CN102432533A - Method for preparing high-optical purity pitavastatin calcium - Google Patents
Method for preparing high-optical purity pitavastatin calcium Download PDFInfo
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- CN102432533A CN102432533A CN2011104292984A CN201110429298A CN102432533A CN 102432533 A CN102432533 A CN 102432533A CN 2011104292984 A CN2011104292984 A CN 2011104292984A CN 201110429298 A CN201110429298 A CN 201110429298A CN 102432533 A CN102432533 A CN 102432533A
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Abstract
The invention relates to a method for preparing high-optical purity pitavastatin calcium. The method comprises the following steps of: deprotecting (3R,5S)-dyhydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dyhydroxyl-3,5-Oisopropylidene-6-tert-butyl heptenoate (I) serving as an initial raw material by using acid, and removing impurities under a certain pH value; adding excessive D-(+)benzyl methylamine, and crystallizing to extract heptenoic acid amine salt (IV); and adding calcium chloride to obtain the pitavastatin calcium. The method has the advantages that the reaction condition is mild, the purity of the product is high, the optical purity is more than or equal to 99.5 percent, the yield is more than or equal to 50 percent, the problems of high difficulty of separation and purification and low yield in the conventional method for synthesizing the pitavastatin calcium, and the method is suitable for industrialization.
Description
Technical field
The present invention relates to a kind of preparation method of anticholesteremic agent, especially the preparation method of anticholesteremic agent pitavastatin calcium.
Background technology
Pitavastatin calcium (Pitavastatin Calcium) is first the complete synthesis HMG-CoA reductase inhibitor by the common exploitation of daily output chemical company and Kowa company Ltd; In in November, 1999 at Japan registration, and on July 17th, 2003 first in Japan's approval listing.Abroad render a service and be described as " super he spit of fland " with the powerful lipopenicillinase that shows in its clinical trial.Reach and the comparison of the similar product that gone on the market abroad according to existing clinical test results, its lipid-lowering effect is very good, is the fat-reducing medicament of imitating the most by force up to now.
The chemical name of pitavastatin calcium is (+)-two { (3R; 5S; 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3; 5-dihydroxyl-6-heptenoic acid } calcium salt, its chemical structural formula is:
The pitavastatin calcium pharmacological action is: pitavastatin reduces the biosynthesizing of SUV through auxilliary A (HMG-CoA) reductase enzyme of competitive inhibition hydroxyl first glutaryl.The reduction of blood vessel inner cholesterol concentration can make low-density lipoprotein one SUV in the liver, and (receptor down-regulated of LDL-C) is accelerated the removing of LDL-C from blood.
The synthetic route of document Chinese Journal of Pharmaceuticals 2007.38 (3): 177-180 report is: 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carboxylic acid ethyl ester through KBH4/ZnCl2 reduction, bromo, make phosphonium ylide after; With (3R; 5S)-6-oxo-3; 5-dihydroxyl-3,5.0-isopropylidene tert-butyl acrylate carry out Wittig-Homor reaction, deprotection and lactonize, the hydrolysis salify makes pitavastatin calcium.This route Wittig-Honor reaction needed-78 ℃ low-temp reaction condition, and this product is difficult for purifying, optical purity≤98%, total recovery≤30% is not suitable for industriallization.
The patent EP0535548 of European Union, EP0304063, Chinese patent CN101219991, CN1876633 report: with the anthranilic acid is starting raw material, with the amino of Tosyl chloride protection anthranilic acid, again through the Friedel-Crafts acylation reaction; The deprotection base gets benzophenone, and benzophenone and β-cyclopropyl-β-oxo ethyl propionate obtains quinoline ethyl formate through Friedl nder reaction cyclization, is reduced into quinoline methanol with LiAlH4 or DIBAL again; Quinoline methanol is oxidized to quinoline aldehyde through PCC; Quinoline aldehyde obtains the quinoline vinyl cyanide through the Witting-Horner reaction, is reduced into the quinoline propenal by DIBAL again, and quinoline propenal and methyl acetoacetate obtain quinoline hydroxyl ketone heptenoic acid methyl esters through the Aldol condensation; Process NaBH4 Stereoselective reduction at low temperatures obtains erythro quinoline dihydroxy heptenoic acid methyl esters; Be hydrolyzed into calcium salt and lyophilize at last and obtain pitavastatin calcium (seeing Scheme2), this method reaction is complicated, severe reaction conditions; Reduction obtains two chiral centres; Exist to produce four chiral isomers, be difficult for purifying, yield is low.
Scheme?2：
Summary of the invention
Main purpose of the present invention be through be simple and easy on the market raw material, synthetic high optical purity pitavastatin amine salt, and then preparation high optical purity pitavastatin calcium, this method operation steps is simple, is fit to suitability for industrialized production.
In order to achieve the above object, the present invention realizes through following technical scheme:
A kind of preparation method of high optical purity pitavastatin calcium, with (3R, 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxyl-3,5-O isopropylidene-6-heptenoic acid tert-butyl ester (I) is a starting raw material, comprises the steps:
A: starting raw material (I) is in solvent, and acid exists, deprotection generation under the certain temperature (3R, 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid tert-butyl ester (II), reaction formula:
B: (3R; 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(the E)-heptenoic acid tert-butyl ester (II) alkaline hydrolysis generation (3R; 5S)-and dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid (III), use the SX impurity elimination then, regulate pH; Use the SX impurity elimination again, reaction formula:
C: (3R; 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid (III) in; Add excessive D-(+) benzyl methylamine; Generate (3R, 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid amine salt (IV), reaction formula:
；
D: (3R, 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid amine salt (IV) is in solvent, and at a certain temperature, adding alkali, calcium chloride make high optical purity pitavastatin calcium (V), reaction formula:
。
The present invention can also further optimize:
Acid in the described A step is a kind of in hydrochloric acid, sulfuric acid, phosphoric acid, tosic acid, the acetate.
Solvent is C1-C4 alcohols, ethers or ketone in the described A step; Described C1-C4 alcohols is methyl alcohol, ethanol or Virahol; Ethers is a THF; Ketone is an acetone, is preferably methyl alcohol, THF.
Temperature of reaction is 5～50 ℃ in the described A step, preferred 20-25 ℃.
After described A step reaction finishes,, directly in reaction, carry out the alkaline hydrolysis of B step without aftertreatment.
Solvent is aromatic hydrocarbons, halogenated alkane or ethers in the described B step; Described aromatic hydrocarbons is toluene, YLENE, and described halogenated alkane is chloroform, methylene dichloride, and described ethers is ether, sherwood oil, MTBE, preferred methylene dichloride, MTBE.
The said pH of described B step is 2～7, preferred 4～5.
The amount that described C step adds ɑ-phenylethylamine be with raw material (3R, 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxyl-3, the 2-5 molar equivalent of 5-O isopropylidene-6-heptenoic acid tert-butyl ester, preferred 3 molar equivalents.
The described solvent of described D step is the protic polar solvent, chooses methyl alcohol, ethanol or water, preferably water.
Described D step reaction temperature is 5～45 ℃, preferred 20～25 ℃.
The invention has the advantages that reaction conditions is gentle, optical purity of products is high, optical purity >=99.5%, and yield >=50% is fit to industriallization.
Embodiment
Embodiment 1
In 1000 milliliters of four-hole bottles, add 600 ml methanol, 33g (0.0638mol) (3R; 5S)-and dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxyl-3, the 5-O isopropylidene-6-heptenoic acid tert-butyl ester (I); 10 ℃, the hydrochloric acid 85ml of adding 1mol/L reacted 1 hour; (3R, 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(the E)-heptenoic acid tert-butyl ester (II) methanol solution.
In the methanol solution of above-mentioned (II), add 1mol/L sodium hydroxide solution 85ml, stirred 2 minutes, and then add 1mol/L sodium hydroxide solution 64ml, reacted 2 hours.55 ℃ of reclaim under reduced pressure when remaining about 100-200ml, stop to reclaim; Benefit adds water to 250 milliliters, and each is with 300 milliliters of dichloromethane extractions twice, the water layer acid adjustment to pH be 4-5; Use the 300ml dichloromethane extraction; 50ml purifying washing, (3R, 5S)-dichloromethane solution of dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid (III).
In the dichloromethane solution of above-mentioned (III), add 20g (0.165mol) ɑ-phenylethylamine; Stir suction filtration after 10 minutes, smoke, get (3R; 5S)-and dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid amine salt (IV), front three steps total recovery is 65%.
In the 1000ml four-hole boiling flask, and adding 13 grams (3R, 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid amine salt (IV), add the 217ml purified water again.5 ℃, the sodium hydroxide solution 27ml of dropping 1mol/L in system, stirring reaction 2 hours drips the 215ml aqueous solution that contains 1.6g calcium chloride in above-mentioned solution; After dropwising, stirred 5 hours, suction filtration washs with the 1000ml purified water; 40 ℃ of vacuum of gained solid are smoked, and are product (+)-two { (3R, 5S; 6E)-and 7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxyl-6-heptenoic acid } calcium salt, yield 80%.Optical purity >=99.7%.
Embodiment 2
In 1000 milliliters of four-hole bottles, add 600 milliliters of THFs, 33g (0.0638mol) (3R; 5S)-and dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxyl-3, the 5-O isopropylidene-6-heptenoic acid tert-butyl ester (I); 50 ℃, the sulfuric acid 100ml of adding 1mol/L reacted 1 hour; (3R, 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(the E)-heptenoic acid tert-butyl ester (II) tetrahydrofuran solution.
In the tetrahydrofuran solution of above-mentioned (II), add 1mol/L sodium hydroxide solution 85ml, stirred 2 minutes, and then add 1mol/L sodium hydroxide solution 64ml, reacted 2 hours.55 ℃ of reclaim under reduced pressure when remaining about 100-200ml, stop to reclaim; Benefit adds water to 250 milliliters, and each is with 300 milliliters of MTBE extracted twice, the water layer acid adjustment to pH be about 5; Extract with the 300m MTBE; 50ml purifying washing, (3R, 5S)-the methyl tertbutyl ethereal solution of dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid (III).
In the methyl tertbutyl ethereal solution of above-mentioned (III), add 38g (0.314mol) ɑ-phenylethylamine; Stir suction filtration after 10 minutes, smoke, get (3R; 5S)-and dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid amine salt (IV), front three steps total recovery is 68%.
In the 1000ml four-hole boiling flask, and adding 13 grams (3R, 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid amine salt (IV), add the 217ml purified water again.25 ℃, the sodium hydroxide solution 27ml of dropping 1mol/L in system, stirring reaction 2 hours drips the 215ml aqueous solution that contains 1.6g calcium chloride in above-mentioned solution; After dropwising, stirred 5 hours, suction filtration washs with the 1000ml purified water; 40 ℃ of vacuum of gained solid are smoked, and are product (+)-two { (3R, 5S; 6E)-and 7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxyl-6-heptenoic acid } calcium salt, yield 82%.Optical purity >=99.6%.
Embodiment 3
In 1000 milliliters of four-hole bottles, add 600 milliliters of ethanol, 33g (0.0638mol) (3R; 5S)-and dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxyl-3, the 5-O isopropylidene-6-heptenoic acid tert-butyl ester (I); 25 ℃, the hydrochloric acid 85ml of adding 1mol/L reacted 1 hour; (3R, 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(the E)-heptenoic acid tert-butyl ester (II) ethanolic soln.
In the ethanolic soln of above-mentioned (II), add 1mol/L sodium hydroxide solution 85ml, stirred 2 minutes, and then add 1mol/L sodium hydroxide solution 64ml, reacted 2 hours.55 ℃ of reclaim under reduced pressure when remaining about 100-200ml, stop to reclaim; Benefit adds water to 250 milliliters, and each is with 300 milliliters of extracted in toluene twice, the water layer acid adjustment to pH be 2-3; Use the 300ml dichloromethane extraction; 50ml purifying washing, (3R, 5S)-dichloromethane solution of dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid (III).
In the dichloromethane solution of above-mentioned (III), add 16g (0.132mol) ɑ-phenylethylamine; Stir suction filtration after 10 minutes, smoke, get (3R; 5S)-and dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid amine salt (IV), front three steps total recovery is 62%.
In the 1000ml four-hole boiling flask, and adding 13 grams (3R, 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid amine salt (IV), add 217ml ethanol again.45 ℃, the sodium hydroxide solution 27ml of dropping 1mol/L in system, stirring reaction 2 hours drips the 215ml aqueous solution that contains 1.6g calcium chloride in above-mentioned solution; After dropwising, stirred 5 hours, suction filtration washs with the 1000ml purified water; 40 ℃ of vacuum of gained solid are smoked, and are product (+)-two { (3R, 5S; 6E)-and 7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxyl-6-heptenoic acid } calcium salt, yield 81%.Optical purity >=99.5%.
Embodiment 4
In 1000 milliliters of four-hole bottles, add 600 ml methanol, 33g (0.0638mol) (3R; 5S)-and dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxyl-3, the 5-O isopropylidene-6-heptenoic acid tert-butyl ester (I); 25 ℃, the hydrochloric acid 85ml of adding 1mol/L reacted 1 hour; (3R, 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(the E)-heptenoic acid tert-butyl ester (II) methanol solution.
In the methanol solution of above-mentioned (II), add 1mol/L sodium hydroxide solution 85ml, stirred 2 minutes, and then add 1mol/L sodium hydroxide solution 64ml, reacted 2 hours.55 ℃ of reclaim under reduced pressure when remaining about 100-200ml, stop to reclaim; Benefit adds water to 250 milliliters, and each is with 300 milliliters of MTBE extracted twice, the water layer acid adjustment to pH be 6-7; Use the 300ml dichloromethane extraction; 50ml purifying washing, (3R, 5S)-dichloromethane solution of dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid (III).
In the dichloromethane solution of above-mentioned (III), add 30g (0.248mol) ɑ-phenylethylamine; Stir suction filtration after 10 minutes, smoke, get (3R; 5S)-and dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid amine salt (IV), front three steps total recovery is 70%.
In the 1000ml four-hole boiling flask, and adding 13 grams (3R, 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid amine salt (IV), add the 217ml purified water again.25 ℃, the sodium hydroxide solution 27ml of dropping 1mol/L in system, stirring reaction 2 hours drips the 215ml aqueous solution that contains 1.6g calcium chloride in above-mentioned solution; After dropwising, stirred 5 hours, suction filtration washs with the 1000ml purified water; 40 ℃ of vacuum of gained solid are smoked, and are product (+)-two { (3R, 5S; 6E)-and 7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxyl-6-heptenoic acid } calcium salt, yield 83%.Optical purity >=99.7%.
It should be noted that above what enumerate only is several specific embodiments of the present invention.Obviously, the invention is not restricted to above embodiment, many distortion can also be arranged.All distortion that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention all should be thought protection scope of the present invention.
Claims (10)
1. the preparation method of a high optical purity pitavastatin calcium; It is characterized in that: with (3R, 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxyl-3; 5-O isopropylidene-6-heptenoic acid tert-butyl ester (I) is a starting raw material, comprises the steps:
A: starting raw material (I) is in solvent, and acid exists, deprotection generation under the certain temperature (3R, 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid tert-butyl ester (II), reaction formula:
B: (3R; 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(the E)-heptenoic acid tert-butyl ester (II) alkaline hydrolysis generation (3R; 5S)-and dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid (III), use the SX impurity elimination then, regulate pH; Use the SX impurity elimination again, reaction formula:
C: (3R; 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid (III) in; Add excessive D-(+) benzyl methylamine; Generate (3R, 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid amine salt (IV), reaction formula:
D: (3R, 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid amine salt (IV) is in solvent, and at a certain temperature, adding alkali, calcium chloride make high optical purity pitavastatin calcium (V), reaction formula:
。
2. the preparation method of a kind of high optical purity pitavastatin calcium as claimed in claim 1 is characterized in that: the acid in the described A step is a kind of in hydrochloric acid, sulfuric acid, phosphoric acid, tosic acid, the acetate.
3. the preparation method of a kind of high optical purity pitavastatin calcium as claimed in claim 1, it is characterized in that: solvent is C1-C4 alcohols, ethers or ketone in the described A step; Described C1-C4 alcohols is methyl alcohol, ethanol or Virahol; Ethers is a THF; Ketone is an acetone, is preferably methyl alcohol, THF.
4. the preparation method of a kind of high optical purity pitavastatin calcium as claimed in claim 1, it is characterized in that: temperature of reaction is 5～50 ℃ in the described A step, preferred 20-25 ℃.
5. the preparation method of a kind of high optical purity pitavastatin calcium as claimed in claim 1 is characterized in that: after described A step reaction finishes, without aftertreatment, directly in reaction, carry out the alkaline hydrolysis of B step.
6. the preparation method of a kind of high optical purity pitavastatin calcium as claimed in claim 1, it is characterized in that: solvent is aromatic hydrocarbons, halogenated alkane or ethers in the described B step; Described aromatic hydrocarbons is toluene, YLENE, and described halogenated alkane is chloroform, methylene dichloride, and described ethers is ether, sherwood oil, MTBE, preferred methylene dichloride, MTBE.
7. the preparation method of a kind of high optical purity pitavastatin calcium as claimed in claim 1, it is characterized in that: the said pH of described B step is 2～7, preferred 4～5.
8. the preparation method of a kind of high optical purity pitavastatin calcium as claimed in claim 1; It is characterized in that: the amount that described C step adds ɑ-phenylethylamine is and raw material (3R; 5S)-dihydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3; 5-dihydroxyl-3, the 2-5 molar equivalent of 5-O isopropylidene-6-heptenoic acid tert-butyl ester, preferred 3 molar equivalents.
9. the preparation method of a kind of high optical purity pitavastatin calcium as claimed in claim 1, it is characterized in that: the described solvent of described D step is the protic polar solvent, chooses methyl alcohol, ethanol or water, preferably water.
10. the preparation method of a kind of high optical purity pitavastatin calcium as claimed in claim 1, it is characterized in that: described D step reaction temperature is 5～45 ℃, preferred 20～25 ℃.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102898367A (en) * | 2012-11-15 | 2013-01-30 | 江苏阿尔法药业有限公司 | Preparation method of pitavastatin calcium crude drug midbody |
| CN108383780A (en) * | 2018-01-06 | 2018-08-10 | 湖北荆江源制药股份有限公司 | A kind of Pitavastatin（Ⅲ）Process for purification |
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| CN102898367A (en) * | 2012-11-15 | 2013-01-30 | 江苏阿尔法药业有限公司 | Preparation method of pitavastatin calcium crude drug midbody |
| CN108383780A (en) * | 2018-01-06 | 2018-08-10 | 湖北荆江源制药股份有限公司 | A kind of Pitavastatin（Ⅲ）Process for purification |
| CN108383780B (en) * | 2018-01-06 | 2023-01-31 | 湖北荆江源制药股份有限公司 | Refining method of pitavastatin (III) |
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Application publication date: 20120502 |