CN110790693A - Preparation method of (S) (-) -amisulpride - Google Patents
Preparation method of (S) (-) -amisulpride Download PDFInfo
- Publication number
- CN110790693A CN110790693A CN201810868996.6A CN201810868996A CN110790693A CN 110790693 A CN110790693 A CN 110790693A CN 201810868996 A CN201810868996 A CN 201810868996A CN 110790693 A CN110790693 A CN 110790693A
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- CN
- China
- Prior art keywords
- amisulpride
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- hours
- aqueous solution
- dichloromethane
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- 229960003036 amisulpride Drugs 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- NTJOBXMMWNYJFB-UHFFFAOYSA-N amisulpride Chemical compound CCN1CCCC1CNC(=O)C1=CC(S(=O)(=O)CC)=C(N)C=C1OC NTJOBXMMWNYJFB-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 12
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 claims abstract description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims abstract description 4
- 235000011090 malic acid Nutrition 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- UNRBEYYLYRXYCG-UHFFFAOYSA-N (1-ethylpyrrolidin-2-yl)methanamine Chemical compound CCN1CCCC1CN UNRBEYYLYRXYCG-UHFFFAOYSA-N 0.000 abstract description 2
- XKXZMLYERTWVDI-UHFFFAOYSA-N 4-amino-5-ethylsulfonyl-2-methoxybenzoyl chloride Chemical compound COC1=C(C(=O)Cl)C=C(C(=C1)N)S(=O)(=O)CC XKXZMLYERTWVDI-UHFFFAOYSA-N 0.000 abstract 1
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- OJVNCXHGGYYOPH-UHFFFAOYSA-N 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid Chemical compound CCS(=O)(=O)C1=CC(C(O)=O)=C(OC)C=C1N OJVNCXHGGYYOPH-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of (S) (-) -amisulpride. The method comprises the following steps: condensing 4-amino-5- (ethylsulfonyl) -2-methoxybenzoyl chloride and 1-ethyl-2-aminomethyl pyrrolidine to obtain amisulpride, and using D-malic acid to make resolution to obtain (S) (-) -amisulpride.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and mainly relates to preparation of (S) (-) -amisulpride.
Background
Amisulpride (Amisulpride), chemically known as 4-amino-N- [ (1-ethyl-2-pyrrolidinyl) methyl ] -5- (ethylsulfonyl) -2-methoxybenzamide, was developed by Sanofi-Sythelabo, france and is a novel atypical antipsychotic drug mainly used for the treatment of the positive and negative symptoms of acute or chronic schizophrenia. Compared with racemate, the pharmacological activity of the levorotatory (S) (-) -amisulpride is more than 2 times, and the levorotatory (S) (-) -amisulpride has smaller toxic and side effects and higher safety.
Disclosure of Invention
The invention provides a preparation method of (S) (-) -amisulpride shown as a formula (I).
The preparation method comprises the following steps:
(1) in an organic solvent, condensing the compound to obtain amisulpride (IV);
(2) the amisulpride (IV) is split to obtain (S) (-) -amisulpride (I).
In the process of the present invention, the compound (II) in step (1) can be obtained by reacting commercially available 4-amino-5- (ethylsulfonyl) -2-methoxybenzoic acid with oxalyl chloride under basic conditions.
Preferably, the reaction temperature of the step (1) is 10-20 ℃.
Preferably, the solvent used in step (1) is selected from one or more of dichloromethane, tetrahydrofuran, DMF and acetonitrile. Still more preferably, the solvent used is dichloromethane.
Preferably, the base used in step (1) is selected from triethylamine, sodium tert-butoxide, sodium carbonate, potassium carbonate.
Preferably, the molar ratio of the compound (II) to the compound (III) in the step (1) is 1: 1.0-1.2.
In the method, the splitting method in the step (2) comprises the following steps: the amisulpride (IV) and an acid resolution reagent form salt, and then an alkaline reagent is used for reducing the salt into free alkali, so that the pure optical isomer (S) (-) -amisulpride (I) is obtained.
The acidic resolution reagent is D-malic acid.
The alkaline reagent is sodium carbonate or potassium carbonate.
The solvent used for the reaction is methanol or ethanol, preferably ethanol.
The amount of the solvent is preferably 5 to 10 times, preferably 8 to 10 times (volume to mass ratio) the amount of the compound IV.
The reaction temperature for adding the inorganic base is room temperature.
The reaction time with the inorganic base is recommended to be 1 to 3 hours, and preferably 2 hours.
The reagent used in the invention is a conventional reagent, and has little pollution to the environment.
The reagent used in the invention is a conventional reagent, and is cheap and easy to obtain.
Detailed Description
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto.
Example 1:
in a 500mL three-necked flask, 25.9g (0.1 mol) of 4-amino-5- (ethylsulfonyl) -2-methoxybenzoic acid and 259mL of dichloromethane are added, stirred, and a catalytic amount of DMF is added, 12.6g (0.1 mol) of oxalyl chloride is added dropwise under ice bath, and the mixture is reacted at 10-20 ℃ for 1.5 h. Vacuum distilling to remove dichloromethane, adding 13.7g (0.12 mol) of 1-ethyl-2-aminomethyl pyrrolidine and 260mL of acetonitrile, stirring, adding 12.5g (0.12 mol) of triethylamine, heating to 80 ℃ for reaction for 2h, cooling to room temperature after the reaction is finished, vacuum distilling to remove the solvent, adding 200mL of water into the residue, separating out a solid, carrying out suction filtration, and drying to obtain 30.8g of a white solid, wherein the yield is as follows: 86.8 percent.
30.00 g of the white solid obtained above was dissolved in anhydrous ethanol, and 12g D-malic acid dissolved in anhydrous ethanol was added with stirring, and after stirring at room temperature for 2 hours, the mixture was left overnight, filtered by suction, and dried. The solid obtained was added in portions to a solution of 37.2g of sodium carbonate, 347.5mL of water and 300mL of dichloromethane, stirred for 1.5h after complete dissolution, the layers were separated, the aqueous layer was extracted twice with 300mL of dichloromethane, the organic layers were combined, and anhydrous sodium sulfate 60.0 was dried overnight. Filtering, and distilling the filtrate under reduced pressure to remove the solvent to obtain (S) (-) -amisulpride with yield of 64.7% and ee of more than 98%.
Claims (8)
- A process for the preparation of (S) (-) -amisulpride, characterized by comprising the steps of:1) in an organic solvent, condensing the compound to obtain amisulpride (IV);
2) the amisulpride (IV) is split to obtain (S) (-) -amisulpride (I). - 2. The method according to claim 1, wherein the organic solvent used in step 1 is one or more selected from dichloromethane, tetrahydrofuran, DMF, and acetonitrile, preferably dichloromethane, and the amount of the solvent is 5 to 15 times, preferably 8 to 10 times (volume molar ratio) of the compound II.
- 3. The method according to claim 1, wherein the reaction temperature used in step 1 is preferably 10 to 20 ℃.
- 4. The process according to claim 1, wherein the reaction time in step 1 is 1 to 3 hours, preferably 1.5 hours.
- 5. The process according to claim 1, wherein the base used in step 1 is selected from the group consisting of triethylamine, sodium tert-butoxide, sodium carbonate, potassium carbonate.
- 6. The process according to claim 1, wherein the acidic resolving agent used in step 2 is D-malic acid.
- 7. The process according to claim 1, wherein the reaction time of step 2, formula IV and the aqueous solution of an inorganic base is preferably 1 to 3 hours, preferably 2 hours.
- 8. The process according to claim 1, wherein the aqueous solution of an inorganic base in the step 2 is an aqueous solution of sodium carbonate or an aqueous solution of potassium carbonate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810868996.6A CN110790693A (en) | 2018-08-02 | 2018-08-02 | Preparation method of (S) (-) -amisulpride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810868996.6A CN110790693A (en) | 2018-08-02 | 2018-08-02 | Preparation method of (S) (-) -amisulpride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110790693A true CN110790693A (en) | 2020-02-14 |
Family
ID=69425506
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810868996.6A Pending CN110790693A (en) | 2018-08-02 | 2018-08-02 | Preparation method of (S) (-) -amisulpride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110790693A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4401822A (en) * | 1978-01-20 | 1983-08-30 | Societe De'etudes Scientifiques Et Industrielles De L'ile-De France | Derivatives of 4-amino-5-alkyl sulphonyl orthoanisamides |
| CN102838520A (en) * | 2012-08-28 | 2012-12-26 | 北京德众万全药物技术开发有限公司 | Amisulpride preparation method |
| WO2018098497A1 (en) * | 2016-11-28 | 2018-05-31 | Lb Pharmaceuticals Inc. | Psychotropic agents and uses thereof |
-
2018
- 2018-08-02 CN CN201810868996.6A patent/CN110790693A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4401822A (en) * | 1978-01-20 | 1983-08-30 | Societe De'etudes Scientifiques Et Industrielles De L'ile-De France | Derivatives of 4-amino-5-alkyl sulphonyl orthoanisamides |
| CN102838520A (en) * | 2012-08-28 | 2012-12-26 | 北京德众万全药物技术开发有限公司 | Amisulpride preparation method |
| WO2018098497A1 (en) * | 2016-11-28 | 2018-05-31 | Lb Pharmaceuticals Inc. | Psychotropic agents and uses thereof |
Non-Patent Citations (1)
| Title |
|---|
| 张恺等: "(S)-(-)-氨磺必利-D-(-)-酒石酸盐的合成", 《药物化学》 * |
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| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20200214 |