Edoxaban manufacturing method

Abstract

To provide an improved method for producing edoxaban.SOLUTION: For example, according to the production method shown by the following formula.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an improved method for preparing edoxaban, which has low cost, high reaction efficiency, short consumption time, and high product purity, and is suitable for large-scale industrial production. [Background technology]

[0002] As disclosed in Patent Documents 1 to 5, the following compound 1a and its pharmacologically acceptable salts or hydrates exhibit FXa inhibitory activity and are useful as prophylactic and / or therapeutic agents for thrombotic diseases and / or embolic diseases.

[0003] [ka]

[0004] The following scheme shows a general synthesis of edoxaban 1, in which tert-butyl ((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate oxalate 4 is reacted with 2-((5-chloropyridin-2-yl)amino)-2-oxoacetic acid 5 to produce the key intermediate tert-butyl ((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-(dimethylcarbamoyl)cyclohexyl)carbamate 6. Subsequent treatment of intermediate 6 under acidic conditions affords N1-((1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide 3, which is coupled with 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid 2 to produce edoxaban 1. HOBt and EDCI coupling reagents are commonly used for the coupling reaction.

[0005] [ka] [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2004 / 058715 [Patent Document 2] International Publication No. 2003 / 016302 [Patent Document 3] International Publication No. 2003 / 000680 [Patent Document 4] International Publication No. 2005 / 047296 [Patent Document 5] International Publication No. 2007 / 032498 Summary of the Invention [Problem to be solved by the invention]

[0007] The known method for synthesizing edoxaban 1 involves two coupling reactions and one boc deprotection reaction. The coupling reaction reagents used are EDCI and HOBt. tert-Butyl ((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-(dimethylcarbamoyl)cyclohexyl)carbamate 6 is a key intermediate for the synthesis of edoxaban.

[0008] WO 2003 / 000680 describes a compound represented by formula 6, tert-butyl ((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-(dimethylcarbamoyl)cyclohexyl)carbamate. In the above patent document, as shown in the following scheme, tert-butyl ((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate oxalate 4 reacts with lithium 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate 5 to give tert-butyl ((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-(dimethylcarbamoyl)cyclohexyl)carbamate 6.

[0009] [ka]

[0010] WO 2010 / 104078 discloses a method for preparing compound 6 by treating tert-butyl ((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate oxalate 4 with ethyl-2-((5-chloropyridin-2-yl)amino)-2-oxoacetate hydrochloride 7.

[0011] [ka]

[0012] Later, acid (H +) conditions to give N1-((1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide 3. Compound 3 is reacted with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate 2a (WO 2003 / 00680) or 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride 2 to give edoxaban 1 (WO 2003 / 00680).

[0013] [ka]

[0014] WO 2003 / 000680 also discloses a method for preparing edoxaban 1 by coupling an amine compound represented by the following general formula 3 with an active ester compound 8 in the presence of an alkali metal (tri)phosphate. The drawback of this method is that the preparation of ester 8 and the use of a combination of an expensive palladium catalyst and a phosphine ligand make mass production difficult.

[0015] [ka]

[0016] Most of the patent documents use 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBT) as carboxyl activators in the coupling reaction (step). EDC reagents are widely used in the field of organic synthesis, but have the disadvantages of being expensive, low reactivity, and unsuitable for mass production. HOBT reagents are explosive reagents during mass production, and there are significant hazards in handling these reagents. In addition, long reaction times are required. By carrying out the above-mentioned coupling reaction, compound 6 or edoxaban 1 can be obtained with a yield of 80-85%. In contrast, the improved production method of the present invention can achieve a relatively high purity of 99.9% or more, a short reaction time, and a yield of 90-95%. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] In order to solve the above-mentioned problems, the present invention is characterized by a method for preparing edoxaban, which includes the following steps: The present invention relates to a method for preparing edoxaban 1, which includes coupling of intermediates 3 and 2. Intermediate 3 is prepared from compound 6 under acidic conditions. Intermediate 6 is synthesized by coupling of intermediates 4 and 5. In order to maximize the reactivity for on-site preparation under mild reaction conditions, the present invention describes the following four techniques to provide an improved method for preparing edoxaban 1.

[0018] a) Process for compound 6 using 1,1'-carbonyldiimidazole (CDI) 9 b) Process for compound 6 using novel intermediate 5a c) A method for preparing edoxaban 1 by coupling compound 2 with compound 3 using CDI9 d) Method for preparing edoxaban 1 using novel chloro intermediate 11

[0019] a) The present invention relates to a process for the preparation of intermediate 6, which comprises coupling tert-butyl ((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate oxalate 4 and 2-((5-chloropyridin-2-yl)2-oxaacetic acid 5 in the presence of a coupling reagent 1,1'-carbonyldiimidazole (CDI) 9, an amine base pyridine or triethylamine, and a solvent dichloromethane (DCM) or dimethylformamide (DMF) to produce intermediate 6. To produce 6, CDI 9 and an amine base can be used in a molar ratio of CDI:amine base=1:1-1.5:2.0-4.0, with 1:1-1.2:2.0-3.0 being the optimum condition. The base used in this method may be a tertiary amine such as diisopropylethylamine, a heterocyclic amine such as pyridine, or an inorganic base such as sodium carbonate. The solvent used in this method may be N,N-dimethylformamide, dichloromethane, chloroform, or tetrahydrofuran.

[0020] [ka]

[0021] b) The present invention also relates to a method for preparing intermediate 6. A novel chloride intermediate 5a is generated from amine 10 using oxalyl chloride. Amine 4 is then reacted with chloro compound 5a in the presence of triethylamine or pyridine to generate compound 6. The base used in this process is a tertiary amine such as tri(C1-C4 alkyl)amine, diisopropylethylamine, etc., or a heterocyclic amine such as 1-methylpyrrolidine, 1-methylpiperidine, 4-methylmorpholine, pyridine, or lutidine, etc. The solvent used in this process may be an organic aprotic solvent such as dichloromethane, chloroform, or tetrahydrofuran, etc.

[0022] [ka]

[0023] c) The present invention also relates to a method for preparing edoxaban 1. The key intermediate 3 is generated from 6 under acidic conditions. Then, N1-((1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide 3 and 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid 2 are coupled in the presence of coupling reagent 1,1'-carbonyldiimidazole (CDI) 9, amine base pyridine or triethylamine, and solvent dichloromethane to generate edoxaban 1. The base used in this process may be a tertiary amine such as tri(C1-C4 alkyl)amine, diisopropylethylamine, etc., or a heterocyclic amine such as 1-methylpyrrolidine, 1-methylpiperidine, 4-methylmorpholine, pyridine, etc. The solvent used in this method may be an amide solvent such as N,N-dimethylformamide, or an aprotic organic solvent such as dichloromethane, chloroform, tetrahydrofuran, etc. Conventionally, EDCI and HOBt coupling reagents have been used, but these tend to be expensive and have low reactivity, and require long reaction times. In contrast, the use of CDI9 is ​​more efficient due to its good reactivity, high reaction yield, and short reaction time.

[0024] [ka]

[0025] d) The present invention also relates to a process for the preparation of edoxaban 1. The key intermediate 3 is generated from 6 under acidic conditions. A novel chloride intermediate 11 is generated from amine 2 using thionyl chloride. Then, N1-((1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide 3 is reacted with 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl chloride 11 in the presence of triethylamine or pyridine to generate edoxaban 1. The base used in this process may be a tertiary amine such as tri(C1-C4 alkyl)amine, diisopropylethylamine, etc., or a heterocyclic amine such as 1-methylpyrrolidine, 1-methylpiperidine, 4-methylmorpholine, 4-(N,N-dimethylamino)pyridine, pyridine, lutidine, collidine, etc. The solvent used in this process may be a chlorinated solvent such as dichloromethane, chloroform, and the like, or an organic aprotic solvent such as tetrahydrofuran, and the like.

[0026] [ka]

[0027] Edoxaban 1 and intermediate 6 synthesized by a) and c) The stoichiometric reaction molar ratio between the starting material and the amine base is 1.0:2-4. The coupling reaction proceeds smoothly in the range of 20°C to 35°C. In consideration of commercial mass production, it is preferable to carry out the reaction at around room temperature (approximately 20°C to 30°C). When the coupling reaction is carried out under the above reaction conditions, the reaction can be completed within 3 hours. In order to further improve the reactivity, an amine base can be used. Examples of the amine base include at least one selected from tri(C1-C6 alkyl)amines, N-(C1-C6 alkyl)morpholines, pyridines, quinolines, etc. Specific examples of the amine base include trialkylamines such as trimethylamine, triethylamine, triisopropylamine, etc.; morpholines such as N-methylmorpholine, N-propylmorpholine, etc.; and aromatic amines such as pyridine, quinoline, etc.

[0028] Edoxaban 1 and intermediate 6 synthesized by a), b), c) and d) can be purified by recrystallization using the following solvent. The solvent used for recrystallization can be selected from alcohols such as methanol, ethanol, isopropyl alcohol, halogenated hydrocarbons such as dichloromethane, aliphatic hydrocarbons such as hexane, nitriles such as acetonitrile, ethers such as tetrahydrofuran, etc. The recrystallization solvent is at least one selected from the above group, preferably an alcohol solvent, and particularly preferably isopropyl alcohol. The crystallization method can be performed by a method commonly used by those skilled in the art. EXAMPLES

[0029] The above description of the present invention is a detailed description of the manufacturing method in the embodiment. Note that the following examples are provided to aid in understanding the present invention, and the present invention is not limited to these examples.

[0030] Example 1: Preparation of tert-butyl ((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-(dimethylcarbamoyl)cyclohexyl)carbamate 6 2-((5-chloropyridin-2-yl)amino)-2-oxoacetic acid 5 (2.67 g, 13.32 mmol) was added to dichloromethane (50 ml) in a flask. CDI 9 (2.16 g, 13.32 mmol) was then added to the flask at room temperature. Pyridine (1.07 ml, 13.32 mmol) was added to this at 20-25°C. The reaction mixture was then stirred at room temperature for 2 hours. After that, amine 3 (5 g, 13.32 mmol) was added at room temperature, followed by pyridine (2.15 ml, 26.64 mmol). The reaction mixture was then stirred at room temperature for 2 hours. After TLC showed the reaction was complete, purified water (50 mL) was added. The organic phase was then separated and the aqueous phase was extracted with dichloromethane (2 x 25 ml). The combined organic phase was dried over MgSO4 and concentrated under vacuum to give a white solid. The title compound obtained was dried in an oven at 40-45° C. for 15 hours (5.6 g, 90%). 1 H-NMR (CDCl3): 1.25-1.55 (2H,m), 1.45 (9H, s), 1.60-2.15 (5H,m), 2.56-2.74 (1H,brs), 2.95(3H,s), 3.06(3H,s), 3.90-4.01(1H,m), 4.18-4.27 (1H,m), 4.70-4.85 (1H, brs), 5.70-6.00(1H, brs), 7.70(1H,m), 7.75-8.00(1H,brs), 8.16(1H, m), 8.30(1H, d), 9.73 (1H,s)

[0031] [ka]

[0032] Example 2: Preparation of tert-butyl ((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-(dimethylcarbamoyl)cyclohexyl)carbamate 6 5-Chloropyridin-2-amine 10 (10.0 g, 77.78 mmol) was added to dichloromethane (100 ml). It was cooled to 0°C and oxalyl chloride (11.84 g, 93.34 mmol) was added slowly to it. The reaction mixture was stirred for 2 h. Then, the reaction mixture was concentrated under rotary centrifugation. The obtained solid was added to 100 ml of dichloromethane. It was then cooled to 0-5°C. To this was added tert-butyl ((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate oxalate 4 (29.2 g, 77.78 mmol) followed by Et3N (19.74 g, 195.45 mmol) at the same temperature. After stirring for 1 h, the cooling bath was removed and the mixture was stirred at room temperature for 2 h. After confirming the completion of the reaction by TLC, dichloromethane (50 mL) and purified water (100 mL) were added. After stirring at room temperature for 30 minutes, the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate (1 g), concentrated under reduced pressure, and then crystallized from isopropyl alcohol (125 mL) to obtain the title compound 6 (32.75 g, 90%).

[0033] [ka]

[0034] Example 3: Synthesis of N1-((1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide 2,2,2-trifluoroacetate 3a or N1-((1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide 3 under acidic conditions tert-Butyl ((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-(dimethylcarbamoyl)cyclohexyl)carbamate 6 (10.0 g, 21.3 mmol) was added to dichloromethane (30 ml). Trifluoroacetic acid (19.5 g, 170 mmol) was added to it at room temperature. The mixture was then stirred at room temperature for 4 hours. After TLC showed the reaction was complete, the reaction mixture was rotary evaporated to give the TFA salt amine 3a. This salt was added to water and treated with NaHCO3 (50 ml) at room temperature to give a solid solution, which was filtered to give the free amine 3 (7.07 g, 90%).

[0035] [ka]

[0036] Example 4: Production of Edoxaban 1 In a flask, 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid 2 (4.0 g, 17.04 mmol) was added to dichloromethane (40 ml). CDI 9 (2.76 g, 17.04 mmol) was then added to the flask at room temperature. Pyridine (1.37 ml, 17.04 mmol) was added to this at 20-25°C. The reaction mixture was then stirred at room temperature for 1 hour. After that, amine 3 (6.26 g, 17.04 mmol) was added at room temperature, followed by pyridine (2.75 ml, 34.08 mmol). The reaction mixture was then stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC, purified water (40 mL) was added. The organic phase was then separated and the aqueous phase was extracted with dichloromethane (2 x 20 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo to give a white solid, which was dried in an oven at 40°C for 15 hours to give the title compound (8.85g, 95%). 1H-NMR (CDCl3) δ: 1.62-1.69(1H), 1.78-1.84(m,1H), 1.90-1.96(m,1H), 2.06-2.14(m,3H), 2.52(s,3H), 2.79-2.89(m,3H), 2.95(s,3H), 2.93-2.96(m,2H), 3.06(s,3H), 3.70(d, 1H, J=16.0 Hz), 3.73(d, 1H, J=16.0Hz), 4.09-4.13(m,1H), 4.67-4.70(m,1H), 7.39(d, 1H, J=8.5Hz), 7.68(dd, 1H, J=9.0, 2.5Hz), 8.03(d, 1H, J=8.5Hz), 8.17(dd, 1H, J=9.0,0.5 Hz), 8.30(dd, 1H, J=2.5, 0.5Hz), 9.72(s,1H).

[0037]

change

[0038] Example 5: Generation of エドキサバン1 In a flask, 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid 2 (5.0 g, 21.3 mmol) was added to dichloromethane (25 ml). To this was added catalytic amount of N,N-dimethylformamide. To this flask was then added thionyl chloride (5.07 g, 42.6 mmol) slowly at room temperature. The reaction mixture was then heated to reflux for 1 h and the solvent was removed under rotary vacuum. The resulting solid 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl chloride 11 was added to 25 ml of dichloromethane. It was then cooled to 0-5 °C. To this was added amine 3 (7.83 g, 21.3 mmol) followed by Et3N (8.6 g, 85.21 mmol) at the same temperature. After stirring for 1 hour, the cooling bath was removed and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC, dichloromethane (15 mL) and purified water (50 mL) were added. After stirring at room temperature for 30 minutes, the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate (1 g), concentrated under reduced pressure, and then crystallized from isopropyl alcohol (25 mL) to obtain the title compound 1 (10.5 g, 90%). 1 H-NMR (CDCl3) δ: 1.62-1.69(1H), 1.78-1.84(m,1H), 1.90-1.96(m,1H), 2.06-2.14(m,3H), 2.52(s,3H), 2.79-2.89(m,3H), 2.95(s,3H), 2.93-2.96(m,2H), 3.06(s,3H), 3.70(d, 1H, J=16.0 Hz), 3.73(d, 1H, J=16.0Hz), 4.09-4.13(m,1H), 4.67-4.70(m,1H), 7.39(d, 1H, J=8.5Hz), 7.68(dd, 1H, J=9.0, 2.5Hz), 8.03(d, 1H, J=8.5Hz), 8.17(dd, 1H, J=9.0,0.5 Hz), 8.30(dd, 1H, J=2.5, 0.5Hz), 9.72(s,1H).

[0039] [ka]

[0040] Comparative Example 1: Preparation of tert-butyl ((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-(dimethylcarbamoyl)cyclohexyl)carbamate 6 WO 2003 / 000680 (Example 68) To a solution of the compound (3.0 g) in N,N-dimethylformamide (10 ml), acid (2.88 g), 1-hydroxybenzotriazole monohydrate (2.08 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.95 g) were added at room temperature. After stirring for 3 days, the reaction mixture was concentrated under reduced pressure, and methylene chloride (30 ml), saturated sodium bicarbonate (150 ml) and water (150 ml) were added to the residue. The resulting colorless precipitate was collected by filtration, and the precipitate was dried to obtain the title compound (5.21 g).

[0041] Comparative Example 2: Production of tert-butyl ((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-(dimethylcarbamoyl)cyclohexyl)carbamate 6 WO 2010 / 104078 (Example 3) To a suspension of tert-butyl {(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate (100.0 g) in acetonitrile (550 ml), triethylamine (169 ml) was added at 60° C. At this temperature, {5-chloropyridin-2-yl}amino](oxo)acetate monohydrochloride (84.2 g) was added and stirred for 6 hours, followed by stirring for 16 hours. Water was added to the reaction solution, and the mixture was stirred at 10° C. for 1.5 hours. The precipitated crystals were collected by filtration and dried to obtain the title compound (106.6 g, 85.4%).

[0042] Comparative Example 3: Production of Edoxaban 1 WO 2003 / 000680 (Example 310) A compound obtained from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDCI (155 mg) and 1-hydroxybenzotriazole monohydrate (90 mg) was added to N,N-dimethylformamide (5 ml) so that the compound (117 mg) was dissolved in the solution, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure using a vacuum pump, and methylene chloride and a saturated aqueous solution of sodium bicarbonate were added to the residue and the layers were separated. The obtained organic phase was washed with a saturated sodium chloride solution and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound.

[0043] Comparative Example 4: Production of Edoxaban 1 International Publication No. 2010 / 104078 (Reference Example 4) To a suspension containing tert-butyl [(1R,2S,5S)-2-({(5-chloropyridin-2-yl)amino}(oxo)acetyl)amino]-5-dimethylaminocarbonyl)cyclohexyl]carbamate (95.1 g) in acetonitrile (1900 ml), methanesulfonic acid (66 ml) was added at room temperature, and the mixture was stirred at room temperature for 2 hours, and the reaction solution of trimethylamine (155 ml) and 5-methyl-4,5,6,7-tetrahydro[1,3]thiazo[5,4-c]pyridine-2-carboxylic acid hydrochloride (46.8 g) was added under ice cooling, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added to the mixture, and the mixture was stirred under ice cooling for 1 hour. Then, the crystals were collected by filtration to obtain the title compound (103.2 g).

[0044] Comparative Example 5: Production of Edoxaban 1 WO 2015 / 125710 (Example 10) A 50 ml flask was charged with the amine compound (1.0 g, 2.16 mmol), activated ester (1.18 g, 4.31 g), K3PO4 (1.83 g, 8.64 mmol) and DMF (10 ml), and the mixture was stirred at room temperature for 3 days. H2O (20 mL) was added to the reaction solution, and the resulting slurry was stirred at room temperature for 1 hour, then cooled to 0-5°C and stirred for an additional hour, after which the solid was filtered. The resulting solid was washed with H2O (10 ml) and dried under reduced pressure to give the title compound (0.99 g, 83.9%) as a white solid.

[0045] The yield, reaction time and purity of tert-butyl ((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-(dimethylcarbamoyl)cyclohexyl)carbamate 6 produced by the coupling reactions shown in Examples 1 and 2 and Comparative Examples 1 and 2 are shown in Table 1 below.

[0046] [Table 1]

[0047] The yield, reaction time and purity of edoxaban 1 produced by the coupling reactions in Examples 4 and 5 and Comparative Examples 3 to 5 are shown in Table 2 below.

[0048] [Table 2]

Claims

1. The following formula 1: 【Chemistry 1】 A method for producing a compound represented by the formula: (a) The following formula 2: 【Chemistry 2】 In the presence of a base, a carboxylate represented by the following formula 9: 【Chemistry 3】 and 1,1-carbonyldiimidazole (CDI) represented by the formula: (b) stirring the reaction mixture at room temperature for 1 hour; (c) adding to the reaction mixture a compound of formula 3 or 3a: 【Chemistry 4】 to produce a compound represented by formula 1. The manufacturing method comprising the steps of:

2. The process according to claim 1 , wherein the base is a tertiary amine or a heterocyclic amine.

3. The method according to claim 1 or 2, wherein the base is a tri(C1-C4 alkyl)amine, diisopropylethylamine, 1-methylpyrrolidine, 1-methylpiperidine, 4-methylmorpholine, pyridine, or lutidine.

4. A manufacturing method described in any one of claims 1 to 3, wherein the mixing in step (a) is carried out in a solvent.

5. The method according to claim 4 , wherein the solvent is an amide solvent or an aprotic organic solvent.

6. The method according to claim 4 or 5, wherein the solvent is N,N-dimethylformamide, dichloromethane, chloroform or tetrahydrofuran.

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