CN100506796C - Method for preparing high optical purity pitavastatin calcium raw material drug - Google Patents
Method for preparing high optical purity pitavastatin calcium raw material drug Download PDFInfo
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- CN100506796C CN100506796C CNB2005100266415A CN200510026641A CN100506796C CN 100506796 C CN100506796 C CN 100506796C CN B2005100266415 A CNB2005100266415 A CN B2005100266415A CN 200510026641 A CN200510026641 A CN 200510026641A CN 100506796 C CN100506796 C CN 100506796C
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Abstract
The invention relates the method of preparing the raw material of high optical purity pravastatin calcium. The method comprises the following steps: adding the 2- cyclopropyl-4-(4- fluorophenyl)-3-quinoline aldehyde II and (3R)-3- alkoxy silane-5- carbonyl-6- triphenyl phosphor heptene acid ester III in dissolvent, getting (E)-7- [2-2- cyclopropyl-4-(4- fluorophenyl)-3- chinoline]-5- carbonyl-(3R)-3- alkoxy silane-6- triphenyl phosphor heptene acid ester IV, removing the protection of IV, getting (E)-7- [2-2- cyclopropyl-4-(4- fluorophenyl)-3- chinoline]-5- carbonyl-(3R)- hydroxyl -6- triphenyl phosphor heptene acid ester V, deacidizing it in the mixture dissolvent of alcohol and ether with NaBH4 or KBH4 at -100-0Deg.C, getting (E)-7- [2-2- cyclopropyl-4-(4- fluorophenyl)-3- chinoline]-(3R, 5S)- dihydroxy -6- triphenyl phosphor heptene acid ester VI, hydrolyzing it with alkali, and getting pravastatin calcium. The material is used to prepare HMG-CoA reductase inhibiting agent.
Description
Technical field:
The present invention relates to a kind of preparation method of anticholesteremic agent, is the new preparation method of anticholesteremic agent (HMG-CoA reductase inhibitor) pitavastatin calcium raw material drug (I):
Technical background:
Pitavastatin Calcium (I), be that the spy opens flat 1-279866 communique, EP304063, disclosed in the United States Patent (USP) 5011930 as blood lipid-lowering medicine (HMG-CoA reductase inhibitor), Pitavastatin Calcium is that Japanese Nissan chemical industry Co., Ltd. develops, and by Nissan Chemical Ind Ltd, Kowa company Ltd and Sankyo Co., Ltd's co-applications, getting permission to go on the market in Japan in July, 2003 is used for the treatment of hypercholesterolemia, and commodity are by name
, the preparation specification is the thin membrane coated tablet of 1mg and 2mg.
Since first statins lovastatin listing in 1987,3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor has obtained clinical and immense success market.
A large amount of clinical trials and research show that the statins treatment has prevention and reduces the effect of primary and Secondary cases coronary heart disease risk and mortality ratio thereof, and coronary heart disease then is one of topmost cause of the death of world today's population.Analytical results to various a large amount of datas also discloses, and to reduce the amplitude of low density lipoprotein cholesterol (LDL-C) level relevant and be linear positive correlation with their in the above-mentioned effect of statins.Therefore, farthest reduce serum cholesterol level and will obtain bigger clinical benefit.But the part hyperlipidemia patient is accepted to still have significant proportion patient's lipid level can not reach controlled target after the existing statins treatment, and also objective requirement is clinical has lipopenicillinase and render a service stronger Statins new drug for this.
Pitavastatin Calcium is better than the statins that has gone on the market to the inhibition activity of HMG-CoA reductase enzyme, and its clinical effective dose 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 bad drug interaction is less.Pitavastatin Calcium will provide a kind of new selection for the clinical treatment of hyperlipidaemia, and development and production this product will have important social and economic implications.
Open flat 1-279866 communique the spy, EP304063, report is converted into α beta-unsaturated carboxylic acid ester with 2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline aldehyde in the United States Patent (USP) 5011930, and the rear oxidation that reduces becomes aldehyde, with the methyl aceto acetate condensation after obtain the Pitavastatin Calcium of raceme.The document of relevant this compound of preparation is as described below: Bio ﹠amp; Med Chem.2001,9, after raw material 2-amido-4 '-fluoro-benzophenone and the 3-cyclopropyl-3-oxygen-ethyl propionate cyclization, obtain 2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline aldehyde in the synthetic route (Scheme-1) of 2727-2743 report through DIBAL reduction and PCC oxidation.Side chain is synthetic to be that hydrolysis must prolong the aldehyde of carbochain through formyl radical and the condensation of ethoxy ethene, and obtains raceme after the methyl aceto acetate condensation.Obtain racemic end product through Stereoselective reduction.
In another synthetic route of document report, obtain 2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline aldehyde simultaneously with method.Side chain is synthetic to be through formyl radical and the condensation of cyanogen methyl acid phosphate diethyl ester, reduces to obtain prolonging the aldehyde of carbochain, and obtains raceme after the methyl aceto acetate condensation, obtains racemic end product through Stereoselective reduction.
Document Tetrahedron Letter.1993,34, the earlier synthetic side chain of the synthetic route of 8267-8270 report, the pairs of anion condensation of trimethyl silicon based propynal of raw material and methyl aceto acetate, reduce raceme.Method through splitting obtains optically pure side chain, encircles with mother to be connected again.Existence has four optical isomers from mesotomy, and it is big to split difficulty, the problem that yield is lower.
Document Bull.Chem.Soc.Jpn.1995,68, the middle side chain of the synthetic route (Scheme-4) of 2649-2656 report is synthetic to be to start to walk from raw material (R)-2-(the tertiary butyl dimethyl-silicon ethyl-acetylene) oxyethane that has a chiral carbon, with obtaining 3 (S)-hydroxyl-5-(tertiary butyl dimethyl is silica-based)-4-cyanoacetylene after the potassium cyanide open loop, again with the bromo-acetic acid tert-butyl condensation.Obtain optically pure side chain through chirality reductive method, encircle with mother again and be connected.Need to use highly toxic product potassium cyanide in the reactions steps; Side chain and female ligation agents useful for same relative complex of encircling.
Document Bull.Chem.Soc.Jpn.1995; 68 (1); in the synthetic route in 364-372 road (Scheme-5); the synthetic of side chain protected (S with TBS; S)-and the disodium salt condensation of tartrate diisopropyl ester and tert-butyl acetoacetate, obtained optically active intermediate through the methods of two step selective reductions.Have four optical isomers, the purifying difficulty is big, the problem that yield is lower.
Document Tetrahydron Asymemetry.1993,4, side chain synthetic is from having the chloromethyl propylene oxide starting of a chiral centre in the synthetic route (Scheme-6) of 201-204 report, encircles with mother and introduces another chiral centre again after being connected.Noble metal reagent is all used in the growth of carbochain and the introducing of chiral centre, for the control geometric configuration has also been introduced thiophenyl group on mother's ring.Exist reactions steps many, complex operation, the problem of reagent costliness.
Document Bull.Chem.Soc.Jpn.1995; 68 (1); the synthetic of side chain is raw material 4 (S) in the synthetic route of 350-363 report; 7; 7-trimethylammonium-3-is outer-and (1-naphthalene) dicyclo [2.2.1] heptane-2 is outer-and alcohol and methyl acetoacetate carry out the product that transesterify obtains and encircle the acyl group condensation that increases by two carbon with mother again, and reduction obtains two chiral centres to product through two steps.Exist the starting raw material to be difficult for preparation, the reduction of two steps produces four chiral isomers, is difficult for the problem of purifying.
The synthetic route of document JP 93310700 reports) in; the synthetic of side chain is with diethyl methoxyl group borine and sodium borohydride reduction 7-phenyl-3; 5-dioxy-6 (E)-heptenoic acid methyl esters; product and 2; the two hydroxyls of 2-Propanal dimethyl acetal reaction protection; decompose the form obtain aldehyde with ozone then, again with 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-ylmethyl p diethylaminobenzoic acid ester condensation after, deprotection obtains target product.Reaction scheme is simple and direct, but the two carbonyls of a step selective reduction obtain a pair of enantiomer, exist the separation and purification difficulty big, the problem that yield is lower.
Summary of the invention:
The objective of the invention is to be to provide a kind of method for preparing high optical purity pitavastatin calcium raw material drug (I).It is big to solve existing preparation pitavastatin calcium raw material drug separation and purification difficulty, the technical problem that yield is lower.
Technical scheme is: the first step reaction: 2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline aldehyde is a kind of compound of compound (II) and (3R)-3-alkyl siloxy-5-carbonyl-6-triphenyl phosphorus heptenoic acid esters (III) in solvent and in certain temperature range, reacts by Wittg to obtain (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline]-5-carbonyl-(3R)-3-alkyl siloxy-6-heptenoic acid alkyl ester is suc as formula (IV) described compound.
Reacting employed solvent is nitrile solvents such as acetonitrile, propionitrile, tetrahydrofuran (THF), dioxane, ether, propyl ether, isopropyl ether, methyl tertiary butyl ether ether solvent, esters solvent such as ethyl acetate, butylacetate, varsols such as benzene,toluene,xylene, normal hexane, hexanaphthene and sherwood oil.A kind of in preferred acetonitrile, propionitrile or the tetrahydrofuran (THF).
In this step reaction, the consumption of compound (III) is 0.5-5 a times of compound (II), and preferred 1.0-1.5 doubly.This temperature of reaction can be from 10～100 ℃, preferred 70～85 ℃.
The reaction of second step; Compound (IV) is sloughed protecting group with deprotection agent and is obtained (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline in ether or acetonitrile equal solvent]-the 5-carbonyl-(3R)-hydroxyl-6-heptenoic acid esters is compound (V).
Wherein deprotection agent is: hydrofluoric acid or tetrabutyl fluoride amine, preferred hydrofluoric acid.
Three-step reaction: compound (V) is used NaBH in specific solvent
4Or KBH
4And selective reduction under the effect of specific ligand, obtain highly purified (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline]-(3R, 5S)-dihydroxyl-6-heptenoic acid esters is compound (VI).
Wherein the specific solvent of indication is a kind of pure and mild a kind of ether compound according to the mixed solvent of 5% to 99% ratio.Used alcohol such as methyl alcohol, ethanol, propyl alcohol, and used ether compound includes but not limited to ether, tetrahydrofuran (THF), propyl ether, dioxane etc.
The part of this reaction indication is a Lewis acid, as ZnCl
2, ZnSO
4, Ti (OR)
4, or boron-containing compound, as BEt
3, BMe
3, BEt
2Ome, B (OMe)
3, B (OEt)
3Deng.Used reductive agent is NaBH
4Or KBH
4Or their mixture.
This reacts used temperature can be-100 ℃ to 0 ℃, preferred-80 ℃ to-50 ℃.
Four-step reaction: (VI) with basic hydrolysis and become calcium salt, just obtained the Pitavastatin Calcium (I) of high-optical-purity.
In the above-mentioned chemical structural formula that responds: R
1Alkyl or benzyl for C1～C8 include but not limited to methyl, ethyl, propyl group, butyl, the tertiary butyl, benzyl; R
2Be hydroxyl protecting group, include but not limited to trimethyl silicon based, tertiary butyl dimethyl is silica-based, tert-butyl diphenyl is silica-based, the sec.-propyl dimethyl is silica-based, triisopropylsilyl and methoxymethyl.
The invention has the beneficial effects as follows:, can under comparatively gentle reaction conditions, make the Pitavastatin Calcium of the high-optical-purity that conforms with medicinal requirements with lower cost by method of the present invention.And the method for bibliographical information mostly is the non-optical pure DL body of preparation.
Embodiment: enumerate embodiment so that the present invention is done detailed description, but the present invention is not limited to these embodiment.
Embodiment 1:
1:(E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline]-preparation of 5-carbonyl-(3R)-3-(tertiary butyl dimethyl Si base)-6-heptenoic acid methyl esters
Reaction formula:
Operation steps
27g Compound I I and 62.5g (1.25eq) phosphorus ylide 1 are dropped in the 1L single port reaction flask, add anhydrous acetonitrile 680ml and stir, be heated to 70～80 ℃ of reactions 24 hours, TLC monitoring primitive reaction is complete.Steaming desolventizes, and resistates is through the isolating soup compound 45.7g of post.Yield 90%.
[α]
D 25：-8.29(c，1.2；MeOH))
HNMR(CDCl
3)δ：0.00(s，3H)，0.05(s，3H)，0.8(s，9H)，1.10(q，2H)，1.40(s，2H)，2.30(m，1H)，2.46(m，2H)，2.69(m，2H)，4.57(p，1H)，3.66(s，3H)，6.3(d，1H)，7.63(d，1H)，7.1-8.0(8H)
MASS：(Base)548.7(M+1)
C
32H
38FNO
4Si：cal.547.7
2:(E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline]-preparation of 5-carbonyl-(3R)-hydroxyl-6-heptenoic acid methyl esters
Reaction formula:
Operation steps:
45g compound 2 is dropped into the 2L reaction flask, and adding anhydrous acetonitrile 750ml makes dissolving, hydrofluoric acid 20ml is dissolved among the anhydrous acetonitrile 430ml add reaction flask, and room temperature reaction 10～24 hours, TLC monitoring primitive reaction is complete.
After the cooling, add saturated sodium bicarbonate solution and transfer pH to 7～8, use ether extraction.Extracting solution with anhydrous magnesium sulfate drying after, steaming desolventizes, oily matter, through column chromatography for separation, the ethyl acetate petroleum ether wash-out, concentrate solid 27.3g, yield 76.7%.
[α]
D 25：+13.2(c，1.2；CHCl3)
Fusing point: 78.9-79.9 ℃
HNMR(CDCl
3)δ：1.10(dd，2H)，1.40(q，2H)，2.35(m，1H)，2.50(d，2H)，2.70(d，2H)，4.45(m，1H)，3.72(s，3H)，6.35(d，2H)，7.65(d，2H)，7.12-7.98.0(m，8H)
MASS：(Base)434(M+1)
C
26H
24FNO
4cal.433
3:(E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline]-(3R, 5S)-preparation of dihydroxyl-6-heptenoic acid methyl esters
Reaction formula:
Operation steps:
27g compound 3 is dropped in three mouthfuls of reaction flasks of 2L; add anhydrous tetrahydro furan 700ml and anhydrous methanol 70ml; feed nitrogen protection; low temperature-78 ℃ stirring; drip 1M diethyl methoxyl group borine solution 125ml; low temperature-78 ℃ stirring added sodium borohydride 3.4g after 3 hours in batches, and low temperature-78 ℃ stirring is after 3 hours.TLC monitoring primitive reaction is complete.
After being raised to room temperature, adding saturated sodium bicarbonate solution and transfer pH, use ether extraction to neutral.Extracting solution is washed with saturated common salt, and behind the anhydrous magnesium sulfate drying, steaming desolventizes, and residual solid gets pure product 18.4g, yield 68.1% with ether and sherwood oil recrystallization.HPLC detects purity 99.6%, isomer 0.1%.
Fusing point: 90.6-91.8 ℃
[α]
D 25：+7.81(c，1.2；CHCl
3)
HNMR(CDCl
3)：1.0(d，2H)，1.32(m，1H)，1.35(d，2H)，1.4(m，1H)，1.59(bs，2H)，2.45(m，2H)，3.05(s，1H)，3.58(s，1H)，3.74(s，3H)，4.13(bs，1H)，4.40(bs，1H)，5.60(dd，1H)，6.63(d，1H)，7.13-7.96.0(m，8H)
MASS：(Base)436(M+1)
C
26H
26FNO
4cal.435
4:(E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline]-(3R, 5S)-preparation of dihydroxyl 6-heptenoic acid sodium
Reaction formula:
Operation steps:
14g compound 4 is dropped in three mouthfuls of reaction flasks of 1000ml, add ethanol 670ml, stir, 1.29g sodium hydroxide is dissolved in 64ml (0.5N) distilled water, splash in the reaction flask, the stirring at room reaction is after 1 hour.The TLC monitoring reaction is complete.Steaming desolventizes, and resistates adds distilled water makes the product dissolving, after with the ether washing, divides water-yielding stratum, and evaporate to dryness gets white solid 13.5g, yield 94.5%.
Fusing point: 111.3-111.8 ℃
HNMR(DMSO-d
6)：1.02(m，2H)，1.06(m，1H)，1.18(m，2H)，1.34(m，1H)，1.75(m，1H)，1.95(m，1H)，2.27(m，1H)，3.52(m，1H)，4.11(q，1H)，5.58(dd，1H)，6.45(d，1H)，7.22-7.84(8H)
MASS:(Base) 422 (free carboxy acid's molecular weight is 421)
C
25H
23FNNaO
4cal.443
5:(+)-two (3R, 5S, 6E)-and 7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxyl-6-heptenoic acid } single calcium salt
Reaction formula:
Operation steps:
13g compound 5 is dropped in the 500ml single port reaction flask, and the stirring of adding 260ml distilled water makes molten entirely, in addition 3.25g calcium chloride is dissolved in the 60ml distilled water, splash in the reaction flask, separate out white solid immediately, stirring at room 0.5 hour, suction filtration, lyophilize get product 10.7g, yield 83.1%.It is 99.6%. isomer 0.1% that HPLC detects purity.
Fusing point: 210.5-212.2 ℃
[α]
D 25：+23.42(c，0.6；50％MeOH：H
2O)
HNMR(DMSO-d
6)：1.02(dd，2H)，1.10(p，1H)，1.19(dd，2H)，1.40(p，1H)，1.90(dd，1H)，2.07(dd，1H)，3.62(m，1H)，4.12(m，1H)，4.90(bs，1H)，5.58(dd，1H)，5.96(bs，1H)，6.48(d，1H)，7.23-7.84(m，8H).
MASS:(base) 422 (C
50H4
6CaF
2N
2O
8, the monocarboxylic acid molecular weight is: 421)
Embodiment 2:
1:(E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline]-preparation of 5-carbonyl-(3R)-3-(tertiary butyl dimethyl Si)-6-heptenoic acid ethyl ester
Reaction formula:
Operation steps
18g Compound I I and 66.01 (2.0eq) phosphorus ylide 1 is dropped in the 1L single port reaction flask, add anhydrous THF700ml and stir, be heated to 60～70 ℃ of reactions 48 hours, TLC monitoring primitive reaction is complete.Steaming desolventizes, and resistates is through the isolating soup compound 27.4g of post, but yield drops to 81%.
[α]
D 25：-8.10(c，1.1；MeOH)。
Embodiment 3:
1:(E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline]-preparation of 5-carbonyl-(3R)-3-(tertiary butyl dimethyl Si)-6-heptenoic acid ethyl ester
Reaction formula:
Operation steps
18g Compound I I and 59.4 (1.8eq) phosphorus ylide 1 is dropped in the 1L single port reaction flask, add dry toluene 600ml and stir, be heated to 100 ℃ of reactions 12 hours, TLC monitoring primitive reaction is complete.Steaming desolventizes, and resistates is through the isolating soup compound 28.4g of post, and yield is 85%.
[α]
D 25：-8.10(c，1.1；MeOH)
Embodiment 4:
1:(E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline]-(3R, 5S)-preparation of dihydroxyl-6-heptenoic acid methyl esters
Reaction formula:
Operation steps
3g compound 3 is dropped in three mouthfuls of reaction flasks of 250L, add anhydrous diethyl ether 80ml and anhydrous methanol 10ml, feed nitrogen protection; low temperature-90 ℃ stirring drips 1M boron triethyl solution 7ml, and low temperature-90 ℃ stirring is after 3 hours; add sodium borohydride 0.38g, low temperature-90 ℃ stirring is after 3 hours in batches.TLC monitoring primitive reaction is complete.
Naturally after being raised to room temperature, adding saturated sodium bicarbonate solution and transfer pH, use ether extraction to neutral.Extracting solution is washed with saturated common salt, and behind the anhydrous magnesium sulfate drying, steaming desolventizes, and residual solid gets product 1.8g, yield 60.0% with ether and sherwood oil recrystallization.But HPLC detects purity 98.9%, isomer 0.8%
Embodiment 5:
1:(E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline]-(3R, 5S)-preparation of dihydroxyl-different methyl esters of 6-heptenoic acid
Reaction formula:
Operation steps:
3g compound 3 is dropped in three mouthfuls of reaction flasks of 250L, add anhydrous diethyl ether 80ml and anhydrous methanol 10ml, feed nitrogen protection; low temperature-50 ℃ stirring drips 1M boron triethyl solution 7ml, and low temperature-50 ℃ stirring is after 3 hours; add sodium borohydride 0.38g, low temperature-50 ℃ stirring is after 3 hours in batches.TLC monitoring primitive reaction is complete.
Naturally after being raised to room temperature, adding saturated sodium bicarbonate solution and transfer pH, use ether extraction to neutral.Extracting solution is washed with saturated common salt, and behind the anhydrous magnesium sulfate drying, steaming desolventizes, and residual solid gets pure product 1.9g, yield 63.3% with ether and sherwood oil recrystallization.HPLC detects purity 97.0%, isomer 2.1%
Embodiment 6:
1:(E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline]-(3R, 5S)-preparation of dihydroxyl-6-heptenoic acid propyl ester
Reaction formula:
Operation steps:
4.61g compound 5 is dropped in three mouthfuls of reaction flasks of 250L; add anhydrous dioxane 40ml and anhydrous methanol 10ml; feed nitrogen protection; low temperature-70 ℃ stirring; drip 1M diethyl methoxyl group borine solution 12ml; low temperature-70 ℃ stirring added sodium borohydride 0.38g after 3 hours in batches, and low temperature-50 ℃ stirring is after 3 hours.TLC monitoring primitive reaction is complete.
Naturally after being raised to room temperature, adding saturated sodium bicarbonate solution and transfer pH, use ether extraction to neutral.Extracting solution is washed with saturated common salt, and behind the anhydrous magnesium sulfate drying, steaming desolventizes, and residual solid gets pure product 3.8g, yield 82.3% with ether and sherwood oil column chromatography.HPLC detects purity 99.0%, isomer 0.6%
MASS：(Base)464(M+1)
C
26H
26FNO
4cal.463
Embodiment 7:
1:(E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline]-(3R, 5S)-preparation of dihydroxyl-6-heptenoic acid tert-butyl ester
Reaction formula:
Operation steps:
4.8g compound 7 is dropped in three mouthfuls of reaction flasks of 250L, add anhydrous diethyl ether 40ml and anhydrous methanol 10ml, feed nitrogen protection; low temperature-70 ℃ stirring adds the 1.5g zinc dichloride in batches, and low temperature-70 ℃ stirring is after 1 hour; add POTASSIUM BOROHYDRIDE 0.38g, low temperature-70 ℃ stirring is after 3 hours in batches.TLC monitoring primitive reaction is complete.
Naturally after being raised to room temperature, add the molten water liquid of yellow soda ash, transfer pH, use ether extraction to neutral.Extracting solution is washed with saturated common salt, and behind the anhydrous magnesium sulfate drying, steaming desolventizes, and residual solid gets pure product 2.4g, yield 50.1% with ether and sherwood oil column chromatography.HPLC detects purity 91.0%, isomer 8.6%
Embodiment 8:
1:(E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline]-(3R, 5S)-preparation of dihydroxyl-6-heptenoic acid propyl ester
Reaction formula:
Operation steps:
4.61g compound 5 is dropped in three mouthfuls of reaction flasks of 250L; add anhydrous dioxane 40ml and anhydrous methanol 10ml; feed nitrogen protection; low temperature-30 ℃ stirring; drip 1M diethyl methoxyl group borine solution 12ml; low temperature-30 ℃ stirring added POTASSIUM BOROHYDRIDE 0.38g after 3 hours in batches, and low temperature-30 ℃ stirring is after 3 hours.TLC monitoring primitive reaction is complete.
Naturally after being raised to room temperature, adding saturated sodium bicarbonate solution and transfer pH, use ether extraction to neutral.Extracting solution is washed with saturated common salt, and behind the anhydrous magnesium sulfate drying, steaming desolventizes, and residual solid gets pure product 3.65g, yield 79.3% with ether and sherwood oil column chromatography.HPLC detects purity 98.6%, isomer 3.6%
MASS：(Base)464(M+1)
C
26H
26FNO
4cal.463
Claims (15)
1; a kind of method for preparing pitavastatin calcium raw material drug; it is characterized in that this method may further comprise the steps: 2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline aldehyde II and (3R)-3-alkyl siloxy-5-carbonyl-6-triphenyl phosphorus heptenoic acid esters III is reacted (E)-7-[2-cyclopropyl-4-(4-the fluorophenyl)-3-quinoline that obtains in solvent]-the 5-carbonyl-(3R)-3-alkyl siloxy-6-heptenoic acid esters IV; IV sloughs protection with deprotection agent and obtains (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline]-the 5-carbonyl-(3R)-hydroxyl-6-heptenoic acid esters V, it is used NaBH in a kind of mixed solvent of pure and mild a kind of ether compound
4Or KBH
4And selective reduction under the effect of part, temperature of reaction is-100 ℃ to 0 ℃, obtains (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline]-(3R, 5S)-dihydroxyl-6-heptenoic acid esters VI, it is become calcium salt with basic hydrolysis, just obtain Pitavastatin Calcium;
Preparation method's chemical reaction skeleton symbol is as follows:
R in the chemical equation
2O is an alkyl siloxy, R
1Be alkyl or benzyl.
2, a kind of method for preparing pitavastatin calcium raw material drug according to claim 1 is characterized in that: R in each reaction product chemical structural formula
1Be C1～C8 alkyl or benzyl.
3, a kind of method for preparing pitavastatin calcium raw material drug according to claim 1 is characterized in that: described R
2For trimethyl silicon based, tertiary butyl dimethyl is silica-based, tert-butyl diphenyl is silica-based, the sec.-propyl dimethyl is silica-based, a kind of in the triisopropylsilyl.
4, a kind of method for preparing pitavastatin calcium raw material drug according to claim 1 is characterized in that second step reaction deprotection agent is hydrofluoric acid or tetrabutyl fluoride amine.
5, a kind of method for preparing pitavastatin calcium raw material drug according to claim 4 is characterized in that second step reaction deprotection agent is a hydrofluoric acid.
6, a kind of method for preparing pitavastatin calcium raw material drug according to claim 1, it is characterized in that: the first step range of reaction temperature is 10～100 ℃.
7, a kind of method for preparing pitavastatin calcium raw material drug according to claim 6, it is characterized in that: the first step range of reaction temperature is 70-85 ℃.
8, a kind of method for preparing pitavastatin calcium raw material drug according to claim 1, it is characterized in that: in the wittg of the first step reaction, reaction solvent is selected from a kind of in acetonitrile, propionitrile, tetrahydrofuran (THF), dioxane, ether, propyl ether, isopropyl ether, methyl tertiary butyl ether, ethyl acetate, butylacetate, benzene,toluene,xylene, normal hexane, hexanaphthene or the sherwood oil.
9, a kind of method for preparing pitavastatin calcium raw material drug according to claim 8, it is characterized in that: reaction solvent is selected from acetonitrile, tetrahydrofuran (THF).
10, a kind of method for preparing pitavastatin calcium raw material drug according to claim 1 is characterized in that: in the second step deprotection reaction, reaction solvent is a kind of in acetonitrile, propionitrile or the tetrahydrofuran (THF).
11, a kind of method for preparing pitavastatin calcium raw material drug according to claim 1 is characterized in that: in the 3rd step during selective reduction, the solvent of use is a kind of pure and mild a kind of ether compound according to the mixed solvent of 5% to 99% ratio.
12, a kind of method for preparing pitavastatin calcium raw material drug according to claim 1 is characterized in that: when the 3rd went on foot selective reduction, the part that uses was Lewis acid or boron compound, and employed reductive agent is KBH
4Or NaBH
4Or their mixture.
13, a kind of method for preparing pitavastatin calcium raw material drug according to claim 12, it is characterized in that: Lewis acid is ZnCl
2, ZnSO
4, Ti (OR)
4In a kind of.
14, a kind of method for preparing pitavastatin calcium raw material drug according to claim 12, it is characterized in that: boron compound is BEt
3, BMe
3, BEt
2OMe, B (OMe)
3Or B (OEt)
3In a kind of.
15, a kind of method for preparing pitavastatin calcium raw material drug according to claim 1 is characterized in that: be-80 ℃ to-50 ℃ in the 3rd step selective reduction temperature of reaction.
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Cited By (3)
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| WO2011141934A1 (en) | 2010-05-13 | 2011-11-17 | Matrix Laboratories Ltd. | An improved process for the preparation of an intermediate of hmg-coa reductase inhibitors |
| 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 |
| WO2013080219A2 (en) | 2011-11-28 | 2013-06-06 | Mylan Laboratories Ltd | NOVEL PROCESS FOR THE PREPARATION OF INTERMEDIATES OF HMG-CoA REDUCTASE INHIBITORS |
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| EP3178812A1 (en) * | 2010-11-12 | 2017-06-14 | Hetero Research Foundation | Novel polymorphs of pitavastatin calcium |
| CN103848784B (en) * | 2012-12-05 | 2016-12-21 | 安徽省庆云医药化工有限公司 | Crystal formation of Pitavastatin ester and preparation method thereof |
| 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 |
| CN108976168B (en) * | 2017-06-02 | 2020-09-25 | 浙江京新药业股份有限公司 | Pitavastatin semi-calcium salt crystal form and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011141934A1 (en) | 2010-05-13 | 2011-11-17 | Matrix Laboratories Ltd. | An improved process for the preparation of an intermediate of hmg-coa reductase inhibitors |
| WO2013080219A2 (en) | 2011-11-28 | 2013-06-06 | Mylan Laboratories Ltd | NOVEL PROCESS FOR THE PREPARATION OF INTERMEDIATES OF HMG-CoA REDUCTASE INHIBITORS |
| 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 |
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|---|---|
| CN1876633A (en) | 2006-12-13 |
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