CN1324010C - Preparation of miglitol - Google Patents
Preparation of miglitol Download PDFInfo
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- CN1324010C CN1324010C CNB2005100376754A CN200510037675A CN1324010C CN 1324010 C CN1324010 C CN 1324010C CN B2005100376754 A CNB2005100376754 A CN B2005100376754A CN 200510037675 A CN200510037675 A CN 200510037675A CN 1324010 C CN1324010 C CN 1324010C
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Abstract
The present invention relates to a preparing method of mitiglinide, which is characterized in that a chiral center is provided by L-phenylalanine, and a chemical separating method or an asymmetric hydrogenation method is avoided. The method of the present invention has high efficiency and good optical purity.
Description
Technical field
The present invention relates to a kind of preparation method of mitiglinide.
Background technology
Mitiglinide is an antidiabetic drug, and its mechanism of action is similar to sulfonylurea hypoglycemic agent, mainly acts on the ATP susceptibility K of beta cell
+Passage promotes insulin secretion.The mitiglinide preparation method is many, mainly contains chemical resolution method and asymmetric hydrogenation method.
Chemical resolution method has the R-isomer of half to utilize, and yield is low, cost height (method 1).The expensive rhodium complex of asymmetric hydrogenation method needs (rhodium/(2S, 4S)-N-butoxy carbonyl-4-diphenylphosphino-2-diphenylphosphino crassitude), make production cost improve greatly, be unfavorable for suitability for industrialized production (method 2).
Method 1: chemical resolution method
Method 2: asymmetric hydrogenation method
Summary of the invention
The object of the invention provides a kind of preparation method of mitiglinide, and its chiral carbon atom provides chirality by the L-phenylalanine.
Purpose of the present invention can reach by following measure:
X is chlorine, bromine halogen atom among its Chinese style II, and Z and Z` are cyano group, ester group or amide group in the formula III.
The present invention has following advantage compared to existing technology:
Chiral carbon atom in the mitiglinide is provided by the L-phenylalanine, avoided chemical resolution method to have the R-isomer of half to utilize, and the expensive rhodium complex of asymmetric hydrogenation method needs (rhodium/(2S, 4S)-N-butoxy carbonyl-4-diphenylphosphino-2-diphenylphosphino crassitude).The starting material that the inventive method adopted are cheap and easy to get, the processing condition gentleness, and the optical purity of products height is convenient to suitability for industrialized production.
Embodiment
Embodiment 1
(S)-2-chlorobenzene propionic acid
In the 5000ml reaction flask, add 6N hydrochloric acid 3000ml, cryosel is bathed cooling and is added L-phenylalanine-3,4-quinone 30g (2mol) down, stir, drip 36% sodium nitrite in aqueous solution 850g below 0 ℃, drip off room temperature reaction and spend the night, tell little yellow organic layer, water layer merges and adds an amount of anhydrous sodium sulfate drying with ethyl acetate extraction.Remove ethyl acetate under reduced pressure, get the about 360g of little yellow raffinate, [α]
D 20=+4.5 ° (methyl alcohol), yield 97.5% (directly the next step).
(S)-2-chlorobenzene ethyl propionate
In the 3000ml reaction flask, add (S)-2-chloro-3-phenylpropionic acid 351g (1.90mol), methylene dichloride 770ml, 98% sulfuric acid 7.8ml, the ice bath cooling drips dehydrated alcohol 1000ml down, drip off stirring at room reaction 48hr, the washing of 2N saleratus water liquid, anhydrous sodium sulfate drying, decompression is steamed to slip and is collected 118～122 ℃/5mmHg cut 282.5g, yield 70.0%, [α]
D 20=+18.6 ° (dehydrated alcohol).
(S)-the 2-bromo-hydrocinnamic acid
In the 3000ml reaction flask, add 6N hydrochloric acid 1500ml, cryosel is bathed cooling and is added L-phenylalanine 165g (1mol) down, stir, drip 20% sodium nitrite in aqueous solution 500g below 0 ℃, drip off room temperature reaction and spend the night, tell little yellow organic layer, water layer merges and adds an amount of anhydrous sodium sulfate drying with ethyl acetate extraction.Remove ethyl acetate under reduced pressure, get the about 200g of little yellow raffinate, [α]
D 20=-9.5 ° (methyl alcohol).
(S)-2-bromo-hydrocinnamic acid ethyl ester
Method is with (S)-2-chlorobenzene ethyl propionate, yield 65%, [α]
D 20=+8.6 ° (methylene dichloride).
Embodiment 2
(S)-2-benzyl Succinic Acid
In the 1000ml reaction flask, add anhydrous N, dinethylformamide 625ml, activity methene compound (0.4mol), cryosel is bathed to be cooled to and is added 50% sodium hydrogen 48g (1mol) below 0 ℃, stir down and drip (S)-2-halo-3-phenylpropionic acid ethyl ester (0.4mol), keep cryosel and bathe stirring reaction 30min, again in stirring at room.In the about 500g trash ice of reaction solution impouring, ethyl acetate extraction, anhydrous sodium sulfate drying, remove solvent under reduced pressure, get the yellowish brown raffinate, add acetate 400ml, 37% hydrochloric acid 400ml, heating reflux reaction, be evaporated to small volume, crystallization spends the night in the impouring trash ice, gets white solid (the results are shown in Table 1).
| Formula II | Formula III | Reaction times | Yield | Specific optical rotation (ethyl acetate) |
| X＝Cl | Z＝CN；Z`＝COOEt | 6h | 55％ | -27.8° |
| X＝Br | Z＝CN；Z`＝COOEt | 4h | 68％ | -28.4° |
| X＝Cl | Z＝Z`＝CN | 6h | 75％ | -28.5° |
| X＝Br | Z＝Z`＝CN | 6h | 83％ | -27.9° |
| X＝Cl | Z＝Z`＝COOEt | 8h | 43％ | -23.6° |
Embodiment 3
(S)-2-benzyl Succinic anhydried
In the 1000ml reaction flask, add (S)-2-benzyl Succinic Acid 62.5g (0.3mol), diacetyl oxide 220ml (2.33mol), in 75-80 ℃ of reaction 1hr.Cooling back adds the about 415ml of isopropyl ether, puts that crystallization spends the night in the refrigerator, gets white solid 39.7g, and mp122-125 ℃, yield 69.6%, [α]
D 20=+55.6 ° (ethyl acetate).
Embodiment 4
Mitiglinide
In the 1000ml reaction flask, add (S)-2-benzyl Succinic anhydried 38.0g (0.20mol), methylene dichloride 815ml, cryosel is bathed cooling, drips (cis)-hexahydroisoindoline, and room temperature reaction 2hr, concentrating under reduced pressure get light yellow dope 89g, [α]
D 20=-3.5 ° (C=1.0, methyl alcohol).
The mitiglinide calcium salt
In the 1000ml reaction flask, mitiglinide 89g, water 500ml, strong aqua 30ml stir gradually moltenly entirely, drip the Calcium Chloride Powder Anhydrous aqueous solution, and gradually the adularescent solid is separated out, and again in stirred overnight at room temperature, filters after dripping off, and the aqueous ethanolic solution recrystallization gets calcium salt 65g, [α]
D 20=+5.7 ° (C=1.0, methyl alcohol).
Claims (1)
1. the preparation method of a formula I compound (S)-2-benzyl Succinic Acid monocarboxylic acid derivative,
It is characterized in that L-phenylalanine or its ester are made formula II (S)-2-halogeno-benzene propionic acid or ester through the diazotization halo:
The active methylene reaction of formula II and formula III obtains formula IV:
X is chlorine, bromine halogen atom among its Chinese style II, and Z and Z` are cyano group, ester group or amide group in the formula III, and R is hydrogen, ethyl in the structural formula of formula II or formula IV and L-phenylalanine or its ester;
Formula IV obtains formula V (S)-2-benzyl Succinic Acid through the hydrolysis decarboxylation reaction:
Formula V dehydration generates acid anhydrides and obtains formula I with the hexahydroisoindoline reaction again:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100376754A CN1324010C (en) | 2005-01-12 | 2005-01-12 | Preparation of miglitol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100376754A CN1324010C (en) | 2005-01-12 | 2005-01-12 | Preparation of miglitol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1680321A CN1680321A (en) | 2005-10-12 |
| CN1324010C true CN1324010C (en) | 2007-07-04 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005100376754A Expired - Fee Related CN1324010C (en) | 2005-01-12 | 2005-01-12 | Preparation of miglitol |
Country Status (1)
| Country | Link |
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| CN (1) | CN1324010C (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100441570C (en) * | 2006-05-24 | 2008-12-10 | 严洁 | Preparation of mitiglinide calcium and its quality control method |
| CN102382033B (en) * | 2010-08-31 | 2013-04-03 | 凯瑞斯德生化(苏州)有限公司 | Preparation methods for optical activity mitiglinide ester and mitiglinide salt |
| CN102911107B (en) * | 2012-09-28 | 2015-11-25 | 迪沙药业集团有限公司 | The preparation method of S 21403 |
| CN104693109A (en) * | 2013-12-05 | 2015-06-10 | 陕西师范大学 | A preparing method of a miglitol intermediate |
| CN107879927A (en) * | 2017-11-17 | 2018-04-06 | 中国药科大学 | A kind of method for preparing α chlorinated carboxylic acids |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5202335A (en) * | 1991-03-30 | 1993-04-13 | Kissei Pharmaceutical Co., Ltd. | Succinic acid compounds |
| CN1261879A (en) * | 1997-07-03 | 2000-08-02 | 阿迪尔公司 | Method for preparing substituted perhydroisoindole |
| CN1320595A (en) * | 2000-02-25 | 2001-11-07 | 阿迪尔公司 | Process for preparing isoindoline |
| WO2003062186A1 (en) * | 2002-01-22 | 2003-07-31 | Kissei Pharmaceutical Co., Ltd. | Metal salts of (3s)-3-methoxycarbonyl-4-phenylbutyric acid and usage thereof |
| CN1616427A (en) * | 2003-11-13 | 2005-05-18 | 中国科学院上海药物研究所 | A new method for preparing antidiabetic drug mitiglinide |
-
2005
- 2005-01-12 CN CNB2005100376754A patent/CN1324010C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5202335A (en) * | 1991-03-30 | 1993-04-13 | Kissei Pharmaceutical Co., Ltd. | Succinic acid compounds |
| CN1261879A (en) * | 1997-07-03 | 2000-08-02 | 阿迪尔公司 | Method for preparing substituted perhydroisoindole |
| CN1320595A (en) * | 2000-02-25 | 2001-11-07 | 阿迪尔公司 | Process for preparing isoindoline |
| WO2003062186A1 (en) * | 2002-01-22 | 2003-07-31 | Kissei Pharmaceutical Co., Ltd. | Metal salts of (3s)-3-methoxycarbonyl-4-phenylbutyric acid and usage thereof |
| CN1616427A (en) * | 2003-11-13 | 2005-05-18 | 中国科学院上海药物研究所 | A new method for preparing antidiabetic drug mitiglinide |
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| CN1680321A (en) | 2005-10-12 |
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Owner name: JIANGSU PROVINCIAL INSTITUTE OF MATERIA MEDICA CO. Free format text: FORMER OWNER: JIANGSU PROVINCIAL INSTITUTE OF MATERIA MEDICA Effective date: 20101224 |
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Effective date of registration: 20101224 Address after: 210009, Ma 26 street, Xuanwu Gate, Jiangsu, Nanjing Patentee after: Jiangsu Provincial Institute of Materia Medica Co., Ltd. Address before: 210009, Ma 26 street, Xuanwu Gate, Jiangsu, Nanjing Patentee before: Jiangsu Provincial Institute of Materia Medica |
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| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: Changzhou Tianhua Pharmaceutical Co., Ltd. Assignor: Jiangsu Provincial Institute of Materia Medica Co., Ltd. Contract record no.: 2011320000025 Denomination of invention: Preparation of miglitol Granted publication date: 20070704 License type: Exclusive License Open date: 20051012 Record date: 20110127 |
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