CN110790693A - 一种(s)(-)-氨磺必利的制备方法 - Google Patents
一种(s)(-)-氨磺必利的制备方法 Download PDFInfo
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- 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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- amisulpride
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种(S)(‑)‑氨磺必利的制备方法。该方法包括：4‑氨基‑5‑(乙基磺酰基)‑2‑甲氧基苯甲酰氯与1‑乙基‑2‑氨甲基吡咯烷缩合得氨磺必利，再用D‑苹果酸拆分得(S)(‑)‑氨磺必利。
Description
技术领域
本发明属于药物化学领域，主要涉及(S)(-)-氨磺必利的制备。
背景技术
氨磺必利（Amisulpride），化学名为4-氨基-N-[(1-乙基-2-吡咯烷基)甲基]-5-(乙基磺酰基)-2-甲氧基苯甲酰胺，由法国Sanofi-Sythelabo公司开发，是一种新型非典型抗精神病药，主要用于治疗急性或慢性精神分裂症的阳性及阴性症状。与消旋体相比，左旋体(S)(-)-氨磺必利的药理活性达2倍以上，毒副作用更小，安全性更高。
发明内容
本发明提供式（Ⅰ）所示的(S)(-)-氨磺必利的制备方法。
本发明制备方法，包含以下步骤：
（1）在有机溶剂中，所示化合物缩合得氨磺必利（Ⅳ）；
（2）氨磺必利（Ⅳ）经过拆分得到(S)(-)-氨磺必利（Ⅰ）。
在本发明的方法中，步骤（1）化合物（Ⅱ）可由市售4-氨基-5-(乙基磺酰基)-2-甲氧基苯甲酸在碱性条件下与草酰氯反应制得。
优选地，步骤（1）的反应温度为10~20℃。
优选地，步骤（1）所用溶剂选自二氯甲烷、四氢呋喃、DMF、乙腈中的一种或多种。再优选地，所用溶剂为二氯甲烷。
优选地，步骤（1）所用的碱选自三乙胺、叔丁醇钠、碳酸钠、碳酸钾。
优选地，步骤（1）中化合物（Ⅱ）与化合物（Ⅲ）的摩尔比为1:1.0~1.2。
本发明方法中，步骤（2）拆分方法步骤如下：氨磺必利（Ⅳ）与酸性拆分试剂成盐，再用碱性试剂还原为游离碱，得纯的光学异构体(S)(-)-氨磺必利（Ⅰ）。
所述酸性拆分试剂为D-苹果酸。
所述碱性试剂为碳酸钠或碳酸钾。
反应使用溶剂为甲醇或乙醇，优选为乙醇。
溶剂用量建议为化合物Ⅳ的5~10倍，优选8~10倍（此处为体积质量比）。
加入无机碱的反应温度为室温。
和无机碱反应时间建议为1~3小时，优选2小时。
本发明所用试剂为常规试剂，对环境污染小。
本发明所用试剂为常规试剂，便宜易得。
具体实施方式
以下通过实施例进一步说明本发明，但不作为对本发明的限制。
实施例1：
于500ml三口烧瓶中，加入25.9g（0.1mol）4-氨基-5-(乙基磺酰基)-2-甲氧基苯甲酸、259mL二氯甲烷，搅拌，加入催化量DMF，冰浴下滴加12.6g（0.1mol）草酰氯，10~20℃反应1.5h。减压蒸馏出去二氯甲烷，加入13.7g（0.12mol）1-乙基-2-氨甲基吡咯烷、260mL乙腈，搅拌，加入12.5g（0.12mol）三乙胺，升温至80℃反应2h，反应完毕冷却至室温，减压蒸馏除去溶剂，残留物加入200ml水，析出固体，抽滤，干燥，得白色固体30.8g，收率：86.8%。
前述所得的白色固体30.00 g，以无水乙醇溶解，搅拌下加入无水乙醇溶解的12g D-苹果酸，室温搅拌2h后放置过夜，抽滤，干燥。所得固体分批加入37.2g碳酸钠和347.5mL水、300mL二氯甲烷溶液中，溶解完全后搅拌1.5h，分液，水相用300mL二氯甲烷萃取两次，合并有机相，无水硫酸钠60.0干燥过夜。抽滤，滤液减压蒸馏出去溶剂得(S)(-)-氨磺必利，收率64.7%，ee>98%。
Claims (8)
1.(S)(-)-氨磺必利的制备的制备方法，其特征在于，包括以下步骤：
1）在有机溶剂中，所示化合物缩合得氨磺必利（Ⅳ）；
2）氨磺必利（Ⅳ）经过拆分得到(S)(-)-氨磺必利（Ⅰ）。
2.根据权利要求1的方法，其步骤1采用的有机溶剂选自二氯甲烷、四氢呋喃、DMF、乙腈中的一种或多种，优选为二氯甲烷，溶剂用量是化合物Ⅱ的5~15倍，优选8~10倍（此处为体积摩尔比）。
3.根据权利要求1的方法，其步骤1采用的反应温度优选为10~20℃。
4.根据权利要求1的方法，其步骤1反应时间为1~3个小时，优选1.5个小时。
5.根据权利要求1的方法，其步骤1采用的碱选自三乙胺、叔丁醇钠、碳酸钠、碳酸钾。
6.根据权利要求1的方法，其步骤2采用的酸性拆分试剂为D-苹果酸。
7.根据权利要求1的方法，其步骤2式Ⅳ和无机碱水溶液反应时间建议为1~3小时，优选2小时。
8.根据权利要求1的方法，其步骤2中无机碱水溶液为碳酸钠水溶液或碳酸钾水溶液。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810868996.6A CN110790693A (zh) | 2018-08-02 | 2018-08-02 | 一种(s)(-)-氨磺必利的制备方法 |
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| CN201810868996.6A CN110790693A (zh) | 2018-08-02 | 2018-08-02 | 一种(s)(-)-氨磺必利的制备方法 |
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| CN110790693A true CN110790693A (zh) | 2020-02-14 |
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| CN201810868996.6A Pending CN110790693A (zh) | 2018-08-02 | 2018-08-02 | 一种(s)(-)-氨磺必利的制备方法 |
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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 (zh) * | 2012-08-28 | 2012-12-26 | 北京德众万全药物技术开发有限公司 | 氨磺必利的制备方法 |
| 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/zh 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 (zh) * | 2012-08-28 | 2012-12-26 | 北京德众万全药物技术开发有限公司 | 氨磺必利的制备方法 |
| 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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