CN101591301B - Preparation method of 3, 5-dihydroxy heptyl-6-gadoleic acid derivative - Google Patents
Preparation method of 3, 5-dihydroxy heptyl-6-gadoleic acid derivative Download PDFInfo
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Abstract
The invention improves a preparation method of 3, 5-dihydroxy heptyl-6-gadoleic acid derivative. Asymmetric reduction is performed on intermediate 3-hydroxy-5-oxo-6-heptenoic acid ester derivative, alkali hydrolysis is performed on the obtained 3, 5-dihydroxy heptyl-6-heptenoic acid ester derivative crude product which is treated by alkali hydrolysis to obtain 3, 5-dihydroxy heptyl-6-gadoleic acid sodium salt derivative which is extracted and purified to obtain 3, 5-dihydroxy heptyl-6-gadoleic acid sodium salt derivative solution, then 3, 5-dihydroxy heptyl-6-gadoleic acid sodium salt derivative is converted into 3, 5-dihydroxy heptyl-6-gadoleic acid derivative, and 3, 5-dihydroxy heptyl-6-gadoleic acid sodium salt derivative is again converted into 3, 5-dihydroxy heptyl-6-gadoleic acid ester derivative with high yield, and purification methods such as recrystallization are performed to obtain purified 3, 5-dihydroxy heptyl-6-gadoleic acid ester derivative. The purified 3, 5-dihydroxy heptyl-6-gadoleic acid ester derivative is then hydrolyzed into 3, 5-dihydroxy heptyl-6-gadoleic acid sodium salt derivative which is finally converted into 3, 5-dihydroxy heptyl-6-gadoleic acid calcium salt derivative. 3, 5-dihydroxy heptyl-6-gadoleic acid derivative with high quality is obtained.
Description
Technical field
The present invention relates to the preparation method of rosuvastain calcium.The present invention is based on the synthetic method that EP0521471 provides, improvement by asymmetric reduction, synthesized the Rosuvastatin ester, ester hydrolysis prepares the Rosuvastatin free acid, obtain the Rosuvastatin sodium salt solution through purification, then sodium salt is converted into Rosuvastatin acid, with the Rosuvastatin acid of preliminary purification once more high yield conversion be the Rosuvastatin ester, obtain pure Rosuvastatin ester by means of purification such as recrystallizations.Pure Rosuvastatin ester is hydrolyzed into the Rosuvastatin sodium salt again, is converted into the Rosuvastatin calcium salt at last.The preparation method of rosuvastain calcium provided by the invention, productive rate height not only, cost is low, the quality height, and got rid of difficult extensive operations of making such as needing column chromatography in the technology, make operational path can really adapt to suitability for industrialized production based on EP0521471.
Background technology
His spit of fland (statins) is the most effective medicine that is available for lowering low-density lipoprotein (LDL) granule density in patient's blood flow of suffering from cardiovascular disorder danger at present.Therefore, his spit of fland is used to treat hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.High-level LDL in the blood flow is relevant with the formation of the coronary artery pathological changes of block blood flow, and blood examination is broken and promotes blood examination to form.Goodman and Gilman, The Pharmacological Basis of Therapeutics, the 879th page (1996 the 9th edition).
Statins suppresses the biosynthesizing of cholesterol in the human body by competitive inhibition 3-hydroxy-3-methyl-glutaryl coenzyme A (" HMG-CoA ") reductase enzyme.HMG-CoA reductase enzyme catalysis HMG is converted into mevalonic acid class material, and it is the rate-limiting step in the cholesterol biosynthesizing.The formation of cholesterol reduces and has caused the increase of ldl receptor number and the corresponding attenuating of the concentration of LDL particle in blood flow.The attenuating of the LDL level in the blood flow has reduced the danger of coronary artery disease.J.A.M.A.1984，251，351-74。
Present obtainable Statins comprises lovastatin, Simvastatin, Pravastatin, fluvastatin, Cerivastatin and atorvastatin.Lovastatin (being disclosed in patent US4231938) and Simvastatin (being disclosed in patent US4444784) are with the lactone form administration.After absorption, lactonic ring is opened by chemistry and enzymically hydrolyse in liver, has produced activity hydroxy acid.Pravastatin (being disclosed among the patent US4346227) is with the sodium-salt form administration.Fluvastatin (being disclosed among the patent US4739073) and Cerivastatin (being disclosed among patent US5006530 and the US5177080) are also with the sodium-salt form administration, be complete synthetic compound, structurally part is different from this class fungi derivative that contains the hexahydro naphthalene ring.
" super he spit of fland " Rosuvastatin that atorvastatin and two kinds are new and pitavastatin are with the calcium salt forms administration.Rosuvastain calcium (E)-7-[4-(4-fluorophenyl)-6-sec.-propyl]-2-[methyl (methylsulfonyl) amino] pyrimidine-5-base (3R, 5S)-3,5-dihydroxy heptan-6-olefin(e) acid calcium salt is the HMG-CoA reductase inhibitor, develop by Shionogi, be used for oral administration hyperlipidaemia (Ann Rep once a day, Shionogi, 1996; Direct communications, Shionogi, on February 8th, 1999 and on February 25th, 2000).Rosuvastain calcium is so-called super his spit of fland, compares with first-generation medicine, and it can more effectively reduce LDL-cholesterol and triglyceride level.Rosuvastain calcium has following chemical formula:
Rosuvastatin is commercially available with the title of CRESTOR, is used for the treatment of for example people of Mammals.According to the manufacturers of CRESTOR, it with every day about 5mg to the per daily dose administration of about 40mg.The patient of lowering or having the myopathy predisposing factor for the less demanding LDL-C of needs, recommend 5mg dosage, and for common patient, recommend 10mg dosage, for having significant hypercholesterolemia and demanding lipid target (＞l90mg/dL) patient, recommend 20mg dosage, and, recommend 40mg dosage for than the responseless patient of low dosage.
Synthesizing of rosuvastain calcium at first by SHIONOGI﹠amp; CO (JP) is disclosed in European patent EP 0521471 (priority date: on July 1st, 1991).Technical process of the present invention is as follows:
This patent disclosure and claimed Rosuvastatin, its calcium salt (2: 1) and its lactone form.The method of EP0521471 patent by allow 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methyl sulphonyl amino)-5-pyrimidine formaldehyde (pyrimidinecarbardehyde) with (3R)-3-(t-butyldimethylsilyloxy base)-5-oxo-positive phosphorus of 6-triphenyl pitch basic methyl caproate in the second eyeball under refluxing reaction prepare Rosuvastatin.Silylation is used the hydrogen fluoride cracking then, subsequently with the NaBH4 reduction, obtains the methyl esters of Rosuvastatin.This ester then in ethanol at the room temperature sodium hydroxide hydrolysis, remove ethanol subsequently, add ether, obtain the sodium salt of Rosuvastatin.Sodium salt is converted into calcium salt with multistep method then.Sodium salt is soluble in water, remain under the nitrogen atmosphere.Then calcium chloride is joined in the solution, cause rosuvastain calcium (2: 1) precipitation.
The Shionogi laboratory is published in Bioorganic﹠amp; Medicinal Chemistry, Vol.5, NO.2, pp 437-444,1997 have reported the synthetic method of rosuvastain calcium equally, the document is consistent with the method for patent EP0521471 synthesizing rosuvastatin spit of fland calcium.
ASTRAZENECA UK LTD (GB) patent WO0042024 (right of priority order: on January 9th, 1999) reported the crystal formation rosuvastain calcium.
ASTRAZENECA UK LTD (GB), SHIONOGI﹠amp; The patent WO0049014 of CO co-applications such as (JP) (priority date: on February 17th, 1999) set forth the synthetic of rosuvastain calcium equally.Its synthetic route is as follows:
This patent route synthetic method and compound patent exist than big difference; this route has adopted the 2-[(4R that contains two chiral centres; 6S)-6-formyl radical-2; 2-dimethyl-1; 3-dioxane-4-yl] tert.-butyl acetate is as side chain; with main chain phosphorus ylide reagent phenylbenzene [[4-(4-fluorophenyl)-6-sec.-propyl-2-[methyl (methylsulfonyl) amino] pyrimidine]-5-yl] methyl] phosphorus oxide generation Wittig condensation; sour water is freed the acetonylidene protection then; the alkaline hydrolysis saponification is converted into calcium salt with sodium salt at last.
Lonza AG has applied for that (priority date: on March 10th, 1999), described the intermediates preparation of synthesizing rosuvastatin spit of fland calcium, this intermediate can be used for the synthetic route that WO0049014 provides to the EP1035127 patent.
ASTRAZENECA AB (SE) patent WO0154668 and WO0154669 (priority date: on January 26th, 2000) report Rosuvastatin calcium compositions.This pharmaceutical composition contains Rosuvastatin or its salt and multivalence three subphosphates.(priority date: on February 15th, 2000) reported the Rosuvastatin crystal salt, these crystal salt can be used for the purifying rosuvastain calcium to the WO0160804 of ASTRAZENECA AB (SE) application.ASTRAZENECA AB (SE) patent WO0241895 (priority date: on November 22nd, 2000) disclose treatment heterozygous familial hyperlipidemia.
CLS LABORATORIES; on April 9th, 2002) INC. applied for WO03087112 (priority date: reported the improvement of phosphorus ylide reagent; by biological enzyme pentanedioic acid diester is glutaric acid monoester; change into the tert-butyl ester of protected silane then, obtain and the different phosphorus ylide reagent of EP0521471 ester group.This patent subsequent reactions and EP0521471 basically identical.
RANBAXY LAB LTD (IN) application WO03097614 (priority date: on May 21st, 2002) described main chain aldehyde and described main chain aldehyde N-[4-(4-fluorophenyl)-5-carboxaldehyde radicals-6-(1-methylethyl)-2-pyrimidyl]-synthesis technique of N-methyl-amsacrine improves the synthetic method of finished product and EP0521471 basically identical.
ASTRAZENECA UK LTD (GB) patent WO2004014872 (priority date: on August 13rd, 2002) described rosuvastain calcium salify process modification, improved the processing condition generation and exceed filter solid.
ASTRAZENECA UK LTD (GB) patent WO2004108691 (priority date: on June 5th, 2003) described rosuvastain calcium salify process modification.This improves mainly the preparation method of the rosuvastain calcium of describing based on patent WO0049014.
CIBA SPECIALTY CHEMICALS HOLDING INC. patent WO2004/103977 (priority date: on May 21st, 2003) described the improvement of rosuvastain calcium pyrimidine heterocyclic intermediate synthetic method.
The patent WO2005023778 of TEVA PHARMA (IL) application (priority date: on August 28th, 2003) reported that the industrially scalable preparation is substantially free of the method for the rosuvastain calcium of impurity, the preparation method of Rosuvastatin ester, the method of the patent EP0521471 description of still using, and how to prepare not report of high purity Rosuvastatin ester.
ASTRAZENECA UK LTD (GB) WO2005042522 (priority date: on October 24th, 2003) described the synthetic method based on WO0049014, fractional crystallization intermediate preparation Rosuvastatin.
(priority date: on June 29th, 2005) report is that intermediate synthesizing rosuvastatin spit of fland calcium etc. is improved one's methods with the Rosuvastain statin lactone to ZENTIVA A S (CZ) patent WO2005068435 (priority date: on 01 16th, 2004) WO2007/000121.
CIBA SPECIALTY CHEMICALS HOLDING INC. patent WO2006079611 (priority date: on January 31st, 2005) reported other crystal formations (crystal form B, C) of rosuvastain calcium.
(priority date: on February 22nd, 2005) synthesis technique of having reported rosuvastain calcium improves Teva pharmaceutical industries Ltd.WO2006091771.This patent route and patent EP0521471 basically identical, the main difference part is the side chain ester group is replaced with the tert-butyl ester by methyl esters, and according to this patented method, it is still very difficult to make the high purity Rosuvastatin.
The patent CN1872841 of Xinyi pharmaceutical factory application (priority date: on June 1st, 2005) described the recrystallization method of compound (5), compound (5) carries out recrystallization with toluene ether mixed solvent and obtains purity and reach and intermediate more than 98%, but the Rosuvastatin methyl esters still needs column chromatography purification, and purity is still very low, diastereomer content is 0.5%, other impurity summations 1%.
On June 24th, 2005) LEK PHARMACEUTICALS D D (SI) patent WO2006136408 (priority date: described the method that the Rosuvastatin ester prepares rosuvastain calcium and other salt.
Teva pharmaceutical industries Ltd. patent WO2007022488 (priority date: on August 16th, 2005) reported rosuvastain calcium crystallization of intermediate and preparation method thereof.
Along with the clinical trial lipid-lowering effect of rosuvastain calcium is reported significantly, and on February 19th, 2003 first in Canada listing, the research of rosuvastain calcium is subjected to extensive concern, the report of other operational paths and process modification is seen patent: CN1687087, CN1733737, CN1733774, CN1763015, CN1807418, CN1958593, LV13268, US20040176401, US20040259946, US20050153407, US20050154213, US20058222415, US20060040898, US20070123550, US20070037979, WO03064382, WO03097614, WO2004011420, WO2004052867, WO2004113314, WO2005092867, WO2006067456, WO2006100689, WO2006106526, WO2006126035, WO2007007119, WO2007017117.
Though patent EP0521471 discloses the synthetic method of rosuvastain calcium, the applicant synthesizes according to this patented method, and the purity of the rosuvastain calcium that obtains is low, and total recovery is low, the cost height.The present invention is the improvement of patent EP0521471 rosuvastain calcium synthesis technique, and EP0521471 introduces as reference.Rosuvastain calcium can be used for treating hypercholesterolemia, hyperproteinemia and arteriosclerosis.The present invention relates to the crystallization of intermediate that is used for this chemical synthesis process equally.
Summary of the invention
Based on the Rosuvastatin synthetic route of the report of patent EP0521471 the earliest, and related art, be difficult to obtain highly purified rosuvastain calcium, be difficult to realize the large-scale industrialization manufacturing.
The easypro fluvastatin methyl ester of EP0521471 patent China and Sweden is undertaken still being described as syrup behind the purifying by column chromatography, and prior art Rosuvastatin methyl esters all is described as syrup, is difficult to recrystallization purifying, and purity generally is lower than 97%, and diastereomer is greater than 0.5%.In ethanol, be hydrolyzed into sodium salt in the patent, obtain crystallinity sodium salt crystal formation powder with the ether making beating then.Concentrated sodium salt obtains the thickness soup compound, adds diethyl ether to pull an oar into pressed powder and can realize in the laboratory, but the unusual difficulty of amplifieroperation, and refining effect is undesirable, can not remove diastereomer by this operation.With the directly synthetic calcium salt of sodium salt, calcium salt is difficult to carry out purifying by means such as recrystallizations in the patent.Directly the Rosuvastatin methyl esters for preparing with the EP0521471 patent is used for synthesizing rosuvastatin spit of fland calcium, and the content of the diastereomer in the product is generally about 0.8%, also has a plurality of greater than 0.1% unknown impuritie.Be prepared rosuvastain calcium according to this patent, be difficult to obtain the high purity rosuvastain calcium, be difficult to extensive manufacturing.
The applicant is based on patent EP0521471, by further investigation, the synthetic method of having invented an improved rosuvastain calcium.It is characterized in that having optimized the borine asymmetric reduction, obtained the Rosuvastatin ester crude product of low diastereomer content, Rosuvastatin ester crude product is by after being hydrolyzed into water-soluble sodium salt, with solvent extraction remove can not be water-soluble impurity after, high again yield changes into the higher ester of purity, obtain pure Rosuvastatin ester by recrystallization means purifying then, be converted into rosuvastain calcium at last with high yield.
The present invention efficiently solves Control of Impurities and the extensive manufacturing issue based on patent EP0521471 route rosuvastain calcium, has solved by this route to be difficult to prepare the bulk drug problem that meets ICH guide specification of quality.The reprocessing technique of defective Rosuvastatin ester, acid, lactone, salt is provided simultaneously.
The invention solves how to prepare high purity rosuvastain calcium problem, especially preparation contains the rosuvastain calcium problem of low diastereomer purity.
Particularly, the scope that contains of the present invention comprises following claim:
1, the method for the molecule shown in a kind of preparation formula (1), it comprises:
A) the negative son of the hydrogen under the complexing of dialkyl group methoxyl group boron of the molecule shown in the formula (2) shifts asymmetric reduction production (3).
R wherein
1Be 1-10 carbon alkyl, benzyl etc.
R wherein
2Be the C2-8 alkyl: ethyl, propyl group, butyl, isobutyl-, 1,2-dimethyl propyl, cyclohexyl etc.
B) formula (3) alkaline hydrolysis production (4).
C) formula (4) acidifying obtains formula (5).
D) formula (5) alkaline condition down and halohydrocarbons reaction carry out esterification and obtain formula (6).
R wherein
3Position 1-10 carbon alkyl, benzyl, X are halogen Cl, Br, I, TsO, leaving groups such as TfO.
E) hydrolysis of formula (6) sodium hydroxide alkalescence obtains formula (4) once more.
F) formula (4) adds calcium acetate and is converted into formula (1).
2, in claim 1 step a), adopt hydride transfer reduction under the complexing of alkyl methoxyl group boron, alkyl methoxyl group boron is selected from diethyl methoxyl group boron, dipropyl methoxyl group boron, dibutyl methoxyl group boron, diisobutyl methoxyl group boron, two (1, the 2-dimethyl propyl) methoxyl group boron, dicyclohexyl methoxyl group boron etc.
3, in claim 1 step a), after reduction reaction finishes, drip Glacial acetic acid and destroy reductive agent, underpressure distillation solvent then, but directly apply mechanically behind the gained mixed solvent resize ratio.
4, in claim 1 step b), solvent is selected from tetrahydrofuran (THF), alcohols, acetonitrile etc.Consumption 1.05eq～the 2.0eq of alkali sodium hydroxide, temperature of reaction-10～80 ℃.The optimum solvent should be selected acetonitrile for use, and sodium hydroxide concentration is preferably 1.1eq, and temperature should be at 20 ℃-40 ℃.
5, in claim 1 step b), remove impurity, The suitable solvent such as ethyl acetate, ether etc. with non-water mutual solvents extraction.
6, in claim 1 step c), solvent is selected from ester class, ethers, halohydrocarbon, preferred ether.
7, in claim 1 step c), add solid weak base, carbonate.
8, claim 1 step d), haloalkane are 1-8 carbon alkyl, benzyl.
9, according to claim 8, preferred bromo iso-pentane.
10, claim 1 step d), alkali is selected from carbonate, hydrosulfate, hydrophosphate, dihydrogen phosphate, organic amine.
11, according to claim 10, preferred salt of wormwood.
12, claim 1 step d), solvent are selected from ketone, non-proton senior property solvent DMF, DMSO, HMPA etc.
13, according to claim 12, preferred acetone.
14, claim 1 step d) adds phase-transfer catalyst in the reaction system, quaternary ammonium salt, crown ether, polyoxyethylene glycol etc.
15, according to claim 14, preferred Tetrabutyl amonium bromide.
16, claim 1 step d), range of reaction temperature-40～80 ℃
17, according to claim 16,20 ℃ of preferable reaction temperature.
18, claim 1 step d), Rosuvastatin ester recrystallisation solvent is selected from multiple solvents such as ethers, ester class, alcohols, and the mixed solvent of these solvents and alkane or water composition.
19, according to claim 18, the preferred solvent ether.
20, claim 1 step g), solvent is selected from tetrahydrofuran (THF), alcohols, acetonitrile etc.Consumption 1.05eq～the 2.0eq of alkali sodium hydroxide, temperature of reaction-10～80 ℃.The optimum solvent should be selected acetonitrile for use, and sodium hydroxide concentration is preferably 1.1eq, and temperature should be at 20 ℃-40 ℃.
21, claim 1 step g) is removed impurity, The suitable solvent such as ethyl acetate, ether etc. with non-water mutual solvents extraction.
22, claim 1 step h), calcium acetate or U-Ramin MC consumption are 1.0eq～1.2eq.
23, according to claim 21, preferred calcium acetate consumption is 1.05eq.
24, claim 1 step h), water layer is through acidifying, and solvent extraction, sodium hydroxide salify are converted into calcium salt then, directly recycles fully.
25, the method for describing according to claim 8-24 is used to purify or reprocesses Rosuvastatin ester, acid, salt, lactone.
26, according to claim 1-25, the preparation rosuvastain calcium.
Below be to further describe to of the present invention:
The Rosuvastatin calcium salt is difficult to directly purify by the recrystallization means, particularly removes diastereomer and enantiomer and some other specific impurities.Prior art EP0521471 pulls an oar into crystal by Rosuvastatin sodium in ether, can remove some low polar impurities, but rosuvastain calcium isomer and other specific impurities are worked hardly.Rosuvastain calcium can crystallization in acetonitrile-water (WO0042024), but crystallization to purity improve help little.Prior art shows and tests and shows, can play purification (WO0160804) by Rosuvastatin ammonium salt or other salt, and is effective concerning most of impurity, but inoperative basically to photodegradation impurity and optical isomer.By being converted into Rosuvastain statin lactone (WO2005068435), make with extra care, can remove partial impurities, but still also not remarkable to isomer and some specific impurities effects.Therefore, in the synthesis technique based on the rosuvastain calcium of patent EP0521471, the purity of control Rosuvastatin ester is necessary, the especially control of diastereomer content.
According to patent EP0521471 and prior art; with (3R; 6E)-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-[methyl (methyl sulphonyl) amino]-the 5-pyrimidyl]-Rosuvastatin methyl esters that the reduction of 3-hydroxyl-5-oxo-6-heptenoic acid methyl esters obtains is an oily matter, is difficult to direct recrystallization.Even according to this patent Rosuvastatin methyl esters column chromatography purification, the quality of the rosuvastain calcium that obtains at last is not high yet, diastereomer content is generally greater than 0.5%, and other impurity sum totals are generally greater than 1.5%.Adopt sodium borohydride asymmetric reduction under the complexing of diethyl methoxyl group borine according to bibliographical information, though selectivity is very high, generally greater than 98: 2, but still be difficult to avoid reduction process can produce diastereomer, the content of general diastereomer is between 0.5-2.0%, obtain higher non-enantiomeric purity (de value), must carry out purifying through means such as recrystallizations.
The applicant finds that nearly all Rosuvastatin ester all can crystallization, but the character of these esters particularly exists than big difference the crystal property aspect.The wherein the most difficult crystallization of Rosuvastatin methyl esters, in general purity is lower than 80%, and it is impossible that crystallization almost becomes, purity is lower than 95%, crystallization is relatively slow, needs the adding crystal seed to induce or stirring for a long time, also can crystallizations in the solvent in many if purity is very high.Rosuvastatin ethyl ester, propyl ester, isopropyl ester, positive butyl ester, secondary butyl ester, isobutyl ester, the tert-butyl ester all have crystal property preferably.And the Rosuvastatin isopentyl ester has better crystal property, though purity low also easily in many in the solvent crystallization separate out.The applicant thinks that the quality Control that solves the Rosuvastatin ester can adopt different esters to be achieved.At side chain chiral raw material (R)-3-[[(1, the 1-dimethyl ethyl) dimethyl is silica-based] the oxygen base]-make change on 5-oxo-6-(triphenyl inferior phosphorus base)-capronate, adopt ethyl ester or other esters all to have certain technical difficulty, patent WO03087112 report side chain adopts the tert-butyl ester, and is still very difficult according to the preparation technology of this patent side chain.And it is more directly to carry out the transesterification reaction side reaction by the Rosuvastatin ester, does not have practical significance.The applicant discovers that Rosuvastatin acid can the high yield esterification, optimizes under the improved condition even can reach transformation efficiency about 99.0%, although such conversion has increased operation steps, does not therefore lose large-tonnage product.Therefore, the applicant improves the EP0521471 operational path: after the hydroxyketone asymmetric reduction is Rosuvastatin ester crude product, alkaline hydrolysis obtains the Rosuvastatin sodium salt, remove impurity through solvent extraction and obtain the Rosuvastatin sodium salt solution, then the sodium salt acidifying is converted into Rosuvastatin acid, Rosuvastatin acid is reacted once more high yield conversion with halohydrocarbon and other alkylating reagents under alkaline condition be the Rosuvastatin ester, obtains pure Rosuvastatin ester by means of purification such as recrystallizations.Pure Rosuvastatin ester is hydrolyzed into the Rosuvastatin sodium salt again, is converted into the Rosuvastatin calcium salt at last.Improved synthetic route is schematically as follows:
By such conversion, the result is the most of impurity that can remove in the very disadvantageous crude product Rosuvastatin of the crystallization ester, can be converted into crystallization to the ester of crystallization difficulty if necessary and be easy to ester.Diastereomer and other impurity all can be easy to remove by newly-generated ester being carried out the recrystallization operation.Obtain the preparation that the enough Rosuvastatin esters of purity are used for rosuvastain calcium.
Specifically:
With reference to EP0521471, adopt tetrahydrofuran (THF) and methyl alcohol to make solvent, under low temperature-78 ℃, add dialkyl group methoxyl group boron, then reductive agent such as sodium borohydride, the TP-13 reduction obtains the Rosuvastatin methyl esters, different borane reagents obtains different selectivity, generally comes water, and alkyl is big more, the space is crowded more, and selectivity is high more.Dialkyl group methoxyl group boron is selected from diethyl methoxyl group boron, dipropyl methoxyl group boron, dibutyl methoxyl group boron, diisobutyl methoxyl group boron, two (1, the 2-dimethyl propyl) methoxyl group boron, dicyclohexyl methoxyl group boron etc.Low temperature reaction necessity, reaction solvent are 2 with the ratio of tetrahydrofuran (THF) and methyl alcohol generally: 1-5: between 1, and preferred 3: 1-4: 1, quantity of solvent is greatly generally favourable, generally doubly measures at 10-80, and preferential 30-50 doubly measures.
Rosuvastatin ester alkaline hydrolysis solvent can be selected for use from tetrahydrofuran (THF), alcohols, acetonitrile etc., the consumption 1.05eq～2.0eq of alkali sodium hydroxide, temperature of reaction-10～80 ℃.The optimum solvent should be selected acetonitrile for use, and sodium hydroxide concentration is preferably 1.1eq, and temperature should be at 20 ℃-40 ℃.After reaction finishes, behind the adjusting pH, remove impurity, The suitable solvent such as ethyl acetate, ether etc. with non-water mutual solvents extraction.
Rosuvastatin acid is syrup, and poor stability, is converted into the Rosuvastain statin lactone easily.The Rosuvastatin sodium salt is converted into sour suitable condition, adds and the immiscible solvent of water in the aqueous solution, and The suitable solvent has ether/ethyl acetate etc.Add mineral acid or organic acid, make Rosuvastatin acid dissociate out, and continuous stirring and dissolving is in organic solvent.Suitable acid has hydrochloric acid/sulfuric acid, formic acid, Glacial acetic acid etc.PH is 1～6 in control, and optimum pH is 3～5.Leave standstill separatory, the water layer organic solvent extraction merges organic layer.The siccative drying.Add appropriate bases, alkali is selected from yellow soda ash, and weak base such as salt of wormwood can be controlled the speed that lactonizes.Controlled temperature is no more than 60 ℃, and temperature preferably is no more than 40 ℃, concentrating under reduced pressure.
Esterification is carried out in Rosuvastatin acid should not adopt acidic conditions.Under the acidic conditions, strong acid higher temperature conditions particularly, Rosuvastatin acid very easily is converted into lactone, and allylic (5-hydroxyl position) racemization also is very easy to take place.Rosuvastatin acid preparation Rosuvastatin ester should be selected alkalescence or neutral enzymatic synthesis condition for use, and under these conditions, the trend that lactonizes is still obvious, and the ester of generation still can be converted into lactone in the long-time higher temperature conditions of alkaline condition.For addressing these problems, the applicant has done to study in great detail, low impurity, and high yield has been synthesized the Rosuvastatin ester.High yield is important because Rosuvastatin acid manufacture height, if can reach 97～99% transformation efficiency, such conversion just is worth.The effective rate of utilization of Rosuvastatin is not because the operation of two steps obviously reduces, and ester is hydrolyzed into efficient 97%～99%, the two step total recoverys that can reach of Rosuvastatin of sodium salt greater than 94%.Rosuvastatin acid and alkylating reagent are in the alkaline condition esterification, and halogen atom is chlorine, bromine, iodine in the suitable haloalkane, preferably is bromine, iodine, and other suitable alkylating reagents are as alkyl p-toluenesulfonic esters, alkyl triflate etc.Suitable basic cpd can be a strong base-weak acid salt, as yellow soda ash, and sodium bicarbonate, salt of wormwood, saleratus etc., organic bases is as triethylamine etc.The suitable solvent can be selected from non-alcoholic solvents such as ketone, ester, DMF.Suitable proportioning halohydrocarbon 1.0eq～5.0eq, alkali 1.0eq～3.0eq.Suitable temperature of reaction is-40～80 ℃.When solid alkali in solvent during poor solubility, add phase-transfer catalyst and can promote the carrying out that react, phase-transfer catalyst can be selected quaternary ammonium salt, crown ether etc.Optimized conditions is halohydrocarbon 1.1eq～3.0eq, alkali 1.0eq～1.5eq.Suitable temperature of reaction is 0～40 ℃, and the phase-transfer catalyst consumption is 0.2eq～1.5eq.To preparing methyl esters with methyl iodide, top condition: methyl iodide 3.0eq, salt of wormwood 1.2eq, temperature of reaction is 20 ℃, phase-transfer catalyst Tetrabutyl amonium bromide 1.0eq.When employing bromo iso-pentane was prepared isopentyl ester, top condition was bromo iso-pentane 2.5eq, salt of wormwood 1.1eq, and temperature of reaction is 40 ℃, phase-transfer catalyst Tetrabutyl amonium bromide 0.5eq, and potassiumiodide 0.5eq.
The hydrolysis of Rosuvastatin ester prepares sodium salt, and The suitable solvent can be selected from tetrahydrofuran (THF), alcohols, acetonitrile etc.Alkali is selected sodium hydroxide for use, the consumption 1.05eq～2.0eq of sodium hydroxide, temperature of reaction-10～80 ℃.The optimum solvent should be selected acetonitrile for use, and sodium hydroxide concentration is preferably 1.1eq, and temperature should be at 20 ℃-40 ℃.After reaction finished, with mineral acid or organic acid for adjusting pH value, the pH value was controlled at 7-11, and the best is 9.Remove impurity, The suitable solvent such as ethyl acetate, ether etc. with non-water mutual solvents extraction.Concentrating under reduced pressure is removed the organic solvent in the residuary water, obtains pure sodium-salt aqueous solution.
The consumption of calcium acetate should be controlled at 1.05eq-1.3eq, and optimum is 1.1eq, and water layer can directly be used acidifying, and solubilizing agent extracts, and concentrates, and acid is converted into sodium-salt aqueous solution, prepares rosuvastain calcium once more.The quality product that water layer reclaims is suitable with the quality product of directly preparation.The pure Rosuvastatin ester that obtains almost can be realized quantitative utilization.
Prepare rosuvastain calcium by these technology and can obtain very big benefit.Adopt improved method that the specification of quality of intermediate is reduced significantly; intermediate (the 3R of front; 6E)-3-[[(1; the 1-dimethyl ethyl) dimethyl is silica-based] the oxygen base]-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-[methyl (methyl sulphonyl) amino]-the 5-pyrimidyl]-5-oxo-6-heptenoic acid esters; (3R; 6E)-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-[methyl (methyl sulphonyl) amino]-the 5-pyrimidyl]-3-hydroxyl-5-oxo-6-heptenoic acid esters can be without column chromatography and recrystallization purifying; purity is low also to be acceptable, and the Rosuvastatin ester crude product that obtains so also can be used for the preparation of Rosuvastatin finished product.Method based on the synthesizing rosuvastatin spit of fland calcium of patent EP0521471 possesses the broad operational condition, avoids exacting terms control, does not all use column chromatography in the whole production flow process.Technology is controlled easily, stable and reliable product quality, and cost can be accepted, and really can adapt to extensive manufacturing.By these technology, make synthetic route can prepare the high purity rosuvastain calcium based on patent EP0521471, typical purity can be synthesized the rosuvastain calcium (99.9%) that is substantially free of impurity greater than 99.5% by repeatedly exquisite.
These technology can be applied to: Rui Shu cuts down the preparation of spit of fland calcium and the reprocessing of defective rosuvastain calcium.When adopting other synthetic method synthetic Rosuvastatin ester purity not enough, when Rosuvastain statin lactone purity is not high, when the various salt non-conformity of qualities of synthetic Rosuvastatin close when requiring, adopt methods such as hydrolysis, be converted into Rosuvastatin acid, handle according to previously described method, obtain the higher product of quality.
Accompanying drawing 1 is: typical RSP HPLC related substance collection of illustrative plates
Accompanying drawing 2 is: typical RS HPLC related substance collection of illustrative plates
Embodiment
Embodiment:
1, reduction
In 500mL dry reaction bottle, add anhydrous THF 300mL and anhydrous methanol 85mL, add 6.3g TP-13,, be stirred to TP-13 and all dissolve with the nitrogen replacement reaction system.To-80～-85 ℃, drip 1M diethyl methoxyl group borine tetrahydrofuran solution 12.8mL with liquid nitrogen cooling, the control rate of addition is to keep temperature between-80～-85 ℃, and about 30min drips off.Holding temperature-80～-85 a ℃ continuation was stirred 55～60 minutes.Evenly add the 0.7g sodium borohydride then in batches, after adding in about 80～90 minutes, holding temperature-80～-85 ℃, this process approximately needs 5.5～6 hours, and reaction finishes.Be warming up to 20～30 ℃ in 2 hours, continue insulation reaction after 2～3 hours, behind the adding 1.2g Glacial acetic acid, 45～55 ℃ of following underpressure distillation are to remove methyl alcohol-tetrahydrofuran (THF) mixed organic solvents.Add 50mL dissolve with methanol oily matter, 45～55 ℃ of following underpressure distillation are to remove methyl alcohol.Add 50mL dissolve with methanol oily matter once more, 45～55 ℃ of following underpressure distillation obtain oily matter and residue in the still to remove methyl alcohol.
Add 50mL ethyl acetate and 50mL water then, stirred 10～15 minutes, leave standstill separatory, water layer stirred 10～15 minutes with ethyl acetate extraction (30mL * 2) at every turn, left standstill separatory, merge organic layer, with saturated sodium bicarbonate aqueous solution washing (40mL * 1), saturated sodium-chloride water solution washing (40mL * 2) was stirred 10～15 minutes at every turn successively, leave standstill separatory, water layer discarded, organic layer add the 2g anhydrous sodium sulphate and stirred 30 minutes, and suction filtration is removed anhydrous sodium sulphate.40～50 ℃ of following underpressure distillation of filtrate get 6.0g RSM oily matter to remove the ethyl acetate organic solvent.
2, hydrolysis
In the 500mL reaction flask, add the 150mL acetonitrile, add 18g RSM, after treating to dissolve fully, add the 40mL purified water, be heated to 35～40 ℃, begin to drip 1N sodium hydroxide solution 42mL, the control rate of addition is to keep temperature (whole dropping process approximately needs 10～15 minutes) between 35～40 ℃, continue reaction and approximately need 2～2.5 hours, reaction finishes, 40～50 ℃ of following underpressure distillation are to remove the acetonitrile organic solvent, add purified water 30mL then, open the chuck water coolant and fall content temperature to 25～30 ℃, with ether washing (50mL * 3), stirred 10～15 minutes at every turn, leave standstill separatory, collect water layer, add the 3g gac then, 35～40 ℃ of heating holding temperatures stirred 50～60 minutes, suction filtration, with 10mL purified water washing leaching cake, merging filtrate and washing lotion, be cooled to 15～20 ℃, add the 90mL ether, transfer pH between 4～5 with 0.5N hydrochloric acid, stirred 10～15 minutes, leave standstill separatory, water layer ether extraction (60mL * 2), the each stirring 10～15 minutes left standstill separatory, merges organic layer, with saturated nacl aqueous solution washing (60mL * 2), leave standstill separatory, water layer discarded adds the 6g anhydrous sodium sulphate and stirred 30～35 minutes in organic layer, suction filtration is removed anhydrous sodium sulphate, 20～30 ℃ of following underpressure distillation of filtrate add 50gDMF to remove the ether organic solvent, add salt of wormwood 2.5g, 20～30 ℃ of following underpressure distillation 1～2 hour to be removing ether, the about 69.6g of DMF solution of RSA.
3, esterification
Add DMF 200mL in the 500mL reaction flask, add the DMF solution 69.6g that contains 17.1g RSA and salt of wormwood 2.5g approximately, 26.8g bromo iso-pentane, Tetrabutyl amonium bromide, potassiumiodide is heated to 35～40 ℃, begins reaction, show raw material RSA content≤1% in the reaction solution until TLC, this process approximately needs 1.5～2.5 hours.In reaction solution, add 660mL water and 340mL ethyl acetate successively, stirred 10～15 minutes, leave standstill separatory, water layer ethyl acetate extraction (100mL * 2), the combined ethyl acetate organic layer is with saturated nacl aqueous solution washing (180mL * 3), the each stirring 10～15 minutes, leave standstill separatory, add the 9g anhydrous sodium sulphate and stirred 30～35 minutes in organic layer, suction filtration is removed anhydrous sodium sulphate.Filtrate is transferred to 500mL lass lining concentration kettle, opens vacuum, keep vacuum tightness-0.080～-0.085MPa, open the jacket steam heating temperature risen to 40～50 ℃ of following underpressure distillation to remove the organic solvent ethyl acetate.Residual feed liquid is evacuated in the 100mL glass-lined kettle, add 80mL isopropyl ether stirring and dissolving, liter content temperature to 68～75 ℃, in 2～3 hours, fall in the feed liquid temperature to 0～5 ℃, stop to stir, left standstill crystallization 8～12 hours, stirred then 50～60 minutes, suction filtration, vacuum-drying obtains 15.2g RSP crude product.
In the 100mL reaction flask, add 130mL ether and 1.6mL acetonitrile, drop into the RSP crude product of above-mentioned oven dry, the temperature rising reflux dissolving, stirred 30～35 minutes, normal pressure steams the mixed solvent of 25～29mL ether and acetonitrile, stop to stir, 2～3 hours internal cooling to 0～5 ℃, left standstill crystallization 8～12 hours.Suction filtration, filter cake obtain the wet product of RSP with 5mL ether washed twice at every turn.About 3～5 hours of 35～40 ℃ of following vacuum-drying obtains 12.5g RSP.
4, finished product preparation
In the 200mL reaction flask, add the 80mL acetonitrile, open and stir, add 12.5g RSP, be heated to 35～40 ℃, add the 25mL purified water, begin to drip 1N sodium hydroxide solution 25mL, the control rate of addition is to keep temperature (whole dropping process approximately needs 10～15 minutes) between 35～40 ℃, keep feed temperature and continue reaction for 35～40 ℃, this process approximately needs 2～2.5 hours, 35～40 ℃ of following underpressure distillation are to remove organic solvent acetonitrile, add purified water 25mL in the thing to residual heating up in a steamer then, the pH that regulates feed liquid with the about 3g of 0.5N glacial acetic acid solution is 9, open the chuck water coolant and fall content temperature to 25～30 ℃, water layer washs (30mL * 3) with ether, the each stirring 10～15 minutes, leave standstill separatory, water layer keep vacuum tightness-0.080～-0.085MPa, open the jacket steam heating temperature is risen to 30～40 ℃ of following underpressure distillation to remove residual ether, the water layer suction filtration is to becoming in the salt oven, with 20mL purified water washing reaction still and pipeline, merge washing lotion and filtrate and be cooled to 15～20 ℃, drip filtering 1N calcium acetate solution 13.5mL, the control rate of addition is to keep temperature (whole dropping process approximately needs 25～30 minutes) between 15～20 ℃, keep feed temperature then and stirred 2 hours for 15～20 ℃, suction filtration after suction filtration, solid are pulled an oar with 15-20 ℃ of purified water 40mL.Vacuum-drying gets RS 7.3g.Mother liquor merges to be handled by laxative remedy.
5, mother liquor reclaims
Mother liquor adds in the 1000mL reaction flask, adds the 200mL ether, and the pH that uses 0.5N hydrochloric acid adjusting water layer stirred 10～15 minutes between 3～4, left standstill separatory.Water layer washs (100mL * 2) with ether, the each stirring 10～15 minutes, leave standstill separatory, merge organic layer, with purified water washing (150mL * 2), the each stirring 10～15 minutes, leave standstill separatory, water layer discarded, organic layer adds the 4g anhydrous sodium sulphate and stirred 30 minutes, suction filtration is removed anhydrous sodium sulphate, and filtrate concentrates.35～40 ℃ are distilled down to remove the organic solvent ether, steam till about 250～300mL, add purified water 40mL in the thing to residual heating up in a steamer then, open chuck cooling and fall content temperature to 25～30 ℃, drip the about 7.5～9.2mL of sodium hydroxide solution of 1N, keep pH 10～11, stirred 50～60 minutes, the pH that regulates feed liquid with 0.5N glacial acetic acid solution 2g is 9, leaves standstill separatory.Water layer stirred 10～15 minutes with ether washing (10mL * 2) at every turn.Leave standstill separatory, 30～40 ℃ of following underpressure distillation of water layer are to remove residual ether, be cooled to 15～20 ℃, begin to drip the filtering 1N calcium acetate solution of filtering dropping 4～5mL, the control rate of addition keeps temperature (whole dropping process approximately needs 25～30 minutes) between 15～20 ℃, keep 15～20 ℃ of feed temperatures then and stir 2 little solids with the back suction filtrations of 15～20 ℃ of purified water 10mL making beating, obtain the wet product of finished product.Vacuum-drying 2.5g.
Claims (11)
1. the method for the molecule shown in the preparation formula (1), it comprises:
A) the negative son of the hydrogen under the complexing of dialkyl group methoxyl group boron of the molecule shown in the formula (2) shifts asymmetric reduction production (3):
R wherein
1Be 1-10 carbon alkyl or benzyl,
R wherein
2Be the C2-8 alkyl, described C2-8 alkyl is ethyl, propyl group, butyl, isobutyl-, 1,2-dimethyl propyl or cyclohexyl;
B) formula (3) alkaline hydrolysis production (4):
C) formula (4) acidifying obtains formula (5):
D) formula (5) under alkaline condition with R
3The X reaction is carried out esterification and is obtained formula (6):
R wherein
3Be 1-10 carbon alkyl or benzyl, X is a leaving group, and described leaving group is Cl, Br, I, TsO or TfO;
E) hydrolysis of formula (6) sodium hydroxide alkalescence obtains formula (4) once more:
F) formula (4) adds calcium acetate and is converted into formula (1):
2. the method for the molecule shown in a kind of preparation formula as claimed in claim 1 (1), wherein in the step a), adopt hydride transfer reduction under the complexing of alkyl methoxyl group boron, alkyl methoxyl group boron is selected from diethyl methoxyl group boron, dipropyl methoxyl group boron, dibutyl methoxyl group boron, diisobutyl methoxyl group boron, two (1, the 2-dimethyl propyl) methoxyl group boron, dicyclohexyl methoxyl group boron.
3. the method for the molecule shown in a kind of preparation formula as claimed in claim 1 (1) wherein in the step a), after reduction reaction finishes, drips Glacial acetic acid and destroys reductive agent, underpressure distillation solvent then, but directly apply mechanically behind the gained mixed solvent resize ratio.
4. the method for the molecule shown in a kind of preparation formula as claimed in claim 1 (1), wherein in the step b), solvent is tetrahydrofuran (THF), alcohols or acetonitrile, the consumption 1.05eq～2.0eq of alkali sodium hydroxide, temperature of reaction-10～80 ℃.
5. the method for the molecule shown in a kind of preparation formula as claimed in claim 4 (1), wherein in the step b), solvent is an acetonitrile, and the consumption of sodium hydroxide is preferably 1.1eq, and temperature is 20 ℃-40 ℃.
6. the method for the molecule shown in a kind of preparation formula as claimed in claim 1 (1) wherein in the step b), is removed impurity with non-water mutual solvents extraction, and described non-water mutual solvents is ethyl acetate and ether.
7. the method for the molecule shown in a kind of preparation formula as claimed in claim 1 (1), wherein in the step c), solvent is ester class, ethers or halohydrocarbon.
8. the method for the molecule shown in a kind of preparation formula as claimed in claim 1 (1), wherein in the step c), solvent is an ether.
9. the method for the molecule shown in a kind of preparation formula as claimed in claim 1 (1), step d) wherein, R
3Be 1-8 carbon alkyl or benzyl.
10. the method for the molecule shown in a kind of preparation formula as claimed in claim 1 (1), step d) wherein, R
3X is the bromo iso-pentane.
11. the method for the molecule shown in a kind of preparation formula as claimed in claim 1 (1), step d) wherein, alkali is carbonate, hydrophosphate, dihydrogen phosphate or organic amine.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101107091A CN101591301B (en) | 2008-05-27 | 2008-05-27 | Preparation method of 3, 5-dihydroxy heptyl-6-gadoleic acid derivative |
| CA2725052A CA2725052C (en) | 2008-05-27 | 2009-05-27 | Preparation method of rosuvastatin calcium and its intermediates |
| US12/994,520 US8653265B2 (en) | 2008-05-27 | 2009-05-27 | Preparation method of rosuvastatin calcium and its intermediates |
| EP09753494.5A EP2298745B1 (en) | 2008-05-27 | 2009-05-27 | Preparation method of rosuvastatin calcium and its intermediates |
| PCT/CN2009/072018 WO2009143776A1 (en) | 2008-05-27 | 2009-05-27 | Preparation method of rosuvastatin calcium and its intermediates |
| US13/785,960 US8765947B2 (en) | 2008-05-27 | 2013-03-05 | Preparation method of Rosuvastatin calcium and its intermediates |
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| CN2008101107091A CN101591301B (en) | 2008-05-27 | 2008-05-27 | Preparation method of 3, 5-dihydroxy heptyl-6-gadoleic acid derivative |
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| CN103709107B (en) * | 2012-09-29 | 2016-04-20 | 安徽省庆云医药化工有限公司 | New crystal of Rosuvastatin methyl esters and preparation method thereof |
| CN103044339A (en) * | 2012-10-15 | 2013-04-17 | 武汉市江润精细化工有限责任公司 | Preparation method of rosuvastatin calcium intermediate |
| CN104230817B (en) * | 2013-06-19 | 2016-09-14 | 南京欧信医药技术有限公司 | The preparation method of 3,5-dihydroxy heptyl-6-gadoleic acid derivatives |
| CN103936680B (en) * | 2014-04-18 | 2016-08-24 | 润泽制药(苏州)有限公司 | The preparation method of rosuvastain calcium known impurities |
| CN104030989A (en) * | 2014-05-16 | 2014-09-10 | 南通常佑药业科技有限公司 | Preparation method of rosuvastatin calcium |
| CN104529909B (en) * | 2014-12-26 | 2016-08-24 | 江西富祥药业股份有限公司 | A kind of method for crystallising of rosuvastain calcium intermediate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0521471A1 (en) * | 1991-07-01 | 1993-01-07 | Shionogi Seiyaku Kabushiki Kaisha | Pyrimidine derivatives as HMG-CoA reductase inhibitors |
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2008
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0521471A1 (en) * | 1991-07-01 | 1993-01-07 | Shionogi Seiyaku Kabushiki Kaisha | Pyrimidine derivatives as HMG-CoA reductase inhibitors |
Non-Patent Citations (1)
| Title |
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| EP 0521471 A1,全文. |
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