EtOAc) After stirring for 63 hours, aq. EtOAc (EtOAc) The organic layer was combined, washed with saturated brine (150 ml), dried over anhydrous sodium sulfate and evaporated. The title compound (l〇.9g) was obtained. 'H-NMR (CDCl3) &lt;5: 1.41 (3H, t, J = 7.0 Hz), 4.42 (2H, q, J = 7.0 Hz), 6.96 (lH, d, J = 16.6 Hz), 7.30-7.40 (3H,m), 7.53(2H,d,J = 6.8Hz), 7.63(lH,d,J=16.6Hz), 8.20(lH,s).

[Engineering 2] 2-[(E)-2-Styrosyl]oxazole-4-carbaldehyde

A solution of ethyl 2-[(E)-2-styryl]oxazole-4-carboxylate (8.57 g) in dichloromethane (80 mL) Equivalent hexane solution, 66 ml). After stirring for 15 minutes, methanol (1 ml) was added dropwise, and the mixture was warmed to room temperature over 1 hour. The reaction mixture was filtered through celite, and the obtained mixture was dissolved in ethyl acetate (yield: ethyl acetate) . The organic layer was combined and washed with a saturated aqueous solution of sodium bicarbonate (100 ml) and brine (100 ml), and the filtrate was filtered and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography chromatography chromatography ^H-NMIUCDCh) (5:6.96(lH,d,J=16.6Hz), 7.3 5 - 7 · 4 5 (3 Η,m), 7.56(2H,d,J = 6.4Hz), 7.67 (1Η, d, J = 1 6.6 Hz), 8.26 (lH, s), 9.98 (lH, s), MS (FAB) m/z: 200 (M + H) + .

[Engineering 3] 2-[(E)-2-Styrosyl]-4-vinylcarbazole

A solution of (methyl)triphenyliron bromide (8.16 g) in tetrahydrofuran (80 ml) was added dropwise n-butyllithium (1.54 hexanes, 14.2 ml) at 0 ° C and stirred at room temperature for 30 min. The reaction mixture was recooled to a solution of 2-[(E)-2-styryl] B-azole-4-carbaldehyde (3.64 g) in tetrahydrofuran (20 ml). After stirring for 2 hours, water (200 ml) and ethyl acetate (100 ml) were evaporated and evaporated. The organic layer was combined, washed with brine (100 ml) and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut elut elut elut elut elut elut elut L.5, 10.7 Hz), 5.98 (lH, dd, J = 1.5, 17.6 Hz), 6.5 6 (1H, dd, J = 1 0.7, 1 7.6 Hz), -58- 200909437 6.95 (lH, d, J =1 1- 7.4 Hz), 7.3 1-7.42 (3H, m), 7.4 9 - 7.5 6 (4H, m). MS (FAB) m/z: 198 (M + H) + .

[Engineering 4] 2-{2-[(E)-2-Styrosyl]oxazol-4-yldi 1-ethanol

In a solution of 2-[(E)-2-styryl]-4-vinylcarbazole (13.0 g) in tetrahydrofuran (500 ml), 9-borbicyclo[3.3.1]decane (0.5) Equivalent to tetrahydrofuran (158 ml), stirred at room temperature for 15 h. The reaction mixture was successively added with water (10 ml), 3N aqueous sodium hydroxide (80 ml) and hydrogen peroxide (80 ml), and the mixture was stirred at room temperature for 6 hours. After the reaction mixture was combined with EtOAc (EtOAc) The organic layer was combined, washed with brine (200 ml) and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography eluting elut elut elut elut 'H-NMR (CDCh) δ: 2.69 (lH, br.s), 2.80 (2H, t, J = 5.6 Hz), 3.90- 3.97 (2H, m), 6.9 1 (1 H, d, J = 1 6.6H z), 7.3 0 - 7.4 2 (4H, m), 7.43-7.56 (3H, m). MS (FAB) m/z: 216 (M + H) + .

[Engineering 5] 2-(2-{2-[(£)-2- Styryl]oxazol-4-yl}ethyl)-111-isoindole 哚-1,3(2H)-dione

A solution of 2-{2-[(E)-2-styryl]oxazol-4-yl b-ethanol (292 mg) in tetrahydrofuran (15 ml) at rt. Phosphine (35 7 mg) -59-200909437 and diethyl azodicarboxylate (0.214 ml) were stirred for 4 hours. The solvent was distilled off under reduced pressure in the reaction mixture. The residue was purified by silica gel chromatography chromatography eluting 'H-NMR (CDCl3) (5: 2.98 (2H, t, J = 7.2 Hz), 4.0 3 (2H, t, J = 7.2 Hz), 6.88 (lH, d, J = 16.6 Hz), 7.2 8- 7.4 5 (5 H, m), 7.4 8 (2H, d, J = 7.3 H z), 7.71 (2H, dd, J = 2.9, 5.4 Hz), 7.84 (2H, dd, J = 2.9, 5.4 Hz) MS (FAB) m / z: 345 (M + H) + .

[Engineering 6] 2-{2-[(E)-2-Styrosyl]oxazol-4-yl}ethylaminecarboxylic acid tert-butyl ester

2-(2-{2-[(E)-2-Styryl]oxazol-4-yl}ethyl)-1Η-isoindole-1,3(2H)-dione (6.40 g) A solution of ethanol (150 ml) was added to hydrazine monohydrate (1.50 ml) at room temperature. After stirring for 1 hour, hydrazine monohydrate (0.500 ml) was added at room temperature and stirred for 2 hours. The reaction mixture was diluted with methylene chloride (150 ml), saturated aqueous sodium hydrogen carbonate (150 ml) and dibutyl succinate (13.4 g). After stirring for 30 minutes, the layers were separated and the aqueous layer was evaporated. The organic layer was combined and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography chromatography eluting elut elut elut 'H-NMR (CDCl3) 5 : 1.45 (9H, s), 2.7 5 (2 Η , t, J = 6.6H z), 3.46 (2H, dt, J = 5.9, 6.6 Hz), 4.9 2 (1 H , br. s), 6.9 1 (1 H, d , J = 1 6.6 Hz), 7.29-7.45 (4H, m), 7.4 8 (1 H, d, J = 1 6.6H z), 7.52 ( 2H,d, J = 7.3Hz). -60- 200909437 MS(FAB)m/z: 315(M + H) +, 259(M-isobutene + H) +, 315(M-Boc + H) + [Engineering 7] 2-[(E)-2-Styrosyl]-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-carboxylic acid tert-butyl ester

a solution of 2-{2-[(E)-2-styryl]oxazol-4-yl}ethylaminecarboxylic acid tert-butyl ester (190 mg) in toluene (15 ml) at room temperature with triacetaldehyde (54.5 mg) And p-toluenesulfonic acid (7.2 mg). After heating under reflux for 1 hour, it was allowed to cool, and ethyl acetate (1 5 m 1) and saturated aqueous sodium hydrogen carbonate (1 5 m 1) were added to the mixture. After the aqueous layer was extracted with ethyl acetate (10 ml), the organic layer was combined and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (hexane:EtOAc: 'H-NMR CCD Ch) 5 : 1.50 (9H, s), 2.67 (2H, br.s), 3.73 (2H, br.s), 4.55 (2H, s), 6.90 (lH, d, J = 16.1 Hz) , 7.29-7.42(3H,m), 7.46(lH,d,J = 16.1Hz), 7.52(2H,d,J = 7.3Hz). MS(FAB)m/z:327(M + H) +, 27 1 (M-isobutene + H) +, 227 (M-Boc + H) + .

[Engineering 8] 2-Mercapto-6,7-dihydrocarbazo[5,4_(:]pyridine_5(4;^)-carboxylic acid tert-butyl ester

2-[^)-2-Styryl]-6,7-dihydrooxazolo[5,4-called pyridine_5 (tetrahydrofuran (803 mg) in tetrahydrofuran (16 ml)) The solution was stirred at room temperature with acetone (8.0 ml), water (4.0 ml), N-methylmorpholine N-oxide (577 mg) and 0.039 m. After adding ethyl acetate (50 ml) and a 10% aqueous sodium thiosulfate solution (50 ml), the aqueous layer was extracted with ethyl acetate (30 ml). The solvent was evaporated under reduced pressure. EtOAc (EtOAc) (EtOAc) The reaction mixture was combined with ethyl acetate (30 ml) and EtOAc (EtOAc) After drying, the solvent was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ' H-NMR (CDCh) (5: 1.49 (9H, s), 2.77 (2H, br.s), 3.77 (2H, br.s), 4.62 (2H, s), 9.70 (lH, s).

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

a solution of 2-methylmercapto-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (225 mg) in methanol (9.0 ml) at room temperature Sodium cyanide (220 mg) and manganese dioxide (78 mg) were stirred for 30 minutes, and then filtered over Celite using ethyl acetate. The filtrate was washed with water (50 m: 1) and brine (50 ml) and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography chromatography eluting elut elut elut 'H-NMRCCDCh) (5: 1.49 (9H, s), 2.73 (2H, br.s), 3, 74 (2H, br.s), 4.01 (3H, s), 4.59 (2H, s). 62- 200909437 MS(FAB)m/z: 283 (M + H) + .

[Engineering 10] 5-Methyl-4,5,6,7-tetrahydrocarbazo[5,4-(:]pyridine-2-carboxylic acid lithium salt (16-d)

6,7-Dihydrooxazolo[5,4-c]pyridine-2,5(4H)-dicarboxylic acid 5-(t-butyl)2-methyl ester (500 mg) in dichloromethane (15 ml) The solution was added trifluoroacetic acid (15 ml) at room temperature and stirred for 10 min. The reaction mixture was concentrated under reduced pressure. dichloromethane (20 ml), triethylamine (0.495 ml), acetic acid (205 ml), formaldehyde (0.230 ml) and sodium triethoxy hydride hydride (570 mg) . After stirring for 15 minutes, the mixture was combined with methylene chloride (20 ml) and EtOAc (EtOAc) The organic layer was combined, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography chromatography chromatography chromatography 'H-NMR CCDCh) 5 : 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-〇CH3) + .

[Reference Example 35] 5-Methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole-2-carboxylic acid lithium salt (16-e) [Engineering 1] 5--benzenesulfonate Mercapto)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole

Under ice cooling, phenylsulfonamide (6 3 8 mg) and 4,5-bis(bromomethyl)thiazide-63- 200909437 (M_A1.Hariri, 〇.Galley, F.Pautet, H.Fillion, Eur .J.Org.Chem.199 8,593-5 94.) ( 1.lOg) dissolved in N,N-dimethylformamide (10ml), one-half sodium hydrogenation (60% oily '3 57mg) Stir at room temperature for 3 hours. The mixture was combined with EtOAc (EtOAc m. . 'H-NMR (CDCl3) &lt;5: 4.60-4.63 (2H, m), 4.70-4.7 3 (2H, m), 7.52- 7.64 (3H, m), 7.8 8 - 7.9 2 (2H, m), 8.71 (lH, s). MS (FAB) m / z: 267 (M + H) + .

[Engineering 2] 5,6-Dihydro-4H-pyrrolo[3,4-d]thiazole 2 hydrobromide

5-(Benzenesulfonyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole (800 mg), phenol (800 #1) and 47% aqueous hydrobromic acid (5.00 ml) The mixture was heated to reflux for 2 hours. After cooling to room temperature, ethyl acetate and water were added to separate the layers, and the aqueous layer was evaporated under reduced pressure. The residue was combined with ethyl acetate. 'H-NMR (DMSO-d6) &lt;5: 4.42 (2H, br s), 4.56 (2H, br s), 9.14 (lH, s). MS (FAB) m/z: 127 (M + H) + .

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

The title compound was obtained from [5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-hydrobromide. -64- 200909437 'H-NMR (CDCl3) (5: 2.67 (3H, s), 3.95-3.99 (2H, m), 4.01-4.05 (2H, m), 8.69 (lH, s). MS (ESI) m/z: 141 (M + H) + .

[Engineering 4] 5-Methyl-5,6-dihydro-4H-pyrido[3,4-d]pyrazole-2-carboxylic acid lithium salt (16-e)

The title compound was obtained from 5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole as described in [Comp. 5]. *H-NMR (DMSO-d6) 5 : 2.52 (3H, s), 3.7 3 (2 Η, t, J = 3.2 Η z), 3.87 (2H, t, J = 3.2 Hz).

[Reference Example 36] 5-methyl-5,6,7,8-tetrahydro-4: «-thiazolo[5,4-6]azepine-2-carboxylic acid lithium salt (16-f) [ Engineering 1] 5-[(4-Tolyl)sulfonyl]-5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]azepin-2-amine

[y-nh; 3-bromo-1-K4-tolyl)sulfonyl]-4-azepine (I. Chem. Soc. Perkin Trans., 1995, Vol. 1, p. 23 5 5 (6.54g) of N,N-dimethylformamide (10〇1111) solution, added with thiourea (1.442), at 60° (: heating and stirring at night. After evaporation of the solvent under reduced pressure, add two to the residue) The organic layer was combined with dichloromethane (100 ml), and the organic layer was combined and dried over anhydrous magnesium sulfate. The obtained residue was added with ethyl acetate U OOrnl), and the precipitated thin yellow-65-200909437 powder was collected by filtration to obtain 5·[(4-methylphenyl)sulfonyl]-5,6,7,8-tetra. Hydrogen-4H-thiazolo[5,4-c]azepine-2-ylcarboxamide (1.86 g). The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (methanol: methylene chloride =1:1) to give 5-[(4-methylphenyl)sulfonyl]-5,6,7,8- A mixture of hydrogen-411-thiazolo[5,4-indene:]azepin-2-ylcarboxamide and the title compound (4.01 g). This mixture was combined with the above crude product, suspended in dioxane (50 ml), EtOAc (EtOAc) The solvent was evaporated under reduced pressure, and dichloromethane (250 ml) and saturated aqueous sodium carbonate (200 ml) was applied to the mixture, and the oil layer was dried over anhydrous magnesium sulfate and evaporated. The residue was combined with diisopropyl ether (100 ml). 'H-NMR (CDCh) (5: 1.7 5 - 1. 8 7 (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) &gt; 7.61 (2H, d, J = 8.5 Hz). MS (ESI) m /z:324(M + H) + .

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

5-[(4-Tolyl)sulfonyl]-5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]azepin-2-ylamine, imitation [Reference Example 35] [Engineering 2] treatment, the title compound was obtained. 'H-NMRC DMSO-de) 5 : 1. 9 5 (2H, br. s), 2.7 0 - 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) + . -66- 200909437 [Engineering 3] 5-methyl-5,6,7,8-tetrahydro-41 thiazole And [5,4-〇]吖heptin-2-ylamine

5,6,7,8-Tetrahydro-4H-thiazolo[5,4-c]azepin-2-ylamine hydrobromide (2.73g) was suspended in methanol under ice cooling. Triethylamine (2.30 ml), acetic acid (45 3 to 1), 37% aqueous formaldehyde solution (668 #1) and sodium cyanoborohydride (544 mg). After stirring overnight at room temperature, a saturated aqueous solution of sodium hydrogencarbonate (20 ml) was evaporated and evaporated. The residue was purified by silica gel chromatography (methanol: dichloromethane = 3:17). Methanol (100 ml) and anhydrous sodium carbonate (2 〇g) were added to the obtained crude product, and the mixture was stirred at room temperature for 30 minutes, and then the insoluble material was filtered. After the filtrate was concentrated under reduced pressure, dichloromethane (250 ml) and methanol (50 ml) were added to the residue, and the insoluble material was filtered. The filtrate was concentrated under reduced pressure. EtOAc (EtOAc) 'H-NMR (CDCl3) &lt;5: 1.7 0- 1. 8 5 (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: 1 84 (M + H) + .

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

Let 5-methyl-5,6,7,8-tetrahydro-411-thia[1 sit and [5,4-(:][1丫gyne-2-amine (1 · 1 3 g) suspended in Water (10 m 1), add 4 8 % aqueous hydrobromic acid solution (7 · 0 m 1), stir under ice-cooling. Carefully drip the aqueous solution containing sodium nitrite (6 3 9 mg) (3.0 ml) After the end of the dropwise addition, the suspension was stirred at room temperature overnight -67-200909437. Under ice cooling, methylene chloride (丨00 ml) was added to the reaction mixture, and saturated aqueous sodium carbonate solution was added thereto for neutralization after stirring. The aqueous layer was extracted with methylene chloride (m.p. EtOAc) (yield: EtOAc (EtOAc: EtOAc) IH-NMR (CDCl3) 6: 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)+.

[Engineering 5] 5-Methyl-5,6,7,8-tetrahydro-411-thiazolo[5,4-(:]azepine-2-carboxylate (16-f)

[Project 5] [Reference Example 32], titled by 2-bromo-5-methyl-5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]azepine Compound. iH-NMIUDMSO-de) &lt;5: 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-carboxylate lithium salt (16-g) [Project 1 6-Methyl-5,6,7,8-tetrahydro-411-thiazolo[4,5-(1]azepin-2-ylamine

[Law 3] [Reference 3], from 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin-2-ylamine (Special Kaiping 2-45489) Bulletin) 'title compound-68- 200909437 'H-NMR (CDCl3) (5: 2.44 (3H, s), 2.66-2.69 (2H, m), 2.7i (4Hs) 2.80-2.83 (2H, m), 4.66 (2H, s). MS (ESI) m/z: 184 (M + H) + .

[Engineering 2] 2-bromo-6-methyl-5,6,7,8-tetrahydro-41 azolo[4,5_(1][^庚医1

[Engineering 4] of [Reference Example 32] consists of 6-methyl-5,6,7,8-tetrahydro-4H-thiazeto[4,5-d]azepin-2-ylamine, The title compound was obtained. 'H-NMR CCD Ch) (5: 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) + .

[Engineering 3] 6-Methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine-2-carboxylic acid lithium salt (16_g)

[Reference Example 32] [Engineering 5] 'By the title of 2-bromo-6-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine Compound. H-NMR (DMSO-d6) (5: 2.33 (3H, s), 2.56-2.63 (4H, m), 2.77-2.93 (4H, m). MS (ESI) m/z: 213 (M + H ) + .

[Example l] (lS,3R,4S)-4-amino-3-[(t-butoxycarbonyl)amino]cyclohexanecarboxylic acid ethyl ester 1 oxalate (17a) -69- 200909437

〒o2h co2h \ V, a 50 ml four-necked flask was used as a reaction vessel, and (lS,3R,4R)-4-methanesulfonyl-3-[(tatabutoxycarbonyl)amino]cyclohexanecarboxylic acid was added. Ethyl ester (l〇g, 27.4 mmol) (5), tetrabutylammonium chloride (2.27 £, 13.7111111〇1), sodium azohydride (3.562, 54.9 mol) and N-methyl-2-pyrrolidone (20ml). The suspension was stirred at an internal temperature of 60 ° C for 60 hours. The reaction mixture was cooled to room temperature, then ethyl acetate (7 5 m 1) and water (75 ml) were added and the organic layer was separated. The aqueous layer was extracted with EtOAc (EtOAc) (EtOAc) (EtOAc) Add ethanol (100 ml) to the obtained organic layer, and sequentially add 7_5%-Pd-C (Type PH) (1.5 g) and ammonium formate (3.80 g) under stirring, and heat to an internal temperature of 5 0 °. Stir for 1 hour with C. The reaction solution was cooled to room temperature (about 25 ° C). Pd-C was filtered through a glass filter, and the filtered Pd-C was washed with ethanol (20 ml). The filtrate was concentrated to 53.86 g of EtOAc. This solution was added dropwise to a solution of oxalic acid (2.63 g, 20.9 mmol) in ethyl acetate (50 ml). The mixture was stirred for 3 hours, and crystals were crystallised eluted eluted ethyl acetate (5 ml). The crystals were dried under reduced pressure to give the title compound (17a) (yield: 7.49 g) (yield: 73.4%), which was obtained as a mixture of the isomer (20a) (4.5% by HPLC area). MS (ESI) m / z: 287 (M - C2 〇 4H) + '&gt; 'H-NMR (DMSO-d6) (5: 1.15 - 19.19 (3H, t, J = 7.3 Hz), 1.36- 1.45 ( 10H,m), 1.5 8- 1.67(3H,m), 1.85(2H,m), 2.71- 2.77(lH,m), 3 .1 7 - 3.20 (1 H, m), 4.02( 1 H,br ) 4. 〇 5 (2H, q , -70- 200909437 J = 7.3 Hz), 7.06 (lH, d, J = 8.9 Hz). Separation of the title (17a) from the isomer (20a) by HPLC The following conditions: AgilentllOO system (DET: G1315A/PUMP: DE9 1 60762) or Shimadzu CLASS-VP system (SCL10Avp/SCL-10AVP/SPD-M10AVP); Column: CAPCELLPAK-CN UG120 (4.6mmx250mm) analytical column: Flow rate: 1.0 ml/min; Dissolution solvent (same solvent): 30% acetonitrile / 70% - 20 mM phosphate buffer (pH 7.0: containing 20 mM sodium dodecyl sulfate); Detection: UV (210 nm). Retention time: Title compound U7a) 21.0; isomer (20a) 23.3 [Example 2] (lS,3R,4S)-4-amino-3·[(t-butoxycarbonyl)amino]cyclohexanecarboxylate Ethyl acetate 1 (DL)-malate (17b) C〇2Et

A 1-liter four-necked flask was used as a reaction vessel, and ethyl (lS,3R,4R)-4-methylsulfonyl-3_[(t-butoxycarbonyl)amino]cyclohexanecarboxylate (5) was added (5) 250 g, 0.68 mol), tetraethylammonium chloride (34.0 g, 〇.2 〇mol), sodium azohydride (89 g, 1.36 mol) and N-methyl-2-pyrrolidone (0.5 1). The suspension was stirred at an internal temperature of 60 ° C for 60 hours. The reaction mixture was cooled to room temperature and ethyl acetate (1.88 1) and water (1.88 1) The aqueous layer was re-extracted with ethyl acetate (0.63 1) and combined with the previous organic layer, washed with 5% aqueous sodium bicarbonate (2.5 1) and water (1.25 1). -71- 200909437 The resulting ethyl acetate solution was concentrated to 0.75, and then ethanol (1.75 1) was added and concentrated under reduced pressure to 0.75 1 (this operation was carried out 2 times). Add ethanol to the concentrated residue and adjust the total amount to 1.5 1. The solution was sequentially added with 7.5% - Pd- &lt;: (made by Chuanxiong Chemical Co., Ltd.: D. 7?6?:») (37.5 §) and ammonium formate (95 §), and heated to an internal temperature of 4 (TC, Stir for 1 hour. The reaction mixture was cooled to room temperature (about 25 ° C), Pd-C was filtered through a glass filter, and the filtered Pd-C was washed with ethanol (0.5 1). The filtrate was concentrated to 0.75 1, plus Acetonitrile (1.75 1), concentrated to 0.75 1 (repeated this operation twice). Add acetonitrile to the concentrated residue to make a total amount of 1.5 1. In this solution, add (DL)-malic acid at an internal temperature of about 30 ° C ( 66g, 0.71mol), the internal temperature is 20 ° C for 1 hour, the internal temperature is 10 ° C for 1 hour, and the mixture is cooled in stages, and finally stirred at an internal temperature of 0 ° C for 2-4 hours. The crystals are separated by filtration and crystallized to cool acetonitrile 0.25 1 The crystals obtained were washed under reduced pressure at 40 ° C to give the titled product, U7b) (223 g, yield: 77.6%), which was obtained as a mixture with an isomer (in terms of HPL area of 0.86%). 'H-NMR (DMS0-d6) &lt;5:1.15-1.19 (3H, t, J = 7.1 Hz), 1.39-1.49 (10H, m), 1.58-1.66 (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 (lH, m), 3.17-3.20 (lH, m), 3.84-3.91 (lH, m), 4.02 (lH, br) 4.07 (2H, q, J = 7.3 Hz), 7.02 (lH, d, J = 8.9 Hz).

[Example 3] (lS,3R,4S)-4-amino-3-[(t-butoxycarbonyl)amino]cyclohexanecarboxylic acid ethyl ester 1 (L)-malate (21) - 72- 200909437

A 100 ml four-necked flask was used as a reaction vessel, and ethyl (lS,3R,4R)-4-methylsulfonyl-3-[(t-butoxycarbonyl)amino]cyclohexanecarboxylate (5) (20 g) was added. , 54.7 mmol), tetraethylammonium chloride (4,54 g, 27.4 mmol), sodium azohydride (7.12 g, 109.4 f mol) and N-methyl-2-pyrrolidone (40 ml). The suspension was stirred at an internal temperature of 60 ° C for 66 hours. The reaction mixture was cooled to room temperature and ethyl acetate (150 ml) and water (150 ml) The aqueous layer was re-extracted with ethyl acetate (50 mL) and combined with EtOAc EtOAc (EtOAc) The obtained ethyl acetate solution was concentrated to 30 ml, and the residue was evaporated to ethyl ether (100 ml), and concentrated to a total amount of 60 ml (this operation was carried out twice). Ethanol was added to the concentrated residue to adjust the total amount to 200 ml. The solution was stirred while stirring. 7.5%-Pd-C (Type PH) (3.0 g) and ammonium formate (7.59 g) were heated to an internal temperature of 40 ° C and stirred for 1 hour. The reaction mixture was cooled to room temperature (about 25 ° C), and Pd-C was filtered through a glass filter, and the filtered Pd-C was washed with ethanol (40 ml). The filtrate was concentrated to 60 mL, EtOAc (EtOAc)EtOAc. The concentrated acetonitrile solution was divided into two portions, and acetonitrile was added in half amount to prepare a total amount of 80 ml. A total amount of 80 ml of an 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 precipitated crystals were kept uniform -73-200909437 and stirred at room temperature overnight, and then stirred at an internal temperature of 3 to 5 ° C for 2 hours. The crystals were collected by chromatography, washed with EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH obtain. 'H-NMR(DMSO-d6) ό : 1.1 5-1.1 9(3Η,t,J = 7.1 Hz), 1.36-1.45 (10H,m), 1.5 8- 1.67(3H,m), 1.85(2H, m), 2.3 0 (dd, J = 1 5.8, 4.1 Hz) 2.48-2.55 (2H, m) 2.71-2.77 (lH, m), 3 .1 7 - 3.2 2 (1 H, m), 3.85-3.89 (lH,m), 4.02 (1 H ,br )4.07 (2H, q, J = 7. 1 H z), 7.04 (lH,d, J = 8.7Hz).

[Example 4] (lS,3R,4S)-4-amino-3-[(t-butoxycarbonyl)amino]cyclohexanecarboxylic acid ethyl ester 1 (D)-malate (22) C02Et

The solution remaining in the above-mentioned [Example 3] was divided into two parts, and acetonitrile was added to prepare a total amount of 80 ml, and a 100 ml four-necked flask was placed. To the solution was added (D)-malic acid (3.06 g, 22.8 mmol) for stirring. The precipitated crystals were kept in the same manner and stirred at room temperature overnight, and then stirred at 3 to 5 ° C for 2 hours. The crystals were collected by chromatography, washed with EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH obtain. 'H-NMR (DMSO-d6) (5:1.14-1.19 (3H, t, J = 7.3 Hz), 1.39-1.45 (l〇H, m), 1.5 8 - 1.67 (3H, m), 1.85 (2H ,m), 2.29 (dd, J= 1 5.5 , -74- 200909437 3.6Hz) 2.48-2.54(2H,m)2.71-2.77(lH,m), 3 .1 7 - 3.2 1 (l Η, m) , 3.84-3.91(lH,m), 4.02(1H ' br)4.07(2H,q, J = 7.3Hz), 7.〇2(lH, d,J = 8.9Hz).

[Example 5] 1-(5-chloropyridin-2-yl)-indole-[(13,211,43)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[ 5,4-c]pyridin-2-yl)carbonyl]amino}-4-(ethoxycarbonyl)cyclohexyl]ethanedioxanamide (2-a)

(lS,3R,4S)-4-Amino-3-[(tatabutoxycarbonyl)amino]cyclohexanecarboxylic acid ethyl ester 1 (DL)-malate (17b) (10.0 g, 23-8 mmol) , N-(5-chloropyridin-2-yl) oxalic acid ethyl ester (6.94 g, 26.2 mmol) and triethylamine (9.63 g, 95.2 mmol) in acetonitrile (40 ml) at internal temperature 65~ Stir at 70 ° C for 5 hours. The reaction mixture was cooled to 40 ° C, and water was added thereto, and the mixture was stirred at an internal temperature of 30 to 40 ° C for 1 hour, and then extracted with toluene (70 ml). After the extract was washed twice with water (30 ml), the toluene was concentrated under reduced pressure. To the residue obtained was added acetonitrile (1 〇〇 ml), and the mixture was subjected to reduced pressure and concentrated, and the solvent was replaced by acetonitrile. To the obtained residue in acetonitrile, acetonitrile was added to give a full amount of 1 〇〇ml, and methanesulfonic acid (1. 4 g, l 19 mmol) was added, and the mixture was stirred at 30 ° C for 1 hour. After the reaction mixture was dissolved in triethylamine (12.8 g, 126 mmo; l), hydroxybenzotriazole (364 mg, 2.38 mmol), 5·methyl-4,5,6,7-tetrahydro- Thiazino[5,4-c]D-pyridin-2-carboxylic acid hydrochloride (5.87 g, 25.0 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride (5.01 g, 26.2 mmol) was stirred at room temperature overnight. After adding triethylamine (2.89 g, 28.6 mmol) to the reaction mixture, water (80 ml), -75-200909437 at room temperature for 3 hours, stirring at 3 to 5 ° C for 4 hours, and then crystallized by filtration, followed by acetonitrile. Washed with water (1/1) (20 ml), water (20 ml) and acetonitrile/water (1/4) (20 ml) and dried to give the title compound (2-a) (1 l. %), obtained as a mixture with an isomer (0.1% by area or less based on HPLC area). The following conditions were used for separation according to HPLC. Device: AgilentllOO system (〇£!': 〇1315 八/?111^?: 9£9 1 60762) or Shimadzu CLASS-VP system (SCL10Avp/SCL-10AVP/SPD-M10AVP); Column: CAPCELLPAK-CN UG120 ( 4.6mmx250mm) analytical column; flow rate: 1.0ml/min; dissolution solvent (same solvent): 35% acetonitrile: 65%-20mM phosphate buffer (pH7.0) detected: UV (220nm). Hold time: title compound ( 2-a) 13.9 minutes; isomer 14.7. MS (ESI) m/z: 549 (M + H) + ; 'H-NMR CCD Ch (5: 1.26- 1.29 (3H, t, J = 7.1 Ηz), 1.61-1.78 (2H,m), 1.96-2.22(4H,m), 2.45-2.64(4H,m), 2.7 9 - 2.8 9 (2H, m) 2.94-2.96(2H,m)3.68- 3.77(2H,m), 4.65-4.68( 1 H,m), 4.13-4.19 (2H,q,J = 7.1Hz), 7.3 8 (1 H, d, J = 8.7H z), 7.67-7.7 0 ( 1 H, dd, J = 9.1, 2.4 Hz), 8.07 (lH, dJ = 7.9 Hz), 8. 1 7 (1 H , d J = 8.7 H z), 8.31 (lH, dJ = 2.9 Hz), 8.31 (lH, s).

[Example 6] 屮-(5-chloropyridin-2-yl)-N2-[(lS,2R,4S)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazole) And [5,4-c]pyridin-2-yl)carbonyl]amino}-4-(ethoxycarbonyl)cyclohexyl]ethanedioxanamide (2-a) -76- 200909437

((lS,3R,4S)-4-Amino-3-[(t-butoxycarbonyl)amino]cyclohexanecarboxylic acid ethyl ester 1 oxalate (17a) (2.0 g, 5.31 mmol), Ethyl-(5-chloropyridin-2-yl)oxalyl ethyl ester (1.4 82, 5.5 6111111〇1) and triethylamine (3.441111, 26.5 5111111〇1) in acetonitrile (10 ml) at an internal temperature of 65~ After stirring at 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 successively water (8 ml), 5% brine (6 ml) and saturated brine / 4% After washing with a mixture of sodium hydrogen carbonate and water (1 ml) (12 ml), MgSO4. The acid (1.53 g, 15.9 mmol) was stirred for 4 hours. After the reaction mixture was dissolved with triethylamine ( 1.737 g, 17.5 mmol), 1-hydroxybenzotriazole (7 2 mg, 0.53 mmol), 5-A was added. 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-di Methylaminopropyl)carbodiimide hydrochloride (1.12 g, 5.84 mmol), stirred at room temperature for one night. After adding water (7.5 ml) to the reaction mixture, add three Ethylamine (0.65 g, 6.37 mmol), further added with water (22.5 ml) and stirred for 2 hours. Crystallization was precipitated by filtration, followed by acetonitrile / water (1/2) (7.5 ml), water (2.5 ml) and acetonitrile / After washing with water (4/1) (2.5 ml), the title compound (2-a) (2.31 g, yield: 85.3%) was obtained to give an isomer (with HPLC area % of 0.1% or less). The mixture of the compounds was obtained in accordance with the data of the compound produced in [Example 5]. [Example 6] -(5-chloropyridin-2-yl)-indole-[(13, 2 ,43)-2-{[(5-methyl--77- 200909437 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino-4-b 4- (carboxy) cyclohexyl]ethanediamine (3-a)

1^-(5-chloropyridin-2-yl)-N2-[(1S,2R,4S)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5 , 4-c]pyridin-2-yl)carbonyl]amino}-4-(ethoxycarbonyl)cyclohexyl]ethanedioxanamide (2-a) (5.0 g, 9.1 mmol) was added to 500 ml of 4 The flask was stirred with a 6N aqueous solution of hydrochloric acid (50 ml) at rt. The reaction solution was cooled, and 4N aqueous sodium hydroxide solution (50 ml) was added at an internal temperature of 20 ° C or less, and then methanol (60 ml) was added to obtain a homogeneous solution. Further, 4N aqueous sodium hydroxide solution was added, and the pH was adjusted to 3.78 (using a 4N aqueous sodium hydroxide solution of 15 to 25 ml), and the mixture was stirred for 15 hours. The crystals were collected by filtration, washed with water, and then dehydrated at 40 ° C. The title compound (3-a) (3.41 g, yield 71.8%, yield: 99.3% by HPLC) was obtained. [Example 7] 屮-(5-chloropyridin-2-yl)-N2-[( lS,2R,4S)-2-{[(5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4- (fluorenyl)cyclohexyl]ethanediamine (4-a)

屮-(5-chloropyridin-2-yl)-indole-[(13,211,43)-2-{[(5-methyl-4,5,6,7. tetrahydrothiazolo[5,4- c]pyridin-2-yl)carbonyl]amino}-4-(ethoxycarbonyl)cyclo-78- 200909437 hexyl]ethanediamine (2-a) (15.0 g, 27.3 mmol) plus dimethylene飒 (150 ml) and 8 equivalents (8N) of aqueous sodium hydroxide (10.25 ml) were stirred at room temperature 3 Ot for 3 hours. After cooling the reaction mixture to 8 ° C, concentrated hydrochloric acid (9.34 ml) and hydrazine hydrate (3.32 ml, 68.3 mmol) were added, and then adjusted to ρ Η9·4 with concentrated hydrochloric acid. Here, acetonitrile (75 ml), 1-hydroxybenzotriazole monohydrate (2.09 g, 13.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added. (6.81 g, 35.5 mmol), stirred at an internal temperature of 20 ° C (in stirring, to maintain pH 7.7 to 8.3 of the reaction solution, 8 N aqueous sodium hydroxide solution). After the reaction mixture was stirred for one night, the mixture was cooled to an internal temperature, and then aq. EtOAc (3 mL) was evaporated, and then, and the mixture was stirred for 1 hour, and the mixture was stirred for 2 hours, and the mixture was stirred for 2 hours. After washing with water (75 ml), the title compound (4 - a) (1. MS (ESI) m / z: 5 3 5 (M + H) + ; 'H-NMR (CDCl3) ά : 1.64- 1.70 (3H, m), 1. 7 9 - 1 . 8 8 ( 1 Η, m ), 2.01- 2.13(4H,m), 2.3 6 - 2.4 3 ( 1 Η, 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-k 4.12 (lH, m), 4.66-4_69 (lH, m), 6.96 (lH, s), 7.39-7.4i (iH, d, J = 8.3 Hz), 7.67-7.70 (lH, ddJ = 8.9, 2.6 Hz), 8.06 (1 Η, d J = 7.6H z), 8.16 (lH, dJ = 8.3 Hz), 8.31 (lH, d, J = 2.6 Hz) ).

[Example 8] 屮-(5-chloropteridin-2-yl)-N2-[(lS,2R,4S)-2-{[(5-methyl-4,5,6,7-tetrahydro) Thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(pen:indolyl)cyclohexyl]ethanedioxylamine (4-a) -79- 200909437

1^-(5-chloropyridin-2-yl)---[(15,211,43)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4- c]pyridin-2-yl)carbonyl]amino}-4-(ethoxycarbonyl)cyclohexyl]acetamidine diamine (2-a) (30_0g, 54-9 mmol) plus 6N aqueous hydrochloric acid (300 ml) Stir at 18 ° C for 17 hours. The reaction solution was cooled, and aq. EtOAc (EtOAc) After the reaction mixture was stirred, hydrazine hydrate (6-7 ml, 137 mmol) was added, and after adding 6 N aqueous sodium hydroxide solution to adjust to pH 7.0, the force [] 1-hydroxybenzotriazole (2.2 g, 16.3 mM) was added. And 1-ethyl_3_(3-dimethylaminopropyl)carbodiimide hydrochloride (11.6 g, 60.5 mmol). Further, a 6 N aqueous sodium hydroxide solution was added under stirring with the reaction mixture to adjust to ρη 7.2. Since the pH was lowered by the precipitation of the crystals, the aqueous solution of sodium hydroxide was added thereto to adjust to ρ Η 6.4 to 7.2, and the mixture was stirred at room temperature for 20 hours. The crystals were collected by filtration, washed with water (3 MeOH), EtOAc (EtOAc) (EtOAc) The various spectral enthalpies of this compound are consistent with those of [Example 6]. [Example 9] 屮-(5-chloropyridin-2-yl)-N2-[(lS,2R,4S)-2-{[(5-methyl. 4,5,6,7-tetrahydrothiazole) And [5,4-c]pyridin-2-yl)carbonyl]amino}-4-([1,3,4]oxadiazol-2-yl)cyclohexyl]ethanedioxanamide (1-a ) -80- 200909437

In 1^-(5-chloropyridin-2-yl)-N2-[(lS,2R,4S)-2-U(5-methyl-4,5,6,7-tetrahydrothiazolo[5, 4-c]pyridin-2-yl)carbonyl]amino}_4-(indolylcarbonyl)cyclohexyl] phenylene diamine (4-&amp;) (8. ,£, 15. 〇111111〇1) plus two Methylacetamide (4〇1111), triethyl orthoformate (16 ml) and 47% boron trifluoride-tetrahydrofuran (6.30 g, 45 mmol) were stirred at an internal temperature of 45 to 50 ° C for 2 hours. The reaction liquid was added with triethylamine (5.3 1 g, 5 2 · 5 m ο 1) and ethanol (1 6 m 1 ) water 8 2 m 1 '泸 to precipitate crystals, which were washed with water (80 m 1 ). Dry under reduced pressure to give the title compound (7.6 g). [Example 10] as -(5-chloropyridin-2-yl)-N2-[(1S,2R,4S)4-dimethylaminemethylmercapto-2-U(5-methyl- 4,5, 6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-cyclohexyl]ethanedioxanamide (la-a)

11^1-(5-gas 卩 ratio 11 -2-yl)-]^2-[(13,211,43)-2-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(ethoxycarbonyl)cyclohexyl]ethene-amine (2-a) (10.0 g, 18.2 mmol), Dimethyl hydrazine (100 ml) and 8 equivalents (8 N) of aqueous sodium hydroxide solution (6.8 ml) were stirred at an internal temperature of 30 ° C for 4.5 hours. After the reaction mixture was cooled to 8.0, concentrated hydrochloric acid (6 · 25 m 丨) and 40% aqueous dimethylamine solution (5 · 8 m 1 , 4 5 · 5 mm ο 1 ), and then added - 81 - 200909437 Concentrated hydrochloric acid to adjust the pH to around 9.4. To the reaction mixture was added 1-hydroxybenzotriazole monohydrate (1.38 g, 0.91 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.54 g). 20.1 mmol), stirred at room temperature for 2 hours under nitrogen atmosphere. Add acetonitrile (50 ml), 40% aqueous dimethylamine solution (1.0 ml, 8.0 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride to the reaction mixture ( Stir at 0.68g ' 20. lmmol) for one night. Water (100 ml) was added to the reaction mixture, and 8N aqueous sodium hydroxide solution was added thereto to adjust to pH = 9.0, and the mixture was stirred at an internal temperature of 8 ° C for 3 hours. The crystals were separated by filtration, washed with water (50 ml), MS (ESI) m / z: 548 (M + H) + . 'H-NMIUCDCh:^: 1.62-1.7 2 (lH, qd, J = 12.8, 4.0 Hz), 1.77-1.87 (lH, m), 1 .93- 1.96(lH,m), 2.02 - 2.1 4 (3 H, m), 2.52(3H,s)2.79-2.90(5H,m)2.95(3H,s), 2.9 8 - 3.0 2 ( 1 H , m), 3.06(3H,s), 3.72 (2H,q,J = 8.0Hz), 4.0 8 - 4.1 5 (1 H , m), 4.67 - 4.7 0 ( 1 H, m), 7.41 (1H, d, J = 7.6 Hz), 7.67-7.70 (lH, dd, J = 8.8, 2.0 Hz), 8.05 (lH, d, J = 8.8 Hz), 8.30-8.31 (lH, d, J = 6.4 Hz), 9.7(lH,s). [Simple description of the diagram] Μ 〇 [Key component symbol description] 〇/\ w -82-

Claims (1)

200909437 X. Patent application scope: 1. A method for preparing a compound of formula U), which is characterized by the following compound of formula (4) (wherein R1 is a hydrogen atom, a halogen group, a linear or branched chain C1 to C4 alkyl group, a halogenated Cl~C4 alkyl group, a linear or branched chain C1 to C4 alkoxy group or a nitrate R2 is a hydrogen atom, a halogen group, a linear or branched chain C1 to C4 alkyl group or a linear or branched chain C1 to C4 alkoxy group; R3 and R4 may be the same or different hydrogen Aromatic or linear or branched chain C1~C4 alkyl; R5 is a hydrogen atom or a fluorenyl group; a benzene ring, a thiophene ring or a pyridine ring; a partially constructed ring B Is 4,5,6,7-tetrahydrothiazolo[5,4-(:]pyridine ring, 4,5,6,7-tetrahydrocarbazo[5,4-c]pyridine ring, 5,6 ,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine ring, 5,6,7,8-tetrahydro-4H-salzolo[4,5-c]azepine Ring or 5,6-dihydro- 200909437 4H-pyrrolo[3,4-d]thiazole ring), in the presence of a Lewis acid in an aprotic polar solvent, with orthoformic acid or normal acetate Treated by the following formula (1) (wherein R6 is a hydrogen atom or a methyl group, R1, R2, r3, r4, ring A and ring B are the same as defined above). 2 . The method for preparing a compound of the formula (3), which is characterized in that the compound of the following formula (2) (wherein R1 is a hydrogen atom, a halogen group, a linear or branched chain C1 to C4, a C1 to C4 alkyl group, a linear or branched chain, a C4 alkoxy group or a nitrate R2 is a nitrogen atom, a halogen group, a linear or branched chain C1 to C4 alkyl group or a linear or branched chain C1 to C4 alkoxy group; R3 and R4 may be the same or different hydrogen Aromatic or linear or branched chain C1-C4 alkyl; R7 is a linear or branched chain C1~C4 alkyl; -84 - 200909437 Partially constructed ring A Θ is a benzene ring, thiophene ring Or a cyclic structure of a pyridine ring moiety is 4,5,6,7-tetrahydrothiazolo[5,4_C;|pyridine ring, 4,5,6,7-tetrahydrocarbazole oxime [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 or a 5,6-dihydro-4-indole-pyrrolo[3,4-d]thiazole ring), hydrolyzed to give a compound of the following formula (3) (wherein R1, R2, R3, R4, ring A and ring B are the same as defined above). A process for the preparation of a compound of the formula (1), which is characterized by the compound of the following formula (2) (wherein R1 is a hydrogen atom, a halogen group, a linear or branched chain C1 to C4 alkyl group, a halogen C1 to C4 alkyl group, a linear or branched chain ci~C4 alkoxy group or a nitrate -85- 200909437 R2 is a hydrogen atom, a halogen group, a linear or branched chain Cl ~ C4 alkyl group or a linear or branched chain C1-C4 alkoxy group; R3 and R4 may be the same Or a C 1~C 4 alkyl group which is a hydrogen atom or a linear or branched chain; R 7 is a linear or branched chain C 1 -C 4 alkyl group; a benzene ring, a thiophene ring or a pyridine ring; a partially constructed ring B Is 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine ring, 4,5,6,7-tetrahydrocarbazo[5,4-(;]pyridine ring, 5,6 ,7,8-tetrahydro-411-thiazolo[4,5-〇1]azepine ring, 5,6,7,8-tetrahydro-4H-thiazepine[4,5-c]卩丫Gengine ring or 5,6-monohydro-4H-port ratio slightly [3,4-d]thiazole ring), hydrolyzed to obtain the compound of formula (3) CO.H (wherein R1, R2, R3, R4, ring A and ring B are as defined above) are condensed with an anthracene derivative in the presence of a condensing agent, so that the following compound of the formula (4) is obtained -86-200909437 (wherein R5 is a hydrogen atom or a carbenyl group, R1, R2, r3, r4, ring a and ring B are the same as defined above), and in the presence of a Lewis acid in an aprotic polar solvent, orthoformate Or a positive acetate treatment to obtain a compound of the following formula (1) (wherein R6 is a hydrogen atom or a methyl group; R1, R2, R3, R4, ring A and ring B are the same as defined above). I 4. The method of claim 3, wherein in the process of producing the compound (4) from the compound (2) via the compound (3), the compound (3) is not separated from the same reaction system (single bottle) Compound (4) is produced from Compound (2). 5. The method of claim 1 or 3, wherein R5 in the compound (4) is a hydrogen atom. 6. The method of claim 1 or 3, wherein the anthracene derivative is hydrazine hydrate. 7. The method of claim 1 or 3, wherein the condensing agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (water-soluble carbodiimide-87) - 200909437 Amine) or hydrazine, Ν-dicyclohexylcarbodiimide. 8. The method of claim 1 or 3, wherein the condensing agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (water-soluble carbodiimide) . 9. The method of claim 1 or 3 wherein the Lewis acid is a boron trifluoride-solvent complex. 10. The process of claim 1 or 3 wherein the boron trifluoride-solvent complex is a boron trifluoride-tetrahydrofuran complex. 1 1. The method of claim 1 or 3, wherein the aprotic polar solvent is hydrazine, hydrazine-dimethylformamide, hydrazine, hydrazine-dimethylacetamide, hydrazine-methyl-2 - pyrrolidone or dimethyl hydrazine. The process of claim 1 or 3, wherein the orthoformate or n-acetate is trimethyl orthoformate 'triethyl orthoformate, trimethyl orthoacetate or triethyl orthoacetate. 13. The process of claim 1 or 3 wherein the orthoformate or n-acetate is trimethyl orthoformate or triethyl orthoformate. 1 4 · A process for the preparation of a compound of the formula (1 a), characterized in that the compound of the formula (2) is co2r (wherein R1 is a hydrogen atom, a halogen group, a linear or branched chain C1 to C4 alkyl group, a halogen Cb C4 alkyl group, a linear or branched chain ci~C4 alkoxy group or a nitrate -88- 200909437 R2 is a hydrogen atom, a halogen group, a straight bond or a branched chain of a Cl~C4 alkyl group or a linear or branched chain C1~C4 alkoxy; R3 and R4 may be the same Or a C 1 ~ C 4 courtyard group having a hydrogen atom or a linear or branched chain; R7 is a linear or branched chain C1 to C4 alkyl; a benzene ring, a thiophene ring or a pyridine ring; a partially constructed ring B Is 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine ring, 4,5,6,7-tetrahydroindeno[5,4-c]pyridinium 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-411_disazo[3,4-d]thiazole ring), hydrolyzed, resulting in the following compound of formula (3) (wherein R1, R2, R3, R4, ring A and ring B are the same as defined above), which are condensed with a diamine in the presence of a condensing agent to give a compound of the following formula (la) -89- 200909437 (wherein R8 and R9 may be the same or different from a methyl group or an ethyl group, and R1, R2, R3, R4, ring A and ring B are the same as defined above). 1 5. The method of claim 14, wherein in the process of producing the compound (la) from the compound (2) by the compound (3), the compound (3) is not separated from the same reaction system ( The compound (la) is produced from the compound (2) in a single pot. The method of any one of claims 2, 3 and 14 wherein R7 is methyl or ethyl. 17. The method of claim 14, wherein R8 and R9 are methyl groups. The process according to any one of claims 2, 3 and 14, wherein the hydrolysis of the compound (3) produced by the compound (2) is acid hydrolysis. 1 9 The method of claim 18, wherein the acid used for the acid hydrolysis is an aqueous hydrochloric acid solution, an aqueous sulfuric acid solution or an aqueous phosphoric acid solution. 20. The method of claim 18, wherein the acid is 4 equivalents (4N) or more of aqueous hydrochloric acid. 2 1. The process according to claim 18, wherein the acid is 6 equivalents (6 N) or more of an aqueous hydrochloric acid solution. The process according to any one of claims 2, 3 and 4, wherein the hydrolysis of the compound (3) produced by the compound (2) is a base hydrolysis in the presence of an aprotic polar solvent. -90-200909437 23_ The method of the invention of claim 22 wherein the base used for the alkali hydrolysis is an aqueous solution of sodium hydroxide, potassium hydroxide or lithium hydroxide. 24. The method of claim 22, wherein the base is an aqueous solution of sodium hydroxide. 25. The method of claim 22, wherein the base is an aqueous solution of sodium hydroxide of 5 equivalents (5 N) or more. 26. The method of claim 22, wherein the base is an aqueous solution of sodium hydroxide of 8 equivalents (8 N) or more. 27. The method of any one of claims 22 to 26 wherein the aprotic polar solvent is N,N-dimethylformamide, N,N-dimethylacetamide, N-A Base-2-pyrrolidone or dimethyl hydrazine. 2 8. Part of the construction of the formula (1), (la), (2), (3) and (4) of the method of claim 1, 2, 3 and 14 Is 4-fluorophenyl, 4-bromophenyl, 4-chlorophenyl, 4-chloro-3-tolyl, 4-chloro-2-fluorophenyl, 4-chloro-2-methylphenyl, 4-chloro _3-nitrophenyl, 4-chloronitrophenyl, 3,4-difluorophenyl, 4-chloro-3-fluorophenyl, 4-chloro-3-methoxyphenyl, 4-chloro-2- Trifluorotolyl, 4-chloro-2-methoxyphenyl, 5-bromo-2-pyridinyl, 5-chloro-2-pyridyl, 5-methyl-2-pyridinyl or 5-chloro- 2-Thienyl. For example, the method of applying for any of the items 1, 2, 3 and 14 of the patent scope, in which part (1), (la), (2), (3) and (4) is constructed /*** D1 It is 5-chloro-2-pyridinyl. 200909437 3. For example, the method of applying for any of the scopes 1, 2, 3 and 14 of the patent, wherein part of the formula (1)' (la), (2), (3) and (4) is constructed as 5- (C C4 alkyl)-4,5,6,7-tetrathiathiazolo[5,4-c]pyridin-2-yl, 5-((:diphenyl-4-alkyl)-4,5,6,7 -tetrahydropurine 11 sits and [5,4-〇]pyridin-2-yl,6-(C1~C4 alkyl)-5,6,7,8-tetrahydro-4H-carbazole[4 , 5-d] anthraquinone-2-yl, 5-((:1~匚4 alkyl)-5,6,7,8-tetrahydro--thiazolo[4,5-(:]吖Heptin-2-yl or 5-(Cl~C4 alkyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl. 3 1. Patent application number 1 The method of any one of the items 2, 3, and 4, wherein part of the structures of the formulas (1), (la), (2), (3), and (4) Is 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]indole ratio D-but-2-yl, 5-ethyl-4,5,6,7-tetrahydro Thiazolo[5,4-c]pyridin-2-yl, 5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl, 5-methyl -4,5,6,7-tetrahydro Dfoxazolo[5,4-c]pyridin-2-yl, 6-methyl-5,6,7,8-tetrahydro-411-thiazolo[4, 5-(1) azepine-2-yl, 5-methyl-5,6,7,8-tetrahydro-41^thiazolo[4,5-(:]azepin-2-yl or 5 -Methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl. 3 2. As claimed in any of claims 1, 2, 3 and 14 The method of the item, in which part of the structures (1), (la), (2), (3) and (4) It is 5-methyl-4,5,6,7-tetrahydrothiazino[5,4-c]pyridin-2-yl. -92- 200909437 VII. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the symbol of the representative figure 4E. j \ \\ VIII. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: 〇 j\w