CN103772247B - A kind of preparation method that can be used for synthesizing the acry radical donor of simvastatin ammonium salt - Google Patents
A kind of preparation method that can be used for synthesizing the acry radical donor of simvastatin ammonium salt Download PDFInfo
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Abstract
<b>the preparation method that the present invention relates to a kind of acry radical donor that can be used for synthesizing simvastatin ammonium salt, under nitrogen protection,</b><b>2-</b><b>mercaptoethanol with</b><b>2,2-</b><b>dimethyl-butyrylchlorine first exists</b><b>-5 ~+5</b><b>react at DEG C</b><b>2 ~ 6</b><b>hour, then exist</b><b>20 ~ 30</b><b>react at DEG C</b><b>8 ~ 12</b><b>hour, generate</b><b>2,2-</b><b>acid dimethyl</b><b>-2-</b><b>mercapto is for ethanol ester, then</b><b>2,2-</b><b>acid dimethyl</b><b>-2-</b><b>mercapto exists for ethanol ester and chloroacetic chloride</b><b>0 ~ 10</b><b>react at DEG C</b><b>2 ~ 3</b><b>hour, then exist</b><b>20 ~ 30</b><b>react at DEG C</b><b>6 ~ 12</b><b>hour, generate the acry radical donor of simvastatin ammonium salt side chain</b><b>2,2-</b><b>acid dimethyl</b><b>-2-</b><b>mercapto is for ethoxyacetic acid ester. The acry radical donor of simvastatin ammonium salt side chain in the present invention</b><b>2,2-</b><b>acid dimethyl</b><b>-2-</b><b>mercapto is cheap and easily-available for the synthesis material of ethoxyacetic acid ester, and synthesis technique is simple, it is easy to amplify;</b><b>2-</b><b>mercaptoethanol boiling point is low, it is easy to recovery, reduces and pollutes, reduce further cost, and product competitiveness is strong.</b>
Description
Technical field
The invention belongs to pharmaceutical technology field, the preparation method being specifically related to a kind of acry radical donor that can be used for synthesizing simvastatin ammonium salt.
Background technology
The blood lipid-lowering medicine of the Statins (statin) that simvastatin is developed by Merck company, for hydroxy-methyl-glutaryl coenzyme A (HMG-COA) reductase inhibitor, it is suppressed that the synthesis of endogenous cholesterol, for lipid regulating agent. These product were in Initial Public Offering in 1988, in December, 1991 obtains U.S. FDA approval, the simvastatin (Zocor) of Merck in 2000 comes second place on global marketing list, sales volume is 52.8 hundred million dollars, calendar year 2001 reaches 66.7 hundred million dollars, 2002 is 55.8 hundred million dollars, has the huge market demand.
Simvastatin is that its synthetic schemes is as follows with lovastatin for the semi-synthetic HMG-CoA reductase inhibitor of raw material, the synthesis of derivatives of aspergillus terreus tunning:
Current industrial quarters produces the method for simvastatin and is broadly divided into chemical synthesis, fermentation method and biotransformation method, wherein, biotransformation method with its environmental protection, the clear superiority such as low cost and will progressively substitute existing chemical method and fermentation method.
Biotransformation method, disclosed patent CN201080055195.X in the recent period, CN201080043600.6, CN200780027455.0 and WO2011/041233A1 by use process LAN LovD coli strain and can the thioesters dimethyl butyryl-S-methyl mercapto propionic ester (DMB-S-MMP of permeates cell membranes, methyl3-(2,2,-dimethylbutanoylthio) propanoate), develop the Whole Cell Biocatalysis method that citrinin J acid (CAS:132748-10-8) is converted into simvastatin acid. This patent does not only disclose the restructuring acetyltransferase LovD participating in this bioconversion and the relevant zymologic property of mutant thereof, and discloses the different types of simvastatin acry radical donor participating in this bioconversion. And thioesters dimethyl butyryl-S-methyl mercapto methyl propionate (DMB-S-MMP) is efficient acry radical donor disclosed in such patent of invention. There is the problem that 1, acry radical donor methyl ester side chain synthesis material cost is high; 2, the 3-mercapto-propionate poor stability that acry radical donor methyl ester side chain produces in reaction system, it is easy to hydrolysis produces 3-mercaptopropionic acid; 3,3-mercaptopropionic acids, water solublity is big, and boiling point is high, reclaims difficulty and increases cost of material, it is easy to contaminated environment; 4,3-mercaptopropionic acids easily make simvastatin product degrade, and affect the quality of product; 5, solvent makes consumption big, and production cost is high, and product competitiveness in the market is limited.
Summary of the invention
The technical problem to be solved is to provide a kind of preparation method synthesizing the low acry radical donor of cost.
For solving above technical problem, the present invention adopts the following technical scheme that:
A kind of preparation method of the acry radical donor for synthesizing simvastatin ammonium salt; under nitrogen protection; 2 mercapto ethanol and 2; 2-dimethyl-butyrylchlorine first reacts 2��6 hours at-5��+5 DEG C; then react 8��12 hours at 20��30 DEG C; generate 2; 2-acid dimethyl-2-mercapto is for ethanol ester; then 2 described in; 2-acid dimethyl-2-mercapto reacts 2��3 hours at 0��10 DEG C for ethanol ester and chloroacetic chloride; then react 6��12 hours at 20��30 DEG C, generate described acry radical donor 2,2-acid dimethyl-2-mercapto for ethoxyacetic acid ester.
Preferably, the mass ratio of described 2 mercapto ethanol and 2,2-described dimethyl-butyrylchlorines is 0.5��0.75:1.
Preferably, 2,2-described acid dimethyl-2-mercaptos are 1.5��2:1 for the mass ratio of ethanol ester Yu described chloroacetic chloride.
Preferably, the mass ratio of described 2 mercapto ethanol and described chloroacetic chloride is 0.7��0.8:1.
The preparation method of above-mentioned acry radical donor, specifically includes following steps:
Step (1): under nitrogen protection, described 2 mercapto ethanol and described 2,2-dimethyl-butyrylchlorine reacts in presence of organic solvent and generates described 2,2-acid dimethyl-2-mercapto, for ethanol ester crude product, then adds frozen water in reaction system, and regulating pH is 6.5��7.5, separate organic facies, described organic facies drying, filtration, rotation obtain 2,2-described acid dimethyl-2-mercaptos for ethanol ester after steaming;
Step (2): under nitrogen protection; described 2; 2-acid dimethyl-2-mercapto reacts generation 2 for ethanol ester and described chloroacetic chloride under the existence of described organic solvent; 2-acid dimethyl-2-mercapto, for ethoxyacetic acid ester crude product, then adds frozen water in reaction system, and regulating pH is 6.5��7.5; separate organic facies; described organic facies drying, filtration, rotation obtain 2,2-described acid dimethyl-2-mercaptos for ethoxyacetic acid ester after steaming.
More specifically, the mixture that described organic solvent is dichloromethane and triethylamine.
The preparation method of above-mentioned acry radical donor, specifically includes following steps:
Step (1): under nitrogen protection, described 2 mercapto ethanol reacts in presence of organic solvent with 2,2-described dimethyl-butyrylchlorines and generates 2,2-described acid dimethyl-2-mercaptos for ethanol ester crude product;
Step (2): drip described chloroacetic chloride in the reaction system of step (1), reaction generation 2,2-acid dimethyl-2-mercapto is for ethoxyacetic acid ester crude product, then in reaction system, add frozen water, regulating pH is 6.5��7.5, separates organic facies, after described organic facies drying, filtration, rotation are steamed, obtain 2,2-described acid dimethyl-2-mercaptos for ethoxyacetic acid ester.
More specifically, described organic solvent is one or more the mixture in dichloromethane, triethylamine, ethyl acetate methyl tertiary butyl ether(MTBE).
More specifically, described reaction also carries out under the existence of Anhydrous potassium carbonate or natrium carbonicum calcinatum.
Due to the enforcement of above technical scheme, the present invention compared with prior art has the advantage that
In the present invention, acry radical donor 2,2-acid dimethyl-2-mercapto is cheap and easily-available for the synthesis material (2 mercapto ethanol, potassium carbonate, sodium carbonate, ethanol) of ethoxyacetic acid ester, and synthesis technique is simple, it is easy to amplify; Its hydrolyzate 2 mercapto ethanol boiling point (157��158 DEG C/760mmHg) is lower than 3-mercaptopropionic acid (freezing point 16-17 DEG C in original patent (CN201080055195.X), boiling point: 217.3 DEG C/760mmHg), it is easily recycled and applies mechanically, reduce and pollute, reduce further cost so that product competitiveness is strong.
Accompanying drawing explanation
Accompanying drawing 1 is that ST20-2-mercapto is for ethanol ester nuclear magnetic spectrogram;
Accompanying drawing 2 is that ST20-2-mercapto is for ethoxyacetic acid ester nuclear magnetic spectrogram.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention will be further described in detail, but the present invention is not limited to following example. The implementation condition adopted in embodiment can do further adjustment according to specifically used different requirement, and not marked implementation condition is the condition in normal experiment.
Embodiment 1:2,2-acid dimethyl-2-mercapto is for the preparation method (two-step method) of ethoxyacetic acid ester
Step 1:2,2-acid dimethyl-2-mercapto is for the synthesis of ethanol ester, and its reaction equation is as follows:
In 50mL there-necked flask, N2Protection, under zero degree, adds dichloromethane 25mL; triethylamine 7.5g (74.25mmol; 2eq), 2 mercapto ethanol 3.5 grams (44.6mmol, 1.2eq) is added; dropping 2; 2-dimethyl-butyrylchlorine 5 grams (37.2mmol, 1eq), interior temperature control is about zero degree; drip off, react 2 hours under zero degree. Warming naturally to about 25 degree, GC detects reaction process, continues reaction 12 hours, and raw material 2 mercapto ethanol converts completely, and reaction system adds 30mL frozen water, and it is 7 that 2M hydrochloric acid regulates pH value of reaction system.Separating dichloromethane layer, water layer is with dichloromethane extraction twice, each 10mL. Merging organic facies dichloromethane layer, dry through anhydrous magnesium sulfate, filter, rotation boils off solvent and obtains 6.23 grams of colorless oil of product, yield 95%. (1HNMR is shown in accompanying drawing 1)
Step 2:2,2-acid dimethyl-2-mercapto is for the synthesis of ethoxyacetic acid ester, and its reaction equation is as follows:
In 50mL there-necked flask, N2 protects, under zero degree; add dichloromethane 25mL, triethylamine 10.13g (100mmol, 2eq); add 2; 2-acid dimethyl-2-mercapto, for ethanol ester 8.82 grams (50mmol, 1eq), drips 4.71 grams of (60mmol of chloroacetic chloride; 1.2eq); interior temperature control, about zero degree, drips off, and reacts 2 hours under zero degree. Warming naturally to about 25 degree, GC detects raw material 2,2-acid dimethyl-2-mercapto and converts completely for ethanol ester, and reaction system adds 10mL frozen water, and it is 7 that 2M hydrochloric acid regulates pH value of reaction system. Separating dichloromethane layer, water layer is with dichloromethane extraction twice, each 5mL. Merging organic facies dichloromethane layer, dry through anhydrous magnesium sulfate, filter, rotation boils off solvent and obtains 10.5 grams of colorless oil of product, yield 96.5%. (1HNMR is shown in accompanying drawing 2)
Embodiment 2:2,2-acid dimethyl-2-mercapto is for the preparation method (one-step method) of ethoxyacetic acid ester, and its reaction equation is as follows:
In 100mL there-necked flask, N2Protection; under zero degree, add 50mL dichloromethane, triethylamine 25.4g (250mmol; 2.5eq); add 2 mercapto ethanol 9.38 grams (120mmol, 1.2eq), drip 2; 13.5 grams of (100mmol of 2-dimethyl-butyrylchlorine; in 1eq), temperature control is about zero degree, drips off, and reacts 3 hours under zero degree. Warming naturally to about 25 degree, GC detects reaction process, continues reaction 12 hours, and raw material 2,2-dimethyl-butyrylchlorine converts completely.
Reaction system is cooled to zero degree, dropping chloroacetic chloride 11.78 grams (150mmol, 1.5eq), and interior temperature control, about zero degree, drips off, and reacts 3 hours under zero degree. Warming naturally to about 25 degree, GC detects reaction process, continues reaction 12 hours, and raw material 2,2-acid dimethyl-2-mercapto converts completely for ethanol ester and 2 mercapto ethanol. Reactant liquor joins 50mL frozen water, and it is 7 that 2M hydrochloric acid regulates pH value of reaction system. Separating dichloromethane layer, water layer is with dichloromethane extraction twice, each 20mL. Merge organic facies dichloromethane layer, saturated sodium bicarbonate solution washing organic facies dichloromethane layer twice, each 20mL. Collecting organic facies dichloromethane layer, dry through anhydrous magnesium sulfate, filter, rotation boils off solvent and obtains 21.1 grams of colorless oil of product, yield 96.4%.
Embodiment 3:2,2-acid dimethyl-2-mercapto is for the preparation method of ethoxyacetic acid ester, and its reaction equation is with embodiment 2
In 250mL there-necked flask, N2Protection; under 5 degree, add 100mL ethyl acetate, Anhydrous potassium carbonate 34.6g (250mmol; 2.5eq); add 2 mercapto ethanol 9.38 grams (120mmol, 1.2eq), drip 2; 13.5 grams of (100mmol of 2-dimethyl-butyrylchlorine; in 1eq), temperature control was at about 5 degree, drips off, in 5 degree of lower reactions 3 hours. Warming naturally to about 25 degree, GC detects reaction process, continues reaction 8 hours, and raw material 2,2-dimethyl-butyrylchlorine converts completely.
Reaction system was cooled to 5 degree, dropping chloroacetic chloride 11.78 grams (150mmol, 1.5eq), and interior temperature control, at about 5 degree, drips off, in 5 degree of lower reactions 3 hours. Warming naturally to about 25 degree, GC detects reaction process, continues reaction 8 hours, and raw material 2,2-acid dimethyl-2-mercapto converts completely for ethanol ester and 2 mercapto ethanol.Crossing and filter insoluble matter, filtrate joins 100mL frozen water, and it is 7 that 2M hydrochloric acid regulates pH value of reaction system. Separating ethyl acetate layer, water layer is with extraction into ethyl acetate twice, each 30mL. Merging organic facies ethyl acetate layer, dry through anhydrous magnesium sulfate, filter, rotation boils off solvent and obtains 20.59 grams of colorless oil of product, yield 94.3%.
Embodiment 4:2,2-acid dimethyl-2-mercapto is for the preparation method of ethoxyacetic acid ester, and its reaction equation is with embodiment 2
In 250mL there-necked flask, N2Protection; subzero 5 degree, add 100mL methyl tertiary butyl ether(MTBE), natrium carbonicum calcinatum 26.5g (250mmol; 2.5eq); add 2 mercapto ethanol 9.38 grams (120mmol, 1.2eq), drip 2; 13.5 grams of (100mmol of 2-dimethyl-butyrylchlorine; in 1eq), temperature control was at subzero about 5 degree, drips off, in subzero 5 degree of lower reactions 6 hours. Warming naturally to about 25 degree, GC detects reaction process, continues reaction 12 hours, and raw material 2,2-dimethyl-butyrylchlorine converts completely.
Reaction system was cooled to 10 degree, dropping chloroacetic chloride 11.78 grams (150mmol, 1.5eq), and interior temperature control, at about 10 degree, drips off, in 10 degree of lower reactions 3 hours. Warming naturally to about 25 degree, GC detects reaction process, continues reaction 6 hours, and raw material 2,2-acid dimethyl-2-mercapto converts completely for ethanol ester and 2 mercapto ethanol. Crossing and filter insoluble matter, filtrate joins 100mL frozen water, and it is 7 that 2M hydrochloric acid regulates pH value of reaction system. Separating methyl tert-butyl ether layers, water layer is with methyl tertiary butyl ether(MTBE) extracting twice, each 30mL. Merging organic facies methyl tert-butyl ether layers, dry through anhydrous magnesium sulfate, filter, rotation boils off solvent and obtains 21.4 grams of colorless oil of product, yield 97.6%.
Embodiment 5:2,2-acid dimethyl-2-mercapto is used for synthesizing simvastatin ammonium salt for ethoxyacetic acid ester, and its reaction equation is as follows:
In 500mL there-necked flask, add 33.8 grams of citrinin J acid (100mmol, 1eq), 200mL deionized water, add 20.4 grams of ammonia (25% mass percent concentration, 300mmol, 3eq). 6M concentrated hydrochloric acid regulates pH=9.5��9.8. Adding activated carbon (100��200 order), add 35.8mL and recombinate acyltransferase enzyme liquid, add 2,2-acid dimethyl-2-mercaptos for ethoxyacetic acid ester (26.2 grams, 120mmol, 1.2eq), 6M concentrated hydrochloric acid regulates pH=9.5��9.8. HPLC monitoring reaction course, reacts 50 hours, conversion ratio 99.3%.
Reactant liquor obtains solid by centrifugation. Solid is joined in 180mL methanol, 40-50 degree dissolve refilter, filtrate concentrates to obtain solid, through vacuum (40 degrees Celsius) dry white crystalline product weighs 37.8 grams, purity 97.3%. Content 97.8%, yield 86.4%.
Main raw material(s) market can be bought, and restructuring acyltransferase is purchased in Suzhou Chinese biotechnology of enzymes company limited (commercial disignation EW-215).
Above the present invention is described in detail; its object is to allow the personage being familiar with this art will appreciate that present disclosure and to be carried out; can not limit the scope of the invention with this; the equivalence that all spirit according to the present invention are made changes or modifies, and all should be encompassed in protection scope of the present invention.
Claims (4)
1. one kind can be used for the preparation method that synthesizes the acry radical donor of simvastatin ammonium salt; it is characterized in that: under nitrogen protection; 2 mercapto ethanol and 2; 2-dimethyl-butyrylchlorine first reacts 2 ~ 6 hours at-5 ~+5 DEG C; then react 8 ~ 12 hours at 20 ~ 30 DEG C; generate 2; 2-acid dimethyl-2-mercapto is for ethanol ester; then 2 described in; 2-acid dimethyl-2-mercapto reacts 2 ~ 3 hours at 0 ~ 10 DEG C for ethanol ester and chloroacetic chloride, then reacts 6 ~ 12 hours at 20 ~ 30 DEG C, generates described acry radical donor 2; 2-acid dimethyl-2-mercapto is for ethoxyacetic acid ester
The mass ratio of described 2 mercapto ethanol and 2,2-described dimethyl-butyrylchlorines is 0.5 ~ 0.75:1,
2,2-described acid dimethyl-2-mercaptos are 1.5 ~ 2:1 for the mass ratio of ethanol ester Yu described chloroacetic chloride,
The mass ratio of described 2 mercapto ethanol and described chloroacetic chloride is 0.7 ~ 0.8:1.
2. the preparation method of acry radical donor according to claim 1, it is characterised in that: specifically include following steps:
Step (1): under nitrogen protection, described 2 mercapto ethanol and described 2,2-dimethyl-butyrylchlorine reacts in presence of organic solvent and generates described 2,2-acid dimethyl-2-mercapto, for ethanol ester crude product, then adds frozen water in reaction system, and regulating pH is 6.5 ~ 7.5, separate organic facies, described organic facies drying, filter, remove solvent after, obtain 2,2-described acid dimethyl-2-mercaptos for ethanol ester;
Step (2): under nitrogen protection, described 2,2-acid dimethyl-2-mercapto reacts generation 2 for ethanol ester and described chloroacetic chloride under the existence of described organic solvent, 2-acid dimethyl-2-mercapto, for ethoxyacetic acid ester crude product, then adds frozen water in reaction system, and regulating pH is 6.5 ~ 7.5, separate organic facies, described organic facies drying, filter, remove solvent after, obtain 2,2-described acid dimethyl-2-mercaptos for ethoxyacetic acid ester;
Described organic solvent is the mixture of dichloromethane and triethylamine.
3. the preparation method of acry radical donor according to claim 1, it is characterised in that: specifically include following steps:
Step (1): under nitrogen protection, described 2 mercapto ethanol reacts in presence of organic solvent with 2,2-described dimethyl-butyrylchlorines and generates 2,2-described acid dimethyl-2-mercaptos for ethanol ester crude product;
Step (2): drip described chloroacetic chloride in the reaction system of step (1), reaction generation 2,2-acid dimethyl-2-mercapto is for ethoxyacetic acid ester crude product, then in reaction system, add frozen water, regulating pH is 6.5 ~ 7.5, separates organic facies, described organic facies drying, filter, remove solvent after, obtain 2,2-described acid dimethyl-2-mercaptos for ethoxyacetic acid ester;
Described organic solvent is one or more the mixture in dichloromethane, triethylamine, ethyl acetate, methyl tertiary butyl ether(MTBE).
4. the preparation method of acry radical donor according to claim 3, it is characterised in that: described reaction also carries out under the existence of Anhydrous potassium carbonate or natrium carbonicum calcinatum.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2007139871A2 (en) * | 2006-05-24 | 2007-12-06 | The Regents Of The University Of California | Methods and materials for making simvastatin and related compounds |
| CN102712678A (en) * | 2009-09-30 | 2012-10-03 | 科德克希思公司 | Improved LOV-D acyltransferase mediated acylation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2007139871A2 (en) * | 2006-05-24 | 2007-12-06 | The Regents Of The University Of California | Methods and materials for making simvastatin and related compounds |
| CN102712678A (en) * | 2009-09-30 | 2012-10-03 | 科德克希思公司 | Improved LOV-D acyltransferase mediated acylation |
Non-Patent Citations (2)
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| Synthesis and Biological Evaluation of Phosphate Prodrugs of 4-Phospho-D-erythronohydroxamic Acid, an Inhibitor of 6-Phosphogluconate Dehydrogenase;Gian Filippo Ruda 等;《ChemMedChem》;20070706;第2卷(第8期);第1169-1180页 * |
| Versatile thiolated thermosensitive polymers synthesized by ATRP of MEO2MA and AcSEMA, a new methacrylic monomer with a protected thiol group;Marta Liras 等;《Polymer Chemistry》;20130712;第4卷(第24期);第5751-5759页 * |
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