A method for industrial production of amisulpride

Abstract

The invention belongs to the field of drug synthesis, and in particular to a method for industrial production of amisulpride, wherein the reaction steps include: 4-amino-5-ethylthio-2-methoxybenzoic acid methyl ester undergoes oxidation reaction in the presence of sodium tungstate, hydrogen peroxide, and an organic solvent to generate an intermediate compound II, and the intermediate compound II and compound III are heated by microwaves in a metal ion liquid to generate amisulpride. The metal ion liquid used in the present invention can be used as both a catalyst and a reaction solvent, and can be recycled, so that the reaction can be carried out efficiently and quickly without other organic solvents, and no additional alkali catalyst is required, the reaction temperature is low, the reaction time is short, and the post-processing operation is simple, the production cost is greatly reduced, the trend of green chemical industry is met, and it is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and particularly relates to a method for industrially producing amisulpride. Background Art

[0002] Amisulpride, also known as Amisulpride, trade name Solyon, chemical name 4-amino- N -[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide, white crystalline powder, CAS registration number: 71675-85-9, melting point is 124~128℃, molecular formula C17H27N3O4S, structural formula: .

[0003] Amisulpride is a new non-classical antipsychotic drug developed by Sanofi-Synthelabo of France that has significant advantages for negative symptoms. It was first launched in Portugal in 1986, in the United States in January 1997, and in China in 2001. Amisulpride belongs to the class of benzamide neuroleptics, which can selectively bind to the DA2 and DA3 dopamine receptors of the limbic system, but not to serotonergic receptors or other histamine, cholinergic receptors, and adrenergic receptors. In animal experiments, it was found that compared with the striatum, high doses of amisulpride mainly blocked dopaminergic neurons in the central part of the limbic system to treat positive symptoms, which can also explain why the neuroleptic effect of amisulpride is greater than the extrapyramidal side effects; low doses of amisulpride mainly block presynaptic DA2 and DA3 dopamine receptors to treat negative symptoms.

[0004] "Xue Na, Zhang Kai, Yu Wenguo, et al. Synthesis of amisulpride. Chinese Journal of New Drugs, 2009, 18(16):1554-1556" discloses a route for synthesizing amisulpride using 4-amino-2-methoxy-5-mercaptobenzoic acid as a raw material. Under alkaline conditions, 4-amino-2-methoxy-5-mercaptobenzoic acid undergoes ethylation reaction with diethyl sulfate to obtain 4-amino-2-methoxy-5-ethylthiobenzoic acid, which is then oxidized with peracetic acid to obtain 4-amino-2-methoxy-5-ethylsulfonylbenzoic acid. Finally, under the action of an organic base and ethyl chloroformate, the 4-amino-2-methoxy-5-mercaptobenzoic acid is reacted with diethyl sulfate to obtain 4-amino-2-methoxy-5-ethylthiobenzoic acid. N -ethyl-2-aminomethylpyrrolidine reacts to obtain amisulpride.

[0005]

[0006] However, the last step of the reaction route requires the use of an organic base and an organic solvent, and during the reaction, the raw material ethyl chloroformate is used, which is a highly toxic substance, will cause safety problems, and is not conducive to environmental protection.

[0007] CN102838520A discloses a method for preparing amisulpride, wherein 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid reacts with N-ethyl-2-aminomethylpyrrolidine in the presence of phenyl chloroformate or oxalyl chloride to obtain amisulpride under alkaline conditions. However, the reaction route uses phenyl chloroformate or oxalyl chloride, which will decompose violently when it encounters water or alcohol, and phenyl chloroformate will produce toxic gases when it encounters water or heat, which has high requirements for reaction conditions and personnel operation, and is not conducive to safe production. The specific synthesis route is as follows:

[0008]

[0009] CN101898991A discloses a method for synthesizing (S) (-)-amisulpride D-(-)-tartrate, using glycerol as a solvent, reacting 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid with a lower alcohol to obtain a lower alcohol ester, and then condensing with (S) (-)-1-ethyl-2-aminomethylpyrrole to obtain (S) (-)-amisulpride. When preparing amisulpride, glycerol is used as a solvent. Since the melting point of glycerol is 17.8°C and the viscosity is relatively large, it is very inconvenient to use, and glycerol will be transesterified with 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid methyl ester during the reaction, and a byproduct 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid glycerol ester will be produced. The byproduct is difficult to remove in the subsequent processing process, which seriously affects the quality of the amisulpride finished product.

[0010] CN 112624951 B discloses a method for preparing amisulpride: 4-amino-2-methoxy-5-ethylsulfonylbenzoic acid methyl ester, N-ethyl-2-aminomethylpyrrolidine and a solvent are subjected to a condensation reaction at 50-100° C. under the condition that an organic base is used as a catalyst. After the reaction is completed, the reaction solution is concentrated to remove the solvent, filtered and dried to obtain amisulpride. The reaction route is:

[0011]

[0012] However, the above reaction requires the use of a large amount of sodium alcoholate organic base and organic solvent, which is costly and not conducive to environmental protection. In addition, the reaction conditions of this route are harsh (high reaction temperature and long reaction time), which is not suitable for industrial production.

[0013] Based on this, there is an urgent need to develop a new method for preparing amisulpride with mild reaction conditions, green environmental protection, and suitable for industrial production. Summary of the invention

[0014] In view of the problems existing in the prior art, the purpose of the present invention is to provide a method for industrial production of amisulpride to solve the problems existing in the prior art such as harsh reaction conditions, high cost, environmental pollution, and unsuitability for industrial production.

[0015] The present invention is achieved through the following technical solutions:

[0016] A method for industrial production of amisulpride comprises the following steps:

[0017] Step 1: Preparation of intermediate compound II

[0018] Methyl 4-amino-5-ethylthio-2-methoxybenzoate undergoes oxidation reaction in the presence of sodium tungstate, hydrogen peroxide, and an organic solvent to generate intermediate compound II. The reaction formula is:

[0019]

[0020] Step 2: Preparation of Amisulpride

[0021] Intermediate compound II and compound III are heated by microwave in metal ion liquid to generate amisulpride, and the reaction formula is:

[0022]

[0023] Among them, the structural formula of the metal ion liquid is: .

[0024] In some embodiments, the step of reacting the metal ionic liquid is as follows:

[0025] Step 1: Preparation of ionic liquid intermediate Di-mim

[0026]

[0027] Under nitrogen protection, N,N'-carbonyldiimidazole and 1-chlorobutane were reacted. After the reaction was completed, the solution was cooled to room temperature, and petroleum ether and ethyl acetate were added to the solution to precipitate a brown viscous liquid. The mixture was then extracted by a separatory funnel, and the residual solvent was removed by rotary evaporation and vacuum drying to obtain the ionic liquid intermediate Di-mim.

[0028] Step 2: Metal ionic liquid Di-mim / SnCl 5 Preparation

[0029]

[0030] Under nitrogen protection, the ionic liquid intermediate Di-mim and SnCl prepared in step 1 were 4 ·5H 2After the reaction, the solvent was removed by rotary evaporation and vacuum dried to obtain the metal ion liquid Di-mim / SnCl 5 .

[0031] In some embodiments, the organic solvent in step 1 is selected from one or more of methanol, ethanol and isopropanol, preferably methanol;

[0032] In some embodiments, the mass fraction of the hydrogen peroxide in step 1 is 30-50%, preferably 30%.

[0033] In some embodiments, the molar ratio of methyl 4-amino-5-ethylthio-2-methoxybenzoate to sodium tungstate in step 1 is 1: (0.005-0.015); the reaction temperature is 30-60° C., and the reaction time is 0.5-5 h.

[0034] In some embodiments, after the reaction in step 1 is completed, a sodium thiosulfate aqueous solution is slowly added dropwise in an ice bath, and the excess hydrogen peroxide shown by starch potassium iodide test paper is removed and stirred, filtered, and dried to obtain the intermediate compound II.

[0035] In some embodiments, the molar ratio of the intermediate compound II to the compound III in step 2 is 1: (1-1.2); the mass ratio of the compound II to the metal ion liquid is 1: (3-6).

[0036] In some embodiments, the reaction temperature of step 2 is 25-40° C. and the reaction time is 20-40 min.

[0037] In some embodiments, after the reaction in step 1 is completed, water is added to the reaction mixture, the solid is precipitated and filtered, water is added to the obtained solid and slurried for 30 to 60 minutes, filtered and washed, and then the obtained solid is vacuum dried to obtain amisulpride.

[0038] The present invention has achieved the following beneficial effects:

[0039] 1) The metal ion liquid used in the present invention can be used as both a catalyst and a reaction solvent, so that the transesterification reaction can be carried out efficiently and quickly without other organic solvents, and no additional base catalyst needs to be added. The reaction temperature is low, the reaction time is short, and the post-treatment operation is simple, which greatly reduces the production cost, conforms to the trend of green chemical industry, and is suitable for industrial production.

[0040] 2) The present invention adopts microwave heating to accelerate the reaction rate and reduce side reactions, thereby improving the yield and purity.

[0041] 3) The filtrate after filtration in the present invention is subjected to reduced pressure distillation to remove the residual solvent, and the residue is vacuum dried to obtain the ionic liquid Di-mim / SnCl 5 , can continue to be recycled. DETAILED DESCRIPTION

[0042] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0043] The endpoints and any values ​​of the scope described in the present invention are not limited to the precise scope or value, and these scopes or values ​​should be understood to include values ​​close to these scopes or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be considered as specifically disclosed in this article.

[0044] Preparation Example 1: Metal Ionic Liquid Di-mim / SnCl 5 Preparation

[0045] Step 1: Preparation of ionic liquid intermediate Di-mim

[0046]

[0047] Under nitrogen protection, N,N'-carbonyldiimidazole (0.1 mol) was added to a round-bottom flask equipped with a magnet, and it was completely dissolved with acetonitrile (100 mL) and ethanol (10 ml), followed by dropwise addition of 1-chlorobutane (0.22 mol), heating to 60 °C and reflux stirring for 24 h. After the reaction was completed, it was cooled to room temperature, and petroleum ether and ethyl acetate were added to the solution to precipitate a brown viscous liquid. The mixture was then extracted with a separatory funnel, and the residual solvent was removed by rotary evaporation. Finally, the collected viscous liquid was placed in a vacuum drying oven for 12 hours to obtain the ionic liquid intermediate Di-mim with a yield of 32.5%.

[0048] Step 2: Metal ionic liquid Di-mim / SnCl 5 Preparation

[0049]

[0050] Under nitrogen protection, the ionic liquid intermediate Di-mim (0.1 mol) prepared in step 1 was added to a round-bottom flask equipped with a magnet, and then SnCl was quickly added under magnetic stirring. 4 ·5H 2O (0.2 mol), heated to 80 ° C and stirred for 5 h. After the reaction, the solvent was removed by rotary evaporation and vacuum dried at 80 ° C for 24 h to obtain the metal ion liquid Di-mim / SnCl 5 , the yield was 95.3%.

[0051] 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.61 (s, 2H), 7.18 (s, 2H), 6.90 (s, 2H), 3.95-3.89 (s, 4H), 1.67-1.59 (s, 4H), 1.25-1.16 (s, 4H), 0.93-0.82 (s, 6H).

[0052] Example 1 Preparation of Amisulpride

[0053] Step 1: Preparation of intermediate compound II

[0054]

[0055] 4-amino-5-ethylthio-2-methoxybenzoic acid methyl ester (Compound I, 24.0 g, 0.1 mol), sodium tungstate (0.36 g, 0.001 mol) and methanol (200 mL), maintaining the temperature below 10°C, slowly add 30% mass fraction hydrogen peroxide (30 mL), after the addition is complete, heat to 30°C and continue stirring for 1.0 h. After the reaction is completed, slowly add 10% sodium thiosulfate aqueous solution under ice bath, remove excess hydrogen peroxide as shown by starch potassium iodide test paper, stir, filter, and dry to obtain 25.8 g of compound II as a white powder solid, with a yield of 94.5% and a HPLC purity of 99.6%.

[0056] LC-MS (ESI): [M+H] + =273.9.

[0057] Step 2: Preparation of Amisulpride

[0058]

[0059] Compound II (27.3 g, 0.1 mol), Compound III (14.0 g, 0.11 mol) and the metal ionic liquid obtained in Preparation Example 1 (100 g) were added to a microwave-specific reactor equipped with a stirrer, and the mixture was heated to 30°C and stirred for 30 min. After the reaction was completed, water (300 mL) was added to the reaction mixture, and the solid was filtered after precipitation. Water (200 mL) was added to the obtained solid and slurried for 30 min, filtered and washed, and then the obtained solid was vacuum dried at 80°C for 5 h to obtain 35.3 g of amisulpride as a white solid, with a yield of 95.7% and an HPLC purity of 99.8%.

[0060] The filtrate after filtration was distilled under reduced pressure to remove the residual solvent, and the residue was dried under vacuum to obtain the ionic liquid Di-mim / SnCl 5 , can continue to be recycled.

[0061] LC-MS (ESI): [M+H] + =370.1.

[0062] 1 H-NMR (500 MHz, CDCl3): δ(ppm): 8.51 (s, 1H), 8.05 (s, 1H), 6.21 (s, 1H), 5.54 (s, 2H), 3.92 (s, 3H), 2.16-3.73 (m, 9H), 1.61-1.90(m,4H), 1.27(t,3H), 1.13(t,3H).

[0063] Example 2 Preparation of Amisulpride

[0064] Step 1: Preparation of intermediate compound II

[0065]

[0066] 4-amino-5-ethylthio-2-methoxybenzoic acid methyl ester (Compound I, 24.0 g, 0.1 mol), sodium tungstate (0.36 g, 0.001 mol) and isopropanol (200 mL), maintaining the temperature below 10°C, slowly add 30% mass fraction hydrogen peroxide (40 mL), and after the addition is complete, heat to 40°C and continue stirring for 1.0 h. After the reaction is completed, slowly add 10% sodium thiosulfate aqueous solution under ice bath, remove excess hydrogen peroxide as shown by starch potassium iodide test paper, stir, filter, and dry to obtain 26.3 g of compound II as a white powder solid, with a yield of 96.3% and a HPLC purity of 99.7%.

[0067] LC-MS (ESI): [M+H] +=273.9.

[0068] Step 2: Preparation of Amisulpride

[0069]

[0070] Compound II (27.3 g, 0.1 mol), Compound III (15.4 g, 0.12 mol) and the metal ionic liquid obtained in Preparation Example 1 (120 g) were added to a microwave-specific reactor equipped with a stirrer, and the mixture was heated to 40°C and stirred for 30 min. After the reaction was completed, water (300 mL) was added to the reaction mixture, and the solid was filtered after precipitation. Water (300 mL) was added to the obtained solid and slurried for 30 min, filtered and washed, and then the obtained solid was vacuum dried at 80°C for 5 h to obtain 35.8 g of amisulpride as a white solid, with a yield of 97.0% and a HPLC purity of 99.85%.

[0071] The filtrate after filtration was distilled under reduced pressure to remove the residual solvent, and the residue was dried under vacuum to obtain the ionic liquid Di-mim / SnCl 5 , can continue to be recycled.

[0072] LC-MS (ESI): [M+H] + =370.1.

[0073] 1 H-NMR (500 MHz, CDCl3): δ(ppm): 8.51 (s, 1H), 8.05 (s, 1H), 6.21 (s, 1H), 5.54 (s, 2H), 3.92 (s, 3H), 2.16-3.73 (m, 9H), 1.61-1.90(m,4H), 1.27(t,3H), 1.13(t,3H).

[0074] Comparative Example 1

[0075] Based on Example 1,

[0076] Replace with .

[0077] Step 1: Preparation of intermediate compound II (same as Example 1)

[0078] Step 2: Preparation of Amisulpride

[0079] Compound II (27.3 g, 0.1 mol), compound III (14.0 g, 0.11 mol) and ionic liquid

[0080] (100 g) was added to a microwave-specific reactor equipped with a stirrer, and the mixture was heated to 30°C with stirring for 30 min. After the reaction was completed, water (300 mL) was added to the reaction mixture, and the solid was filtered after precipitation. Water (200 mL) was added to the obtained solid and slurried for 30 min, filtered and washed, and then the obtained solid was vacuum dried at 80°C for 5 h to obtain 23.1 g of amisulpride as a white solid, with a yield of 62.6% and a HPLC purity of 98.3%.

[0081] LC-MS (ESI): [M+H] + =370.1.

[0082] The above embodiments are merely examples for clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the protection scope of the invention.

Claims

1. A method for industrial production of amisulpride, characterized in that, The steps include: Step 1: Preparation of intermediate compound II Methyl 4-amino-5-ethylthio-2-methoxybenzoate undergoes oxidation reaction in the presence of sodium tungstate, hydrogen peroxide, and an organic solvent to generate an intermediate compound II. The reaction formula is: Step 2: Preparation of Amisulpride The intermediate compound II and compound III are heated by microwave in a metal ion liquid to generate amisulpride, and the reaction formula is: Among them, the structural formula of the metal ion liquid is: ; The reaction temperature of step 2 is 25-40°C and the reaction time is 20-40min; After the reaction in step 2 is completed, water is added to the reaction mixture, and the precipitated solid is filtered, and water is added to the obtained solid to slurry for 30 to 60 minutes, filtered and washed, and then the obtained solid is vacuum dried to obtain amisulpride.

2. The method according to claim 1, characterized in that The organic solvent in step 1 is selected from one or more of methanol, ethanol and isopropanol.

3. The method according to claim 1, characterized in that The mass fraction of the hydrogen peroxide in step 1 is 30-50%.

4. The method according to claim 1, characterized in that In step 1, the molar ratio of methyl 4-amino-5-ethylthio-2-methoxybenzoate to sodium tungstate is 1: (0.005-0.015); the reaction temperature is 30-60° C., and the reaction time is 0.5-5 h.

5. The method according to claim 1, characterized in that: After the reaction in step 1 is completed, a sodium thiosulfate aqueous solution is slowly added dropwise in an ice bath, and the excess hydrogen peroxide shown by starch potassium iodide test paper is removed, stirred, filtered, and dried to obtain the intermediate compound II.

6. The method according to claim 1, characterized in that The molar ratio of the intermediate compound II to the compound III in step 2 is 1: (1-1.2); the mass ratio of the compound II to the metal ion liquid is 1: (3-6).

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