CN103058925B - A kind of preparation method of Pitavastatin Calcium - Google Patents
A kind of preparation method of Pitavastatin Calcium Download PDFInfo
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- CN103058925B CN103058925B CN201110341373.1A CN201110341373A CN103058925B CN 103058925 B CN103058925 B CN 103058925B CN 201110341373 A CN201110341373 A CN 201110341373A CN 103058925 B CN103058925 B CN 103058925B
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- 0 C*C(C[C@@](C[C@@](C=C[C@](C1c(cc2)ccc2F)C(C2CC2)=Nc2c1cccc2)O)O)=O Chemical compound C*C(C[C@@](C[C@@](C=C[C@](C1c(cc2)ccc2F)C(C2CC2)=Nc2c1cccc2)O)O)=O 0.000 description 1
- GUAWMXYQZKVRCW-UHFFFAOYSA-N Cc1ccccc1NC Chemical compound Cc1ccccc1NC GUAWMXYQZKVRCW-UHFFFAOYSA-N 0.000 description 1
Abstract
The present invention relates to a kind of method preparing Pitavastatin Calcium: (a) compound ii C
1~ C
4lower alcohol dissolve, add an acidic catalyst and carry out deprotection reaction and obtain compound III; B () adds the aqueous solution of alkali in step (a) gained compound III solution, be hydrolyzed reaction, with acid for adjusting pH value to 7 ~ 8, concentrated, and add water and fat-soluble solvent extraction, separate aqueous layer obtains pitavastatin sodium solution; Add calcium chloride water in (c) step (b) gained solution, stir, will solid filtering be separated out, washing, dry, obtain Pitavastatin Calcium.The inventive method saves middle purification procedures, simplifies production process, shortens the working hour, improve production efficiency, is more applicable to suitability for industrialized production.
Ⅱ
Description
Technical field
The present invention relates to a kind of preparation method of statins antilipemic drugs, be specifically related to a kind of method that 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 competitive inhibition endogenous cholesterol synthesis rate-limiting enzyme (HMG-CoA) reductase enzyme, block hydroxyl first valeric acid pathways metabolism in cell, thus play reducing blood lipid.Since first statins lovastatin listing in 1987, gone on the market Simvastatin, fluvastatin, atorvastatincalcuim, rosuvastain calcium and Pitavastatin Calcium successively, obtains immense success clinically with market.
Pitavastatin Calcium (I) goes on the market in July, 2003 in Japan, is used for the treatment of hypercholesterolemia and familial hypercholesterolemia, and commodity are called
this medicine is developed by Nissan Chemical Ind Ltd the earliest, is protected by Nissan Chemical Ind Ltd, Kowa company Ltd and Sankyo Co., Ltd co-applications patent EP304063 and US5011930,
The inhibit activities of Pitavastatin Calcium to HMG-CoA reductase is the strongest in the statins gone on the market at present, 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 CYP3A4 metabolism, the possibility causing untoward reaction is less.Develop this product and provide more reasonable, economic preparation technology to have well society and economic implications.
In European patent EP 304063, disclose 2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline aldehyde and be converted into α, beta-unsaturated carboxylic acid ester, reduction rear oxidation becomes aldehyde, again with methyl aceto acetate condensation, after reduction, change into sodium salt, then change into the raceme of Pitavastatin Calcium further.The method not only step is long, complex operation, and lacks chirality selection step, and the product obtained also needs to carry out chiral separation in addition, now seldom applies.
To report with Compound II per (the compound F 17-hydroxy-corticosterone ormula-15b namely in this patent) as initiator prepares the method for Pitavastatin Calcium in WO2007125547 disclosed in 2007:
Take off propylidene protection with hydrochloric acid catalysis, sodium hydroxide hydrolysis obtains sodium salt, and add TERTIARY BUTYL AMINE and obtain pitavastatin tert-butylamine salt, and then react with sodium hydroxide, add calcium chloride and obtain Pitavastatin Calcium, schema is shown in accompanying drawing 1.
Need in process of the present invention to generate pitavastatin tert-butylamine salt, regeneration sodium salt, finally obtains pitavastatin calcium salt, complex steps and yield is low.Acetonitrile selected by the solvent of deprotection reaction in addition, causes speed of response slow (reaching 4 hours), inefficiency.
Chinese patent CN200810201921 discloses following reaction process: the first step, and Compound II per, in tetrahydrofuran solution, adds concentrated hydrochloric acid, room temperature reaction 2-3 hour, in sodium carbonate and after, extract, dry, column chromatography obtains compound III.Second step, compound III is hydrolyzed with sodium hydroxide (5%NaOH solution 0.9ml) in methanol solution again, reacts and obtains sodium salt in 4 hours, and add calcium chloride and separate out Pitavastatin Calcium solid, schema is shown in accompanying drawing 2.
There is following shortcoming in this invention: the first, and the intermediate product (the pitavastatin tert-butyl ester) obtained 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, and need the reaction times of more than 2 hours, efficiency is low.3rd, column chromatography operation is difficult to realize industry's enlarging production, affects product marketization.4th, two-step reaction uses tetrahydrofuran (THF) and methyl alcohol to be solvent respectively, need use two kinds of different solvents, and tetrahydrofuran (THF) is inflammable and explosive, reclaims have higher requirements during production to workshop and solvent.5th, hydrolysis reaction water ratio is too low, and be unfavorable for the generation of hydrolysis reaction, 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 II per.
Summary of the invention
The invention provides a kind of method that one kettle way prepares Pitavastatin Calcium.
The present invention adopts one kettle way, and be that Pitavastatin Calcium prepared by raw material with Compound II per, method is as follows:
(a), Compound II per C
1~ C
4lower alcohol dissolve, 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, be hydrolyzed reaction, with acid for adjusting pH value to 7 ~ 8, concentrated, and add water and fat-soluble solvent extraction, separate aqueous layer obtains pitavastatin sodium solution;
Add calcium chloride water in (c), step (b) gained solution, stir, will solid filtering be separated out, washing, dry, obtain Pitavastatin Calcium.
Compared with conventional art, the inventive method has following advantage: 1, present method adopts one kettle way, save middle purification procedures, simplify production process, shorten the working hour, improve production efficiency, and do not exist in process column chromatography etc. be difficult to industry amplify step, be more applicable to suitability for industrialized production.
2, the solvent that present method adopts is C
1~ C
4lower alcohol; effectively can promote that reaction occurs; the deprotection reaction time of step (a) can realize abundant reaction in 1.5 hours; compared with the tetrahydrofuran (THF) adopted with prior art or acetonitrile; reaction efficiency can be made to be enhanced about more than once, and to decrease and cause by product to increase because the reaction times is long, also avoid and use inflammable and explosive reagent tetrahydrofuran (THF); improve process safety, reduce the explosion-proof cost in production.
3, present method only uses one to be selected from C
1~ C
4lower alcohol as solvent, and prior art different step adopts different organic solvents, therefore The method reduces solvent for use kind, reduces process costs.
Present invention also offers the preferred version of described method.
Preparation method of the present invention, the C selected in step (a)
1~ C
4lower alcohol refer in methyl alcohol, ethanol, propyl alcohol, propyl carbinol, 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 selected in step (a) is hydrochloric acid, sulfuric acid, methylsulfonic acid etc., preferred hydrochloric acid.
Preparation method of the present invention, the alkali employing alkali metal hydroxide that the hydrolysis reaction in step (b) is used, preferred sodium hydroxide.
In the preferred version of preparation method of the present invention, for improving hydrolysis reaction speed, in the hydrolysis reaction in step (b), the ratio of alcohol and water should in 1: 1 ~ 2: 1 scope.In hydrolysis reaction step, add the water of suitable proportion, be not only conducive to the generation of hydrolysis reaction, also can promote the transfer of water-soluble sodium salt, promote that reaction is carried out, Reaction time shorten greatly, can make hydrolysis time shorten in 2 hours.
Preparation method of the present invention, the fat-soluble solvent that extraction step in 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 object removed by the organic impurity in pitavastatin sodium solution, replacement can be equal to, ethyl acetate.
In the preferred version of preparation method of the present invention, an acidic catalyst in step (a), calcium chloride water in the aqueous solution of the alkali in step (b) and step (c) adds fashionable should slowly operation, the mode at the uniform velocity dripped should be adopted if desired to carry out, its object is to the generation that effectively can reduce side reaction, obtain highly purified Pitavastatin Calcium product, make Pitavastatin Calcium purity reach more than 99.6%.
Accompanying drawing explanation
The synthetic route schema of accompanying drawing 1 WO2007125547.
The synthetic route schema of accompanying drawing 2 CN200810201921.
Embodiment
Following examples illustrate of the present invention, should not be construed as limiting scope of the present invention.
Embodiment 1, take 30.0g Compound II per and add in reaction flask, open and stir, add 300ml methyl alcohol, drip 2mol/L hydrochloric acid 58ml, within 20 minutes, add, 10 ~ 40 DEG C of reactions 1 hour after dropwising; Drip 0.5mol/L sodium hydroxide solution 150ml at 0 ~ 50 DEG C, within 20 ~ 30 minutes, add, react 2 hours, drip 1mol/L salt acid for adjusting pH value to 7 ~ 8; Reaction solution concentrating under reduced pressure, adds 700ml purified water and 400ml extraction into ethyl acetate, separate aqueous layer; Gained water layer solution drips the calcium chloride water 115ml of 0.4mol/L at 20 ~ 30 DEG C, separates out a large amount of white solids, stirs filtration in 30 minutes, and washing, vacuum-drying, obtains white Pitavastatin Calcium solid 23.0 grams.Total recovery: 90.2%.Purity 99.67%.
Embodiment 2, take 30.0g Compound II per and add in reaction flask, open and stir, add 300ml methyl alcohol, drip 2mol/L hydrochloric acid 58ml, within 20 minutes, add, 10 ~ 40 DEG C of reactions 1 hour after dropwising; Drip 1mol/L sodium hydroxide solution 70ml at 0 ~ 50 DEG C, within 20 ~ 30 minutes, add, add purified water 80ml, react 2 hours, drip 1mol/L salt acid for adjusting pH value to 7 ~ 8; Reaction solution concentrating under reduced pressure, adds 700ml purified water and 400ml extraction into ethyl acetate, separate aqueous layer; Gained water layer solution drips the calcium chloride water 115ml of 0.4mol/L at 20 ~ 30 DEG C, separates out a large amount of white solids, stirs 30 minutes, filters, and washing, vacuum-drying, obtains white Pitavastatin Calcium solid 23.1 grams.Total recovery: 90.6%.Purity 99.72%.
Embodiment 3, take 30.0g Compound II per and add in reaction flask, open and stir, add 400ml dehydrated alcohol, drip 2mol/L hydrochloric acid 58ml, within 20 minutes, add, 10 ~ 40 DEG C of reactions 1.5 hours after dropwising; Drip 1mol/L sodium hydroxide solution 70ml at 0 ~ 50 DEG C, within 20 ~ 30 minutes, add, add purified water 130ml, react 1 hour, drip 1mol/L salt acid for adjusting pH value to 7 ~ 8; Reaction solution concentrating under reduced pressure, adds 700ml purified water and 400ml extraction into ethyl acetate, separate aqueous layer; Gained water layer solution drips the calcium chloride water 115ml of 0.4mol/L at 20 ~ 30 DEG C, separates out a large amount of white solids; Stir 30 minutes, filter, washing, vacuum-drying, obtains white Pitavastatin Calcium solid 23.3 grams.Total recovery: 91.4%.Purity 99.65%.
Embodiment 4, take 30.0g Compound II per and add in reaction flask, open and stir, add 300ml dehydrated alcohol, drip 2mol/L hydrochloric acid 58ml, within 20 minutes, add, 10 ~ 40 DEG C of reactions 75 minutes after dropwising; Drip 1mol/L sodium hydroxide solution 150ml at 0 ~ 50 DEG C, within 20 ~ 30 minutes, add, add purified water 150ml, react 1.5 hours, drip 1mol/L salt acid for adjusting pH value to 7 ~ 8; Reaction solution concentrating under reduced pressure, adds 700ml purified water and 400ml extraction into ethyl acetate, separate aqueous layer; Gained water layer solution drips the calcium chloride water 115ml of 0.4mol/L at 20 ~ 30 DEG C, separates out a large amount of white solids; Stir 30 minutes, filter, washing, vacuum-drying, obtains white Pitavastatin Calcium solid 23.5 grams.Total recovery: 92.1%.Purity 99.69%.
Comparative example 1,
1, prepare the pitavastatin tert-butyl ester to take 30.0g Compound II per and add in reaction flask, open and stir, add 300ml tetrahydrofuran (THF), add 2mol/L hydrochloric acid 58ml, 10 ~ 40 DEG C of reactions 2.5 hours; Add saturated sodium bicarbonate solution adjust ph to 7 ~ 8, add 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, prepare pitavastatin sodium 22.0g to be cut down the tert-butyl ester and add 2 liters of reaction flasks, add 660ml dehydrated alcohol, add 1mol/L sodium hydroxide solution, react 4 hours, 1mol/L salt acid for adjusting pH value to 7 ~ 8, concentrated, add 700ml purified water, 400ml extraction into ethyl acetate, separate aqueous layer obtains pitavastatin sodium solution.
3, preparing Pitavastatin Calcium adds in 2L reaction flask by pitavastatin sodium solution, drips the calcium chloride water 115ml of 0.4mol/L, separates out a large amount of white solids, stir 30 minutes.Filter, washing, vacuum-drying, obtains white Pitavastatin Calcium solid 19.1 grams.Total recovery 80.0%, purity 98.61%.
Claims (3)
1. prepare a method for Pitavastatin Calcium, it is characterized in that comprising following steps:
A (), compound ii methyl alcohol or dissolve with ethanol, add an acidic catalyst and carry out deprotection reaction and obtain compound III, wherein, described an acidic catalyst is any one in hydrochloric acid, sulfuric acid and methylsulfonic acid;
(b), in step (a) gained compound III solution, add the aqueous solution of alkali, wherein the ratio of alcohol and water is within the scope of 1:1 ~ 2:1, be hydrolyzed reaction, with acid for adjusting pH value to 7 ~ 8, concentrated, add water and fat-soluble solvent extraction, separate aqueous layer obtains pitavastatin sodium solution, wherein, the aqueous solution of described alkali is sodium hydroxide solution;
Add calcium chloride water in (c), step (b) gained solution, stir, will solid filtering be separated out, washing, dry, obtain Pitavastatin Calcium.
2. the method for claim 1, the fat-soluble solvent that it is characterized in that described in step (b) is any one in ethyl formate, ethyl acetate, ether, isopropyl ether and t-butyl methyl ether.
3. the method for claim 1, is characterized in that an acidic catalyst in step (a), and the calcium chloride water in the aqueous solution of the alkali in step (b) and step (c) adds in the mode at the uniform velocity dripped.
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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 |
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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 |
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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. |