CN102212081A - Preparation method of chiral intermediate product for synthesis of statins - Google Patents
Preparation method of chiral intermediate product for synthesis of statins Download PDFInfo
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- CN102212081A CN102212081A CN2010106142309A CN201010614230A CN102212081A CN 102212081 A CN102212081 A CN 102212081A CN 2010106142309 A CN2010106142309 A CN 2010106142309A CN 201010614230 A CN201010614230 A CN 201010614230A CN 102212081 A CN102212081 A CN 102212081A
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- BPRHUIZQVSMCRT-VEUZHWNKSA-N CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c(cc2)ccc2F)c1/C=C/[C@H](C[C@H](CC(O)=O)O)O Chemical compound CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c(cc2)ccc2F)c1/C=C/[C@H](C[C@H](CC(O)=O)O)O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 1
- VGYFMXBACGZSIL-MCBHFWOFSA-N O[C@H](C[C@@H](/C=C/c1c(-c(cc2)ccc2F)c(cccc2)c2nc1C1CC1)O)CC(O)=O Chemical compound O[C@H](C[C@@H](/C=C/c1c(-c(cc2)ccc2F)c(cccc2)c2nc1C1CC1)O)CC(O)=O VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 1
Abstract
The invention relates to a preparation method of a chiral intermediate product for synthesis of statins. The intermediate product is a compound shown as general formula 1, namely (3R)-3-tertbutyldimethylsiloxy-6-dialkoxyphosphono-5-oxo-tertbutyl hexanate, wherein TBS is tertbutyldimethylsiloxy, But is tertbutyl, and R is C1-4 alkyl.
Description
Technical field
The present invention relates to be used for the preparation method of statins synthetic chiral intermediate, more specifically to preparation formula 1 compound, i.e. the preparation method of the special butyl ester of (3R)-3-tertiary butyl dimethylsilyl bis-6-dialkoxy phosphono-5-oxa--caproic acid,
Wherein, it is silica-based that TBS represents the tertiary butyl dimethyl
Bu
tThe expression tertiary butyl;
R represents C
1-4Alkyl.
Background technology
Statins; it is 3-hydroxy-3-methyl-glutaryl--coenzyme A (HMG-CoA) reductase inhibitor; can significantly reduce serum low-density LP cholesterol (LDL-C) level; obviously reduce the incidence and the mortality ratio of cardiovascular event; one-level in coronary heart disease; important effect is arranged in the secondary prevention; therefore; more and more being subjected to people in clinical application pays close attention to; now developed into and comprised lovastatin; Simvastatin; Pravastatin; fluvastatin; atorvastatin; Russell cuts down his spit of fland; a series of product such as pitavastatin; it is the strongest two kinds of lipid-lowering effect wherein that Russell cuts down Ta Ting and pitavastatin, is called as " super he spit of fland ".
Statins molecule stereo structure complexity comprises two chiral centres and a trans double bond, so its synthetic preparation is one all the time and has difficulty and challenging work.Along with the progress of his spit of fland Study of synthesis method in recent years, now common synthesis strategy is to adopt his spit of fland side chain of band chiral centre and main ring condensation to obtain his spit of fland molecule, and condensation generally adopts love and respect one's elder brother alkene reaction (Wittig Reaction) or its improve one's methods (Wittig-Hornor reaction) of dimension to obtain the trans double bond in his the spit of fland molecule.His the synthetic of spit of fland side chain that contains chiral centre is the key of this synthesis strategy, and different side chains and preparation method thereof are the emphasis of Recent study always.
Document US 526440 openly can adopt the method for (3R)-3-(tertiary butyl dimethyl Si)-5-oxa--6-triphenylphosphine heptenoic acid methyl esters (11) as chiral side chain, and the synthetic method of this side chain is provided.This method is a raw material with 3-(tertiary butyl dimethyl Si)-Pyroglutaric acid; with Benzyl Amygdalate and n-Butyl Lithium reaction; hydrogenation removes benzyl protecting group again; with 3-(the tertiary butyl dimethyl Si)-monomethyl glutarate that obtains the R configuration behind the sodium methylate replacement mandelate; after this intermediate activates with chloroformic acid first (second) ester, with methylene tri Phenylphosphine alkane so-called " transylidation " reaction takes place and obtain chiral side chain 11.Document US 526440 discloses simultaneously by this chiral side chain and main ring the method that Wittig prepared in reaction Russell cuts down his spit of fland has taken place, and patent ZL200510026641.5 then discloses the method that Wittig prepared in reaction pitavastatin takes place by this chiral side chain and main ring.
Document JP 7118233 discloses the method for employing (3R)-3-tertiary butyl two silyloxies-5-oxo-6-dimethoxy phosphonic acids Methylheptanoate (12) as chiral side chain, and provide the synthetic method of this side chain, and by this intermediate and main ring the method that Wittig-Hornor prepared in reaction Russell cuts down his spit of fland takes place.
Document WO 2008130678 discloses the method for employing (3R)-3-tertiary butyl two silyloxies-5-oxo-6-dimethoxy phosphonic acids enanthic acid tertiary butyl ester (13) as chiral side chain, this intermediate and formula 12 compounds seemingly, difference is to protect carboxyl with the tertiary butyl.Comparing with formula 12 compounds obviously has two advantages, and at first to compare the methyl protecting group more stable for tertiary butyl protecting group, thereby thereby being difficult for taking place side reaction in its process of preparation influences synthesis yield; Secondly, as document (The Story of Lescol:From Research to Production, Organic Process Research ﹠amp; Development 2001; 5; 519-527) report; methyl as carboxyl-protecting group in follow-up alkali removing process; may generate the lactone intermediate and cause the racemization of 5 hydroxyls; thereby influence the optical purity of product, the tertiary butyl then can be avoided the racemization of alkali deprotection process as carboxyl-protecting group.The synthetic route of document WO 2008130678 disclosed formula 13 compounds is: with 3-(tertiary butyl dimethyl Si)-Pyroglutaric acid is raw material, obtain 3-(the tertiary butyl dimethyl Si)-monomethyl glutarate of racemization with the methyl alcohol open loop, the condensation under the effect of DCC of this monoesters and the trimethyl carbinol obtains 3-(the tertiary butyl dimethyl Si)-pentanedioic acid methyl tertbutyl dibasic acid esters of racemization, this dibasic acid esters removes methyl under the sodium hydroxide effect and obtains 3-(tertiary butyl dimethyl Si)-pentanedioic acid tertiary butyl monoesters, phenylethylamine with the R configuration splits 3-(the tertiary butyl dimethyl Si)-pentanedioic acid tertiary butyl monoesters that obtains the R configuration then, after using the activation of chloroformic acid first (second) ester again, obtain formula 13 compounds with the dimethyl methyl phosphonate reaction.
Document WO 2008130678 simultaneously also openly formula 13 compounds and the Russell main ring that cuts down his spit of fland through the deprotection reaction of the reduction reaction of the silica-based deprotection reaction of Wittig-Hornor reaction, tertiary butyl dimethyl, diethyl methoxyl group borine/sodium borohydride, tertiary butyl ester and and operation such as calcium chloride salify prepare the method that Russell cuts down his spit of fland calcium.
Yet, still need to develop the key intermediate for preparing his spit of fland, i.e. the additive method of formula 1 compound.Described method is passable, for example, compares with the previously known method, is more convenient for using, and is more suitable for scale operation, and yield is higher, and easier production operation does not need complicated purifying process, to environment close friend etc. more.
Summary of the invention
The present invention discloses a kind of synthesis type 1 compound, i.e. the method for the special butyl ester of (3R)-3-tertiary butyl dimethylsilyl bis-6-dialkoxy phosphono-5-oxa--caproic acid,
Wherein, it is silica-based that TBS represents the tertiary butyl dimethyl
Bu
tThe expression tertiary butyl;
R represents C
1-4Alkyl,
Described method comprises the steps:
1) with the compound of formula 4
With
React,
Make formula 5 compounds
2) formula 5 compound debenzylations are reacted, make formula 6 compounds
3) make formula 6 compounds carry out transesterification reaction, make formula 7 compounds
4) make the condensation reaction of formula 7 compounds experience, make formula 8 compounds
5), make formula 9 compounds by basic hydrolysis formula 8 compounds
6) make formula 9 compounds carry out acylation reaction, make formula 10 compounds
7) make formula 10 compounds with
Wherein R suc as formula in 1 define, react, make formula 1 compound
In aforesaid method of the present invention, all do not split.
Perhaps, also can explain the preparation method of the special butyl ester of (3R)-3-tertiary butyl dimethylsilyl bis of the present invention-6-dialkoxy phosphono-5-oxa--caproic acid (1) according to following reaction path:
Below each step reaction that aforesaid method or above-mentioned reaction path utilized is described.
In the first step reaction; 3-(the tertiary butyl dimethyl Si)-Pyroglutaric acid of formula 4 representatives is the starting raw material of the inventive method; wherein, the protecting group of TBS representation hydroxy---tertiary butyl dimethyl Si base, formula 4 compounds can be prepared by known disclosed method.
3-(the tertiary butyl dimethyl Si)-Pyroglutaric acid of formula 4 representative reacts with S configuration Benzyl Amygdalate, obtains formula 5 compounds, i.e. (3S)-3-(tertiary butyl dimethyl Si)-pentanedioic acid, 1-(S)-amygdalic acid benzyl ester.Should use stronger organometallic compound as alkali in this reaction process, comprise: lithium alkylide, lithium diisopropylamine, hexamethl disilamine base lithium, hexamethl disilamine base sodium, sodium tert-butoxide, potassium tert.-butoxide or sodium hydride etc., preferably use n-Butyl Lithium or hexamethl disilamine base lithium.
The reaction solvent that uses in this reaction comprises ethers and alkanes etc., preferably uses tetrahydrofuran (THF) or ether.
This reaction is carried out at a lower temperature, preferred-60 ℃ to-100 ℃ temperature range, more preferably-78 ℃.
In the reaction of second step, formula 5 compounds remove (3S)-3-(tertiary butyl dimethyl Si)-pentanedioic acid that benzyl obtains formula 6 representatives, 1-(S)-mandelate by hydrogenation.The hydrogenation that this reaction process relates to need use catalyzer, as palladium carbon or palladium hydroxide.The preferred ethanol that uses is as solvent.Reaction can be carried out under the hydrogen pressure of preferred normal pressure (i.e. 1 normal atmosphere) at 0-5 normal atmosphere.The method of gained hydrogenated products by ethyl acetate and sherwood oil recrystallization can obtain optical purity (ee%) and surpass 99.5% formula 6 compounds.Preferably react at normal temperatures.
In three-step reaction, in the scope of low temperature, preferred 0 ℃, the methanol solution of formula 6 compounds is splashed in the methanol solution of sodium methylate as-10 ℃ to 10 ℃, so-called transesterification reaction takes place in formula 6 compounds, has obtained (S)-3-(tertiary butyl dimethyl Si)-monomethyl glutarate (7).
In four-step reaction, formula 7 compounds and the trimethyl carbinol react under the effect of DCC condensation reagent and obtain formula 8 compounds, i.e. (R)-3-(tertiary butyl dimethyl Si)-pentanedioic acid methyl tertbutyl dibasic acid esters.Need to use DMAP (dimethyl aminopyridine) as acid binding agent in this reaction.Ethers, ester class, alkanes, alkyl chloride hydro carbons equal solvent be can use, methylene dichloride or chloroform preferably used.Temperature of reaction is-10 ℃ to 40 ℃ a scope, preferred room temperature.
In the reaction of the 5th step, formula 8 compounds can obtain formula 9 compounds through basic hydrolysis, and promptly (R)-3-(tertiary butyl dimethyl Si)-pentanedioic acid tertiary butyl ester preferably adopts sodium hydroxide to carry out basic hydrolysis.Reaction solvent can make water, alcohols, ketone, ethers equal solvent, preferably uses methyl alcohol or ethanol.The temperature of reaction is 0-100 ℃ of scope, preferred 20-70 ℃ of scope, more preferably 45-50 ℃.Adopt TLC to monitor the concluding time of this reaction.
In six-step process, by making the reaction of formula 9 compounds and methyl-chloroformate or Vinyl chloroformate, make formula 10 compounds, wherein R ' is methyl or ethyl.The temperature of reaction in-80 ℃ to 0 ℃ scope, preferred-60 ℃.The preferred toluene that adopts is as solvent.
In the reaction of the 7th step, make the reaction of formula 10 compounds and dialkyl methyl phosphonate, preparation formula 1 compound, the i.e. special butyl ester of (3R)-3-tertiary butyl dimethylsilyl bis-6-dialkoxy phosphono-5-oxa--caproic acid.The temperature of reaction in-100 ℃ to 0 ℃ scope, preferred-78 ℃.
Compare with known references WO2008130678 method, aforesaid method disclosed by the invention does not adopt fractionation, and literature method has adopted method for splitting.As everyone knows, because method for splitting can lose the enantiomer of half at least inevitably, therefore, chirality method of asymmetric synthesis of the present invention is the method for a kind of efficient more, economy, environmental protection.
Relevant abbreviation definition
TBS represents the tertiary butyl dimethyl silica-based
Bu
tThe expression tertiary butyl,
THF represents tetrahydrofuran (THF).
Embodiment
Embodiment 1:(3S)-and 3-(tertiary butyl dimethyl Si)-pentanedioic acid, the preparation of 1-(S)-mandelate (6)
74g (S)-Benzyl Amygdalate drops in the reaction flask, add anhydrous tetrahydro furan 1500ml, dry ice-propanone is cooled to-78 ℃ under bathing, splash into the n-Butyl Lithium 121ml of 2.5mol/l, drip off the back and stirred 20 minutes, splash into 74g 3-(the tertiary butyl dimethyl Si)-Pyroglutaric acid (4) in the anhydrous THF solvent of 300ml.Dropwise, continue reaction 2 hours.With the 2N hcl acidifying to pH=3-4, separatory, water ethyl acetate extraction.The saturated common salt water washing of gained organic phase, drying concentrates, and obtains formula 5 compounds, is thick liquid.Formula 5 compounds are dissolved in 1000ml ethanol, add the palladium-carbon catalyst of 1.5g 10%, normal pressure hydrogenation is inhaled hydrogen to reactant and is stopped.The elimination catalyzer is concentrated into driedly, with ethyl acetate-sherwood oil recrystallization, obtains the 71.6g title compound, is clear crystal, yield 60.0%.
Fusing point: 142-143 ℃
[α]
25D＝-70.8°(CHCl
3，c?0.90)
1H-NMR(CDCl
3)：δ0.04(d，6H)；0.82(s，9H)；2.70(m，4H)；4.62(m，1H)；5.94(s，1H)；7.40-7.48(m，5H)。
Embodiment 2:(S)-preparation of 3-(tertiary butyl dimethyl Si)-monomethyl glutarate (7)
In reaction flask, add 350 milliliters of anhydrous methanols, add 24.7 gram sodium Metal 99.5s under stirring in batches, be cooled to-5 ℃ after the sodium dissolving, drip 60 milliliters of absolute methanol solutions of 40 gram formulas, 6 compounds, add the back and reacted 2 hours down in 0 ℃, TLC detects display type 6 compounds and reacts completely.Reaction solution is poured in hydrochloric acid, methylene dichloride and the frozen water (88 milliliters/400 milliliters/400 milliliters), stirred 10 minutes, separatory, water merges organic phase, salt water washing, anhydrous magnesium sulfate drying with 50 milliliters of dichloromethane extraction 1 time.Filter, pressure reducing and steaming solvent, evaporate to dryness obtain 26.95 gram title compounds, are colourless liquid, yield 96.6%.
1H-NMR(CDCl
3)：δ0.04(d，6H)；0.82(s，9H)；2.58(m，4H)；3.66(s，3H)；4.55(m，1H)。
13C-NMR(CDCl
3)：δ4.91(2Si-CH
3)；17.91(Si-C(CH
3)
3)；25.66(Si-C(CH
3)
3)；42.28-42.34(2-CH
2)；51.68(O-CH
3)；66.14(O-CH)；171.42(-COOCH
3)；177.32(-COOH)。
Embodiment 3:(R)-preparation of 3-(tertiary butyl dimethyl Si)-pentanedioic acid methyl tertbutyl dibasic acid esters (8)
Add 26.95 gram formulas, 7 compounds and 150 milliliters of methylene dichloride in reaction flask, cryosel is bathed and is added 21.6 gram DCC, 29.5 gram DMAP and 78.6 milliliters of trimethyl carbinols when being cooled to 0 ℃, room temperature reaction 60 hours, and TLC detects display type 7 compounds and reacts completely.Filter, the pressure reducing and steaming solvent adds 100 milliliters of sherwood oils and 100 ml waters and stirred the filtering solid 10 minutes, separatory, water merges organic phase with 2 * 50 milliliters of petroleum ether extractions, adds 50 milliliters of 3N hydrochloric acid and stirs 10 minutes, the filtering solid, separatory, organic phase use 50 milliliters of 3N hydrochloric acid, 50 ml waters, 500 milliliters of saturated sodium bicarbonates, 2 * 500 mL of saline to wash anhydrous magnesium sulfate drying successively.Filter, pressure reducing and steaming solvent, vacuum pump are drained and are obtained 33.2 gram title compounds, are orange liquid.
1H-NMR(CDCl
3)：δ0.06(d，6H)；0.85(s，9H)；1.44(s，9H)；2.46-2.56(m，4H)；3.67(s，3H)；4.50(m，1H)。
13C-NMR(CDCl
3)：δ4.95(2Si-CH
3)；17.93(Si-C(CH
3)
3)；25.73(Si-C(CH
3)
3)；28.17(-C(CH
3)
3)；42.33-43.63(2-CH
2)；51.51(O-CH
3)；66.37(O-CH)；80.64(O-C(CH
3)
3)；170.24(-COOCH
3)；171.62(-COOC(CH
3)
3)。
Embodiment 4:(R)-preparation of 3-(tertiary butyl dimethyl Si)-pentanedioic acid tertiary butyl ester (9)
Above-mentioned formula 8 compounds of adding and 160 milliliters of dehydrated alcohols in the reaction flask drip 107 milliliters of 1N sodium hydroxide under 45-50 ℃, add the back and reacted 8 hours down in 45-50 ℃, and TLC detection display type 8 compounds react completely.Reduce to room temperature, pressure reducing and steaming ethanol adds 50 ml waters, 2 * 50 milliliters of petroleum ether extractions, water is neutralized to pH=4-5 with 3N hydrochloric acid, adds 2 * 75 milliliters of petroleum ether extractions, merges organic phase, 2 * 100 milliliters of washings, 100 mL of saline are washed, and organic phase is told, and add 4 gram gacs and stir decolouring 4 hours, filter, use anhydrous magnesium sulfate drying again.Filter, pressure reducing and steaming solvent, vacuum pump drain 26.7 gram title compounds, be weak yellow liquid, yield 86.1%.
1H-NMR(CDCl
3)：δ0.08(d，6H)；0.85(s，9H)；0.91(s，9H)；2.48-2.63(m，4H)；4.50(m，1H)。
13C-NMR(CDCl
3)：δ4.93(2Si-CH
3)；17.94(Si-C(CH
3)
3)；25.74(Si-C(CH
3)
3)；28.16(-C(CH
3)
3)；42.23-43.48(2-CH
2)；66.16(O-CH)；80.86(O-C(CH
3)
3)；170.26(-COOC(CH
3)
3)；177.46(-COOH)。
Embodiment 5:(3R)-the special butyl ester of 3-tertiary butyl dimethylsilyl bis-6-dimethoxy phosphono-5-oxa--caproic acid is (corresponding to formula 1 compound, wherein R=CH
3) preparation
In reaction flask, add 26.7 above-mentioned formula 9 compounds of gram and 300 milliliters of toluene, drip 17.6 milliliters of triethylamines down in-60 ℃, adding the back stirred 30 minutes, drip 12 milliliters of methyl-chloroformates down in-60 ℃, continuation was reacted 1 hour under this temperature, bathe temperature rise to-15 ℃, continue reaction 1 hour, TLC detects display type 9 compounds and reacts completely.Drip 100 ml waters, stirred 10 minutes, separatory, water merges organic phase with 30 milliliters of methylbenzene extraction 1 time, uses 2 * 80 ml waters, 100 milliliters of saturated sodium bicarbonates, the washing of 80 mL of saline successively, anhydrous magnesium sulfate drying.Filter, pressure reducing and steaming solvent, vacuum pump drain 29.5 gram formulas, 10 compounds, be weak yellow liquid.
In reaction flask, add 15.9 gram dimethyl methyl phosphonate and 75 milliliters of tetrahydrofuran (THF)s, in 8.5 milliliters of n-Butyl Lithiums of-78 ℃ of following Dropwise 5s, added the back stirring reaction 2 hours, drip above-mentioned formula 10 compounds of 25 grams, continuation was reacted 1 hour under this temperature, and TLC detects display type 10 compounds and reacts completely.Drip 100 milliliter 20% ammonium chloride solution, be warming up to naturally more than 0 ℃, separatory, water merges organic phase with 50 milliliters of ethyl acetate extraction 1 time, uses 100 milliliters of 1N hydrochloric acid, 100 ml waters, the washing of 2 * 100 mL of saline successively, anhydrous magnesium sulfate drying.Filter, pressure reducing and steaming solvent, vacuum pump drain brown liquid.Column chromatography purification gets 15.75 gram title compounds, is oily matter, yield 57.9%.
1H-NMR(CDCl
3)：δ0.02(d，6H)；0.78(s，9H)；1.37(s，9H)；2.34(m，2H)；2.80(d，2H)；3.04(m，2H)；3.72(d，6H)；4.44(m，1H)。
13C-NMR(CDCl
3)：δ4.82(2Si-CH
3)；17.94(Si-C(CH
3)
3)；25.78(Si-C(CH
3)
3)；28.15(-C(CH
3)
3)；42.01-43.31(3-CH
2)；50.9-53.0(2O-CH
3)；65.56(O-CH)；80.68(O-C(CH
3)
3)；170.19(-COOC(CH
3)
3)；200.08(＝CO)。
Claims (9)
1. synthesis type 1 compound, i.e. the method for the special butyl ester of (3R)-3-tertiary butyl dimethylsilyl bis-6-dialkoxy phosphono-5-oxa--caproic acid,
Wherein, it is silica-based that TBS represents the tertiary butyl dimethyl
Bu
tThe expression tertiary butyl,
R represents C
1-4Alkyl,
Described method comprises the steps:
1) with the compound of formula 4
With
React,
Make formula 5 compounds
2) formula 5 compound debenzylations are reacted, make formula 6 compounds
3) make formula 6 compounds carry out transesterification reaction, make formula 7 compounds
4) make the condensation reaction of formula 7 compounds experience, make formula 8 compounds
5), make formula 9 compounds by basic hydrolysis formula 8 compounds
6) make formula 9 compounds carry out acylation reaction, make formula 10 compounds
7) make formula 10 compounds with
Wherein R suc as formula in 1 define, react, make formula 1 compound
2. the method for claim 1, wherein in step 1), use organometallic compound as alkali, described organometallic compound is preferably from lithium alkylide, lithium diisopropylamine, hexamethl disilamine base lithium, hexamethl disilamine base sodium, sodium tert-butoxide, potassium tert.-butoxide and sodium hydride, more preferably n-Butyl Lithium or hexamethl disilamine base lithium; The reaction solvent that uses comprises ethers and alkanes, preferred tetrahydrofuran (THF) or ether; Be reflected at-60 ℃ to-100 ℃, carry out under preferred-78 ℃ the temperature.
3. the process of claim 1 wherein in step 2) in, formula 5 compounds obtain formula 6 compounds by the hydrogenation debenzylation; Use is selected from the catalyzer of palladium carbon and palladium hydroxide; The preferred ethanol that adopts is as solvent; Preferably react at normal temperatures; React preferred 1 normal atmosphere at 0-5 atmospheric hydrogen pressure.
4. the process of claim 1 wherein in step 3),, carry out under preferred 0 ℃ at-10 ℃ to 10 ℃; Make formula 6 compounds and sodium methylate generation transesterification reaction, obtained formula 7 compounds; The preferred methyl alcohol that adopts is as solvent.
5. the process of claim 1 wherein that in step 4) formula 7 compounds and the trimethyl carbinol react in the presence of DCC condensation reagent and DMAP, obtain formula 8 compounds; The reaction solvent that adopts is methylene dichloride or chloroform; Temperature of reaction is extremely-80 ℃ of room temperatures, preferred room temperature.
6. the process of claim 1 wherein that in step 5) formula 8 compounds can obtain formula 9 compounds through basic hydrolysis, preferably adopt sodium hydroxide to carry out basic hydrolysis; Reaction solvent is methyl alcohol or ethanol; Temperature of reaction is 0-100 ℃, is preferably 20-50 ℃, more preferably normal temperature.
7. the process of claim 1 wherein in step 6),, make formula 10 compounds by making the reaction of formula 9 compounds and methyl-chloroformate or Vinyl chloroformate; The temperature of reaction in-80 ℃ to 0 ℃ scope, preferred-60 ℃; The preferred toluene that adopts is as solvent.
8. the process of claim 1 wherein in step 7), use dimethyl methyl phosphonate or methyl-phosphorous acid diethyl ester; The preferred tetrahydrofuran (THF) that uses is as solvent; The temperature of reaction in-100 ℃ to 0 ℃ scope, preferred-78 ℃; The preferred n-Butyl Lithium that adopts.
9. the method for claim 1 is characterized in that not carrying out splitting.
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| CN103408580A (en) * | 2013-06-03 | 2013-11-27 | 南京欧信医药技术有限公司 | Method for synthesizing intermediate through statins |
| CN103483393A (en) * | 2013-09-05 | 2014-01-01 | 江苏兰健药业有限公司 | Preparation method of chiral intermediate for synthesizing statins |
| CN103896979A (en) * | 2014-03-31 | 2014-07-02 | 南京欧信医药技术有限公司 | Compound synthetic method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103408580A (en) * | 2013-06-03 | 2013-11-27 | 南京欧信医药技术有限公司 | Method for synthesizing intermediate through statins |
| CN103483393A (en) * | 2013-09-05 | 2014-01-01 | 江苏兰健药业有限公司 | Preparation method of chiral intermediate for synthesizing statins |
| CN103483393B (en) * | 2013-09-05 | 2016-08-17 | 江苏兰健药业有限公司 | A kind of preparation method of the chiral intermediate for statins synthesis |
| CN103896979A (en) * | 2014-03-31 | 2014-07-02 | 南京欧信医药技术有限公司 | Compound synthetic method |
| CN103896979B (en) * | 2014-03-31 | 2015-03-18 | 南京欧信医药技术有限公司 | Compound synthetic method |
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