CN103360384A - Synthetic method for key intermediate of HMG-CoA reductase inhibitor - Google Patents

Synthetic method for key intermediate of HMG-CoA reductase inhibitor Download PDF

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CN103360384A
CN103360384A CN201310326726XA CN201310326726A CN103360384A CN 103360384 A CN103360384 A CN 103360384A CN 201310326726X A CN201310326726X A CN 201310326726XA CN 201310326726 A CN201310326726 A CN 201310326726A CN 103360384 A CN103360384 A CN 103360384A
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reaction
compound
hmg
solvent
reductase inhibitor
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朱建荣
华长华
陈见阳
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Zhejiang Jingxin Pharmaceutical Co Ltd
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Zhejiang Jingxin Pharmaceutical Co Ltd
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Abstract

The invention discloses a synthetic method for a key intermediate of an HMG-CoA reductase inhibitor. According to the method, cheap and easily available (S)-3-hydroxyl-4-substituted butyronitrile is used as an initial material; and the key intermediate of the HMG-CoA reductase inhibitor is prepared by four steps of Blaise reaction, reduction, hydroxyl protection and oxidation. The reaction process is simple in operations; products in every step can be purified easily; no silicagel column is needed to carry out purification and separation; and the yield is higher than 80%. The prepared intermediate has relatively high chemical purity and optical purity (tests show that the chemical purity is higher than or equal to 99.4% and the optical purity is higher than or equal to 99.3% ee). The prepared intermediate can be used for industrial production of dihydroxyl acid HMG-CoA reductase inhibitor and has significant economic benefits.

Description

The synthetic method of HMG-CoA reductase inhibitor key intermediate
Technical field
The present invention relates to a kind of preparation method of blood lipid-lowering medicine key intermediate, relate in particular to a kind of preparation method of statins Rosuvastatin side chain key intermediate.
Background technology
HMG-CoA reductase inhibitor (HMG-CoA reductase inhibitor), or claim him the spit of fland (Statin), be the novel lipidemia medicine of a class.Because this class medicine can effectively stop the synthetic of endogenous cholesterol, so can reduce significantly the level of blood cholesterol.Cholesterol source in the blood plasma has exogenous and two kinds of approach of endogenous.Exogenous cholesterol can be controlled intake by regulating foodstuff texture mainly from food; Endogenic then synthetic in liver.In hepatocellular tenuigenin, synthesize endogenous cholesterol by acetic acid through 26 step biosynthesizing steps.Wherein HMG-CoA reductase (3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase enzyme) is the rate-limiting enzyme in this building-up process, can be reduced to mevalonic acid by catalysis HMG-CoA.This step is a crucial step during endogenous cholesterol synthesizes, if suppress the HMG-CoA reductase enzyme, then endogenous cholesterol is synthetic reduces.Statins is exactly by synthetic rate-limiting enzyme (HMG-CoA) reductase enzyme of competitive inhibition endogenous cholesterol, hydroxyl first valeric acid pathways metabolism in the blocking-up cell, make the synthetic minimizing of cell inner cholesterol, thereby feedback irritation cell film surface (being mainly liver cell) low-density lipoprotein (low density lipoprotein, LDL) acceptor quantity and activity increase, make serum cholesterol to remove and increase, level reduces.Be the atherosclerotic choice drug of clinical prevention at present.
Since first statins mevastatin in 1976 comes out, statins has been developed to the third generation, the rosuvastain calcium of new statins-Astrazeneca company, and its effect for reducing fat is powerful, use separately to surpass every other statins, be known as " superstatin ".Statins is efficient, safety, be the choice drug in the fat-reducing medicament.
Statins is because complex structure is synthetic relatively more difficult.Many synthetic methods are arranged in the prior art, but all have the defectives such as yield is low, step is long, cost is high, operational difficulty.United States Patent (USP) WO02098854 discloses a kind of novel synthesis of his spit of fland.The method obtains chirality 3 through deprotection after adopting Julia-Kocienski reaction preparation trans olefins, 5-dihydric heptene acid ester, and the hydrolysis heptenoic acid esters obtains his spit of fland.The method subsequent operations is simple, yield is high, be convenient to purifying, is fit to suitability for industrialized production, but maximum shortcoming is that chirality sulfone reagent preparation cost is large, has limited greatly its industrial application, particularly needs to use the reagent trifluoromethanesulfanhydride anhydride of a large amount of costlinesses.
Summary of the invention
The object of the invention is to, a kind of synthetic method of HMG-CoA reductase inhibitor key intermediate is provided, the method not only reaction process is easy and simple to handle, each goes on foot product and is easy to separation and purification, need not purification by silica gel column chromatography and separate, yield can access the intermediate of higher chemical purity and optical purity more than 80%, and the raw materials cost that adopts is low, remarkable in economical benefits.
Technical scheme of the present invention: a kind of synthetic method of HMG-CoA reductase inhibitor key intermediate may further comprise the steps:
1. compound I I and bromacetate are through Blaise reaction preparation beta-ketoester III;
Figure BDA00003588493900021
In the formula, R 1For
Figure BDA00003588493900031
Methyl or trifluoromethyl;
Figure BDA00003588493900032
In R 4aAlkyl, aralkyl, aryl or cycloalkyl;
Figure BDA00003588493900033
In R 5Hydrogen, alkyl, aralkyl, aryl, CF 3, halogen or nitro;
In Xa be oxygen or sulphur;
R 2Be alkyl, aralkyl, aryl or cycloalkyl;
2. compound III is in the presence of organoboron reagent, through reductive agent reduction preparation dihydroxy compound IV;
Figure BDA00003588493900035
Organoboron reagent is diethyl methoxyl group borine, triethyl-boron or tri butyl boron;
Reductive agent is sodium borohydride or POTASSIUM BOROHYDRIDE;
3. compound IV is carried out hydroxyl protection and prepare compound V;
Figure BDA00003588493900036
In the formula, P1, P2 are hydroxyl protecting group;
4. compound V obtains compound I through peroxidation;
Figure BDA00003588493900041
In the formula, oxygenant is superoxide.
As prioritization scheme, the synthetic method of aforesaid HMG-CoA reductase inhibitor key intermediate may further comprise the steps:
1. compound I I and bromacetate are through Blaise reaction preparation beta-ketoester III;
Figure BDA00003588493900042
In the formula, R 1For
Figure BDA00003588493900043
R 2Be methyl, ethyl, propyl group, the tertiary butyl or benzyl;
The solvent that reacts used is ether, ethylene-propylene ether, tetrahydrofuran (THF), chloroform, glycol dimethyl ether, benzene, toluene or dimethylbenzene, or is the multiple mixed solvent that is comprised of ether, ethylene-propylene ether, tetrahydrofuran (THF), chloroform, glycol dimethyl ether, benzene, toluene or dimethylbenzene;
The metal that reacts used is zinc, iron or magnesium; The feed ratio of compound I I and metal is 1:1～4mol;
React used metal needs activation, the reagent of activated metal is TMSCl, R 3SO 3H or R 3SO 3TMS, wherein, R 3The aromatic hydrocarbon of the saturated or unsaturated hydrocarbons of the C1-C6 class that replaces for the saturated or unsaturated hydrocarbons of hydrogen, C1-C6 class, with halogen, the aromatic hydrocarbon of C6-C12 or the C6-C12 that replaces with halogen;
The feed ratio of bromacetate and metal is 1mol:1.00～1.10mol;
The feed ratio of the reagent of activated metal and compound I I is 1mol:0.05～0.5mol;
Temperature of reaction is 20～110 ℃;
Reaction times is 1.5～4h;
2. compound III is in the presence of organoboron reagent, through reductive agent reduction preparation dihydroxy compound IV;
Figure BDA00003588493900051
Reaction solvent is tetrahydrofuran (THF), ether, methyl alcohol, ethanol, n-propyl alcohol, Virahol or ethylene glycol, or is the multiple mixed solvent that is comprised of tetrahydrofuran (THF), ether, methyl alcohol, ethanol, n-propyl alcohol, Virahol or ethylene glycol;
Organoboron reagent is diethyl methoxyl group borine, triethyl-boron or tri butyl boron;
Reductive agent is sodium borohydride or POTASSIUM BOROHYDRIDE;
Temperature of reaction is-80 ℃～-30 ℃;
3. compound IV is carried out hydroxyl protection and prepare compound V;
Figure BDA00003588493900052
In the formula, P1, P2 are hydroxyl protecting group, are specially silica-based, the trimethyl silicon based or THP trtrahydropyranyl of the dimethyl tertiary butyl, and perhaps P1 and P2 represent together 1,1 ,-two and replace the methylene alkyl;
4. compound V obtains compound I through peroxidation;
Figure BDA00003588493900061
Reaction solvent is methyl alcohol, ethanol, n-propyl alcohol, Virahol or methylene dichloride, or is the multiple mixed solvent that is comprised of methyl alcohol, ethanol, n-propyl alcohol, Virahol or methylene dichloride.
As the optimization to the synthetic method of aforesaid HMG-CoA reductase inhibitor key intermediate, described step 1. in,
R 2Be the tertiary butyl;
The solvent that reacts used is tetrahydrofuran (THF), glycol dimethyl ether or toluene, or is the multiple mixed solvent that is comprised of tetrahydrofuran (THF), glycol dimethyl ether or toluene;
The metal that reacts used is zinc; The feed ratio of compound I I and zinc is 1mol:2.0～3.0mol;
The reagent of activated zinc is methylsulfonic acid or TMSCl;
The feed ratio of monobromo-acetic acid ester and zinc is 1mol:1.00～1.05mol;
The feed ratio of the reagent of compound I I and activated zinc is 1mol:0.1mol;
Temperature of reaction is 40～70 ℃;
Reaction times is 2.5～3 hours;
After reacting end, cool to 0～5 ℃, drip hydrochloric acid, regulate pH value to 1～4, be incubated again 1～2h, use ethyl acetate extraction, obtain compound III behind organic phase washing, drying, the concentrating under reduced pressure.
As the optimization to the synthetic method of aforesaid HMG-CoA reductase inhibitor key intermediate, described step 2. in,
Reaction solvent is tetrahydrofuran (THF), methyl alcohol or ether, or is the multiple mixed solvent that is comprised of tetrahydrofuran (THF), methyl alcohol or ether;
Organoboron reagent is diethyl methoxyl group borine;
Reductive agent is sodium borohydride;
The feed ratio of reaction is compound III: diethyl methoxyl group borine: sodium borohydride=1mol: 1～2mol:1～2mol;
Temperature of reaction is-80 ℃～-60 ℃;
Reaction times is 3～8 hours;
After reaction was finished, mixture was used ethyl acetate extraction after the cancellation reaction, obtained compound IV behind organic phase washing, drying, the concentrating under reduced pressure.
As the optimization to the synthetic method of aforesaid HMG-CoA reductase inhibitor key intermediate, described step 3. in,
Hydroxyl protecting group is silica-based, the trimethyl silicon based or THP trtrahydropyranyl of the dimethyl tertiary butyl;
Solvent for use is methylene dichloride, tetrahydrofuran (THF), acetonitrile, glycol dimethyl ether or DMF, or is the multiple mixed solvent that is comprised of methylene dichloride, tetrahydrofuran (THF), acetonitrile, glycol dimethyl ether or DMF;
The alkali that adopts is salt of wormwood, yellow soda ash, triethylamine, diisopropyl ethyl amine, imidazoles, pyridine or six hydrogen piperidines;
Reaction is carried out under the temperature of solvent refluxing at 0 ℃;
Reaction times is 5～10 hours;
After reaction was finished, the mixture dilute with water was used ethyl acetate extraction again, obtained compound V behind organic phase washing, drying, the concentrating under reduced pressure.
As the optimization to the synthetic method of aforesaid HMG-CoA reductase inhibitor key intermediate, described step 3. in,
Hydroxyl protecting group is that the dimethyl tertiary butyl is silica-based, THP trtrahydropyranyl;
Solvent for use is methylene dichloride.
As the optimization to the synthetic method of aforesaid HMG-CoA reductase inhibitor key intermediate, described step 3. in,
P1 and P2 represent 1,1-dimethylated methylene alkyl together;
Adopt acetone as solvent and reagent;
Need in the reaction to add catalyzer, catalyzer is methylsulfonic acid, tosic acid or Phenylsulfonic acid, or is the combination of methylsulfonic acid, tosic acid or Phenylsulfonic acid;
The feed ratio of reaction mass is compound IV: catalyzer: acetone=1mol:0.01～0.03mol:1000～1500mL;
Reaction is carried out under-10 ℃～50 ℃;
Reaction times is 3.5～5 hours;
After reaction was finished, mixture was used ethyl acetate extraction again with saturated sodium bicarbonate solution cancellation reaction, obtained compound V behind organic phase washing, drying, the concentrating under reduced pressure.
As the optimization to the synthetic method of aforesaid HMG-CoA reductase inhibitor key intermediate, described step 3. in,
Need in the reaction to add catalyzer, catalyzer is tosic acid;
Reaction is carried out under 30 ℃～50 ℃.
As the optimization to the synthetic method of aforesaid HMG-CoA reductase inhibitor key intermediate, described step 4. in,
Reaction solvent is methyl alcohol, ethanol, n-propyl alcohol, Virahol or methylene dichloride, or is the multiple mixed solvent that is comprised of methyl alcohol, ethanol, n-propyl alcohol, Virahol or methylene dichloride;
Oxygenant is hydrogen peroxide;
The reaction catalyst system therefor is Ammonium Molybdate Tetrahydrate;
The feed ratio of reaction mass is: compound V: Ammonium Molybdate Tetrahydrate: hydrogen peroxide=1mol:0.2～0.8mol:5～20mol;
Temperature of reaction is with being 0 ℃～100 ℃;
After reaction was finished, mixture reacted to the nondiscoloration of starch-kalium iodide test paper with the S-WAT cancellation, uses ethyl acetate extraction again, obtained compound I behind organic phase washing, drying, the concentrating under reduced pressure.
As the optimization to the synthetic method of aforesaid HMG-CoA reductase inhibitor key intermediate, described step 4. in,
The reaction solvent for use is the mixed solvent of methylene dichloride and Virahol;
Temperature of reaction is 0 ℃～30 ℃.
Compared with prior art; the present invention replaces butyronitrile as starting raw material take (S)-3-hydroxyl cheap and easy to get-4-; through the Blaise reaction; reduction; hydroxyl protection; the oxidation four-step reaction makes HMG-CoA reductase inhibitor key intermediate; reaction process is easy and simple to handle; each goes on foot product and is easy to separation and purification; need not silicagel column and carry out purifies and separates; yield is more than 80%; the intermediate that makes has higher chemical purity and optical purity (after measured; chemical purity 〉=99.4%; optical purity 〉=99.3%ee), can be used for easily the suitability for industrialized production of dihydroxy acid HMG CoA reductase inhibitor, remarkable in economical benefits.Compare with the synthetic method (United States Patent (USP) WO02098854) of existing HMG-CoA reductase inhibitor key intermediate, total production cost can reduce more than 1/3.
Embodiment
Embodiment 1.The synthetic method of HMG-CoA reductase inhibitor key intermediate, it may further comprise the steps:
1. zinc powder 47.54Kg and tetrahydrofuran (THF) 500L are joined in the reactor, add again methylsulfonic acid 1.20Kg, stirring heating refluxes, add 80Kg (S)-3-hydroxyl-4-(benzothiazole-2-sulfydryl)-butyronitrile behind the 15min, slowly drip bromo-acetic acid tert-butyl 153.6Kg at once, drip rear insulation backflow 3h, reacted rear cooling, under ice-water bath, slowly drip hydrochloric acid, the pH value is 2 rear insulation 2h, with adding ethyl acetate 500L and water 200L, lower floor again with ethyl acetate extraction once, total organic layer water 100L washing three times, the anhydrous sodium sulfate drying organic layer, filter, the concentrated yellow oil that obtains, (S)-5-hydroxyl-6-(benzothiazole-2-sulfydryl)-3-oxo hecanoic acid t-butyl ester 95Kg.
Wherein, zinc powder can substitute with iron powder or the magnesium powder of same molar;
Tetrahydrofuran (THF) is solvent, solvent can also be ether, ethylene-propylene ether, chloroform, glycol dimethyl ether, benzene, toluene or dimethylbenzene, also can be the multiple mixed solvent that is comprised of ether, ethylene-propylene ether, tetrahydrofuran (THF), chloroform, glycol dimethyl ether, benzene, toluene or dimethylbenzene.
2. 95Kg (S)-5-hydroxyl-6-(benzothiazole-2-sulfydryl)-3-oxo hecanoic acid t-butyl ester is dissolved in 1000L tetrahydrofuran (THF) and the 300L methyl alcohol; be cooled to-78 ℃ under the nitrogen protection; add 275L diethyl methoxyl group boron (the THF solution of 1mol/L); behind the stirring reaction 20min; add sodium borohydride 10.42Kg; behind reaction 3h under this temperature; add 200L acetone and 80L30% hydrogen peroxide; behind-60 ℃ of lower reaction 30min reaction system is poured in the 800L water; ethyl acetate extraction (400L * 2); merge organic phase, organic phase washing (100L * 2), anhydrous sodium sulfate drying; obtain oily matter behind the pressure reducing and steaming solvent; (R, S)-3,5-dihydroxyl-6-(benzothiazole-2-sulfydryl) hecanoic acid t-butyl ester 86Kg.
Wherein, tetrahydrofuran (THF) and methyl alcohol are solvent, solvent can also be tetrahydrofuran (THF), ether, methyl alcohol, ethanol, n-propyl alcohol, Virahol or ethylene glycol, also can be the multiple mixed solvent that is comprised of tetrahydrofuran (THF), ether, methyl alcohol, ethanol, n-propyl alcohol, Virahol or ethylene glycol;
Diethyl methoxyl group boron is organoboron reagent, and organoboron reagent also can adopt triethyl-boron or tri butyl boron;
Sodium borohydride is reductive agent, and reductive agent also can adopt POTASSIUM BOROHYDRIDE.
3. (R, S)-3,5-dihydroxyl-6-(benzothiazole-2-sulfydryl) hecanoic acid t-butyl ester oily matter 86Kg is dissolved in 300L acetone, add tosic acid 0.6Kg, behind 50 ℃ of reaction 4h mixture is poured in the saturated sodium bicarbonate aqueous solution (400L), ethyl acetate extraction (300L * 3), merge organic phase, washing (100L * 3), anhydrous sodium sulfate drying obtains oily matter after removing solvent under reduced pressure, (4R, 6S)-and 6-(benzothiazole-2-sulfydryl) methyl-2,2-dimethyl-1,3-dioxane-4-tert.-butyl acetate 93Kg.
Wherein, acetone is solvent, and hydroxyl protection is carried out in the participation reaction;
Tosic acid is catalyzer, and catalyzer can also adopt methylsulfonic acid or Phenylsulfonic acid, also can adopt the combination of methylsulfonic acid, tosic acid or Phenylsulfonic acid.
4. with 93g (4R, 6S)-6-(benzothiazole-2-sulfydryl) methyl-2,2-dimethyl-1,3-dioxane-4-tert.-butyl acetate is dissolved in the mixture of 50L methylene dichloride and 150L Virahol, then after being cooled to 0 ℃, drip the hydrogen peroxide solution of the 220g30% of the Ammonium Molybdate Tetrahydrate that contains 26.6Kg.Slowly be warming up to room temperature after drip finishing, be cooled to 0 ℃ after react, adding Sulfothiorine determines that with starch potassium iodide paper hydrogen peroxide has destroyed.Add water 400L ethyl acetate and 200L water after removing Virahol under reduced pressure; stir layering; water layer with the 400L ethyl acetate extraction once; again water (100L * 3) washing; organic layer is concentrated to be done; add 400L isopropyl ether reflux 2h; cooling, the above suction filtration of stirring at room 2h, solid washs with isopropyl ether; decompression drying obtains 89.6Kg solid (4R; 6S)-and 6-(benzothiazole-2-alkylsulfonyl) methyl-2,2-dimethyl-1,3-dioxane-4-tert.-butyl acetate; detecting chemical pure is 99.5%, and optical purity is 99.6%ee.
Wherein, the mixture of methylene dichloride and Virahol is solvent, and solvent can also be methyl alcohol, ethanol, n-propyl alcohol, Virahol or methylene dichloride, the multiple mixed solvent that also can be comprised of methyl alcohol, ethanol, n-propyl alcohol, Virahol or methylene dichloride.
Embodiment 2.The synthetic method of HMG-CoA reductase inhibitor key intermediate may further comprise the steps:
1. zinc powder 47.54Kg and tetrahydrofuran (THF) 500L are joined in the reactor, add again TMSCl1.50Kg, stirring heating refluxes, add 85Kg (S)-3-hydroxyl-4-(1-phenyl-1H-tetrazole-5-sulfydryl)-butyronitrile behind the 15min, slowly drip bromo-acetic acid tert-butyl 153.6Kg at once, drip rear insulation backflow 3h, reacted rear cooling, under ice-water bath, slowly drip hydrochloric acid, the pH value is 2 rear insulation 2h, with adding ethyl acetate 500L and water 200L, lower floor again with ethyl acetate extraction once, total organic layer water 100L washing three times, the anhydrous sodium sulfate drying organic layer, filter, the concentrated yellow oil that obtains, (S)-5-hydroxyl-6-(1-phenyl-1H-tetrazole-5-sulfydryl)-3-oxo hecanoic acid t-butyl ester 97Kg.
Wherein, zinc powder can substitute with iron powder or the magnesium powder of same molar;
Tetrahydrofuran (THF) is solvent, solvent can also be ether, ethylene-propylene ether, chloroform, glycol dimethyl ether, benzene, toluene or dimethylbenzene, also can be the multiple mixed solvent that is comprised of ether, ethylene-propylene ether, tetrahydrofuran (THF), chloroform, glycol dimethyl ether, benzene, toluene or dimethylbenzene.
2. 97Kg (S)-5-hydroxyl-6-(1-phenyl-1H-tetrazole-5-sulfydryl)-3-oxo hecanoic acid t-butyl ester is dissolved in 1000L tetrahydrofuran (THF) and the 300L methyl alcohol; be cooled to-78 ℃ under the nitrogen protection; add 275L diethyl methoxyl group boron (the THF solution of 1mol/L); behind the stirring reaction 20min; add sodium borohydride 10.42Kg; behind reaction 3h under this temperature; add 200L acetone and 80L30% hydrogen peroxide; behind-60 ℃ of lower reaction 30min reaction system is poured in the 800L water; ethyl acetate extraction (400L * 2); merge organic phase, organic phase washing (100L * 2), anhydrous sodium sulfate drying; obtain oily matter behind the pressure reducing and steaming solvent; (R, S)-3,5-dihydroxyl-6-(1-phenyl-1H-tetrazole-5-sulfydryl) hecanoic acid t-butyl ester 83Kg.
Wherein, tetrahydrofuran (THF) and methyl alcohol are solvent, solvent can also be tetrahydrofuran (THF), ether, methyl alcohol, ethanol, n-propyl alcohol, Virahol or ethylene glycol, also can be the multiple mixed solvent that is comprised of tetrahydrofuran (THF), ether, methyl alcohol, ethanol, n-propyl alcohol, Virahol or ethylene glycol;
Diethyl methoxyl group boron is organoboron reagent, and organoboron reagent also can adopt triethyl-boron or tri butyl boron;
Sodium borohydride is reductive agent, and reductive agent also can adopt POTASSIUM BOROHYDRIDE.
3. with (R, S)-3,5-dihydroxyl-6-(1-phenyl-1H-tetrazole-5-sulfydryl) hecanoic acid t-butyl ester oily matter 83Kg is dissolved in 300L acetone, add tosic acid 0.6Kg, behind 50 ℃ of reaction 4h mixture is poured in the saturated sodium bicarbonate aqueous solution (400L), ethyl acetate extraction (300L * 3), merge organic phase, washing (100L * 3), anhydrous sodium sulfate drying obtains oily matter after removing solvent under reduced pressure, (4R, 6S)-and 6-(1-phenyl-1H-tetrazole-5-sulfydryl) methyl-2,2-dimethyl-1,3-dioxane-4-tert.-butyl acetate 90Kg.
Wherein, acetone is solvent, and hydroxyl protection is carried out in the participation reaction;
Tosic acid is catalyzer, and catalyzer can also adopt methylsulfonic acid or Phenylsulfonic acid, also can adopt the combination of methylsulfonic acid, tosic acid or Phenylsulfonic acid.
4. with 90Kg (4R, 6S)-6-(1-phenyl-1H-tetrazole-5-sulfydryl) methyl-2,2-dimethyl-1,3-dioxane-4-tert.-butyl acetate is dissolved in the mixture of 50L methylene dichloride and 150L Virahol, then after being cooled to 0 ℃, drip the hydrogen peroxide solution of the 220Kg30% of the Ammonium Molybdate Tetrahydrate that contains 26.6Kg.Slowly be warming up to room temperature after drip finishing, be cooled to 0 ℃ after react, adding Sulfothiorine determines that with starch potassium iodide paper hydrogen peroxide has destroyed.Add water 400L ethyl acetate and 200L water after removing Virahol under reduced pressure, stir layering, water layer with the 400L ethyl acetate extraction once, again water (100L * 3) washing, organic layer is concentrated to be done, add 400L isopropyl ether reflux 2h, cooling, the above suction filtration of stirring at room 2h, solid washs with isopropyl ether, decompression drying obtains 87.3Kg solid (4R, 6S)-and 6-(1-phenyl-1H-tetrazole-5-sulfydryl) methyl-2,2-dimethyl-1,3-dioxane-4-tert.-butyl acetate, detecting chemical pure is 99.5%, and optical purity is 99.5%ee.
Wherein, the mixture of methylene dichloride and Virahol is solvent, and solvent can also be methyl alcohol, ethanol, n-propyl alcohol, Virahol or methylene dichloride, the multiple mixed solvent that also can be comprised of methyl alcohol, ethanol, n-propyl alcohol, Virahol or methylene dichloride.
Above-mentioned generality to the invention that relates among the application is described and the description of its embodiment be should not be understood as the restriction that this invention technical scheme is consisted of.Those skilled in the art disclose according to the application's, can be under the prerequisite of related invention integrant, to above-mentioned general the description or/and the public technology feature in the embodiment (comprising embodiment) increases, reduces or makes up, formation belongs to other technical scheme of described invention.

Claims (10)

1.HMG-CoA the synthetic method of reductase inhibitor key intermediate is characterized in that: may further comprise the steps:
1. compound I I and bromacetate are through Blaise reaction preparation beta-ketoester III;
Figure FDA00003588493800011
In the formula, R 1For
Figure FDA00003588493800012
Methyl or trifluoromethyl;
Figure FDA00003588493800013
In R 4aAlkyl, aralkyl, aryl or cycloalkyl;
In R 5Hydrogen, alkyl, aralkyl, aryl, CF 3, halogen or nitro;
Figure FDA00003588493800015
In Xa be oxygen or sulphur;
R 2Be alkyl, aralkyl, aryl or cycloalkyl;
2. compound III is in the presence of organoboron reagent, through reductive agent reduction preparation dihydroxy compound IV;
Organoboron reagent is diethyl methoxyl group borine, triethyl-boron or tri butyl boron;
Reductive agent is sodium borohydride or POTASSIUM BOROHYDRIDE;
3. compound IV is carried out hydroxyl protection and prepare compound V;
Figure FDA00003588493800021
In the formula, P1, P2 are hydroxyl protecting group;
4. compound V obtains compound I through peroxidation;
Figure FDA00003588493800022
In the formula, oxygenant is superoxide.
2. the synthetic method of HMG-CoA reductase inhibitor key intermediate according to claim 1 is characterized in that: may further comprise the steps:
1. compound I I and bromacetate are through Blaise reaction preparation beta-ketoester III;
Figure FDA00003588493800023
In the formula, R 1For
Figure FDA00003588493800024
R 2Be methyl, ethyl, propyl group, the tertiary butyl or benzyl;
The solvent that reacts used is ether, ethylene-propylene ether, tetrahydrofuran (THF), chloroform, glycol dimethyl ether, benzene, toluene or dimethylbenzene, or is the multiple mixed solvent that is comprised of ether, ethylene-propylene ether, tetrahydrofuran (THF), chloroform, glycol dimethyl ether, benzene, toluene or dimethylbenzene;
The metal that reacts used is zinc, iron or magnesium; The feed ratio of compound I I and metal is 1:1～4mol;
React used metal needs activation, the reagent of activated metal is TMSCl, R 3SO 3H or R 3SO 3TMS, wherein, R 3The aromatic hydrocarbon of the saturated or unsaturated hydrocarbons of the C1-C6 class that replaces for the saturated or unsaturated hydrocarbons of hydrogen, C1-C6 class, with halogen, the aromatic hydrocarbon of C6-C12 or the C6-C12 that replaces with halogen;
The feed ratio of bromacetate and metal is 1mol:1.00～1.10mol;
The feed ratio of the reagent of activated metal and compound I I is 1mol:0.05～0.5mol;
Temperature of reaction is 20～110 ℃;
Reaction times is 1.5～4h;
2. compound III is in the presence of organoboron reagent, through reductive agent reduction preparation dihydroxy compound IV;
Reaction solvent is tetrahydrofuran (THF), ether, methyl alcohol, ethanol, n-propyl alcohol, Virahol or ethylene glycol, or is the multiple mixed solvent that is comprised of tetrahydrofuran (THF), ether, methyl alcohol, ethanol, n-propyl alcohol, Virahol or ethylene glycol;
Organoboron reagent is diethyl methoxyl group borine, triethyl-boron or tri butyl boron;
Reductive agent is sodium borohydride or POTASSIUM BOROHYDRIDE;
Temperature of reaction is-80 ℃～-30 ℃;
3. compound IV is carried out hydroxyl protection and prepare compound V;
In the formula, P1, P2 are hydroxyl protecting group, are specially silica-based, the trimethyl silicon based or THP trtrahydropyranyl of the dimethyl tertiary butyl, and perhaps P1 and P2 represent together 1,1 ,-two and replace the methylene alkyl;
4. compound V obtains compound I through peroxidation;
Reaction solvent is methyl alcohol, ethanol, n-propyl alcohol, Virahol or methylene dichloride, or is the multiple mixed solvent that is comprised of methyl alcohol, ethanol, n-propyl alcohol, Virahol or methylene dichloride.
3. the synthetic method of HMG-CoA reductase inhibitor key intermediate according to claim 2 is characterized in that: described step 1. in,
R 2Be the tertiary butyl;
The solvent that reacts used is tetrahydrofuran (THF), glycol dimethyl ether or toluene, or is the multiple mixed solvent that is comprised of tetrahydrofuran (THF), glycol dimethyl ether or toluene;
The metal that reacts used is zinc; The feed ratio of compound I I and zinc is 1mol:2.0～3.0mol;
The reagent of activated zinc is methylsulfonic acid or TMSCl;
The feed ratio of monobromo-acetic acid ester and zinc is 1mol:1.00～1.05mol;
The feed ratio of the reagent of compound I I and activated zinc is 1mol:0.1mol;
Temperature of reaction is 40～70 ℃;
Reaction times is 2.5～3 hours;
After reacting end, cool to 0～5 ℃, drip hydrochloric acid, regulate pH value to 1～4, be incubated again 1～2h, use ethyl acetate extraction, obtain compound III behind organic phase washing, drying, the concentrating under reduced pressure.
4. the synthetic method of HMG-CoA reductase inhibitor key intermediate according to claim 3 is characterized in that: described step 2. in,
Reaction solvent is tetrahydrofuran (THF), methyl alcohol or ether, or is the multiple mixed solvent that is comprised of tetrahydrofuran (THF), methyl alcohol or ether;
Organoboron reagent is diethyl methoxyl group borine;
Reductive agent is sodium borohydride;
The feed ratio of reaction is compound III: diethyl methoxyl group borine: sodium borohydride=1mol:1～2mol:1～2mol;
Temperature of reaction is-80 ℃～-60 ℃;
Reaction times is 3～8 hours;
After reaction was finished, mixture was used ethyl acetate extraction after the cancellation reaction, obtained compound IV behind organic phase washing, drying, the concentrating under reduced pressure.
5. the synthetic method of HMG-CoA reductase inhibitor key intermediate according to claim 4 is characterized in that: described step 3. in,
Hydroxyl protecting group is silica-based, the trimethyl silicon based or THP trtrahydropyranyl of the dimethyl tertiary butyl;
Solvent for use is methylene dichloride, tetrahydrofuran (THF), acetonitrile, glycol dimethyl ether or DMF, or is the multiple mixed solvent that is comprised of methylene dichloride, tetrahydrofuran (THF), acetonitrile, glycol dimethyl ether or DMF;
The alkali that adopts is salt of wormwood, yellow soda ash, triethylamine, diisopropyl ethyl amine, imidazoles, pyridine or six hydrogen piperidines;
Reaction is carried out under the temperature of solvent refluxing at 0 ℃;
Reaction times is 5～10 hours;
After reaction was finished, the mixture dilute with water was used ethyl acetate extraction again, obtained compound V behind organic phase washing, drying, the concentrating under reduced pressure.
6. the synthetic method of HMG-CoA reductase inhibitor key intermediate according to claim 5 is characterized in that: described step 3. in,
Hydroxyl protecting group is that the dimethyl tertiary butyl is silica-based, THP trtrahydropyranyl;
Solvent for use is methylene dichloride.
7. the synthetic method of HMG-CoA reductase inhibitor key intermediate according to claim 4 is characterized in that: described step 3. in,
P1 and P2 represent 1,1-dimethylated methylene alkyl together;
Adopt acetone as solvent and reagent;
Need in the reaction to add catalyzer, catalyzer is methylsulfonic acid, tosic acid or Phenylsulfonic acid, or is the combination of methylsulfonic acid, tosic acid or Phenylsulfonic acid;
The feed ratio of reaction mass is compound IV: catalyzer: acetone=1mol:0.01～0.03mol:1000～1500mL;
Reaction is carried out under-10 ℃～50 ℃;
Reaction times is 3.5～5 hours;
After reaction was finished, mixture was used ethyl acetate extraction again with saturated sodium bicarbonate solution cancellation reaction, obtained compound V behind organic phase washing, drying, the concentrating under reduced pressure.
8. the synthetic method of HMG-CoA reductase inhibitor key intermediate according to claim 7 is characterized in that: described step 3. in,
Need in the reaction to add catalyzer, catalyzer is tosic acid;
Reaction is carried out under 30 ℃～50 ℃.
9. according to claim 5 to the synthetic method of the described HMG-CoA reductase inhibitor of 8 arbitrary claims key intermediate, it is characterized in that: described step 4. in,
Reaction solvent is methyl alcohol, ethanol, n-propyl alcohol, Virahol or methylene dichloride, or is the multiple mixed solvent that is comprised of methyl alcohol, ethanol, n-propyl alcohol, Virahol or methylene dichloride;
Oxygenant is hydrogen peroxide;
The reaction catalyst system therefor is Ammonium Molybdate Tetrahydrate;
The feed ratio of reaction mass is: compound V: Ammonium Molybdate Tetrahydrate: hydrogen peroxide=1mol:0.2～0.8mol:5～20mol;
Temperature of reaction is with being 0 ℃～100 ℃;
After reaction was finished, mixture reacted to starch with the S-WAT cancellation--the potassium iodide starch paper nondiscoloration, use again ethyl acetate extraction, and obtain compound I behind organic phase washing, drying, the concentrating under reduced pressure.
10. the synthetic method of HMG-CoA reductase inhibitor key intermediate according to claim 9 is characterized in that: described step 4. in,
The reaction solvent for use is the mixed solvent of methylene dichloride and Virahol;
Temperature of reaction is 0 ℃～30 ℃.
CN201310326726XA 2013-07-30 2013-07-30 Synthetic method for key intermediate of HMG-CoA reductase inhibitor Pending CN103360384A (en)

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