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A technology of mitiglinide calcium and benzylsuccinic acid, which is applied in the field of preparation of drug mitiglinide calcium, can solve the problems of low chiral separation and waste, and achieve the effect of high chiral separation
Inactive Publication Date: 2011-06-22
周玉莲
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[0004] The synthesis method in recent years, such as the patent application number: 200510200127.9, first synthesizes racemic (±) 2-benzyl-3-(cis-hexahydroisoindole-2-carbonyl)propionic acid during the synthesis process, Then resolve to obtain (2S)-2-benzyl-3-(cis-hexahydroisoindole-2-carbonyl)propionic acid, which not only wastes a lot of raw materials cis-hexahydroisoindole, but also has poor chiral resolution high
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Embodiment 1
[0029] The synthesis of step 1, benzylidene succinic acid
[0030] Under stirring, add sodium metal (1.7 g, 0.072 mol) into absolute ethanol (50 mL), under the protection of argon, heat and stir until the solution refluxes, and the reflux state is maintained for 50 minutes, and benzaldehyde ( 23 mL, 0.183 mol), then diethyl succinate (50 mL, 0.275 mol) was added dropwise, and the reaction was continued to stir for 2.5 hours. LC-Ms detection showed that the proportion of raw material benzaldehyde decreased slowly. After cooling to room temperature, 55wt .% NaOH aqueous solution to adjust the pH ≥ 13.0, then heated to reflux for 3 hours, cooled to room temperature, kept the temperature of the reaction solution < 25 °C, adjusted the pH ≤ 2.0 with concentrated hydrochloric acid, filtered, and recrystallized THF at low temperature, yield: 81.3%;
[0031] The synthesis of step 2, benzylsuccinic acid
[0032] Put benzylidene succinic acid (23.7 g, 0.114 mol) into the reactor, then a...
Embodiment 2
[0042] Similar to the experimental method of step 1 to step 6 of Example 1, except that in step 3, (R)-1-phenylethylamine (61.4 g, 0.359 mol) is used to replace (R)-1-phenylethylamine, other reaction operations The homogeneous phase is similar, and the synthetic yield of this step is: 87.3%.
Embodiment 3
[0044] Similar to the experimental method of step 1 to step 6 of Example 1, except that in step 3, (R)-1-phenyl-2-p-tolylethylamine (90.2 g, 0.374 mol) was used to replace (R)-1- Phenylethylamine, other reaction operations are similar, and the synthetic yield of this step is: 83.4%.
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Abstract
The invention discloses a preparation method of mitiglinide calcium. The method comprises the following steps of: performing Stobble condensation on diethyl succinate and benzaldehyde serving as raw materials in ethanol by using sodium alcoholate; hydrolyzing to obtain toluenyl butane diacid; performing catalytic hydrogenation on the toluenyl butane diacid to obtain DL-2-benzyl butane diacid; resolving the DL-2-benzyl butane diacid with (R)-chiral amine to obtain (S)-2-benzyl butane diacid; reacting the (S)-2-benzyl butane diacid under the action of acetic anhydride to obtain acid anhydride ; reacting the obtained acid anhydride with cis-hexahydroisoindole to obtain mitiglinide acid; and reacting the mitiglinide acid with calcium chloride and ammonia water to generate a mitiglinide calcium bihydrate. The preparation method of the mitiglinide calcium has the advantages of saving of cis-hexahydroisoindole serving as a raw material and high chiral separating degree.
Description
technical field [0001] The invention relates to a preparation method of mitiglinide calcium, a medicine for treating type Ⅱ diabetes. Background technique [0002] Miglinide calcium (mitiglinide calcium), the chemical name is (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl) calcium propionate dihydrate, which is produced by Japan The ATP-dependent potassium ion channel blocker developed by Kissei Pharmaceutical Company was first launched in Japan in 2004 for the treatment of type 2 diabetes. [0003] Miglinide calcium is the third meglitide drug after repaglinide and nateglinide. It is a derivative of phenylalanine. Its mechanism of action is similar to that of sulfonylurea, but its onset speed is faster , and the half-life is short, which is not only beneficial to reduce postprandial blood sugar in diabetic patients, but also can avoid hypoglycemia caused by continuous blood sugar reduction, and has the reputation of "in vitro pancreas". [0004] The synthesis metho...
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