CN106631978B - Synthesis process of mitiglinide intermediate - Google Patents
Synthesis process of mitiglinide intermediate Download PDFInfo
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- CN106631978B CN106631978B CN201611247264.2A CN201611247264A CN106631978B CN 106631978 B CN106631978 B CN 106631978B CN 201611247264 A CN201611247264 A CN 201611247264A CN 106631978 B CN106631978 B CN 106631978B
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- ethyl acetate
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- benzyl
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- perhydroisoindol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
Abstract
The invention relates to the field of drug synthesis, in particular to a synthesis process of a mitiglinide intermediate 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) benzyl butyrate, which comprises the following steps: adding 1,1' -carbonyldiimidazole and S-2-benzylsuccinic acid into ethyl acetate in sequence, adding cis-perhydroisoindole hydrochloride after reaction, adding refined water, adding hydrochloric acid to adjust the pH value, adding refined water into an ethyl acetate layer after standing and liquid separation, adding a NaOH solution to adjust the pH value, adding ethyl acetate into a water layer after standing and liquid separation, adding hydrochloric acid to adjust the pH value, drying, filtering and washing the ethyl acetate layer after standing and liquid separation, adding anhydrous potassium carbonate and benzyl bromide into the obtained ethyl acetate solution in sequence, performing reflux reaction, cooling, adding refined water, standing and liquid separation, crystallizing an organic layer, further performing post-treatment to obtain a target compound crude product, and refining to obtain a target pure product.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a synthesis process of a mitiglinide intermediate.
Background
Benzyl 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) butyrate is an intermediate in the synthesis of mitiglinide, and has the following structural formula:
mitiglinide is an ATP type ion channel blocker developed by Kissei pharmaceutical company of Japan, is first marketed in Japan in 2004, is clinically used for treating type 2 diabetes, and is a postprandial blood sugar regulator which is marketed after repaglinide and nateglinide. The effect of mitiglinide is mainly focused on lowering postprandial blood sugar which can promote mitiglinide to stimulate the release of insulin, and in the presence of glucose, the secretion amount of insulin promoted by mitiglinide is increased by about 50% compared with that in the absence of glucose, so that the mitiglinide acts like an 'in vitro pancreas', and only insulin is provided when needed.
The difference between mitiglinide and the traditional sulfonylurea medicine lies in that the medicine has quick effect after administration, has an action time period, and effectively inhibits postprandial hyperglycemia with the characteristic of type 2 diabetes, thereby avoiding hypoglycemic reaction.
Disclosure of Invention
The invention provides a synthesis process of a mitiglinide intermediate, which is easy to operate and can prepare a mitiglinide intermediate 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) benzyl butyrate (MGN-Bn) with high content and high purity.
The process of the invention has the following synthetic route:
the invention is realized by the following technical processes:
(1) synthesis of benzyl 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) butyrate
a. Adding ethyl acetate into a reaction bottle, cooling to 0-5 ℃, and adding 1,1' -carbonyldiimidazole into the reaction bottle; adding S-2-benzylsuccinic acid into a reaction bottle for 6 times at 0-10 ℃, and stirring for 20min after each addition; after all the materials are added, stirring for 3 hours at 0-5 ℃, keeping the temperature at 0-5 ℃, adding cis-perhydroisoindole hydrochloride, raising the reaction temperature to 25-30 ℃, and stirring for 8 hours;
b. maintaining the temperature at 20-35 ℃, adding refined water into the reaction bottle, stirring for 20min, adding hydrochloric acid, adjusting the pH value to 0.8-1.2 at 15-25 ℃, stirring for 30min at 15-25 ℃, and maintaining the pH value to 0.8-1.2;
c. standing the solution, then discarding a lower water layer, adding refined water into an upper ethyl acetate layer, adding a NaOH solution at 10-30 ℃ to adjust the pH value to 9-10, stirring at 10-30 ℃ for 30min, standing for liquid separation, discarding an upper ethyl acetate layer, and reserving a lower water layer; adding ethyl acetate into the water layer, adding hydrochloric acid to adjust the pH value to be 1.0-1.5, stirring for 30min at 15-25 ℃, and keeping the pH value to be 1.0-1.5; standing, separating liquid and discarding a water layer; adding anhydrous sodium sulfate into the ethyl acetate layer, stirring, filtering and washing to obtain an ethyl acetate solution;
d. adjusting the temperature of the ethyl acetate solution to 15-20 ℃, adding anhydrous potassium carbonate, cooling, and stirring at 10-20 ℃ for 15 min; adding benzyl bromide at 10-20 ℃, slowly heating, and reacting for 5 hours under the reflux condition; cooling to below 60 ℃, adding refined water, and then cooling to 40-50 ℃; standing at 40-50 ℃, separating liquid, discarding a water layer, adjusting the temperature of an organic layer to 30-40 ℃, and crystallizing; stirring for 1h at 30-40 ℃, then cooling to 0-5 ℃, stirring for 2h, and filtering; washing with ethyl acetate at 0-5 ℃, and drying to obtain a crude product of 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) benzyl butyrate.
(2) Purification of benzyl 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) butyrate
a. Adding ethyl acetate into a reaction bottle, stirring, adding a crude product of 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) benzyl butyrate at the temperature of 20-30 ℃, stirring, raising the temperature to 65-75 ℃ to completely dissolve the crude product, stirring for 5min after dissolution, filtering with diatomite, filtering the solution, and washing to obtain an ethyl acetate solution;
b. slowly cooling the ethyl acetate solution to 40 ℃, crystallizing, cooling to 0-5 ℃, stirring for 1h, and filtering; washing with ethyl acetate at 0-5 ℃; drying the wet product at 60 ℃ for 6h to obtain the pure 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) butyric acid benzyl ester.
Preferably, the molar ratio of S-2-benzylsuccinic acid, 1' -carbonyldiimidazole, cis-perhydroisoindole hydrochloride and bromobenzyl in the step (1) is 1: 2.2: 1.2: 1.1.
preferably, the anhydrous potassium carbonate in step (1) is in the form of large particles.
Preferably, the hydrochloric acid concentration in the step (1) is 6mol/L, and the solubility of the NaOH solution is 4 mol/L.
Preferably, in the step (d) in the step (1), the precipitated crystal is washed twice with ethyl acetate at 0 to 5 ℃ by shaking.
Preferably, the crystallization conditions in step (b) in step (2) are: stirring for 40min at 35-40 ℃.
The invention has the beneficial effects that:
the synthesis process has the advantages of high efficiency, low risk, simple operation and the like, is easy to control the reaction, is suitable for industrial production, and can be used for preparing the mitiglinide intermediate benzyl 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) butyrate with high content and high purity.
Detailed Description
The technical solution of the invention is further illustrated below with reference to specific examples, which are not to be construed as limiting the technical solution.
A synthesis process of a mitiglinide intermediate 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) benzyl butyrate comprises the following steps:
(1) synthesis of benzyl 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) butyrate
a. Adding 400ml of ethyl acetate into a reaction bottle, cooling to 0-5 ℃, and adding 137.1g of 1,1' -carbonyldiimidazole into the reaction bottle; adding S-2-benzylsuccinic acid into a reaction bottle at 0-10 ℃ for 6 times, wherein 15g of S-2-benzylsuccinic acid is added each time, and stirring for 20min after each addition is finished; after all the materials are added, stirring for 3 hours at 0-5 ℃, keeping the temperature at 0-5 ℃, adding 74.5g of cis-perhydroisoindole hydrochloride, raising the reaction temperature to 25-30 ℃, and stirring for 8 hours;
b. keeping the temperature at 20-35 ℃, adding 80ml of refined water into a reaction bottle, stirring for 20min, adding 6mol/L hydrochloric acid, adjusting the pH value to 0.8-1.2 at 15-25 ℃, then stirring for 30min at 15-25 ℃, and keeping the pH value between 0.8-1.2;
c. standing the solution, then discarding a lower water layer, adding 240ml of refined water into an upper ethyl acetate layer, adding 4mol/L NaOH solution at 10-30 ℃ to adjust the pH value to 9-10, stirring at 10-30 ℃ for 30min, standing for liquid separation, discarding an upper ethyl acetate layer, and reserving a lower water layer; adding 200ml of ethyl acetate into the water layer, adding 6mol/L hydrochloric acid to adjust the pH value to be 1.0-1.5, stirring for 30min at 15-25 ℃, and keeping the pH value to be 1.0-1.5; standing, separating liquid and discarding a water layer; adding 20g of anhydrous sodium sulfate into the ethyl acetate layer, stirring for 20min, assisting filtration by using diatomite, filtering the anhydrous sodium sulfate, and washing by using 40ml of ethyl acetate to obtain an ethyl acetate solution;
d. adjusting the temperature of the ethyl acetate solution to 15-20 ℃, adding 111.5g of large granular anhydrous potassium carbonate, cooling, and stirring at 10-20 ℃ for 15 min; adding 72.3g of benzyl bromide at the temperature of 10-20 ℃, slowly heating, and reacting for 5 hours under the reflux condition; cooling the reaction system to below 60 ℃, adding 240ml of refined water, and then cooling to 40-50 ℃; standing at 40-50 ℃, separating liquid, discarding an aqueous layer, adjusting the temperature of an organic layer to 30-40 ℃, and crystallizing (about 35 ℃, solid can be separated out); stirring for 1h at 30-40 ℃, then cooling to 0-5 ℃, stirring for 2h, and filtering; washing twice with ethyl acetate of 0-5 ℃ by shaking, wherein 40ml of ethyl acetate is used each time, and 140.7g of crude wet product of benzyl 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) butyrate is obtained; the crude wet product was dried at 50 ℃ for 2h to give 134g of crude benzyl 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) butyrate in 86% yield.
(2) Purification of benzyl 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) butyrate
a. Adding 300ml of ethyl acetate into a reaction bottle, stirring, adding 134g of 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) benzyl butyrate crude product at the temperature of 20-30 ℃, stirring, raising the temperature to 65-75 ℃, completely dissolving the crude product, stirring for 5min after dissolving, assisting filtration by using kieselguhr, filtering the solution, and washing by using 70ml of ethyl acetate to obtain an ethyl acetate solution;
b. slowly cooling the ethyl acetate solution to 40 ℃, separating out crystals, stirring for 40min at 35-40 ℃, then slowly cooling to 0-5 ℃, stirring for 1h, and filtering; washing with 80ml of ethyl acetate at 0-5 ℃; the wet product was dried at 60 ℃ for 6 hours to give 124.6g of a pure benzyl 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) butyrate, the yield was 93%, and then the residue was pulverized to ensure no lump.
Claims (1)
1. A synthesis process of a mitiglinide intermediate is characterized by comprising the following steps:
(1) synthesis of benzyl 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) butyrate
a. Adding 400ml of ethyl acetate into a reaction bottle, cooling to 0-5 ℃, and adding 137.1g of 1,1' -carbonyldiimidazole into the reaction bottle; adding S-2-benzylsuccinic acid into a reaction bottle at 0-10 ℃ for 6 times, wherein 15g of S-2-benzylsuccinic acid is added each time, and stirring for 20min after each addition is finished; after all the materials are added, stirring for 3 hours at 0-5 ℃, keeping the temperature at 0-5 ℃, adding 74.5g of cis-perhydroisoindole hydrochloride, raising the reaction temperature to 25-30 ℃, and stirring for 8 hours;
b. keeping the temperature at 20-35 ℃, adding 80ml of refined water into a reaction bottle, stirring for 20min, adding 6mol/L hydrochloric acid, adjusting the pH value to 0.8-1.2 at 15-25 ℃, then stirring for 30min at 15-25 ℃, and keeping the pH value between 0.8-1.2;
c. standing the solution, then discarding a lower water layer, adding 240ml of refined water into an upper ethyl acetate layer, adding 4mol/L NaOH solution at 10-30 ℃ to adjust the pH value to 9-10, stirring at 10-30 ℃ for 30min, standing for liquid separation, discarding an upper ethyl acetate layer, and reserving a lower water layer; adding 200ml of ethyl acetate into the water layer, adding 6mol/L hydrochloric acid to adjust the pH value to be 1.0-1.5, stirring for 30min at 15-25 ℃, and keeping the pH value to be 1.0-1.5; standing, separating liquid and discarding a water layer; adding 20g of anhydrous sodium sulfate into the ethyl acetate layer, stirring for 20min, assisting filtration by using diatomite, filtering the anhydrous sodium sulfate, and washing by using 40ml of ethyl acetate to obtain an ethyl acetate solution;
d. adjusting the temperature of the ethyl acetate solution to 15-20 ℃, adding 111.5g of large granular anhydrous potassium carbonate, cooling, and stirring at 10-20 ℃ for 15 min; adding 72.3g of benzyl bromide at 10-20 ℃, slowly heating, and reacting for 5 hours under the reflux condition; cooling the reaction system to below 60 ℃, adding 240ml of refined water, and then cooling to 40-50 ℃; standing at 40-50 ℃, separating liquid, discarding a water layer, adjusting the temperature of an organic layer to 30-40 ℃, and crystallizing; stirring for 1h at 30-40 ℃, then cooling to 0-5 ℃, stirring for 2h, and filtering; washing twice with ethyl acetate of 0-5 ℃ by shaking, wherein 40ml of ethyl acetate is used each time, and 140.7g of crude wet product of benzyl 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) butyrate is obtained; drying the crude wet product at 50 ℃ for 2h to obtain 134g of crude 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) butyric acid benzyl ester with the yield of 86%;
(2) purification of benzyl 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) butyrate
a. Adding 300ml of ethyl acetate into a reaction bottle, stirring, adding 134g of crude 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) benzyl butyrate at the temperature of 20-30 ℃, stirring, raising the temperature to 65-75 ℃, completely dissolving the crude product, stirring for 5min after dissolving, assisting filtration by using kieselguhr, filtering the solution, and washing by using 70ml of ethyl acetate to obtain an ethyl acetate solution;
b. slowly cooling the ethyl acetate solution to 40 ℃, separating out crystals, stirring for 40min at 35-40 ℃, then slowly cooling to 0-5 ℃, stirring for 1h, and filtering; washing with 80ml of ethyl acetate at 0-5 ℃; the wet product was dried at 60 ℃ for 6 hours to give 124.6g of a pure benzyl 2-(s) -benzyl-4-oxo- (cis-perhydroisoindol-2-yl) butyrate, the yield was 93%, and then the residue was pulverized to ensure no lump.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0507534A1 (en) * | 1991-03-30 | 1992-10-07 | Kissei Pharmaceutical Co., Ltd. | Succinic acid compounds |
| CN103709092A (en) * | 2013-11-04 | 2014-04-09 | 河北科技大学 | High purity mitiglinide calcium preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013119518A (en) * | 2011-12-06 | 2013-06-17 | Tokuyama Corp | Method for producing (s)-2-benzyl-3-(cis-hexahydro-2-isoindonilylcarbonyl)benzyl propionate |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0507534A1 (en) * | 1991-03-30 | 1992-10-07 | Kissei Pharmaceutical Co., Ltd. | Succinic acid compounds |
| CN103709092A (en) * | 2013-11-04 | 2014-04-09 | 河北科技大学 | High purity mitiglinide calcium preparation method |
Non-Patent Citations (1)
| Title |
|---|
| 米格列奈钙的合成新工艺;王江霞等;《中国新药杂志》;20141231;第23卷(第10期);1201-1203、1209 * |
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