CN106008312B - A kind of preparation method of hypoglycemic medicine Mitiglinide Calcium - Google Patents
A kind of preparation method of hypoglycemic medicine Mitiglinide Calcium Download PDFInfo
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- CN106008312B CN106008312B CN201610667470.2A CN201610667470A CN106008312B CN 106008312 B CN106008312 B CN 106008312B CN 201610667470 A CN201610667470 A CN 201610667470A CN 106008312 B CN106008312 B CN 106008312B
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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
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Abstract
A kind of preparation method of hypoglycemic medicine Mitiglinide Calcium, at 5 DEG C ~ 10 DEG C, by 30 60g, 2 benzylidenes 3（2 carbonyl of cis-hexahydroisoindoline base）Propionic acid is dissolved in 200 500 milliliters of reaction dissolvents, add in 2 5gS configuration aminoalcohol catalysts, 8 15g boron hydrides, 15 25g trim,ethylchlorosilanes, after being stirred to react 48 hours, decompression boils off solvent, add in 400 600 milliliters of water, 46 milliliters of hydrochloric acid, is extracted with ethyl acetate, after combining extraction liquid, extract liquor is dried and is concentrated, concentrate, concentrate is dissolved in the ethyl alcohol of 400 600mL mass concentrations 75% 95%, adds in 3 5g sodium hydroxides, after stirring and dissolving, 8 12g calcium chloride are added in, precipitation is precipitated, Mitiglinide Calcium is obtained after precipitation is filtered.Total recovery greatly improved in this method simple production process, energy conservation and environmental protection, significantly reduces production cost, is easy to industrialized production, is the innovation treated on diabetes medicament, and economic and social benefit is huge.
Description
Technical field
The present invention relates to field of medicaments, particularly a kind of preparation method of hypoglycemic medicine Mitiglinide Calcium.
Background technology
Mitiglinide Calcium（Mitiglinide Calcium）Chemical name it is bis- [（2S）- 2- benzyls -3-（Cis-hexahydroisoindoline
Base -2- carbonyls）Propionic acid]-calcium dihydrate, be phenylalanine derivative, mechanism of action works more similar to sulfonylureas
Soon, effect is stronger, and half-life period is shorter, thus Small side effects, lasting hypoglycemic can be avoided to draw while postprandial blood sugar is effectively reduced
The hypoglycemia of hair is individually used for effectively controlling the antidiabetic drug of the type II diabetes of hyperglycemia through diet and kinesiatrics
Object.
The synthetic method of Mitiglinide Calcium mainly has three classes：The first kind is to prepare the 2- benzyls -3- of racemization（Cis- perhydro
Isoindolyl -2- carbonyls）Then propionic acid obtains S anomeric products by splitting（B）, then into calcium salt [US5202335]；Second class
It is that intermediate S- benzyl succinic acid is prepared by the method for fractionation first, then contracts to obtain with hexahydroisoindoline again（2S）-2-
Benzyl -3-（Cis-hexahydroisoindoline base -2- carbonyls）Propionic acid（B）, be then converted into calcium salt [WO9832736, WO9832727,
Chem Pharm Bull 1997,45:1518-20,CN102898348]；Third class then prepares 2- benzylidenes -3- first
（Cis-hexahydroisoindoline base -2- carbonyls）After propionic acid（A）, by using the noble metals such as rhodium and the catalyst of chiral phosphine ligand complexing
It carries out asymmetric catalytic hydrogenation and obtains S configurations（2S）- 2- benzyls -3-（Cis-hexahydroisoindoline base -2- carbonyls）Propionic acid（B）,
Then into calcium salt [WO990143, CN101346352].
In above-mentioned three kinds of methods, product 2- benzyls -3- that first method is prepared（Cis-hexahydroisoindoline base -2- carbonyls
Base）Propionic acid is raceme, and wherein the invalid R configuration enantiomers of half need to remove by splitting, and cause huge waste
And pollution so that yield reduces, and cost is very high, thus is not applied to industrial production；Although second method is in advance to racemization
Intermediate benzyl succinic acid split, obtain carrying out subsequent reactions again after S- benzyls succinic acid, reduce subsequent step
The loss of middle reagent, but still to give up the benzyl succinic acid raw material of half, while expend the resolving agent of stoichiometry, material consumption compared with
Greatly, it is the main reason for causing Mitiglinide cost higher；Although A efficiently can be passed through asymmetry catalysis by the third method
The method of hydrogenation is converted into B, but rhodium catalyst used and chiral phosphine ligand price are very expensive, and source is very limited, and
It is difficult to recycle, thus is not used to mass production.Exist to the reform gesture of the preparation method of hypoglycemic medicine Mitiglinide Calcium
It must go.
Invention content
For the above situation, to solve the defect of the prior art, it is an object of the invention to provide a kind of hypoglycemic medicine rice
The preparation method of Ge Lienai calcium can effectively solve the generation of R configurational isomers in preparation process, overcome current Mitiglinide life
It needs to give up isomers by splitting in production, causes wastage of material, using noble metal catalyst, the problem of production cost is high.
The technical scheme is that：A kind of preparation method of hypoglycemic medicine Mitiglinide Calcium, at -5 DEG C ~ 10 DEG C, by 30-
60g 2- benzylidenes -3-（Cis-hexahydroisoindoline base -2- carbonyls）Propionic acid is dissolved in 200-500 milliliters of reaction dissolvents, is added in
2-5gS configuration aminoalcohol catalysts（I）, 8-15g boron hydrides, 15-25g trim,ethylchlorosilanes, after being stirred to react 4-8 hours,
Decompression boils off solvent, adds in 400-600 milliliters of water, and 4-6 milliliters of hydrochloric acid is extracted with ethyl acetate, after combining extraction liquid, will extract
Liquid drying concentration, obtains concentrate, concentrate is dissolved in the ethyl alcohol of 400-600mL mass concentrations 75%-95%, add in 3-5g hydrogen-oxygens
Change sodium, after stirring and dissolving, add in 8-12g calcium chloride, precipitation is precipitated, will precipitation filter after Mitiglinide Calcium；
The S configuration aminoalcohol catalysts（I）For（S）Diphenyl（Pyrrolin -2- bases）Methanol,（S）- two（2- methyl
Phenyl）（Pyrrolin -2- bases）Methanol,（S）- two（3- aminomethyl phenyls）（Pyrrolin -2- bases）Methanol,（S）- two（4- aminomethyl phenyls）
（Pyrrolin -2- bases）Methanol,（S）- two（2- chlorphenyls）（Pyrrolin -2- bases）Methanol,（S）- two（4- chlorphenyls）（Pyrrolin-
2- bases）Methanol,（S）- two（2- methoxyphenyls）（Pyrrolin -2- bases）Methanol and（S）- two（4- methoxyphenyls）（Pyrrolin-
2- bases）One kind in methanol；The reaction dissolvent is one in tetrahydrofuran, dioxane, glycol dimethyl ether and acetonitrile
Kind；The boron hydride is potassium borohydride or sodium borohydride.
The application of Mitiglinide Calcium prepared by the present invention in treating diabetes medication.
The present invention is in S configuration amino alcohol asymmetric catalysts（I）In the presence of, use boron hydride（Sodium salt or sylvite）、
Trim,ethylchlorosilane is combined to 2- benzylidenes -3-（Cis-hexahydroisoindoline base -2- carbonyls）It is anti-that propionic acid carries out asymmetric reduction
Should, then into salt.
Mitiglinide Calcium is made, I represents S configuration amino alcohol asymmetric catalysts in formula, and R represents phenyl or substituted-phenyl packet
Include 2- aminomethyl phenyls, 4- aminomethyl phenyls, 3- aminomethyl phenyls, 2- chlorphenyls, 4- chlorphenyls, 2- methoxyphenyls, 4- methoxybenzenes
Base.
Total recovery greatly improved in simple production process of the present invention, energy conservation and environmental protection, significantly reduces production cost, is easy to
Industrialized production, is the innovation treated on diabetes medicament, and economic and social benefit is huge.
Specific embodiment
It elaborates with reference to embodiments to the specific embodiment of the present invention.
The present invention in specific implementation, is realized by following embodiment.
Embodiment 1
The preparation method of hypoglycemic medicine Mitiglinide Calcium of the present invention：At 0 DEG C, by 31.3g 2- benzylidenes -3-（It is cis- complete
Hydrogen isoindolyl -2- carbonyls）Propionic acid is dissolved in 400 milliliters of tetrahydrofurans, adds in 2.8g（S）Diphenyl（Pyrrolin -2- bases）First
Alcohol, 10.8g potassium borohydrides, 21g trim,ethylchlorosilanes, after being stirred to react 6 hours, decompression boils off solvent, adds in 500 milliliters of water,
5 milliliters of hydrochloric acid, is extracted with ethyl acetate, and after combining extraction liquid, extract liquor is dried and is concentrated, concentrate is obtained, concentrate is dissolved in
In the ethyl alcohol of 500mL mass concentrations 75%, 4g sodium hydroxides are added in, after stirring and dissolving, 11g calcium chloride is added in, precipitation is precipitated, it will
Precipitation obtains Mitiglinide Calcium after filtering.
Yield 95%, 98.6% e.e of optical purity.
Nuclear magnetic resonance spectroscopy：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- benzylidenes -3-（It is cis- complete
Hydrogen isoindolyl -2- carbonyls）Propionic acid is dissolved in 200 milliliters of dioxane, adds in 2g（S）- two（4- aminomethyl phenyls）（Pyrrolin-
2- bases）Methanol, 8g sodium borohydrides, 15g trim,ethylchlorosilanes, after being stirred to react 4 hours, decompression boils off solvent, adds in 400 milli of water
It rises, 4 milliliters of hydrochloric acid is extracted with ethyl acetate, and after combining extraction liquid, extract liquor is dried and is concentrated, obtains concentrate, and concentrate is molten
In the ethyl alcohol of 400mL mass concentrations 95%, 3g sodium hydroxides are added in, after stirring and dissolving, 8g calcium chloride is added in, precipitation is precipitated, it will
Precipitation obtains Mitiglinide Calcium after filtering.
Yield 96%, 98.8% e.e of optical purity.
Nuclear magnetic resonance spectroscopy：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- benzylidenes -3-（It is cis- complete
Hydrogen isoindolyl -2- carbonyls）Propionic acid is dissolved in 500 milliliters of glycol dimethyl ethers, adds in 5g（S）- two（4- chlorphenyls）（Pyrroles
Quinoline -2- bases）Methanol, 15g potassium borohydrides, 25g trim,ethylchlorosilanes, after being stirred to react 8 hours, decompression boils off solvent, adds in water
600 milliliters, 6 milliliters of hydrochloric acid is extracted with ethyl acetate, and after combining extraction liquid, extract liquor is dried and is concentrated, obtains concentrate, will be dense
Contracting object is dissolved in the ethyl alcohol of 600mL mass concentrations 80%, addition 5g sodium hydroxides, after stirring and dissolving, is added in 12g calcium chloride, is precipitated
Precipitation obtains Mitiglinide Calcium after precipitation is filtered.
Yield 92%, 98.2% e.e of optical purity.
Nuclear magnetic resonance spectroscopy：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- benzylidenes -3-（Cis- perhydro
Isoindolyl -2- carbonyls）Propionic acid is dissolved in 350 milliliters of acetonitriles, adds in 4g（S）- two（2- aminomethyl phenyls）（Pyrrolin -2- bases）First
Alcohol, 10g sodium borohydrides, 18g trim,ethylchlorosilanes, after being stirred to react 5 hours, decompression boils off solvent, adds in 350 milliliters of water, salt
5 milliliters of acid, is extracted with ethyl acetate, and after combining extraction liquid, after combining extraction liquid, extract liquor is dried and is concentrated, obtains concentrate, will
Concentrate is dissolved in the ethyl alcohol of 450mL mass concentrations 85%, addition 4g sodium hydroxides, after stirring and dissolving, adds in 10g calcium chloride, analysis
Go out precipitation, Mitiglinide Calcium is obtained after precipitation is filtered.
Yield 94%, 98.6% e.e of optical purity.
Nuclear magnetic resonance spectroscopy：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 is prepared for Mitiglinide Calcium using the method for asymmetric reduction, obtains following advantageous effect：Relative to existing
There is the production technology generally used to avoid splitting step, total recovery greatly improved and reach more than 90%, significantly reduce production
Cost reduces at least more than 50%, it is known that resolution process needs give up the invalid isomers generated in reaction, so as to make
Raw material into half is wasted, while is also required to expend resolving agent, and cost is higher；Relative to existing asymmetric catalytic hydrogenation system
Method is made, the prior art uses Noble Metal Rhodium and chiral phosphorous ligand catalyst, and metal rhodium is not only expensive but also reserves are few,
Pharmaceuticals industry production is difficult to use in, the present invention is using aminoalcohol catalyst cheap and easy to get and borohydride reduction agent, section
Can be environmentally friendly, it can be used in industrialized production.It is the innovation treated on diabetes medicament, economic and social benefit is huge.
Claims (4)
1. a kind of preparation method of hypoglycemic medicine Mitiglinide Calcium, which is characterized in that at -5 DEG C ~ 10 DEG C, by 30-60g 2- benzene Asia
Methyl -3-（Cis-hexahydroisoindoline base -2- carbonyls）Propionic acid is dissolved in 200-500 milliliters of reaction dissolvents, adds in 2-5g S configurations
Aminoalcohol catalyst, 8-15g boron hydrides, 15-25g trim,ethylchlorosilanes, after being stirred to react 4-8 hours, decompression boils off solvent,
400-600 milliliters of water is added in, 4-6 milliliters of hydrochloric acid is extracted with ethyl acetate, and after combining extraction liquid, extract liquor is dried and is concentrated, is obtained
Concentrate is dissolved in the ethyl alcohol of 400-600mL mass concentrations 75%-95% by concentrate, adds in 3-5g sodium hydroxides, stirring and dissolving
Afterwards, precipitation is precipitated in addition 8-12g calcium chloride, will obtain Mitiglinide Calcium after precipitation suction filtration；
The S configuration aminoalcohol catalysts are（S）Diphenyl（Pyrrolin -2- bases）Methanol,（S）- two（2- aminomethyl phenyls）
（Pyrrolin -2- bases）Methanol,（S）- two（3- aminomethyl phenyls）（Pyrrolin -2- bases）Methanol,（S）- two（4- aminomethyl phenyls）（Pyrroles
Quinoline -2- bases）Methanol,（S）- two（2- chlorphenyls）（Pyrrolin -2- bases）Methanol,（S）- two（4- chlorphenyls）（Pyrrolin -2- bases）
Methanol,（S）- two（2- methoxyphenyls）（Pyrrolin -2- bases）Methanol and（S）- two（4- methoxyphenyls）（Pyrrolin -2- bases）
One kind in methanol；The reaction dissolvent is one kind in tetrahydrofuran, dioxane, glycol dimethyl ether and acetonitrile；Institute
The boron hydride stated is potassium borohydride or sodium borohydride.
2. the preparation method of hypoglycemic medicine Mitiglinide Calcium according to claim 1, which is characterized in that, will at 0 DEG C
31.3g 2- benzylidenes -3-（Cis-hexahydroisoindoline base -2- carbonyls）Propionic acid is dissolved in 400 milliliters of tetrahydrofurans, is added in
2.8g（S）Diphenyl（Pyrrolin -2- bases）Methanol, 10.8g potassium borohydrides, 21g trim,ethylchlorosilanes are stirred to react 6 hours
Afterwards, decompression boils off solvent, adds in 500 milliliters of water, 5 milliliters of hydrochloric acid is extracted with ethyl acetate, after combining extraction liquid, by extract liquor
Dry concentration, obtains concentrate, concentrate is dissolved in the ethyl alcohol of 500mL mass concentrations 75%, adds in 4g sodium hydroxides, and stirring is molten
Xie Hou, addition 11g calcium chloride, is precipitated precipitation, will obtain Mitiglinide Calcium after precipitation suction filtration.
3. the preparation method of hypoglycemic medicine Mitiglinide Calcium according to claim 1, which is characterized in that, will at -5 DEG C
30g2- benzylidenes -3-（Cis-hexahydroisoindoline base -2- carbonyls）Propionic acid is dissolved in 200 milliliters of dioxane, adds in 2g（S）-
Two（4- aminomethyl phenyls）（Pyrrolin -2- bases）Methanol, 8g sodium borohydrides, 15g trim,ethylchlorosilanes after being stirred to react 4 hours, subtract
Pressure boils off solvent, adds in 400 milliliters of water, and 4 milliliters of hydrochloric acid is extracted with ethyl acetate, after combining extraction liquid, extract liquor is dried dense
Contracting, obtains concentrate, concentrate is dissolved in the ethyl alcohol of 400mL mass concentrations 95%, addition 3g sodium hydroxides, after stirring and dissolving, adds
Enter 8g calcium chloride, precipitation is precipitated, Mitiglinide Calcium is obtained after precipitation is filtered.
4. the preparation method of hypoglycemic medicine Mitiglinide Calcium according to claim 1, which is characterized in that, will at 5 DEG C
50g2- benzylidenes -3-（Cis-hexahydroisoindoline base -2- carbonyls）Propionic acid is dissolved in 350 milliliters of acetonitriles, adds in 4g（S）- two
（2- aminomethyl phenyls）（Pyrrolin -2- bases）Methanol, 10g sodium borohydrides, 18g trim,ethylchlorosilanes after being stirred to react 5 hours, subtract
Pressure boils off solvent, adds in 350 milliliters of water, and 5 milliliters of hydrochloric acid is extracted with ethyl acetate, after combining extraction liquid, extract liquor is dried dense
Contracting, obtains concentrate, concentrate is dissolved in the ethyl alcohol of 450mL mass concentrations 85%, addition 4g sodium hydroxides, after stirring and dissolving, adds
Enter 10g calcium chloride, precipitation is precipitated, Mitiglinide Calcium is obtained after precipitation is filtered.
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Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP4918257B2 (en) * | 2005-12-27 | 2012-04-18 | キッセイ薬品工業株式会社 | 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 |
| CN102101838B (en) * | 2010-12-06 | 2012-09-12 | 周玉莲 | Preparation method of mitiglinide calcium |
| KR101327866B1 (en) * | 2011-10-27 | 2013-11-11 | 주식회사 메디켐코리아 | Improved process for preparing Mitiglinide calcium salt |
| CN102424664B (en) * | 2011-11-04 | 2013-11-13 | 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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