CN106831424B - The method that simvastatin ammonium salt is prepared by Lovastatin - Google Patents
The method that simvastatin ammonium salt is prepared by Lovastatin Download PDFInfo
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- CN106831424B CN106831424B CN201510877939.0A CN201510877939A CN106831424B CN 106831424 B CN106831424 B CN 106831424B CN 201510877939 A CN201510877939 A CN 201510877939A CN 106831424 B CN106831424 B CN 106831424B
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- simvastatin
- lovastatin
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- ammonium salt
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
Abstract
The invention discloses a kind of methods for preparing simvastatin ammonium salt by Lovastatin.Lovastatin of the present invention obtains monacolin J acid after open loop and side-chain hydrolysis; then the acyl moiety of acry radical donor is supplied to the carry out acylation reaction of the C8 hydroxyl of monacolin J acid in the presence of acyltransferase; the acidity of Simvastatin reaction solution is adjusted again; simvastatin acid solid is precipitated, simvastatin acid solid is finally obtained to the simvastatin ammonium salt after salified.The present invention can with reaction step, shorten the operating time, simplify experimentation, reduce to the pollution of environment, improve product quality.
Description
Technical field
The present invention relates to a kind of preparation methods of simvastatin ammonium salt, especially prepare simvastatin ammonium salt by Lovastatin
Method, belong to pharmaceutical technology field.
Background technique
Simvastatin is the hypolipidemic that Merck company develops, and can be used for controlling blood cholesterol level and the prevention heart
Vascular diseases, pharmacological action are the rate-limiting enzyme -3- hydroxy-3-methyls penta for inhibiting cholesterol biosynthesis as competitive inhibitor
The activity of two acyl coenzyme A reductases (HMG-CoA reductase), to reduce the biosynthesis of cholesterol.With same dose
The statins such as Lovastatin compare, Simvastatin can more effectively reduce total cholesterol and low density lipoprotein in blood
Protein cholesterol.
Merck company has synthesized Simvastatin by substrate of Lovastatin, and lists in August, 1989 in the U.S., 1994
Annual sales amount reaches 13.69 hundred million dollars, and ranking accounts for the 5th of all best-selling drugs.From the molecule of Simvastatin and Lovastatin
Structure sees that the two differs only by a methyl, and traditional production technology is to synthesize to obtain through full chemistry using Lovastatin as raw material
Simvastatin.
There are two types of its chemical synthesis routes: first is that the side-chain hydrolysis route of Lovastatin.Simvastatin is Lovastatin
Semi-synthetic derivative, Simvastatin only on the alpha -carbon atom of its C-8 butyric acid ester side chain more than Lovastatin a methyl.
1980, Hoffman etc. was disclosed in patent US4444784 using Lovastatin as starting material, chemical synthesis Simvastatin
Side-chain hydrolysis route, specific chemical reaction mainly includes de- Lovastatin ester hydrolysis hydroxyl protection again, is esterified again and de-
Four steps are protected, but length, yield are low the time required to the route, the by-product of de-esterification is more, thus product is given to separate
Purifying brings adverse effect.
Second is that the direct route of methylation of Lovastatin.Such as improved chemical method is used in patent CN104803959
Synthesize Simvastatin.Upper most commonly used process route is produced as current, overall yield level is 60% to 80%.The route needs
A variety of expensive or dangerous Chemical metal reagents are wanted, and in view of the similarity on Lovastatin and Simvastatin structure, are needed
The residual for controlling Lovastatin, is otherwise difficult to separate the two in the product.It is readily apparent that such method is limited to step
The defects of various, the more consumptions of reagent type are big, and product separation is complicated, and the best approach of nonproductive Simvastatin.
As what molecular biology and metabolic engineering were studied gos deep into, the enzymatic clarification of Simvastatin gradually obtain academia and
The attention of industrial circle.And technology research and production cost an important factor for having become product competition of Simvastatin.Enzyme
The relevant progress of method:
First is that the acquisition and application of monacolin J, by LovD(acyltransferase) the acyltransferase coding of gene coding
Diketone synzyme interrupt after, so that it may accumulate monacolin J or hydrolyze to obtain by Lovastatin.And with monacolin J
For substrate, enzyme' s catalysis Simvastatin.But the monacolin J fermentation level of existing strain is relatively low, it is still difficult to realize extensive work
Industry metaplasia produces.Acyltransferase is a key enzyme in Lovastatin biosynthesis pathway, and the enzyme is for acyl carrier, acyl group
Substrate and receptor have wider Substratspezifitaet.
The esterase catalyzed conversion zone of the existing commercialization of early utilization is selectively lower, can still cause such as chemical synthesis
In reaction step it is complicated the problems such as.But in disclosed patent CN102695792, CN101490271, CN201080043600 and
In CN102712678, disclosing using size in the gene cluster for synthesizing statin in Aspergillus terreus is 46kD albumen LovD and mutant
The synthesis of Simvastatin is carried out, while having screened different types of acry radical donor, by using the Escherichia coli for being overexpressed LovD
Bacterial strain and can penetrating cell film α-dimethyl butyryl thioesters cosubstrate, develop and convert pungent cut down for citrinin J acid
The Whole Cell Biocatalysis method of statin acid.And α-dimethyl butyryl thioesters is the integration ingredient of Simvastatin bioconversion, it
It is efficient acry radical donor disclosed in the patent of invention.Compared to the methylation synthetic route of Lovastatin, the reaction of cell catalysis
Process does not need any chemical protecting agent.Acyl thioester is selected from by α-dimethyl butyryl-S- methyl mercapto propionic ester
(DMB-S-MMP), dimethyl butyryl-S- ehtylmercapto propionic ester (DMB-S-EMP) and dimethyl butyryl-S- methyl mercapto
In the group of acetic acid esters (DMB-S-MTG) and dimethyl butyryl-S- methyl mercapto butyrate (DMB-S-MMB) composition.
In the above prior art, by the acylation reaction of enzymatic, obtained reaction solution, there is enzymes and excessive
Acry radical donor need to be removed by the technological means such as being centrifuged or extracting, and adjusted PH to 2 using hydrochloric acid afterwards and to be settled out and pungent cut down him
Spit of fland acid, equally cut down statin acid can be at preparing Simvastatin after depositing of ammonium salt again.Need cumbersome technological operation step, such as first from
Heart purifies and separates enzyme, extraction remove acry radical donor, and the aqueous solution with 6N HCl is acidified to pH2.0 after, this causes to dissociate
The problems such as Simvastatin of sour form and simultaneously DMB-S-MPA precipitating.
Second is that fermentation method prepares Simvastatin, with the theory of synthetic biology, molecular biology and metabolic engineering hand are utilized
Section, gene needed for combining in microbial body, direct fermentation thallus produce Simvastatin.CN101473040 report, using building
The Aspergillus terreus bacterial strain of genetic engineering transformation produces Simvastatin using fermentation method, but and undeclared Simvastatin yield compared with
The specific raising amount of traditional fermentation process.The summary of other documents also indicates that, carries out metabolic regulation to microorganism to improve day
The method of right product production does not show apparent effect in the production of Simvastatin.
Summary of the invention
The object of the present invention is to provide a kind of methods for preparing simvastatin ammonium salt by Lovastatin.The present invention has
Reaction step is reduced, shortens the operating time, simplify experimentation, reduce to the pollution of environment, improve the advantages of product quality.
In order to solve the above technical problems, technical solution provided by the invention is as follows: preparing Simvastatin ammonium by Lovastatin
The method of salt, comprising the following steps:
A, Lovastatin is obtained to monacolin J acid after open loop and side-chain hydrolysis；
B, acry radical donor and acyltransferase is added, the acyl moiety of acry radical donor is provided in the presence of acyltransferase
Acylation reaction is carried out to the C8 hydroxyl of monacolin J acid, obtains Simvastatin reaction solution；
C, it is acid to adjust Simvastatin reaction solution, simvastatin acid solid is precipitated；
D, by simvastatin acid solid it is salified after obtain simvastatin ammonium salt.
Above-mentioned is prepared in the method for simvastatin ammonium salt by Lovastatin, and in step a, the hydrolysis is to pass through chemistry
Method basic hydrolysis, hydrolysis temperature are 67-77 DEG C；And the hydrolysis reaction system is alcohol and water, alcohol is in methanol, ethyl alcohol, isopropanol
One or more；After the end of the hydrolysis, alcohol is gone using the method for revolving.
Above-mentioned is prepared in the method for simvastatin ammonium salt by Lovastatin, and the alkali is selected from potassium hydroxide, hydroxide
One or more of sodium, sodium carbonate, potassium carbonate.
Above-mentioned to be prepared in the method for simvastatin ammonium salt by Lovastatin, in step a, the hydrolysis is to pass through fixation
Change enzyme hydrolysis, hydrolysis temperature is 30-36 DEG C, and hydrolysis terminates to remove using the method for filtering.
Above-mentioned to be prepared in the method for simvastatin ammonium salt by Lovastatin, in step b, the acry radical donor is selected from α-
Dimethyl butyryl-S- methyl-mercaptopropionic acid ester (DMB-S-MMP), dimethyl butyryl-S- ethyl-mercaptopropionic acid ester (DMB-
S-EMP), dimethyl butyryl-S- methyl mercapto acetic acid esters (DMB-S-MTG), dimethyl butyryl-S- methyl mercapto butyrate
One or more of (DMB-S-MMB).The dosage of acry radical donor and acyltransferase is the C8 hydroxyl for making monacolin J acid
Fully reacting.
Above-mentioned to be prepared in the method for simvastatin ammonium salt by Lovastatin, in step b, the acyltransferase is
LovD。
Above-mentioned to be prepared in the method for simvastatin ammonium salt by Lovastatin, in step b, the ph value of reaction of acylation reaction is
9-10。
PH value in above-mentioned acylation reaction is maintained with alkali, alkali be selected from sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate,
One of potassium carbonate is several.
It is above-mentioned to be prepared in the method for simvastatin ammonium salt by Lovastatin, in step c, adjust Simvastatin reaction solution acid
Property, it is that the hydrochloric acid solution that concentration is 1M-12M is added to Simvastatin reaction solution to adjust pH value to 3-4.
It is above-mentioned to be prepared in the method for simvastatin ammonium salt by Lovastatin, in step c, the precipitation simvastatin acid
Solid is simvastatin acid solid product precipitating to be first precipitated, then with centrifugal method to be separated by solid-liquid separation to obtain simvastatin acid solid
Body, centrifugal condition are 0-10 DEG C, 6000-10000 rpm, 10--30min.
It is above-mentioned to be prepared in the method for simvastatin ammonium salt by Lovastatin, in step d, by simvastatin acid solid ammonium salt
Change, is first to extract simvastatin acid solid in the mixed solution of methanol and ethyl acetate, then extract to simvastatin acid
Take liquid salified, extraction temperature is 0-5 DEG C, and the mixed proportion of methanol and ethyl acetate is 0-0.2:1.
It is above-mentioned to be prepared in the method for simvastatin ammonium salt by Lovastatin, it is salified to simvastatin acid extract liquor, be
Simvastatin acid extract liquor is added to the methanol solution of ammonium hydroxide, in 7-15 DEG C of water bath, after being sufficiently stirred, crystallization is obtained
To simvastatin ammonium salt.
Above-mentioned is prepared in the method for simvastatin ammonium salt by Lovastatin, the methanol solution of the ammonium hydroxide, ammonium hydroxide with
The ratio of methanol is in 1:0-1:5.
Compared with prior art, the present invention needs not move through purifying after Lip river is cut down and is hydrolyzed into monacolin J acid and is directly used in acyl
Glycosylation reaction, and directly can reach pungent without being centrifuged and being extracted work after the reaction of enzymatic acyl group by acidification and cut down
Isolating and purifying for statin acid and fermentation liquid and acry radical donor, finally prepares ammonium salt.Therefore compared with other preparation methods, this hair
It is bright have reduce reaction step, shorten the operating time, simplify experimentation, reduce to the pollution of environment, improve product quality
Advantage.
Specific embodiment
Below with reference to embodiment, the present invention is further illustrated.
Embodiment 1: the one-step method of alkali hydrolysis method and acyl group transfer reaction prepares simvastatin ammonium salt, comprising the following steps:
1) after 12g Lovastatin being packed into reactor, it is sequentially added 32g isopropanol, 10g potassium hydroxide and 0.6g water, is led to
Enter nitrogen or argon gas, be warming up to 72 ± 0.3 DEG C, react 5h, HPLC detects raw material < 1.5%, cools to 50 ± 5 DEG C, is concentrated under reduced pressure
It is steamed to no liquid, water 12g is added, continued distillation and steamed to no liquid, be concentrated under reduced pressure into no liquid and steam, water is then added
12g continues distillation and steams to no liquid, cools to 25 ± 5 DEG C；
2) 8.8g 2,2- diformazan is added with hydrochloric acid tune pH to 9.5 ± 0.5 DEG C in the chemical hydrolysis product for obtaining step 1)
Base bytyry-S- methyl propionate and 4g contain the thallus of acyltransferase, maintain pH to 9.5 ± 0.5 DEG C with 1M sodium carbonate, temperature
25 ± 5 DEG C of degree；
3) it is detected every reaction solution of the 1h to step 2, until the ratio < 2% of Lovastatin hydrolysate；
4) reaction solution of step 2 is placed in 0-5 DEG C of ice-water bath, and hydrochloric acid is added dropwise into reaction solution and terminates instead
It should and continue to be added dropwise to pH 3-4, form solid-liquid two-phase；
5) solid-liquid of step 4) is layered sample, is centrifugated solid-liquid.Condition 8000rpm, 10min, 4 DEG C；Detect supernatant
Middle product assay is simultaneously thrown aside；
6) by step 5) obtained solid, the mixed liquor (methanol: ethyl acetate=1:5) of methanol and ethyl acetate is added
Three times, combining extraction liquid, the process is in 0-5 DEG C of ice-water bath by 200mL, sufficiently extraction；
7) into the water bath that the extract liquor of step 6) is placed in 7-15 DEG C, the methanol solution of ammonium hydroxide, which is added dropwise, to pH is
7-8 has crystal precipitation, continue crystallization 2h, filter white solid is simvastatin ammonium salt；
8) liquid phase detecting step 7) simvastatin ammonium salt that obtains, calculated purity and conversion ratio.
Table one: the product data (cutting down the 12g that feeds intake in Lip river) of the simvastatin ammonium salt of 1 method of embodiment production
Embodiment 2: the one-step method of immobilized enzyme hydrolysis method and acyl group transfer reaction prepares simvastatin ammonium salt, including following
Step:
1) Lovastatin open loop: the sodium hydroxide of 7.5ml anhydrous methanol and 10ml 6N are mixed, the Lip river 22.5g is weighed and cuts down him
Spit of fland is added in the solution.45ml water is finally added again, controlled at 20 DEG C on blender.It is stirred overnight (about 15 hours)；
2) Lovastatin hydrolyzes: the Lovastatin open loop substrate of 30ml being added in the beaker of 100ml, adjusts PH9.5, adds water
It is settled to 90ml or so, heats up 35 DEG C, immobilised enzymes 9g is then added, be hydrolyzed reaction, when hydrolysis is controlled with diluted alkaline
PH9.5, temperature are controlled at 35 DEG C, and reaction is overnight to completion；
3) 2,2- dimethyl butyryl-is added with hydrochloric acid tune pH to 9.5 ± 0.5 DEG C in the enzymic hydrolysates for obtaining step 2
S- methyl propionate and thallus containing acyltransferase maintain pH to 9.5 ± 0.5 DEG C, 25 ± 5 DEG C of temperature with 1M sodium carbonate；
4) it is detected every reaction solution of the 1h to step 2, until the ratio < 2% of Lovastatin hydrolysate；
5) reaction solution of step 2 is placed in 0-5 DEG C of ice-water bath, and hydrochloric acid is added dropwise into reaction solution and terminates instead
It should and continue to be added dropwise to pH 3-4, form solid-liquid two-phase；
6) solid-liquid of step 4) is layered sample, is centrifugated solid-liquid.Condition 8000rpm, 10min, 4 DEG C；Detect supernatant
Middle product assay is simultaneously thrown aside；
7) by step 5) obtained solid, the mixed liquor (methanol: ethyl acetate=1:5) of methanol and ethyl acetate is added
Three times, combining extraction liquid, the process is in 0-5 DEG C of ice-water bath by 200mL, sufficiently extraction；
8) into the water bath that the extract liquor of step 6) is placed in 7-15 DEG C, the methanol solution of ammonium hydroxide, which is added dropwise, to pH is
7-8 has crystal precipitation, continue crystallization 2h, filter white solid is simvastatin ammonium salt；
9) liquid phase detecting step 7) simvastatin ammonium salt that obtains, calculated purity and conversion ratio.
Embodiment 3: the one-step method of alkali hydrolysis method and acyl group transfer reaction prepares simvastatin ammonium salt, comprising the following steps:
1) after 3g Lovastatin being packed into reactor, it is sequentially added 8g isopropanol, 2.5g potassium hydroxide and 0.15g water, is led to
Enter nitrogen or argon gas, be warming up to 72 ± 0.3 DEG C, react 5h, HPLC detects raw material < 1.5%, cools to 50 ± 5 DEG C, is concentrated under reduced pressure
It is steamed to no liquid, water 3g is added, continued distillation and steamed to no liquid, be concentrated under reduced pressure into no liquid and steam, water 3g is then added,
Continue distillation to steam to no liquid, cools to 25 ± 5 DEG C；
2) 2.2g 2,2- diformazan is added with hydrochloric acid tune pH to 9.5 ± 0.5 DEG C in the chemical hydrolysis product for obtaining step 1)
Base bytyry-S- methyl propionate and 1g contain the thallus of acyltransferase, maintain pH to 9.5 ± 0.5 DEG C with 1M sodium carbonate, temperature
25 ± 5 DEG C of degree；
3) it is detected every reaction solution of the 1h to step 2, until the ratio < 2% of Lovastatin hydrolysate；
4) reaction solution of step 2 is placed in 0-5 DEG C of ice-water bath, and hydrochloric acid is added dropwise into reaction solution and terminates instead
It should and continue to be added dropwise to pH 3-4, form solid-liquid two-phase；
5) solid-liquid of step 4) is layered sample, is centrifugated solid-liquid.Condition 8000rpm, 10min, 4 DEG C；Detect supernatant
Middle product assay is simultaneously thrown aside；
6) by step 5) obtained solid, ethyl acetate 50mL is added, sufficiently extracts three times, combining extraction liquid, at the process
In 0-5 DEG C of ice-water bath；
7) into the water bath that the extract liquor of step 6) is placed in 7-15 DEG C, be added dropwise ammonium hydroxide methanol solution (ammonium hydroxide:
Methanol is 1:5) be 7-8 to pH or have a crystal precipitation, continue crystallization 2h, filter white solid is simvastatin ammonium salt；
Liquid phase detecting step 7) simvastatin ammonium salt that obtains, calculated purity and conversion ratio.
Claims (8)
1. the method for preparing simvastatin ammonium salt by Lovastatin, which comprises the following steps:
A, Lovastatin is obtained to monacolin J acid after open loop and side-chain hydrolysis；
B, acry radical donor and acyltransferase is added, is supplied to the acyl moiety of acry radical donor in the presence of acyltransferase red
The C8 hydroxyl of aspergin J acid carries out acylation reaction, obtains Simvastatin reaction solution；
C, it is acid to adjust Simvastatin reaction solution, simvastatin acid solid is precipitated；
D, by simvastatin acid solid it is salified after obtain simvastatin ammonium salt；
In step b, the acyltransferase is LovD；
In step c, Simvastatin reaction solution acidity is adjusted, is molten for the hydrochloric acid of 1M-12M to Simvastatin reaction solution addition concentration
Liquid adjusts pH value to 3-4.
2. the method according to claim 1 for preparing simvastatin ammonium salt by Lovastatin, which is characterized in that in step a,
The hydrolysis is by chemical method basic hydrolysis, and hydrolysis temperature is 67-77 DEG C；And the hydrolysis reaction system is alcohol and water, alcohol choosing
From one or more of methanol, ethyl alcohol, isopropanol；After the end of the hydrolysis, alcohol is gone using the method for revolving.
3. the method according to claim 1 for preparing simvastatin ammonium salt by Lovastatin, which is characterized in that in step a,
The hydrolysis is by immobilized enzyme hydrolysis, and hydrolysis temperature is 30-36 DEG C.
4. the method according to claim 1 for preparing simvastatin ammonium salt by Lovastatin, which is characterized in that in step b,
The acry radical donor is selected from alpha-alpha-dimethyl butyryl-S- methyl-mercaptopropionate, dimethyl butyryl-S- ethyl-mercaptopropionic acid
One or more of ester, dimethyl butyryl-S- methyl mercapto acetic acid esters, dimethyl butyryl-S- methyl mercapto butyrate.
5. the method according to claim 1 for preparing simvastatin ammonium salt by Lovastatin, which is characterized in that in step b,
The ph value of reaction of acylation reaction is 9-10.
6. the method according to claim 1 for preparing simvastatin ammonium salt by Lovastatin, which is characterized in that in step c,
The precipitation simvastatin acid solid is simvastatin acid solid product precipitating to be first precipitated, then carry out solid-liquid with centrifugal method
Isolated simvastatin acid solid, centrifugal condition are 0-10 DEG C, 6000-10000rpm, 10--30min.
7. the method according to claim 1 for preparing simvastatin ammonium salt by Lovastatin, which is characterized in that in step d,
Simvastatin acid solid is salified, it is first to extract simvastatin acid solid in the mixed solution of methanol and ethyl acetate
It takes, then salified to simvastatin acid extract liquor, extraction temperature is 0-5 DEG C, and the mixed proportion of methanol and ethyl acetate is 0-
0.2:1.
8. the method according to claim 7 for preparing simvastatin ammonium salt by Lovastatin, which is characterized in that cut down him to pungent
Spit of fland acid extraction liquid is salified, is the methanol solution that simvastatin acid extract liquor is added to ammonium hydroxide, in 7-15 DEG C of water bath,
After being sufficiently stirred, crystallization obtains simvastatin ammonium salt.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1031086A (en) * | 1987-07-10 | 1989-02-15 | 麦克公司 | The alkylating method of alpha-carbon of Mai Weinuo element and analogue 8-acyl group thereof |
| CN101415833A (en) * | 2003-10-21 | 2009-04-22 | 戴弗萨公司 | Methods for making simvastatin and intermediates |
| CN102712678A (en) * | 2009-09-30 | 2012-10-03 | 科德克希思公司 | Improved LOV-D acyltransferase mediated acylation |
| CN103787881A (en) * | 2013-11-22 | 2014-05-14 | 成都摩尔生物医药有限公司 | Simvastatin ammonium salt |
-
2015
- 2015-12-04 CN CN201510877939.0A patent/CN106831424B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1031086A (en) * | 1987-07-10 | 1989-02-15 | 麦克公司 | The alkylating method of alpha-carbon of Mai Weinuo element and analogue 8-acyl group thereof |
| CN101415833A (en) * | 2003-10-21 | 2009-04-22 | 戴弗萨公司 | Methods for making simvastatin and intermediates |
| CN102712678A (en) * | 2009-09-30 | 2012-10-03 | 科德克希思公司 | Improved LOV-D acyltransferase mediated acylation |
| CN103787881A (en) * | 2013-11-22 | 2014-05-14 | 成都摩尔生物医药有限公司 | Simvastatin ammonium salt |
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