Preparation method of mitiglinide calcium

A technology of mitiglinide calcium and compound is applied in the field of preparation of mitiglinide calcium, a medicine for treating type II diabetes, and can solve the problem that the specificity of chiral reduction products is not particularly strong, the resolution yield is low, and the by-products are many. and other problems, to avoid the problem of location selectivity, reduce production costs, and avoid high costs.

Inactive Publication Date: 2013-02-06
DISHA PHARMA GRP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Food and Drug Journal, 2009, 11 (11), 21-23, discloses " a kind of process improvement of mitiglinide calcium ", and this method is raw material with benzaldehyde, by diethyl succinate or methyl ester and Benzaldehyde undergoes Stobbe condensation, hydrolysis, reduction, splitting, dehydration into acid anhydride, condensation with cis-perhydroisoindole, salt formation, etc. to obtain mitiglinide calcium; this method requires special equipment for high-pressure reaction for hydrogenation reduction ; The yield of chiral resolution is low; the reaction step of perhydroisoindole with expensive materials has many by-products and low effective utilization rate, which not only increases the loss of raw materials, but also greatly increases the purification rate after the reaction to obtain the target. product difficulty
[0006] Literature: Tetrahedron Letters, 1987, 28 (17), 1905-1908; Tetrahedron Letters, 1989, 30 (6), 735-738 discloses a method for asymmetric reduction with a chiral rhodium catalyst; , and cannot be applied repeatedly, there is a problem of high cost, and there is also a disadvantage that the specificity of chiral reduction products is not particularly strong, and there are often enantiomers, resulting in low reaction yields
[0007] Chinese patent CN1680321 discloses a preparation method using chiral amino acids as starting materials; this method avoids the problems of low resolution yield or chiral reduction
However, expensive materials follow the perhydroisoindole reaction step, and there are many by-products,
[0008] The problem of low effective utilization

Method used

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  • Preparation method of mitiglinide calcium
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  • Preparation method of mitiglinide calcium

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Experimental program
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Embodiment 1

[0047] The preparation of embodiment 1, (R)-2-chlorophenylpropionic acid

[0048] In a 2000ml reaction flask, add 1500ml of 3N hydrochloric acid, add 165g (1.0mol) of L-phenylalanine under ice-salt bath cooling, stir, add 76g of sodium nitrite (1.1mol) aqueous solution dropwise below 5°C, and continue to control the temperature React for 2 hours, react overnight at room temperature, then add ethyl acetate to extract twice, add appropriate amount of anhydrous sodium sulfate to dry. Ethyl acetate was distilled off under reduced pressure to obtain about 180 g of slightly yellow residue with a yield of 97.8% (directly to the next step reaction). 1 H-NMR (400MHz, CDCl 3 )δ: 3.05 (1H, dd), 3.40 (1H, dd), 4.51 (1H, t), 7.26-7.38 (5H, m).

[0049] Preparation of (R)-2-chlorophenylpropionic acid methyl ester

[0050] Add 1000ml of anhydrous methanol to the oily substance from the previous step to dissolve, then add 131g (1.1mol) of thionyl chloride at below 10°C, slowly raise the te...

Embodiment 2

[0055] Embodiment 2, the preparation of 3-(2-cis perhydroisoindolyl)-3-oxopropionic acid ethyl ester

[0056] Add 125g (1.0mol) of cis-perhydroisoindole into 600ml of dichloromethane, add 111g (1.1mol) of triethylamine, control the temperature below 20°C, and slowly add 150g (1.0mol) of monoethyl malonate chloride dropwise. mol), the dropwise addition was completed and the reaction was continued for 2 hours, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 228 g of a colorless oily liquid, with a yield of 95.4% (directly proceed to the next step reaction).

Embodiment 3

[0057] Embodiment 3, the preparation of 2-benzyl-4-(2-cis perhydroisoindolyl)-4-oxobutanoic acid methyl ester

[0058] Add 228g (0.95mol) of ethyl 3-(cis-perhydroisoindolyl)-3-oxopropionate into 1300ml dimethyl sulfoxide, control the temperature below 15°C, and add 40g of 60% sodium hydride in batches (1.0mol), after the addition, continue to react for 1 hour, add 190g (0.96mol) of (R)-2-chlorophenylpropionic acid methyl ester, heat up to 55-60°C, react for 6 hours, point the plate to monitor the completion of the reaction, and cool to Below 20°C, add concentrated hydrochloric acid to adjust the pH to neutral, then raise the temperature to 150°C, react for 2 hours, cool down, then pour into ice water, extract twice with n-hexane, combine the organic layers, wash twice with water, dry and concentrate , 266 g of methyl 2-benzyl-4-(2-cis-perhydroisoindolyl)-4-oxobutyrate was obtained as a yellowish oily substance, with a yield of 87.3%. 1 H-NMR (CDCl 3 , 400M) δ: 1.28-1.54 (8...

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Abstract

The invention relates to a preparation method of a bulk drug of mitiglinide calcium used for treating type 2 diabetes mellitus. The mitiglinide calcium is prepared by a series of reaction steps comprising using D-phenylalanine as a starting material, esterification and cis-hexahydroisoindoline reaction. In the reaction, the problem of high cost of special equipment for high pressure hydrogenation and operation as well as chiral catalyst in the traditional process can be solved, the use of chiral resolution and a resolving agent is avoided, and the yield is improved.

Description

[0001] Technical field The present invention relates to a preparation method of mitiglinide calcium, a medicine for treating type II diabetes. Background technique [0002] Miglinide calcium, Chinese chemical name: (+)-bis[(2S)-2-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyrate]calcium. This product can be used alone for patients with type II diabetes whose hyperglycemia cannot be effectively controlled by diet and exercise therapy. Miglinide is the third glinide hypoglycemic drug after repaglinide and nateglinide, and it is a derivative of phenylalanine. [0003] The compound was first synthesized by Tachibana Pharmaceutical Co., Ltd. in Japan. In December 2002, it was applied for controlling postprandial blood sugar in patients with type II diabetes, and it was launched in Japan in April 2004. [0004] According to the methods reported in previous literature and patents, the preparation methods of mitiglinide include the following synthetic methods, all of which use a rel...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/44
Inventor 吴荣贵王兆杰于年余陈云鹏
Owner DISHA PHARMA GRP
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