JP2023116769A - Method for producing edoxaban - Google Patents

Abstract

An improved method for producing edoxaban is provided. For example, according to a manufacturing method shown by the following formula. TIFF2023116769000035.tif49169 [Selection diagram] None

Description

The present invention relates to an improved method for producing edoxaban. The present invention has low cost, high reaction efficiency, short consumption time and high product purity, and is suitable for large-scale industrial production.

The following compound 1a, a pharmacologically acceptable salt or hydrate thereof exhibits an FXa inhibitory action and is a prophylactic agent for thrombotic and/or embolic diseases, as disclosed in Patent Documents 1 to 5. and/or compounds useful as therapeutic agents.

The scheme below shows the general synthesis of edoxaban 1, tert-butyl ((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate oxalate 4, 2-((5 The key intermediate tert-butyl ((1R,2S,5S)-2-(2-((5-chloropyridine) was obtained by reacting with -chloropyridin-2-yl)amino)-2-oxoacetic acid 5. -2-yl)amino)-2-oxoacetamido)-5-(dimethylcarbamoyl)cyclohexyl)carbamate 6 is formed. Subsequent treatment of intermediate 6 under acidic conditions yields N1-((1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide 3 is obtained, which couples with 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid 2 to form edoxaban 1. HOBt and EDCI coupling reagents are commonly used for coupling reactions.

WO2004/058715 WO2003/016302 WO2003/000680 WO2005/047296 WO2007/032498

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

WO 2003/000680 describes the compound of 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 scheme below, tert-butyl ((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate oxalate 4 is lithium 2-((5- Reaction with 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 is obtained.

WO2010/104078 discloses tert-butyl ((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate oxalate 4, ethyl-2-((5-chloropyridine- 2-yl)amino)-2-oxoacetate hydrochloride 7 by treatment with compound 6 is disclosed.

Subsequent boc deprotection of 6 under acid (H ⁺ ) conditions yields N1-((1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridine-2). -yl)oxalamide 3 is obtained. Compound 3 was converted to lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate 2a (WO 2003/00680) or 5-methyl-4, Reaction with 5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride 2 produces edoxaban 1 (WO 2003/00680).

WO 2003/000680 also discloses that an amine compound represented by the following general formula 3 is coupled with an active ester compound 8 in the presence of a (tri)alkali metal phosphate to produce edoxaban 1. discloses a method. A disadvantage of this method is that the preparation of ester 8 and the use of expensive palladium catalyst and phosphine ligand combinations make mass production difficult.

Most of the patent literature uses 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBT) as carboxyl activating agents in coupling reactions (steps). . EDC reagents are widely used in the field of organic synthesis, but have the drawbacks of being expensive, having low reactivity, and being unsuitable for mass production. HOBT reagents are explosive reagents in mass production and there are serious hazards in handling these reagents. In addition, a long reaction time is required. By carrying out the coupling reaction as described above, compound 6 or edoxaban 1 can be obtained in 80-85% yield. In contrast, the improved production method of the present invention can achieve a relatively high purity of 99.9% or higher, a short reaction time, and a yield of 90-95%.

In order to solve the above-mentioned problems, the present invention features a method for producing edoxaban including the following steps. The present invention relates to a process for the preparation of Edoxaban 1 involving the coupling of intermediates 3 and 2. Intermediate 3 is prepared from compound 6 under acidic conditions. Intermediate 6 is synthesized by coupling intermediates 4 and 5. To maximize reactivity for on-site (also referred to as "in situ") production under mild reaction conditions, the present invention provides an improved process for the production of edoxaban 1. We describe the following four techniques for providing

a) Process for compound 6 using 1,1′-carbonyldiimidazole (CDI) 9 b) Process for compound 6 using novel intermediate 5a c) Compound 2 using CDI9 d) Process for the preparation of Edoxaban 1 using novel chloro intermediate 11

a) The present invention relates to a process for the preparation of intermediate 6, comprising coupling reagent 1,1′-carbonyldiimidazole (CDI) 9, amine base pyridine or triethylamine, solvent dichloromethane (DCM) or dimethylformamide tert-butyl ((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate oxalate 4 and 2-((5-chloropyridin-2-yl) in the presence of (DMF) 2-Oxaacetic acid 5 is coupled to produce intermediate 6. To produce compound 6, CDI9 and amine base are used in a molar ratio of CDI:amine base=1:1 to 1.5:2. 0 to 4.0, with 1:1 to 1.2:2.0 to 3.0 being the optimum.The base used in this method is a tertiary amine such as diisopropylethylamine. , heterocyclic amines such as pyridine, etc., or inorganic bases such as sodium carbonate, etc. Solvents used in this process may be N,N-dimethylformamide, dichloromethane, chloroform or tetrahydrofuran. good too.

b) The invention also relates to a process for the preparation of 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 produce compound 6. Bases used in this method include tertiary amines such as tri(C1-C4 alkyl)amine, diisopropylethylamine, etc., or Heterocyclic amines such as Solvents used in this method may be organic aprotic solvents such as dichloromethane, chloroform or tetrahydrofuran.

c) The present invention also relates to a process for the preparation of Edoxaban 1. The key intermediate 3 is produced 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 is coupled to form edoxaban 1. The base used in this method 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. It may be a cyclic amine. Solvents used in this method may be amide solvents such as N,N-dimethylformamide, or aprotic organic solvents such as dichloromethane, chloroform, tetrahydrofuran, and the like. Conventionally, EDCI and HOBt coupling reagents have been used, but they tend to be expensive and have low reactivity, requiring long reaction times. In contrast, the use of CDI9 is more efficient due to its good reactivity, high reaction yield and short reaction time.

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 new 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 in the presence of triethylamine or pyridine Reaction with 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl chloride 11 produces edoxaban 1. Bases used in this method include tertiary amines such as tri(C1-C4 alkyl)amine, diisopropylethylamine, etc., or 1-methylpyrrolidine, 1-methylpiperidine, 4-methylmorpholine, 4-(N,N -dimethylamino)pyridine, pyridine, lutidine, collidine, and the like. Solvents used in this method may be chlorinated solvents such as dichloromethane, chloroform and the like, or organic aprotic solvents such as tetrahydrofuran and the like.

Edoxaban 1 and intermediate 6 synthesized by a) and c)
The stoichiometric reaction molar ratio between starting material and amine base is 1.0:2-4. Also, the coupling reaction proceeds smoothly in the range of 20°C to 35°C. Considering 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. Amine bases can be used to further improve reactivity. Amine bases include at least one selected from tri(C1-C6 alkyl)amine, N-(C1-C6 alkyl)morpholine, pyridine, quinoline, and the like. Specific examples of amine bases include trialkylamines such as trimethylamine, triethylamine, triisopropylamine, etc.; morpholines such as N-methylmorpholine, N-propylmorpholine, etc.; aromatic amines such as pyridine, quinoline, etc. be done.

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

The content of the present invention described above is a detailed description of the manufacturing method according to the embodiment. In addition, the following examples are intended to help understanding of the present invention, and are not limited to these examples.

Example 1: tert-butyl ((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-(dimethylcarbamoyl)cyclohexyl)carbamate Preparation of 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. CDI9 (2.16 g, 13.32 mmol) was then added to the flask at room temperature. To this was added pyridine (1.07ml, 13.32mmol) at 20-25°C. The reaction mixture was then stirred at room temperature for 2 hours. Amine 3 (5 g, 13.32 mmol) was then 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 confirming the completion of the reaction by TLC, purified water (50 mL) was added. The organic phase was then separated and the aqueous phase extracted with dichloromethane (2 x 25 ml). The combined organic phases were dried over _MgSO4 and concentrated under vacuum to give a white solid. The resulting title compound was dried in an oven at 40-45° C. for 15 hours (5.6 g, 90%).
¹ H-NMR (CDCl ₃ ): 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)

Example 2: tert-butyl ((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-(dimethylcarbamoyl)cyclohexyl)carbamate Preparation of 6 5-Chloropyridin-2-amine 10 (10.0 g, 77.78 mmol) was added to dichloromethane (100 ml). Cooled to 0° C. and to it was slowly added oxalyl chloride (11.84 g, 93.34 mmol). The reaction mixture was stirred for 2 hours. The reaction mixture was then concentrated under rotation. The solid obtained 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 Et ₃ N (19 .74 g, 195.45 mmol) was added at the same temperature. After stirring for 1 hour, the cooling bath was removed and stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC, dichloromethane (50 mL) and purified water (100 mL) were added. After stirring for 30 minutes at room temperature, the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate (1 g), concentrated under reduced pressure, and crystallized from isopropyl alcohol (125 mL) to give the title compound 6 (32.75 g, 90%).

Example 3: N1-((1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide 2,2,2-trifluoroacetate Synthesis of 3a or N1-((1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide 3 under acidic conditions Dichloromethane (30 ml ) to 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 this was added trifluoroacetic acid (19.5 g, 170 mmol) at room temperature. The mixture was then stirred at room temperature for 4 hours. After TLC confirmed the completion of the reaction, the reaction mixture was distilled under rotation to give the TFA salt amine 3a. This salt was added to water and treated with NaHCO ₃ (50 ml) at room temperature to give a solid solution which was filtered to give the free amine 3 (7.07 g, 90%).

Example 4: Preparation of Edoxaban 1 In a flask, 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid 2 (4.0 g) was added to dichloromethane (40 ml). , 17.04 mmol) was added. CDI9 (2.76 g, 17.04 mmol) was then added to the flask at room temperature. To this was added pyridine (1.37ml, 17.04mmol) at 20-25°C. The reaction mixture was then stirred at room temperature for 1 hour. Amine 3 (6.26 g, 17.04 mmol) was then 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 extracted with dichloromethane (2 x 20 ml). The combined organic phases were dried over _MgSO4 and concentrated under vacuum to give a white solid. The resulting title compound was dried under an oven at 40° C. for 15 hours (8.85 g, 95%).
¹ H-NMR (CDCl ₃ ) 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=9.0,0.5Hz), 8.30(dd, 1H, J=2.5, 0.5Hz), 9.72(s,1H).

Example 5: Preparation of Edoxaban 1 In a flask, 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid 2 (5.0 g) was added to dichloromethane (25 ml). , 21.3 mmol) was added. To this was added a catalytic amount of N,N-dimethylformamide. Thionyl chloride (5.07 g, 42.6 mmol) was then slowly added to the flask at room temperature. The reaction mixture was then heated to reflux for 1 hour and the solvent was distilled off 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 Et ₃ N (8.6 g, 85.21 mmol) at the same temperature. After stirring for 1 hour, the cooling bath was removed and 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 for 30 minutes at room temperature, the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate (1 g), concentrated under reduced pressure, and crystallized from isopropyl alcohol (25 mL) to give the title compound 1 (10.5 g, 90%).
¹ H-NMR (CDCl ₃ ) 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=9.0,0.5Hz), 8.30(dd, 1H, J=2.5, 0.5Hz), 9.72(s,1H).

Comparative Example 1: tert-butyl ((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-(dimethylcarbamoyl)cyclohexyl)carbamate Generation of 6 WO2003/000680 (Example 68)
Acid (2.88 g), 1-hydroxybenzotriazole monohydrate (2.08 g) and 1-(3-dimethylaminopropyl) were added to a solution of compound (3.0 g) in N,N-dimethylformamide (10 ml). -3-Ethylcarbodiimide hydrochloride (2.95 g) was 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. After collecting the resulting colorless precipitate by filtration, the precipitate was dried to give the title compound (5.21 g).

Comparative Example 2: tert-butyl ((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-(dimethylcarbamoyl)cyclohexyl)carbamate Generation of 6 WO2010/104078 (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) was added 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 and then stirred 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 give the title compound (106.6 g, 85.4%).

Comparative Example 3: Production of Edoxaban 1 WO2003/000680 (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-dimethyl Formamide (5 ml) was added to dissolve in the solution and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure using a vacuum pump, and methylene chloride and saturated aqueous sodium hydrogen carbonate solution were added to the residue to separate the layers. The organic phase obtained was washed with saturated sodium chloride solution and dried over sodium sulphate. The solvent was evaporated under reduced pressure to give the title compound.

Comparative Example 4: Production of Edoxaban 1 WO2010/104078 (Reference Example 4)
tert-butyl [(1R,2S,5S)-2-({(5-chloropyridin-2-yl)amino}(oxo)acetyl)amino]-5-dimethylaminocarbonyl)cyclohexyl] in acetonitrile (1900 ml) To a suspension containing carbamate (95.1 g) was added methanesulfonic acid (66 ml) at room temperature and the mixture was stirred at room temperature for 2 hours, to which the reaction solution trimethylamine (155 ml), 5-methyl- 4,5,6,7-Tetrahydro[1,3]thiaz[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. Stirred. Triethylamine and water were added thereto, and the mixture was stirred for 1 hour under ice-cooling. After that, crystals were collected by filtration to obtain the title compound (103.2 g).

Comparative Example 5: Production of Edoxaban 1 WO2015/125710 (Example 10)
In a 50 ml flask were added the compounds amine (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). was added and the mixture was stirred at room temperature for 3 days. H ₂ O (20 mL) was added to the reaction and the resulting slurry was stirred at room temperature for 1 hour, then cooled to 0-5° C. and stirred for an additional hour before filtering the solids. The solid obtained was washed with H ₂ O (10 ml) and dried under vacuum to give the title compound (0.99 g, 83.9%) as a white solid.

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

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

Claims (20)

Formula 1 below:

A method for producing a compound represented by
Formula 3 or 3a below:

A compound represented by
Formula 11 below:

A compound represented by
in the presence of a base and a solvent to form said compound of formula 1. Formula 1 below:

A method for producing a compound represented by
Formula 3 or 3a below:

A compound represented by
Formula 2 below:

A compound represented by
in a solvent with a base and the following formula 9:

mixing in the presence of 1,1-carbonyldiimidazole (CDI) represented by to produce a compound represented by Formula 1 above. Equation 3 below:

A method for producing a compound represented by
In a solvent of dichloromethane, the following formula 6:

treating a compound represented by with trifluoroacetic acid. Equation 6 below:

A method for producing a compound represented by
Formula 10 below:

The following formula 5a obtained from the compound represented by:

A compound represented by
Equation 4 below:

A compound represented by
in the presence of a base and a solvent to produce the compound of Formula 6 above. Equation 6 below:

A method for producing a compound represented by
Formula 5 below:

A compound represented by
Equation 4 below:

A compound represented by
in a solvent with a base and the following formula 9:

in the presence of 1,1-carbonyldiimidazole (CDI) represented by to produce a compound represented by Formula 6 above. The production method according to claim 1, wherein the base is a tertiary amine or a heterocyclic amine. The base is tri(C1-C4 alkyl)amine, diisopropylethylamine, 1-methylpyrrolidine, 1-methylpiperidine, 4-methylmorpholine, 4-(N,N-dimethylamino)pyridine, pyridine, lutidine or collidine , The manufacturing method according to claim 1 or 6. 8. The method according to any one of claims 1, 6 and 7, wherein the solvent is a chlorinated solvent or an organic aprotic solvent. 9. The production method according to any one of claims 1, 6, 7 and 8, wherein said solvent is dichloromethane, chloroform or tetrahydrofuran. 3. The production method according to claim 2, wherein the base is a tertiary amine or a heterocyclic amine. The production method according to claim 2 or 10, wherein the base is tri(C1-C4 alkyl)amine, diisopropylethylamine, 1-methylpyrrolidine, 1-methylpiperidine, 4-methylmorpholine or pyridine. 12. The production method according to any one of claims 2, 10 and 11, wherein the solvent is an amide solvent or an aprotic organic solvent. The production method according to any one of claims 2, 10, 11 and 12, wherein said solvent is N,N-dimethylformamide, dichloromethane, chloroform or tetrahydrofuran. 5. The production method according to claim 4, wherein the base is a tertiary amine. The production method according to claim 4 or 14, wherein the base is tri(C1-C4 alkyl)amine, diisopropylethylamine, 1-methylpyrrolidine, 1-methylpiperidine, 4-methylmorpholine, pyridine or lutidine. 16. The manufacturing method according to any one of claims 4, 14 and 15, wherein the solvent is an organic aprotic solvent. 17. The method according to any one of claims 4, 14, 15 and 16, wherein said solvent is dichloromethane, chloroform or tetrahydrofuran. 6. The production method according to claim 5, wherein the base is a tertiary amine, a heterocyclic amine or an inorganic base. The production method according to claim 5 or 18, wherein the base is tri(C1-C4 alkyl)amine, diisopropylethylamine, 1-methylpyrrolidine, 1-methylpiperidine, 4-methylmorpholine, pyridine, potassium carbonate or sodium carbonate. . The production method according to any one of claims 5, 18 and 19, wherein said solvent is N,N-dimethylformamide, dichloromethane, chloroform or tetrahydrofuran.