CN106008312A - Method for preparing hypoglycemic drug mitiglinide calcium - Google Patents
Method for preparing hypoglycemic drug mitiglinide calcium Download PDFInfo
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- CN106008312A CN106008312A CN201610667470.2A CN201610667470A CN106008312A CN 106008312 A CN106008312 A CN 106008312A CN 201610667470 A CN201610667470 A CN 201610667470A CN 106008312 A CN106008312 A CN 106008312A
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- 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 a method for preparing a hypoglycemic drug mitiglinide calcium. According to the method, under the temperature of -5 DEG C-10 DEG C, 30-60g of 2-benzylidene-3-(cis-perhydro-isoindolyl-2-carbonyl)propionic acid is dissolved in 200-500 milliliters of a reaction solvent, 2-5 g of a S-configuration aminoalcohol catalyst, 8-15 g of a borohydride and 15-25 g of trimethylchlorosilane are added, the materials are stirred for a reaction for 4-8 hours, pressure reduction is carried out for steaming the solvent, 400-600 milliliters of water and 4-6 milliliters of hydrochloric acid are added, ethyl acetate is used for extraction, an extract is merged, the extract is dried and concentrated to obtain a concentrate, the concentrate is dissolved in 400-600 mL of ethanol with mass concentration of 75-95%, 3-5 g of sodium hydroxide is added, after stirring and dissolving the materials, 8-12 g of calcium chloride is added, precipitate is obtained, and then the precipitate is subjected to pumping filtration to obtain mitiglinide calcium. The preparing method has the advantages of simple process, energy saving and environmental protection, can greatly increase the overall yield and obviously reduce the production cost, is easy to industrial production, is an innovation of a medicine for treating diabetes, and has large economic and social benefits.
Description
Technical field
The present invention relates to field of medicaments, the preparation method of a kind of hypoglycemic medicine Mitiglinide Calcium.
Background technology
Mitiglinide Calcium (Mitiglinide Calcium) chemical name pair [(2S)-2-benzyl-3-(cis-hexahydroisoindoline base-2-carbonyl) propanoic acid]-calcium dihydrate, it it is the derivant of phenylalanine, its mechanism of action is similar to sulfonylureas, but onset is faster, act on higher, half-life is shorter, thus side effect is little, the hypoglycemia that lasting blood sugar lowering can be avoided while effectively reducing post-prandial glycemia to cause, is individually used for can not effectively controlling the hypoglycemic medicine of type Ⅱdiabetes mellitus of hyperglycemia through diet and exercise therapy.
The synthetic method of Mitiglinide Calcium mainly has three classes: the first kind is to prepare the 2-benzyl-3-(cis-hexahydroisoindoline base-2-carbonyl of racemization) propanoic acid, then obtain S anomeric product (B) by fractionation, then become calcium salt [US5202335]；Equations of The Second Kind is first to prepare intermediate S-benzyl succinic acid by the method split, (2S)-2-benzyl-3-(cis-hexahydroisoindoline base-2-carbonyl is obtained the most again with hexahydroisoindoline contracting) propanoic acid (B), it is then converted into calcium salt [WO9832736, WO9832727, Chem Pharm
Bull 1997,45:1518-20,CN102898348]；First 3rd class prepares 2-benzylidene-3-(cis-hexahydroisoindoline base-2-carbonyl) after propanoic acid (A), (2S)-2-benzyl-3-(cis-hexahydroisoindoline base-2-carbonyl of S configuration is obtained by using the catalyst of the noble metals such as rhodium and chiral phosphine ligand complexation to carry out asymmetric catalytic hydrogenation) propanoic acid (B), then calcium salt [WO990143, CN101346352] is become.
In above-mentioned three kinds of methods, the product 2-benzyl-3-(cis-hexahydroisoindoline base-2-carbonyl that first method is prepared) propanoic acid is raceme, the R configuration enantiomers that wherein half is invalid needs to be removed by fractionation, cause huge waste and pollution, yield is reduced, cost is the highest, hence without being applied to commercial production；Although the intermediate benzyl succinic acid of racemization is split by second method in advance, subsequent reactions is carried out again after obtaining S-benzyl succinic acid, decrease the loss of reagent in subsequent step, but still the benzyl succinic acid raw material of half to be given up, expend stoichiometric resolving agent simultaneously, material consumption is relatively big, is the main cause causing Mitiglinide relatively costly；Although A can be converted into B by the method for asymmetric catalytic hydrogenation by the third method efficiently, but rhodium catalyst used and chiral phosphine ligand price are much more expensive, originate very limited, and are difficult to reclaim, thus are not used to large-scale production manufacture.Reform to the preparation method of hypoglycemic medicine Mitiglinide Calcium is imperative.
Summary of the invention
For above-mentioned situation, for solving the defect of prior art, it is an object of the invention to provide the preparation method of a kind of hypoglycemic medicine Mitiglinide Calcium, can effectively solve the generation of R configurational isomer in preparation process, overcome during current Mitiglinide produces and need to give up isomer by fractionation, cause wastage of material, use noble metal catalyst, the problem that production cost is high.
nullThe technical scheme is that the preparation method of a kind of hypoglycemic medicine Mitiglinide Calcium，At-5 DEG C ~ 10 DEG C，By 30-60g 2-benzylidene-3-(cis-hexahydroisoindoline base-2-carbonyl) propanoic acid is dissolved in 200-500 milliliter reaction dissolvent，Add 2-5gS configuration aminoalcohol catalyst (I)，8-15g boron hydride，15-25g trim,ethylchlorosilane，After stirring reaction 4-8 hour，Decompression boils off solvent，Add water 400-600 milliliter，Hydrochloric acid 4-6 milliliter，It is extracted with ethyl acetate，After combining extraction liquid，Extract is dried concentration，Obtain concentrate，Concentrate is dissolved in the ethanol of 400-600mL mass concentration 75%-95%，Add 3-5g sodium hydroxide，After stirring and dissolving，Add 8-12g calcium chloride，Separate out precipitation，Mitiglinide Calcium will be obtained after precipitation sucking filtration；
Described S configuration aminoalcohol catalyst (I) is (S)-diphenyl (pyrrolin-2-base) methanol, (S)-two (2-aminomethyl phenyls) (pyrrolin-2-base) methanol, (S)-two (3-aminomethyl phenyls) (pyrrolin-2-base) methanol, (S)-two (4-aminomethyl phenyls) (pyrrolin-2-base) methanol, (S)-two (2-chlorphenyls) (pyrrolin-2-base) methanol, (S)-two (4-chlorphenyls) (pyrrolin-2-base) methanol, (S)-two (2-methoxyphenyls) (pyrrolin-2-base) methanol and the one in (S)-two (4-methoxyphenyl) (pyrrolin-2-base) methanol；Described reaction dissolvent is the one in oxolane, dioxane, glycol dimethyl ether and acetonitrile；Described boron hydride is potassium borohydride or sodium borohydride.
Mitiglinide Calcium prepared by the present invention application in treating diabetes medication.
The present invention is in the presence of S configuration amino alcohol asymmetric catalyst (I), boron hydride (sodium salt or potassium salt), trim,ethylchlorosilane is used to combine 2-benzylidene-3-(cis-hexahydroisoindoline base-2-carbonyl) propanoic acid carries out asymmetric reduction reaction, then becomes salt.
Preparing Mitiglinide Calcium, in formula, I represents S configuration amino alcohol asymmetric catalyst, and R represents that phenyl or substituted-phenyl include 2-aminomethyl phenyl, 4-aminomethyl phenyl, 3-aminomethyl phenyl, 2-chlorphenyl, 4-chlorphenyl, 2-methoxyphenyl, 4-methoxyphenyl.
Production technology of the present invention is simple, and energy-conserving and environment-protective are greatly improved total recovery, significantly reduce production cost, it is easy to industrialized production, is the innovation on treatment diabetes medicament, and economic and social benefit is huge.
Detailed description of the invention
Below in conjunction with embodiment, the detailed description of the invention of the present invention is elaborated.
The present invention, in being embodied as, is to be realized by following example.
Embodiment
1
The preparation method of hypoglycemic medicine Mitiglinide Calcium of the present invention: at 0 DEG C, by 31.3g 2-benzylidene-3-(cis-hexahydroisoindoline base-2-carbonyl) propanoic acid is dissolved in 400 milliliters of oxolanes, add 2.8g(S)-diphenyl (pyrrolin-2-base) methanol, 10.8g potassium borohydride, 21g trim,ethylchlorosilane, after stirring reaction 6 hours, decompression boils off solvent, add 500 milliliters of water, hydrochloric acid 5 milliliters, it is extracted with ethyl acetate, after combining extraction liquid, extract is dried concentration, obtain concentrate, concentrate is dissolved in the ethanol of 500mL mass concentration 75%, add 4g sodium hydroxide, after stirring and dissolving, add 11g calcium chloride, separate out precipitation, Mitiglinide Calcium will be obtained after precipitation sucking filtration.
Yield 95%, optical purity 98.6% e.e.
Proton nmr spectra:1HNMR(CDCl3) δ:1.26-1.71(10H, m),
2.18-2.29(2H, m), 2.79-3.26(7H, m), 7.20-7.31(5H, m), 13.5-14.4(1H, bs);
Optical value: [α]D 20
:-6.1(C=1.0, MeOH);
Mass spectrum: MS (ESI): 316.2 [M+H]+
。
Embodiment
2
The preparation method of hypoglycemic medicine Mitiglinide Calcium of the present invention: at-5 DEG C, by 30g 2-benzylidene-3-(cis-hexahydroisoindoline base-2-carbonyl) propanoic acid is dissolved in 200 milliliters of dioxane, add 2g(S)-two (4-aminomethyl phenyls) (pyrrolin-2-base) methanol, 8g sodium borohydride, 15g trim,ethylchlorosilane, after stirring reaction 4 hours, decompression boils off solvent, add 400 milliliters of water, hydrochloric acid 4 milliliters, it is extracted with ethyl acetate, after combining extraction liquid, extract is dried concentration, obtain concentrate, concentrate is dissolved in the ethanol of 400mL mass concentration 95%, add 3g sodium hydroxide, after stirring and dissolving, add 8g calcium chloride, separate out precipitation, Mitiglinide Calcium will be obtained after precipitation sucking filtration.
Yield 96%, optical purity 98.8% e.e.
Proton nmr spectra:1HNMR(CDCl3) δ:1.26-1.71(10H, m),
2.18-2.29(2H, m), 2.79-3.26(7H, m), 7.20-7.31(5H, m), 13.5-14.4(1H, bs);
Optical value: [α]D 20
:-6.1(C=1.0, MeOH);
Mass spectrum: MS (ESI): 316.2 [M+H]+
。
Embodiment
3
The preparation method of hypoglycemic medicine Mitiglinide Calcium of the present invention: at-10 DEG C, by 60g 2-benzylidene-3-(cis-hexahydroisoindoline base-2-carbonyl) propanoic acid is dissolved in 500 milliliters of glycol dimethyl ethers, add 5g(S)-two (4-chlorphenyls) (pyrrolin-2-base) methanol, 15g potassium borohydride, 25g trim,ethylchlorosilane, after stirring reaction 8 hours, decompression boils off solvent, add 600 milliliters of water, hydrochloric acid 6 milliliters, it is extracted with ethyl acetate, after combining extraction liquid, extract is dried concentration, obtain concentrate, concentrate is dissolved in the ethanol of 600mL mass concentration 80%, add 5g sodium hydroxide, after stirring and dissolving, add 12g calcium chloride, separate out precipitation, Mitiglinide Calcium will be obtained after precipitation sucking filtration.
Yield 92%, optical purity 98.2% e.e.
Proton nmr spectra:1HNMR(CDCl3) δ:1.26-1.71(10H, m),
2.18-2.29(2H, m), 2.79-3.26(7H, m), 7.20-7.31(5H, m), 13.5-14.4(1H, bs);
Optical value: [α]D 20
:-6.1(C=1.0, MeOH);
Mass spectrum: MS (ESI): 316.2 [M+H]+
。
Embodiment
4
The preparation method of hypoglycemic medicine Mitiglinide Calcium of the present invention: at 5 DEG C, by 50g 2-benzylidene-3-(cis-hexahydroisoindoline base-2-carbonyl) propanoic acid is dissolved in 350 milliliters of acetonitriles, add 4g(S)-two (2-aminomethyl phenyls) (pyrrolin-2-base) methanol, 10g sodium borohydride, 18g trim,ethylchlorosilane, after stirring reaction 5 hours, decompression boils off solvent, add 350 milliliters of water, hydrochloric acid 5 milliliters, it is extracted with ethyl acetate, after combining extraction liquid, after combining extraction liquid, extract is dried concentration, obtain concentrate, concentrate is dissolved in the ethanol of 450mL mass concentration 85%, add 4g sodium hydroxide, after stirring and dissolving, add 10g calcium chloride, separate out precipitation, Mitiglinide Calcium will be obtained after precipitation sucking filtration.
Yield 94%, optical purity 98.6% e.e.
Proton nmr spectra:1HNMR(CDCl3) δ:1.26-1.71(10H, m),
2.18-2.29(2H, m), 2.79-3.26(7H, m), 7.20-7.31(5H, m), 13.5-14.4(1H, bs);
Optical value: [α]D 20
:-6.1(C=1.0, MeOH);
Mass spectrum: MS (ESI): 316.2 [M+H]+
。
The present invention uses the method for asymmetric reduction to be prepared for Mitiglinide Calcium, obtain following beneficial effect: avoid splitting step relative to existing commonly used production technology, total recovery is greatly improved and reaches more than 90%, significantly reduce production cost, reduce more than at least 50%, it is commonly known that resolution process needs to give up the invalid isomer produced in reaction, thus causes the raw material of half to be wasted, it is also required to expend resolving agent simultaneously, relatively costly；Relative to existing asymmetric catalytic hydrogenation manufacture method, prior art uses Noble Metal Rhodium and chiral phosphorous ligand catalyst, metal rhodium is the most expensive but also reserves are few, it is difficult to use in pharmaceuticals industry to produce, the present invention uses aminoalcohol catalyst cheap and easy to get and borohydride reduction agent, energy-conserving and environment-protective, it is possible to for industrialized production.Being the innovation on treatment diabetes medicament, economic and social benefit is huge.
Claims (5)
- null1. the preparation method of a hypoglycemic medicine Mitiglinide Calcium，It is characterized in that，At-5 DEG C ~ 10 DEG C，By 30-60g 2-benzylidene-3-(cis-hexahydroisoindoline base-2-carbonyl) propanoic acid is dissolved in 200-500 milliliter reaction dissolvent，Add 2-5g S configuration aminoalcohol catalyst，8-15g boron hydride，15-25g trim,ethylchlorosilane，After stirring reaction 4-8 hour，Decompression boils off solvent，Add water 400-600 milliliter，Hydrochloric acid 4-6 milliliter，It is extracted with ethyl acetate，After combining extraction liquid，Extract is dried concentration，Obtain concentrate，Concentrate is dissolved in the ethanol of 400-600mL mass concentration 75%-95%，Add 3-5g sodium hydroxide，After stirring and dissolving，Add 8-12g calcium chloride，Separate out precipitation，Mitiglinide Calcium will be obtained after precipitation sucking filtration；Described S configuration aminoalcohol catalyst is (S)-diphenyl (pyrrolin-2-base) methanol, (S)-two (2-aminomethyl phenyls) (pyrrolin-2-base) methanol, (S)-two (3-aminomethyl phenyls) (pyrrolin-2-base) methanol, (S)-two (4-aminomethyl phenyls) (pyrrolin-2-base) methanol, (S)-two (2-chlorphenyls) (pyrrolin-2-base) methanol, (S)-two (4-chlorphenyls) (pyrrolin-2-base) methanol, (S)-two (2-methoxyphenyls) (pyrrolin-2-base) methanol and the one in (S)-two (4-methoxyphenyl) (pyrrolin-2-base) methanol；Described reaction dissolvent is the one in oxolane, dioxane, glycol dimethyl ether and acetonitrile；Described boron hydride is potassium borohydride or sodium borohydride.
- The preparation method of hypoglycemic medicine Mitiglinide Calcium the most according to claim 1, it is characterized in that, at 0 DEG C, by 31.3g 2-benzylidene-3-(cis-hexahydroisoindoline base-2-carbonyl) propanoic acid is dissolved in 400 milliliters of oxolanes, add 2.8g(S)-diphenyl (pyrrolin-2-base) methanol, 10.8g potassium borohydride, 21g trim,ethylchlorosilane, after stirring reaction 6 hours, decompression boils off solvent, add 500 milliliters of water, hydrochloric acid 5 milliliters, it is extracted with ethyl acetate, after combining extraction liquid, extract is dried concentration, obtain concentrate, concentrate is dissolved in the ethanol of 500mL mass concentration 75%, add 4g sodium hydroxide, after stirring and dissolving, add 11g calcium chloride, separate out precipitation, Mitiglinide Calcium will be obtained after precipitation sucking filtration.
- The preparation method of hypoglycemic medicine Mitiglinide Calcium the most according to claim 1, it is characterized in that, at-5 DEG C, by 30g 2-benzylidene-3-(cis-hexahydroisoindoline base-2-carbonyl) propanoic acid is dissolved in 200 milliliters of dioxane, add 2g(S)-two (4-aminomethyl phenyls) (pyrrolin-2-base) methanol, 8g sodium borohydride, 15g trim,ethylchlorosilane, after stirring reaction 4 hours, decompression boils off solvent, add 400 milliliters of water, hydrochloric acid 4 milliliters, it is extracted with ethyl acetate, after combining extraction liquid, extract is dried concentration, obtain concentrate, concentrate is dissolved in the ethanol of 400mL mass concentration 95%, add 3g sodium hydroxide, after stirring and dissolving, add 8g calcium chloride, separate out precipitation, Mitiglinide Calcium will be obtained after precipitation sucking filtration.
- The preparation method of hypoglycemic medicine Mitiglinide Calcium the most according to claim 1, it is characterized in that, at-10 DEG C, by 60g 2-benzylidene-3-(cis-hexahydroisoindoline base-2-carbonyl) propanoic acid is dissolved in 500 milliliters of glycol dimethyl ethers, add 5g(S)-two (4-chlorphenyls) (pyrrolin-2-base) methanol, 15g potassium borohydride, 25g trim,ethylchlorosilane, after stirring reaction 8 hours, decompression boils off solvent, add 600 milliliters of water, hydrochloric acid 6 milliliters, it is extracted with ethyl acetate, after combining extraction liquid, extract is dried concentration, obtain concentrate, concentrate is dissolved in the ethanol of 600mL mass concentration 80%, add 5g sodium hydroxide, after stirring and dissolving, add 12g calcium chloride, separate out precipitation, Mitiglinide Calcium will be obtained after precipitation sucking filtration.
- The preparation method of hypoglycemic medicine Mitiglinide Calcium the most according to claim 1, it is characterized in that, at 5 DEG C, by 50g 2-benzylidene-3-(cis-hexahydroisoindoline base-2-carbonyl) propanoic acid is dissolved in 350 milliliters of acetonitriles, add 4g(S)-two (2-aminomethyl phenyls) (pyrrolin-2-base) methanol, 10g sodium borohydride, 18g trim,ethylchlorosilane, after stirring reaction 5 hours, decompression boils off solvent, add 350 milliliters of water, hydrochloric acid 5 milliliters, it is extracted with ethyl acetate, after combining extraction liquid, extract is dried concentration, obtain concentrate, concentrate is dissolved in the ethanol of 450mL mass concentration 85%, add 4g sodium hydroxide, after stirring and dissolving, add 10g calcium chloride, separate out precipitation, Mitiglinide Calcium will be obtained after precipitation sucking filtration.
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Citations (7)
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|---|---|---|---|---|
| CN101270074A (en) * | 2007-03-21 | 2008-09-24 | 北京德众万全药物技术开发有限公司 | Method for preparing high purity mitiglinide calcium |
| CN101346352A (en) * | 2005-12-27 | 2009-01-14 | 橘生药品工业株式会社 | Asymmetric reduction method |
| CN102101838A (en) * | 2010-12-06 | 2011-06-22 | 张家港田由新材料科技有限公司 | Preparation method of mitiglinide calcium |
| CN102424664A (en) * | 2011-11-04 | 2012-04-25 | 无锡福祈制药有限公司 | Preparation method of mitiglinide calcium |
| WO2013062294A2 (en) * | 2011-10-27 | 2013-05-02 | 주식회사 메디켐코리아 | Improved preparation method for mitiglinide calcium |
| JP2013119518A (en) * | 2011-12-06 | 2013-06-17 | Tokuyama Corp | Method for producing (s)-2-benzyl-3-(cis-hexahydro-2-isoindonilylcarbonyl)benzyl propionate |
| KR101557702B1 (en) * | 2013-10-08 | 2015-10-06 | 보령제약 주식회사 | Method for the preparation of Mitiglinide Calcium Dihydrate |
-
2016
- 2016-08-15 CN CN201610667470.2A patent/CN106008312B/en not_active Expired - Fee Related
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101346352A (en) * | 2005-12-27 | 2009-01-14 | 橘生药品工业株式会社 | Asymmetric reduction method |
| CN101270074A (en) * | 2007-03-21 | 2008-09-24 | 北京德众万全药物技术开发有限公司 | Method for preparing high purity mitiglinide calcium |
| CN102101838A (en) * | 2010-12-06 | 2011-06-22 | 张家港田由新材料科技有限公司 | Preparation method of mitiglinide calcium |
| WO2013062294A2 (en) * | 2011-10-27 | 2013-05-02 | 주식회사 메디켐코리아 | Improved preparation method for mitiglinide calcium |
| CN102424664A (en) * | 2011-11-04 | 2012-04-25 | 无锡福祈制药有限公司 | Preparation method of mitiglinide calcium |
| JP2013119518A (en) * | 2011-12-06 | 2013-06-17 | Tokuyama Corp | Method for producing (s)-2-benzyl-3-(cis-hexahydro-2-isoindonilylcarbonyl)benzyl propionate |
| KR101557702B1 (en) * | 2013-10-08 | 2015-10-06 | 보령제약 주식회사 | Method for the preparation of Mitiglinide Calcium Dihydrate |
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