CN103058925A - Method for preparing pitavastatin calcium - Google Patents
Method for preparing pitavastatin calcium Download PDFInfo
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- CN103058925A CN103058925A CN2011103413731A CN201110341373A CN103058925A CN 103058925 A CN103058925 A CN 103058925A CN 2011103413731 A CN2011103413731 A CN 2011103413731A CN 201110341373 A CN201110341373 A CN 201110341373A CN 103058925 A CN103058925 A CN 103058925A
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Abstract
The invention relates to a method for preparing pitavastatin calcium, comprising the following steps of: (a) adopting C1-C4 lower alcohol to dissolve a compound II, and adding an acid catalyst to carry out deprotection reaction so as to obtain a compound III; (b) adding water liquor of alkali to the compound III liquor obtained in the step (a), carrying out hydrolysis reaction, adjusting pH value to 7-8 with acid, concentrating, extracting with water and fat soluble liquor, and separating a water layer to obtain pitavastatin calcium liquor; and (c) adding calcium chloride liquor to the liquor obtained in the step (b), stirring, filtering the separated solid, washing, and drying to obtain the pitavastatin calcium. The method disclosed by the invention saves the middle steps of separation and purification, so that the production process is simplified, the working time is reduced, the production efficiency is improved, and the method is more suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of statins antilipemic drugs, be specifically related to the method that a kind of one kettle way prepares Pitavastatin Calcium.
Background technology
Statins is class 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, this type of medicine is by synthetic rate-limiting enzyme (HMG-CoA) reductase enzyme of competitive inhibition endogenous cholesterol, hydroxyl first valeric acid pathways metabolism in the blocking-up cell, thus play reducing blood lipid.Since first statins lovastatin listing in 1987, gone on the market successively Simvastatin, fluvastatin, atorvastatincalcuim, rosuvastain calcium and Pitavastatin Calcium have obtained immense success with market clinically.
Pitavastatin Calcium (I) went on the market in Japan in July, 2003, was used for the treatment of hypercholesterolemia and familial hypercholesterolemia, and commodity are by name
This medicine is developed by Nissan Chemical Ind Ltd the earliest, by Nissan Chemical Ind Ltd, Kowa company Ltd and the co-applications patent EP304063 of Sankyo Co., Ltd and US5011930 protection,
Pitavastatin Calcium is the strongest in the statins that has gone on the market at present to HMG-CoA reduction enzymeinhibition activity, and its clinical dosage is 1-2mg/d, is starkly lower than the statins that other have gone on the market.And Pitavastatin Calcium is in vivo without the CYP3A4 metabolism, and the possibility that causes untoward reaction is less.Develop this product and provide more reasonable, economic preparation technology to have good society and economic implications.
In the European patent EP 304063, disclose 2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline aldehyde and be converted into α, the beta-unsaturated carboxylic acid ester, the reduction rear oxidation becomes aldehyde, again with the methyl aceto acetate condensation, after reduction, change into sodium salt, further change into again the raceme of Pitavastatin Calcium.The method not only step is long, complex operation, and lack chirality selection step, the product that obtains also need carry out chiral separation in addition, now seldom uses.
Reported the method for preparing Pitavastatin Calcium take Compound I I (i.e. compound F 17-hydroxy-corticosterone ormula-15b in this patent) as initiator in 2007 among the disclosed WO2007125547:
Take off the propylidene protection with hydrochloric acid catalysis, sodium hydroxide hydrolysis obtains sodium salt, adds TERTIARY BUTYL AMINE and obtains the pitavastatin tert-butylamine salt, and then react with sodium hydroxide, adds calcium chloride and obtains Pitavastatin Calcium, and schema is seen accompanying drawing 1.
Need to generate the pitavastatin tert-butylamine salt in the process of the present invention, the regeneration sodium salt obtains the pitavastatin calcium salt at last, and complex steps and yield are low.The solvent of deprotection reaction is selected acetonitrile in addition, causes speed of response slow (reaching 4 hours), inefficiency.
Chinese patent CN200810201921 discloses following reaction process: the first step, Compound I I adds concentrated hydrochloric acid in tetrahydrofuran solution, room temperature reaction 2-3 hour, in the yellow soda ash and after, extract, drying, column chromatography obtains compound III.Second step, compound III are hydrolyzed with sodium hydroxide (5%NaOH solution 0.9ml) in methanol solution again, react to obtain sodium salt in 4 hours, add calcium chloride and separate out the Pitavastatin Calcium solid, and schema is seen accompanying drawing 2.
There is following shortcoming in this invention: the first, and the intermediate product that obtains (the pitavastatin tert-butyl ester) needs the last handling processes such as neutralization, extraction, drying, complex steps, length consuming time.The second, take tetrahydrofuran (THF) as reaction solvent, speed of response is slow, needs the reaction times more than 2 hours, and efficient is low.The 3rd, the column chromatography operation is difficult to realize industry's enlarging production, affects product marketization.The 4th, two-step reaction uses respectively tetrahydrofuran (THF) and methyl alcohol to be solvent, need to use two kinds of different solvents, and tetrahydrofuran (THF) is inflammable and explosive, during production workshop and solvent recovery is had higher requirements.The 5th, hydrolysis reaction water ratio is excessively low, is unfavorable for the generation of hydrolysis reaction, and the reaction times is long.
Therefore, prior art lack a kind of easier, safe and energy-efficient be the preparation method that starting raw material prepares Pitavastatin Calcium by Compound I I.
Summary of the invention
The invention provides the method that a kind of one kettle way prepares Pitavastatin Calcium.
The present invention adopts one kettle way, prepares Pitavastatin Calcium take Compound I I as raw material, and method is as follows:
(a), Compound I I C
1～C
4Lower alcohol dissolving, add an acidic catalyst and carry out deprotection reaction and obtain compound III;
(b), in step (a) gained compound III solution, add the aqueous solution of alkali, the reaction that is hydrolyzed, concentrated with acid for adjusting pH value to 7～8, add the extraction of water and fat-soluble solvent, separate water layer and get the pitavastatin sodium solution;
(c), add calcium chloride water in step (b) the gained solution, stir, will separate out solid filtering, washing, drying gets Pitavastatin Calcium.
Compare with conventional art, the inventive method has following advantage: 1, present method adopts one kettle way, purification procedures in the middle of having saved, simplified production process, shortened the working hour, improve production efficiency, and do not existed column chromatography etc. to be difficult to the step that industry is amplified in the process, more be fit to suitability for industrialized production.
2, the solvent of present method employing is C
1～C
4Lower alcohol; can effectively promote reaction to occur; the deprotection reaction time of step (a) can be realized abundant reaction in 1.5 hours; compare with tetrahydrofuran (THF) or acetonitrile that prior art adopts; reaction efficiency is enhanced about more than once, and has reduced and cause by product to increase because the reaction times is long, also avoid using inflammable and explosive reagent tetrahydrofuran (THF); improve process safety, reduced the explosion-proof cost in producing.
3, present method is only used a kind of C of being selected from
1～C
4Lower alcohol get final product as solvent, and the prior art different step adopts different organic solvents, so present method reduced the solvent for use kind, reduces process costs.
The present invention also provides the preferred version of described method.
Preparation method of the present invention, the C that selects in the step (a)
1～C
4Lower alcohol refer in methyl alcohol, ethanol, propyl alcohol, propyl carbinol, the isopropylcarbinol any one, listed solvent has similar solvability, can be equal to replacement in the methods of the invention as reaction solvent, wherein particular methanol and ethanol.
Preparation method of the present invention, an acidic catalyst of selecting in the step (a) is hydrochloric acid, sulfuric acid, methylsulfonic acid etc., preferred hydrochloric acid.
Preparation method of the present invention, the used alkali of the hydrolysis reaction in the step (b) adopts alkali metal hydroxide, preferred sodium hydroxide.
In the preparation method's of the present invention preferred version, be to improve hydrolysis reaction speed, the ratio of alcohol and water should be in 1: 1～2: 1 scopes in the hydrolysis reaction in the step (b).Add the water of suitable proportion in the hydrolysis reaction step, not only be conducive to the generation of hydrolysis reaction, also can promote the transfer of water-soluble sodium salt, promote reaction to carry out, Reaction time shorten can make hydrolysis time shorten in 2 hours greatly.
Preparation method of the present invention, the fat-soluble solvent that extraction step in the step (b) adopts is specially ethyl formate, ethyl acetate, ether, isopropyl ether and t-butyl methyl ether, above fat-soluble solvent all can reach the purpose that the organic impurity in the pitavastatin sodium solution is removed, can be equal to replacement, ethyl acetate.
In the preparation method's of the present invention preferred version, an acidic catalyst in the step (a), calcium chloride water in the aqueous solution of the alkali in the step (b) and the step (c) adds fashionable should slowly the operation, should adopt in case of necessity the mode that at the uniform velocity drips to carry out, its purpose is effectively to reduce the generation of side reaction, obtain highly purified Pitavastatin Calcium product, Pitavastatin Calcium purity is reached more than 99.6%.
Description of drawings
The synthetic route schema of accompanying drawing 1 WO2007125547.
The synthetic route schema of accompanying drawing 2 CN200810201921.
Embodiment
Following examples are to specify of the present invention, should not be construed as limiting scope of the present invention.
Embodiment 1, take by weighing 30.0g Compound I I and add in the reaction flask, open and stir, add 300ml methyl alcohol, drip 2mol/L hydrochloric acid 58ml, added in 20 minutes, 10～40 ℃ of reactions are 1 hour after dropwising; 0～50 ℃ of lower 0.5mol/L sodium hydroxide solution 150ml that drips added in 20～30 minutes, reacted 2 hours, dripped 1mol/L salt acid for adjusting pH value to 7～8; The reaction solution concentrating under reduced pressure adds 700ml purified water and 400ml ethyl acetate extraction, separates water layer; Gained water layer solution is separated out a large amount of white solids at 20～30 ℃ of lower calcium chloride water 115ml that drip 0.4mol/L, stirs filtration in 30 minutes, washing, and vacuum-drying gets white Pitavastatin Calcium solid 23.0 grams.Total recovery: 90.2%.Purity 99.67%.
Embodiment 4, take by weighing 30.0g Compound I I and add in the reaction flask, open and stir, add the 300ml dehydrated alcohol, drip 2mol/L hydrochloric acid 58ml, added in 20 minutes, 10～40 ℃ of reactions are 75 minutes after dropwising; 0～50 ℃ of lower 1mol/L sodium hydroxide solution 150ml that drips added in 20～30 minutes, added purified water 150ml, reacted 1.5 hours, dripped 1mol/L salt acid for adjusting pH value to 7～8; The reaction solution concentrating under reduced pressure adds 700ml purified water and 400ml ethyl acetate extraction, separates water layer; Gained water layer solution is separated out a large amount of white solids at 20～30 ℃ of lower calcium chloride water 115ml that drip 0.4mol/L; Stirred 30 minutes, and filtered, washing, vacuum-drying gets white Pitavastatin Calcium solid 23.5 grams.Total recovery: 92.1%.Purity 99.69%.
Comparative Examples 1,
1, prepare the pitavastatin tert-butyl ester and take by weighing in the 30.0g Compound I I adding reaction flask, open and stir, add the 300ml tetrahydrofuran (THF), add 2mol/L hydrochloric acid 58ml, 10～40 ℃ were reacted 2.5 hours; Add saturated sodium bicarbonate solution and regulate pH value to 7～8, add the 30ml acetic acid ethyl dissolution, saturated NaCl solution washing, dry (about 2 hours), column chromatography (about 8 hours) obtains white to light yellow solid powder (the pitavastatin tert-butyl ester) 23.5g.
2, preparation pitavastatin sodium cuts down 2 liters of reaction flasks of tert-butyl ester adding with 22.0g, add the 660ml dehydrated alcohol, add the 1mol/L sodium hydroxide solution, reacted 4 hours, 1mol/L salt acid for adjusting pH value to 7～8, concentrated, add the 700ml purified water, the 400ml ethyl acetate extraction separates water layer and gets the pitavastatin sodium solution.
3, the preparation Pitavastatin Calcium adds the pitavastatin sodium solution in the 2L reaction flask, drips the calcium chloride water 115ml of 0.4mol/L, separates out a large amount of white solids, stirs 30 minutes.Filter, washing, vacuum-drying gets white Pitavastatin Calcium solid 19.1 grams.Total recovery 80.0%, purity 98.61%.
Claims (8)
1. method for preparing Pitavastatin Calcium is characterized in that comprising following steps:
(a), compound ii C
1~ C
4Lower alcohol dissolving, add an acidic catalyst and carry out deprotection reaction and obtain the compound III;
Ⅱ Ⅲ
(b), in step (a) gained compound III solution, add the aqueous solution of alkali, the reaction that is hydrolyzed, concentrated with acid for adjusting pH value to 7 ~ 8, add the extraction of water and fat-soluble solvent, the separation water layer gets the pitavastatin sodium solution;
(c), add calcium chloride water in step (b) the gained solution, stir, will separate out solid filtering, washing, drying gets Pitavastatin Calcium.
2. the method for claim 1 is characterized in that the C described in the step (a)
1~ C
4Lower alcohol be in methyl alcohol, ethanol, propyl alcohol, propyl carbinol and the isopropylcarbinol any one.
3. method as claimed in claim 1 or 2 is characterized in that an acidic catalyst described in the step (a) is any one in hydrochloric acid, sulfuric acid and the methylsulfonic acid.
4. method as claimed in claim 1 or 2 is characterized in that the alkali described in the step (b) is alkali metal hydroxide.
5. method as claimed in claim 4 is characterized in that the alkali described in the step (b) is sodium hydroxide.
6. such as claim 1 or 2 described methods, it is characterized in that alcohol should be in 1:1 ~ 2:1 scope with the ratio of water in the hydrolysis reaction of step (b).
7. such as claim 1 or 2 described methods, it is characterized in that the described fat-soluble solvent of step (b) is any one in ethyl formate, ethyl acetate, ether, isopropyl ether and the t-butyl methyl ether.
8. method as claimed in claim 1 or 2 is characterized in that an acidic catalyst in the step (a), and the calcium chloride water in the aqueous solution of the alkali in the step (b) and the step (c) adds in the mode that at the uniform velocity drips.
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Citations (7)
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|---|---|---|---|---|
| CN1636004A (en) * | 2002-02-21 | 2005-07-06 | 诺瓦提斯公司 | Process for the manufacture of hmg-coa reductase inhibitory mevalonic acid derivatives |
| WO2007125547A2 (en) * | 2006-05-03 | 2007-11-08 | Manne Satyanarayana Reddy | Novel process for statins and its pharmaceutically acceptable salts thereof |
| CN101219991A (en) * | 2007-12-27 | 2008-07-16 | 江苏万邦生化医药股份有限公司 | Method for producing pitavastatin calcium raw material |
| CN101386592A (en) * | 2008-10-30 | 2009-03-18 | 上海交通大学 | Method for preparing pitavastatin calcium raw material medicine using asymmetric hydrogenation |
| CN101492405A (en) * | 2008-01-25 | 2009-07-29 | 石药集团中奇制药技术（石家庄）有限公司 | Method for preparing atorvastatin calcium |
| WO2010077062A2 (en) * | 2008-12-29 | 2010-07-08 | Hanmi Pharm. Co., Ltd. | Preparation method of statin compound and benzothiazolyl sulfone compound used therein |
| WO2010098583A2 (en) * | 2009-02-24 | 2010-09-02 | 한미약품 주식회사 | Novel method for preparing statin compounds or salts thereof, and intermediate compounds used in same |
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2011
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Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1636004A (en) * | 2002-02-21 | 2005-07-06 | 诺瓦提斯公司 | Process for the manufacture of hmg-coa reductase inhibitory mevalonic acid derivatives |
| WO2007125547A2 (en) * | 2006-05-03 | 2007-11-08 | Manne Satyanarayana Reddy | Novel process for statins and its pharmaceutically acceptable salts thereof |
| CN101219991A (en) * | 2007-12-27 | 2008-07-16 | 江苏万邦生化医药股份有限公司 | Method for producing pitavastatin calcium raw material |
| CN101492405A (en) * | 2008-01-25 | 2009-07-29 | 石药集团中奇制药技术（石家庄）有限公司 | Method for preparing atorvastatin calcium |
| CN101386592A (en) * | 2008-10-30 | 2009-03-18 | 上海交通大学 | Method for preparing pitavastatin calcium raw material medicine using asymmetric hydrogenation |
| WO2010077062A2 (en) * | 2008-12-29 | 2010-07-08 | Hanmi Pharm. Co., Ltd. | Preparation method of statin compound and benzothiazolyl sulfone compound used therein |
| WO2010098583A2 (en) * | 2009-02-24 | 2010-09-02 | 한미약품 주식회사 | Novel method for preparing statin compounds or salts thereof, and intermediate compounds used in same |
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|---|
| MASAMICHI WATANABE,等: "Synthesis and Biological Activity of Methanesulfonamide Pyrimidine-and< i> N</i>-Methanesulfonyl Pyrrole-Substituted 3, 5-Dihydroxy-6-heptenoates, a Novel Series of HMG-CoA Reductase Inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
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Effective date of registration: 20191230 Address after: 050035 No. 226, the Yellow River Avenue, hi tech Industrial Development Zone, Hebei, Shijiazhuang Co-patentee after: Stone Pharmaceutical Group Zhongnuo Pharmaceutical Industry (Shijiazhuang) Co., Ltd. Patentee after: Stone Pharmaceutical Group Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. Address before: 050035 No. 226, the Yellow River Avenue, Shijiazhuang, Hebei Patentee before: Stone Pharmaceutical Group Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. |
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