CN103288871A - Intermediate for preparing dihydroxy acid HMG-CoA reductase inhibitor, and preparation method and applications thereof - Google Patents
Intermediate for preparing dihydroxy acid HMG-CoA reductase inhibitor, and preparation method and applications thereof Download PDFInfo
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- CN103288871A CN103288871A CN2012101889451A CN201210188945A CN103288871A CN 103288871 A CN103288871 A CN 103288871A CN 2012101889451 A CN2012101889451 A CN 2012101889451A CN 201210188945 A CN201210188945 A CN 201210188945A CN 103288871 A CN103288871 A CN 103288871A
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Abstract
The invention discloses an intermediate for preparing dihydroxy acid HMG-CoA reductase inhibitor with a general formula shown in the specification, a preparation method of the intermediate, and a method for preparing dihydroxy acid HMG-CoA reductase inhibitor (general formula) or salts or lactones of the dihydroxy acid HMG-CoA reductase inhibitor by using the intermediate. The invention provides an intermediate for preparing a dihydroxy acid HMG-CoA reductase inhibitor. In the case that the intermediate is used for preparing the dihydroxy acid HMG-CoA reductase inhibitor, fewer reaction steps are carried out, the processes are simple and convenient to operate, the pollution is hardly caused, the energy consumption is low, the obtained partial oily matters are directly used for next production step without being refined, the yield of products can reach 85%, the dihydroxy acid HMG-CoA reductase inhibitor with high chemical purity and optical purity can be obtained, the high energy consumption and low area caused by chiral resolution can be avoided, the dihydroxy acid HMG-CoA reductase inhibitor can be conveniently used for industrial production; and the method for preparing the intermediate is simple.
Description
Technical field
the present invention relates to a kind of blood lipid-lowering medicine intermediate and its preparation method and application, relate in particular to a kind of intermediate that dihydroxy acid HMG CoA reductase inhibitor uses and its preparation method and application for preparing.
Background technology
hMG-CoA reductase inhibitor (HMG-CoA reductase inhibitor), or claim him 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.There are exogenous and two kinds of approach of endogenous in cholesterol source in blood plasma.Exogenous cholesterol, mainly from food, can be controlled intake by regulating foodstuff texture; Endogenic synthetic in liver.In hepatocellular tenuigenin, by acetic acid, through 26 step biosynthesizing steps, synthesize endogenous cholesterol.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, endogenous cholesterol is synthetic reduces.The statins medicine 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 to be increased, 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, its effect for reducing fat of rosuvastain calcium of new statins-Astrazeneca company is powerful, uses and surpasses every other statins separately, is known as " superstatin ".Statins is efficient, safety, be the choice drug in fat-reducing medicament.
statins is due to complex structure, synthetic more difficult, and many synthetic methods are arranged in prior art, but at the bottom of all having yield, the defects such as 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 the Julia-Kocienski reaction to prepare 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, be applicable to suitability for industrialized production, but maximum shortcoming is that chirality sulfone reagent preparation cost is large, has limited greatly its industrial application, need to particularly need to use the reagent of a large amount of costlinesses: trifluoromethanesulfanhydride anhydride.
Summary of the invention
the object of the invention is to, a kind of intermediate that dihydroxy acid HMG CoA reductase inhibitor uses and its preparation method and application for preparing is provided.Intermediate of the present invention has the characteristics that prepare, cost is low that are easy to; Utilize this intermediate to prepare the dihydroxy acid HMG CoA reductase inhibitor reactions steps short, process operation is easy, pollute little, energy consumption is low, the part oily matter of gained is directly used in next step production without making with extra care, product yield is high, obtain the dihydroxy acid HMG CoA reductase inhibitor of higher chemical purity and optical purity, avoided high energy consumption and the low area of chiral separation, can be easily for suitability for industrialized production; And the method for preparing this intermediate is simple.
for solving the problems of the technologies described above, technical scheme provided by the invention is as follows:
a kind ofly prepare the intermediate that dihydroxy acid HMG CoA reductase inhibitor is used, general formula is
, wherein X1 is hydroxyl protecting group; X2 is hydrogen or the alkyl that contains a C atom to seven a C atom; X3 is hydrogen or one or more substituting group, alkanoyloxy, halogen, nitro, cyano group or trifluoromethyl that substituting group is selected from alkyl, the hydroxyl that contains a C atom to seven a C atom, the alkoxyl group that contains a C atom to seven a C atom, contains two C atoms to eight C atom; Y is phosphoric acid ester or alkyl phosphonium salt.
aforesaid a kind of the preparation in the intermediate that dihydroxy acid HMG CoA reductase inhibitor uses, described X1 is hydrogen, tertiary butyl dimethylsilyl (TBS), tert-butyl diphenyl silylation (TBDPS), TMS (TMS), THP trtrahydropyranyl (THP) or 1-ethoxyethyl group (E.E); Described X2 is hydrogen or methyl; Described X3 is hydrogen; Described Y is dimethyl phosphate base or p diethylaminobenzoic acid ester group.
aforesaid a kind of the preparation in the intermediate that dihydroxy acid HMG CoA reductase inhibitor uses, X1 is tertiary butyl dimethylsilyl or TMS, and described X2 is methyl or hydrogen.
prepare the method for the intermediate that aforementioned dihydroxy acid HMG CoA reductase inhibitor uses, the steps include:
i. by methyl phosphorodithioate
or methyl trialkyl halogenation phosphine
form corresponding inner salt with the metallization alkane reaction;
ii. the inner salt obtained is reacted and obtains preparing the intermediate that dihydroxy acid HMG CoA reductase inhibitor is used with compound c; The general formula of compound c is 
;
wherein X4 and X5 independently represent the alkyl that contains a C atom to seven a C atom of the alkyl or phenyl replacement that contains a C atom to seven a C atom; X6, X7 and X8 independently represent unsubstituted or are selected from the phenyl that following one or more substituting groups replace: alkyl, the hydroxyl that contains a C atom to seven a C atom, the alkoxyl group that contains a C atom to seven a C atom, the alkanoyloxy, halogen, nitro, cyano group and the trifluoromethyl that contain two C atoms to eight C atom; Hal
-
represent halide anions.
the solvent that this reaction adopts is ethers, halohydrocarbon or aromatic solvents or its mixture, be specially one or more the mixture in ether, ethylene-propylene ether, tetrahydrofuran (THF), chloroform, glycol dimethyl ether, benzene, toluene and dimethylbenzene, preferably the mixture of one or more in tetrahydrofuran (THF), glycol dimethyl ether and toluene.
the metallization alkane that this reaction adopts is n-Butyl Lithium (n-BuLi), isobutyl-lithium (s-BuLi), tert-butyl lithium (BuLi) or two (TMS) Lithamide (LiHMDS).
the feed ratio of reaction is compound III c: alkali: compound III a or IIIb=1mol:2～5mol:2～5mol is preferably compound III c: alkali: compound III a or IIIb=1mol:3.8～4.2mol:3.8～4.2mol.After having reacted, mixture uses salt acid for adjusting pH value to 1 to 4, then is extracted with ethyl acetate, and after organic phase washing, drying, concentrating under reduced pressure, obtains preparing the intermediate that dihydroxy acid HMG CoA reductase inhibitor is used.
temperature of reaction in present method is difference to some extent with the difference of reaction reagent, and general temperature of reaction is-80
o
c～-30
o
at the temperature of C, carry out, preferable reaction temperature is-80
o
c～-60
o
c; Reaction times, the reaction times was generally 1.5～4 hours with the difference of reaction reagent and temperature of reaction and different, and the preferred reaction time is 2.5～3 hours.
a kind ofly utilize aforementioned intermediate to prepare dihydroxy acid HMG CoA reductase inhibitor (general formula
) or the method for its salt or its lactone, it is characterized in that, the method is:
a. intermediate is converted into to Verbindung, the general formula of Verbindung is
, wherein Y1 representation hydroxy or protected hydroxyl, Y2 is hydroxyl or protected hydroxyl, Y3 represents hydrogen, and Y1 and Y2 form cis two alcohol configurations; Or wherein represent together with Y2-O-Alk-O-of Y1 and Alk are the alkylidene group that contains a C atom to seven a C atom, Y3 represents hydrogen, and Y1 and Y2 form cis two alcohol configurations.
in this step, transform and comprise reduction and protect two steps.
reduction step is: with suitable reductive agent reduction intermediate, obtain reducing after product.
reductive agent is metal hydride, the boride with reductibility, the mixture of one or more in preferred sodium borohydride, POTASSIUM BOROHYDRIDE, tetrahydrochysene lithium aluminium, diethyl methoxyl group borine, triethyl-boron and tri butyl boron, the more preferably mixture of one or more in diethyl methoxyl group borine, sodium borohydride and triethyl-boron.
reduction reaction is reacted in inert solvent, as ethers, halohydrocarbon or aromatic solvents or its mixture, be specially one or more the mixture in ether, ethylene-propylene ether, tetrahydrofuran (THF), chloroform, glycol dimethyl ether, benzene, toluene and dimethylbenzene, preferably the mixture of one or more in tetrahydrofuran (THF), glycol dimethyl ether and toluene.
temperature of reaction is difference to some extent with the difference of reaction reagent, and general temperature of reaction is-80
o
c～-30
o
at the temperature of C, carry out, preferable reaction temperature is-80
o
c～-60
o
c; Reaction times, the reaction times was generally 3～8 hours with the difference of reaction reagent and temperature of reaction and different.
the feed ratio of reaction is compound III d: borine: metal hydride=1mol:1～2mol:1～2mol.
the protection step is: utilize the different original reagents of going back to reduce; in the reduction after product that those Y2 representation hydroxies that obtain and Y3 are represented as hydrogen; hydroxyl Y2 is by protected with halide reaction; halogenide is as dimethyl tertiary butyl chloride silane (TBSCl), trimethylchlorosilane (TMSCl); obtain Verbindung, wherein Y1 representation hydroxy or protected hydroxyl, Y2 is protected hydroxyl; Y3 represents hydrogen, and Y1 and Y2 form cis glycol configuration for preparation formula (IIIe) compound.
utilize the different original reagents of going back to reduce; in the reduction after product that those Y2 representation hydroxies that obtain and Y3 are represented as hydrogen; protected hydroxyl Y1 is by processing and be removed as mineral acid hydrochloric acid, sulfuric acid, phosphoric acid with strong acid; obtain Verbindung; wherein Y1 and Y2 representation hydroxy; Y3 represents hydrogen, and Y1 and Y2 formation cis two alcohol configurations.
utilize the different original reagents of going back to reduce, represent hydrogen at those Y1 that obtain representation hydroxy and Y3 together with Y2, and Y1 and Y2 form in cis two alcohol configuration reduction after products, by under alkali exists by Hal-Alk-Hal compound treatment etherificate for formula, obtain Verbindung, wherein represent together with Y2-O-Alk-O-of Y1 and Alk are the C1-C7 alkylidene group, and Y3 represents hydrogen, and Y1 and Y2 formation cis two alcohol configurations.
verbindung, with aldehyde R-CH=O, wittig is occurred to and react, form compound g, the general formula of compound g is
, wherein R is selected from following cyclic group
this reaction is carried out under following material exists: alkali is as alkane basic metal, especially butyllithium; Perhaps hydride is as sodium hydride; Or alkaline carbonate, as salt of wormwood, cesium carbonate; Perhaps large volume amine, as 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene (DBU); This reaction is reacted in organic solvent, as ethers, alcohols or halohydrocarbon or its mixture, be specially one or more the mixture in ether, tetrahydrofuran (THF), chloroform, methylene dichloride, ethanol and Virahol, preferably the mixture of one or more in tetrahydrofuran (THF), methylene dichloride and Virahol.Temperature of reaction is the boiling point to solvent at-78 degree, preferably the temperature from room temperature to 45 degree, carries out, and actual temp depends on alkali used and solvent.
the feed ratio of reaction is compound III e: aldehyde: alkali=1mol:0.5～2mol:0.5～2mol.
after having reacted, mixture filters, and after filtrate decompression is concentrated, obtains compound III g
c. described compound g is removed to hydroxyl protecting group, obtain compound h, the general formula of compound h is
.
remove hydroxyl protecting group or division-O-Alk-O-group by strong acid treatment, described strong acid is hydrochloric acid, sulfuric acid or phosphoric acid, preferably hydrochloric acid.
if wherein protected hydroxyl is siloxy, it will be by processing as tetrabutyl ammonium fluoride with fluoride salt or with sour example hydrochloric acid, sulfuric acid or phosphoric acid, particularly salt acid treatment.
reaction is carried out in as methylene dichloride at inert solvent, and the boiling point of temperature of reaction from 0 degree to solvent, preferably from room temperature to 40 degree.
compound h is obtained to reaction mixture by the strong lye solution, and wherein highly basic is preferably the alkali metal hydroxide that comprises sodium hydroxide or calcium hydroxide; Method for hydrolysis is the routine hydrolysis method.
the reaction mixture of gained in step D is separated, obtain the mixture that product is dihydroxy acid HMG CoA reductase inhibitor and salt and lactone; Separation method is conventional separation method.
by conventional method for transformation, by three kinds of Substance Transformations in mixture, be dihydroxy acid HMG CoA reductase inhibitor or its salt or its lactone;
the method or be:
a. intermediate, with aldehyde R-CH=O, wittig is occurred to and react, form compound g, the general formula of compound g is
, wherein Y2 represents the oxo base together with Y3, Y1 represents protected hydroxyl; Wherein R is selected from following cyclic group
this reaction is carried out under following material exists: alkali for example, as alkane basic metal, butyllithium; Perhaps hydride is as sodium hydride; Or alkaline carbonate, as salt of wormwood, cesium carbonate; Perhaps large volume amine, as 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene (DBU); This reaction is reacted in organic solvent, as ethers, alcohols or halohydrocarbon or its mixture, be specially one or more the mixture in ether, tetrahydrofuran (THF), chloroform, methylene dichloride, ethanol and Virahol, preferably the mixture of one or more in tetrahydrofuran (THF), methylene dichloride and Virahol.Temperature of reaction is the boiling point to solvent at-78 degree, preferably the temperature from room temperature to 45 degree, carries out, and actual temp depends on alkali used and solvent.
the feed ratio of reaction is compound III d: aldehyde: alkali=1mol:0.5～2mol:0.5～2mol.
after having reacted, mixture filters, and after filtrate decompression is concentrated, obtains compound III g.
by removing hydroxyl protecting group, described compound g is converted into to compound i, then described compound i is reduced to compound h, wherein compound i general formula is
, the general formula of compound h is
.
remove hydroxyl protecting group by strong acid treatment, described strong acid is hydrochloric acid, sulfuric acid or phosphoric acid, preferably hydrochloric acid.
if wherein protected hydroxyl is siloxy, also can be by processing as tetrabutyl ammonium fluoride with fluoride salt.
reaction is carried out in as methylene dichloride at inert solvent, and the boiling point of temperature of reaction from 0 degree to solvent, preferably from room temperature to 40 degree.
compound h is obtained to reaction mixture by the strong lye solution, and wherein highly basic is the alkali metal hydroxide that comprises sodium hydroxide or calcium hydroxide; Method for hydrolysis is the routine hydrolysis method.
the reaction mixture of gained in step c is separated, obtain the mixture that product is dihydroxy acid HMG CoA reductase inhibitor and salt and lactone; Separation method is conventional separation method.
by conventional method for transformation, transfer three kinds of materials in mixture to dihydroxy acid HMG CoA reductase inhibitor or its salt or its lactone.
in the aforesaid method for preparing dihydroxy acid HMG CoA reductase inhibitor or its salt or its lactone, described R is preferably
or
.
in the aforesaid method for preparing dihydroxy acid HMG CoA reductase inhibitor or its salt or its lactone, described Alk is preferably 1,1-dimethylated methylene base.
in the present invention can be prepared by following synthetic route by compound c:
specific as follows:
route one:
hydroxyl protection: in certain temperature and solvent, 3-hydroxyl Methyl glutarate (IIIo) and hydroxyl protection radical reaction are prepared to formula (IIIp) compound p.
aminolysis: in certain temperature and solvent, formula (IIIp) compound p reacts with formula (IIIj) compound or its racemic mixture under enzyme catalysis, obtains compound c.
route two:
aminolysis: in certain temperature and solvent, 3-hydroxyl Methyl glutarate (IIIo) reacts the hydroxyl protection radical reaction with formula (IIIj) compound or its racemic mixture and prepares formula (IIIq) compound under enzyme catalysis.
hydroxyl protection: in certain temperature and solvent, formula (IIIq) compound and hydroxyl protection radical reaction are prepared to formula (IIIp) compound p.
but the aminolysis reaction reference that enzyme participates in report, concrete as:
j. Org. Chem.1999,
64,1464-1470 and Tetrahedron:
asymmetrypergamon 14 (2003) 603 – 609.
compared with prior art, the invention provides a kind of intermediate that dihydroxy acid HMG CoA reductase inhibitor is used for preparing, utilize this intermediate kind to prepare the dihydroxy acid HMG CoA reductase inhibitor reactions steps short, process operation is easy, pollute little, energy consumption is low, the part oily matter of gained is directly used in next step production without making with extra care, product yield can reach 85%, obtain the dihydroxy acid HMG CoA reductase inhibitor of higher chemical purity and optical purity, avoided high energy consumption and the low area of chiral separation, can be easily for suitability for industrialized production; And the method for preparing this intermediate is simple.
below the present invention is further illustrated, but not as the foundation to the present invention restriction.
Embodiment
a kind ofly prepare the intermediate that dihydroxy acid HMG CoA reductase inhibitor is used, general formula is
, wherein X1 is hydroxyl protecting group; X2 is hydrogen or the alkyl that contains a C atom to seven a C atom; X3 is hydrogen or one or more substituting group, alkanoyloxy, halogen, nitro, cyano group or trifluoromethyl that substituting group is selected from alkyl, the hydroxyl that contains a C atom to seven a C atom, the alkoxyl group that contains a C atom to seven a C atom, contains two C atoms to eight C atom; Y is phosphoric acid ester or alkyl phosphonium salt.
be preferably hydrogen, tertiary butyl dimethylsilyl (TBS), tert-butyl diphenyl silylation (TBDPS), TMS (TMS), THP trtrahydropyranyl (THP) or 1-ethoxyethyl group (E.E); X2 is preferably hydrogen or methyl; Described X3 is preferably hydrogen; Described Y is preferably dimethyl phosphate base or p diethylaminobenzoic acid ester group.
more elect tertiary butyl dimethylsilyl or TMS as, X2 more elects methyl or hydrogen as.
prepare the method for the intermediate that dihydroxy acid HMG CoA reductase inhibitor uses, the steps include:
i. by methyl phosphorodithioate
or methyl trialkyl halogenation phosphine
form corresponding inner salt with the metallization alkane reaction;
ii. the inner salt obtained is reacted and obtains preparing the intermediate that dihydroxy acid HMG CoA reductase inhibitor is used with compound c; The general formula of compound c is 
;
wherein X4 and X5 independently represent the alkyl that contains a C atom to seven a C atom of the alkyl or phenyl replacement that contains a C atom to seven a C atom; X6, X7 and X8 independently represent unsubstituted or are selected from the phenyl that following one or more substituting groups replace: alkyl, the hydroxyl that contains a C atom to seven a C atom, the alkoxyl group that contains a C atom to seven a C atom, the alkanoyloxy, halogen, nitro, cyano group and the trifluoromethyl that contain two C atoms to eight C atom; Hal
-
represent halide anions.
the solvent that this reaction adopts is ethers, halohydrocarbon or aromatic solvents or its mixture, be specially one or more the mixture in ether, ethylene-propylene ether, tetrahydrofuran (THF), chloroform, glycol dimethyl ether, benzene, toluene and dimethylbenzene, preferably the mixture of one or more in tetrahydrofuran (THF), glycol dimethyl ether and toluene.
the metallization alkane that this reaction adopts is n-Butyl Lithium (n-BuLi), isobutyl-lithium (s-BuLi), tert-butyl lithium (BuLi) or two (TMS) Lithamide (LiHMDS).
the feed ratio of reaction is compound III c: alkali: compound III a or IIIb=1mol:2～5mol:2～5mol is preferably compound III c: alkali: compound III a or IIIb=1mol:3.8～4.2mol:3.8～4.2mol.After having reacted, mixture uses salt acid for adjusting pH value to 1 to 4, then is extracted with ethyl acetate, and after organic phase washing, drying, concentrating under reduced pressure, obtains preparing the intermediate that dihydroxy acid HMG CoA reductase inhibitor is used.
temperature of reaction in present method is difference to some extent with the difference of reaction reagent, and general temperature of reaction is-80
o
c is to-30
o
at the temperature of C, carry out, preferable reaction temperature is-80
o
c is to-60
o
c; Reaction times, the reaction times was generally 1.5 to 4 hours with the difference of reaction reagent and temperature of reaction and different, and the preferred reaction time is 2.5 to 3 hours.
a kind of intermediate that utilizes prepares dihydroxy acid HMG CoA reductase inhibitor (general formula
) or the method for its salt or its lactone, it is characterized in that, the method is:
a. intermediate is converted into to Verbindung, the general formula of Verbindung is
, wherein Y1 representation hydroxy or protected hydroxyl, Y2 is hydroxyl or protected hydroxyl, Y3 represents hydrogen, and Y1 and Y2 form cis two alcohol configurations; Or wherein represent together with Y2-O-Alk-O-of Y1 and Alk are the alkylidene group that contains a C atom to seven a C atom, Y3 represents hydrogen, and Y1 and Y2 form cis two alcohol configurations.
in this step, transform and comprise reduction and protect two steps;
reduction step is: with suitable reductive agent reduction intermediate, obtain reducing after product.
reductive agent is metal hydride, the boride with reductibility, the mixture of one or more in preferred sodium borohydride, POTASSIUM BOROHYDRIDE, tetrahydrochysene lithium aluminium, diethyl methoxyl group borine, triethyl-boron and tri butyl boron, the more preferably mixture of one or more in diethyl methoxyl group borine, sodium borohydride and triethyl-boron.
reduction reaction is reacted in inert solvent, as ethers, halohydrocarbon or aromatic solvents or its mixture, be specially one or more the mixture in ether, ethylene-propylene ether, tetrahydrofuran (THF), chloroform, glycol dimethyl ether, benzene, toluene and dimethylbenzene, preferably the mixture of one or more in tetrahydrofuran (THF), glycol dimethyl ether and toluene.
temperature of reaction is difference to some extent with the difference of reaction reagent, and general temperature of reaction is-80
o
c～-30
o
at the temperature of C, carry out, preferable reaction temperature is-80
o
c～-60
o
c; Reaction times, the reaction times was generally 3～8 hours with the difference of reaction reagent and temperature of reaction and different.
the feed ratio of reaction is compound III d: borine: metal hydride=1mol:1～2mol:1～2mol.
the protection step is: utilize the different original reagents of going back to reduce; in those Y2 representation hydroxies that obtain and Y3 are represented as the hydrogen reduction after product; hydroxyl Y2 is by protected with halide reaction; halogenide is as dimethyl tertiary butyl chloride silane (TBSCl), trimethylchlorosilane (TMSCl); obtain Verbindung, wherein Y1 representation hydroxy or protected hydroxyl, Y2 is protected hydroxyl; Y3 represents hydrogen, and Y1 and Y2 form cis glycol configuration for preparation formula (IIIe) compound.
utilize the different original reagents of going back to reduce; in those Y2 representation hydroxies that obtain and Y3 are represented as the hydrogen reduction after product; protected hydroxyl Y1 is by processing and be removed as mineral acid hydrochloric acid, sulfuric acid, phosphoric acid with strong acid; obtain Verbindung; wherein Y1 and Y2 representation hydroxy; Y3 represents hydrogen, and Y1 and Y2 formation cis two alcohol configurations.
utilize the different original reagents of going back to reduce, represent hydrogen at those Y1 that obtain representation hydroxy and Y3 together with Y2, and Y1 and Y2 form in cis two alcohol configuration reduction after products, by under alkali exists by Hal-Alk-Hal compound treatment etherificate for formula, obtain Verbindung, wherein represent together with Y2-O-Alk-O-of Y1 and Alk are the C1-C7 alkylidene group, and Y3 represents hydrogen, and Y1 and Y2 formation cis two alcohol configurations.
verbindung, with aldehyde R-CH=O, wittig is occurred to and react, form compound g, the general formula of compound g is
, wherein R is selected from following cyclic group
this reaction is carried out under following material exists: alkali is as alkane basic metal, especially butyllithium; Perhaps hydride is as sodium hydride; Or alkaline carbonate, as salt of wormwood, cesium carbonate; Perhaps large volume amine, as 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene (DBU); This reaction is reacted in organic solvent, as ethers, alcohols or halohydrocarbon or its mixture, be specially one or more the mixture in ether, tetrahydrofuran (THF), chloroform, methylene dichloride, ethanol and Virahol, preferably the mixture of one or more in tetrahydrofuran (THF), methylene dichloride and Virahol.Temperature of reaction is the boiling point to solvent at-78 degree, preferably the temperature from room temperature to 45 degree, carries out, and actual temp depends on alkali used and solvent.
the feed ratio of reaction is compound III e: aldehyde: alkali=1mol:0.5～2mol:0.5～2mol.
after having reacted, mixture filters, and after filtrate decompression is concentrated, obtains compound III g
c. described compound g is removed to hydroxyl protecting group, obtain compound h, the general formula of compound h is
.
remove hydroxyl protecting group or division-O-Alk-O-group by strong acid treatment, described strong acid is hydrochloric acid, sulfuric acid or phosphoric acid, preferably hydrochloric acid.
if wherein protected hydroxyl is siloxy, it will be by processing as tetrabutyl ammonium fluoride with fluoride salt or with sour example hydrochloric acid, sulfuric acid or phosphoric acid, particularly salt acid treatment.
reaction is carried out in as methylene dichloride at inert solvent, and the boiling point of temperature of reaction from 0 degree to solvent, preferably from room temperature to 40 degree.
compound h is obtained to reaction mixture by the strong lye solution, and wherein highly basic is preferably the alkali metal hydroxide that comprises sodium hydroxide or calcium hydroxide; Method for hydrolysis is the routine hydrolysis method.
the reaction mixture of gained in step D is separated, obtain the mixture that product is dihydroxy acid HMG CoA reductase inhibitor and salt and lactone; Separation method is conventional separation method.
by conventional method for transformation, by three kinds of Substance Transformations in mixture, be dihydroxy acid HMG CoA reductase inhibitor or its salt or its lactone;
the method or be
a. intermediate, with aldehyde R-CH=O, wittig is occurred to and react, form compound g, the general formula of compound g is
, wherein Y2 represents the oxo base together with Y3, Y1 represents protected hydroxyl; Wherein R is selected from following cyclic group
this reaction is carried out under following material exists: alkali for example, as alkane basic metal, butyllithium; Perhaps hydride is as sodium hydride; Or alkaline carbonate, as salt of wormwood, cesium carbonate; Perhaps large volume amine, as 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene (DBU); This reaction is reacted in organic solvent, as ethers, alcohols or halohydrocarbon or its mixture, be specially one or more the mixture in ether, tetrahydrofuran (THF), chloroform, methylene dichloride, ethanol and Virahol, preferably the mixture of one or more in tetrahydrofuran (THF), methylene dichloride and Virahol.Temperature of reaction is the boiling point to solvent at-78 degree, preferably the temperature from room temperature to 45 degree, carries out, and actual temp depends on alkali used and solvent.
the feed ratio of reaction is compound III d: aldehyde: alkali=1mol:0.5～2mol:0.5～2mol.
after having reacted, mixture filters, and after filtrate decompression is concentrated, obtains compound III g.
by removing hydroxyl protecting group, described compound g is converted into to compound i, then described compound i is reduced to compound h, wherein compound i general formula is
, the general formula of compound h is
.
remove the hydroxyl protecting group group by strong acid treatment, described strong acid is hydrochloric acid, sulfuric acid or phosphoric acid, preferably hydrochloric acid.
if wherein protected hydroxyl is siloxy, also can be by processing as tetrabutyl ammonium fluoride with fluoride salt.
reaction is carried out in as methylene dichloride at inert solvent, and the boiling point of temperature of reaction from 0 degree to solvent, preferably from room temperature to 40 degree.
compound h is obtained to reaction mixture by the strong lye solution, and wherein highly basic is the alkali metal hydroxide that comprises sodium hydroxide or calcium hydroxide; Method for hydrolysis is the routine hydrolysis method.
the reaction mixture of gained in step c is separated, obtain the mixture that product is dihydroxy acid HMG CoA reductase inhibitor and salt and lactone; Separation method is conventional separation method.
by conventional method for transformation, transfer three kinds of materials in mixture to dihydroxy acid HMG CoA reductase inhibitor or its salt or its lactone.
be preferably?
or .Alk is preferably 1,1-dimethylated methylene base.
embodiment 1.
a kind ofly prepare the intermediate that dihydroxy acid HMG CoA reductase inhibitor is used, general formula is
, wherein X1 is tert-butyldimethylsilane base (TBS); X2 is methyl; X3 is hydrogen, and Y is the dimethyl phosphate base, is (R)-4-tertiary butyl dimethyl Si base-2-carbonyl-5-((R)-(1-phenyl-B carbonyl amine)-amyl group dimethyl phosphate.Chemical formula is
the method for preparing this intermediate:
the method of utilizing this intermediate to prepare dihydroxy acid HMG CoA reductase inhibitor is:
by 42.5 g 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-formaldehyde, 100g(R)-4-tertiary butyl dimethyl Si base-2-carbonyl 5-((R)-(1-phenyl-B carbonyl amine)-amyl group dimethyl phosphate joins in the mixing solutions of 500ml methylene dichloride and Virahol ((9:1) volume ratio content ratio) successively, then add 70g salt of wormwood in batches, stirred overnight at room temperature, HPLC follows the tracks of reaction, after raw material reaction is complete, remove by filter insolubles, add 200ml water, then add the 100ml dichloromethane extraction, organic layer 100ml water washing, dry, remove solvent under reduced pressure and obtain oily matter, be directly used in the next step.
add the 430ml dehydrated alcohol in above-mentioned oily matter, after stirring and dissolving, add the hydrochloric acid of 150ml 10%, stirring at room 24 hours, filter, cold ethanol rinsing for filter cake, and vacuum-drying, obtain the 45.0g pale solid, two step yields 65%.
under the noble gas protection, by 36.0g (R)-7-[4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-methoxycarbonyl-2-(N-methyl-N-sulfonyl methane amido) pyrimidine-5-yl]-3-hydroxyl-5-carbonyl-6(E)-after the heptene acyl-((S)-1-phenyl-ethyl) amine is dissolved in the anhydrous THF of 150ml, add the 50ml anhydrous methanol, after being cooled to-78 degree, drip 70g 10% triethyl-boron solution, drip off rear insulation 2 hours, then add the 3.0g sodium borohydride in batches, timing insulation 3 hours, add 10ml Glacial acetic acid cancellation reaction, then be warmed up to room temperature, remove solvent under reduced pressure and obtain oily matter, add the 200ml acetic acid ethyl dissolution, organic phase is washed with 50ml, dry, remove solvent under reduced pressure, and use the t-butyl methyl ether recrystallization, obtain the 34.4g pale solid, yield 95%.
by 30.6g (3R, 5S)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-sulfonyl methane amido) pyrimidine-5-yl]-3, 5-dihydroxyl-6(E)-heptene acyl-((S)-1-phenyl-ethyl) amine is dissolved in the mixed solvent of 500ml water and dehydrated alcohol 1:1, add 16.0g sodium hydroxide, be warmed up to 60 degree reactions, the HPCL monitoring reaction, after raw material disappears, slightly cooling, remove most of ethanol under reduced pressure, add part water, control total Water in the 350ml left and right, then with the extraction of 200ml methyl tertiary butyl ether, organic layer is abandoned it, drip 0.4g/ml calcium acetate solution 6ml in water layer, drip Bi Baowen 2 hours, filter, 100ml purified water washing for filter cake, dry 12 hours of normal pressure 40-50 degree, obtain the 24.4g rosuvastain calcium, productive rate 85%.
by 30.6g (3R, 5S)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-sulfonyl methane amido) pyrimidine-5-yl]-3, 5-dihydroxyl-6(E)-heptene acyl-((S)-1-phenyl-ethyl) amine is dissolved in the mixed solvent of 500ml water and dehydrated alcohol 1:1, add 16.0g sodium hydroxide, be warmed up to 60 degree reactions, the HPCL monitoring reaction, after raw material disappears, slightly cooling, remove most of ethanol under reduced pressure, add part water, control total Water in the 350ml left and right, then with the extraction of 200ml methyl tertiary butyl ether, organic layer is abandoned it, between the salt acid for adjusting pH value to 2 of water layer use 1Mol～3, water layer extracts 3 times by 200 mL ethyl acetate, merge organic layer, concentrating under reduced pressure obtains the acid of 24.8g Rosuvastatin, productive rate 98.4%.
the acid of 4.8g Rosuvastatin is dissolved in 50mL toluene, heating, reflux water-dividing is after 1 hour, slightly cold, removes toluene under reduced pressure and obtains 4.6g Rosuvastain statin lactone, yield 98%.
the acid of 4.8g Rosuvastatin is dissolved in 20mL ethanol, drips 10mL 1Mol sodium hydroxide solution, drip and finish, after reacting half an hour, lyophilize obtains 5.0g Rosuvastatin sodium salt, yield 99%.
5.0g Rosuvastatin sodium salt is dissolved in 20mL water, adds the 20mL ethyl acetate, then drip 1Mol hydrochloric acid, to pH=2～3, adjust and finish, separate organic layer, water extracts by the 20mL ethyl acetate, merge organic layer, concentrating under reduced pressure obtains the acid of 4.6g Rosuvastatin, yield 96%.
4.6g Rosuvastain statin lactone is dissolved in the 20mL medicinal alcohol, drips 10mL 1Mol sodium hydroxide solution, drip and finish, be warmed up to 45 degree, be incubated one hour, after removing most of solvent under reduced pressure, lyophilize obtains 4.8g Rosuvastatin sodium salt, yield 97%.
utilize this intermediate prepare the method for dihydroxy acid HMG CoA reductase inhibitor or be:
by 60g (R)-4-tertiary butyl dimethyl Si base-2-carbonyl-5-[(R)-(1-phenyl-ethylamine carbonyl)]-the amyl group dimethyl phosphate is dissolved in the 200ml methylene dichloride, after stirring and dissolving, the hydrochloric acid that adds 150ml 10%, stirring at room 24 hours, separatory, organic layer washes with water, and concentrating under reduced pressure obtains the 44g colorless oil, yield 97%.
under the noble gas protection, by 36.0g ((R)-4-hydroxyl-2-carbonyl-5-[(R)-(1-phenyl-ethylamine carbonyl)]-after the amyl group dimethyl phosphate is dissolved in the anhydrous THF of 150ml, add the 50ml anhydrous methanol, after being cooled to-78 degree, drip 70g 10% triethyl-boron solution, drip off rear insulation 2 hours, then add the 3.0g sodium borohydride in batches, timing insulation 3 hours, add 10ml Glacial acetic acid cancellation reaction, then be warmed up to room temperature, remove solvent under reduced pressure and obtain oily matter, add the 200ml acetic acid ethyl dissolution, organic phase is washed with 50ml, dry, remove solvent under reduced pressure and obtain 35.1g oily matter, yield 97%.
by (2S, 4R)-2,4-dihydroxyl-5-[(R)-(1-phenyl-ethylamine carbonyl)]-amyl group dimethyl phosphate 18.0g is dissolved in 100 ml acetone, adds tosic acid 1.2g, reflux, after reaction 4h, mixture is poured in water (200ml), ethyl acetate extraction (300ml * 3), merge organic phase, washing (200ml * 3), anhydrous sodium sulfate drying, obtain 19.8g oily matter after removing solvent under reduced pressure.
by 10.0g ((4S, 6R)-2, 2-dimethyl-6-(2-oxo-2-((R)-1-phenylethyl amido) ethyl)-1, 3-dioxane-4-yl) methyl-phosphoric acid dimethyl ester (general formula III e) is dissolved in the anhydrous THF of 50ml, be cooled to 0 degree with ice bath, add 60% sodium hydride 2.2g in batches, finish insulation 0.5 hour, then add 10g 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-formaldehyde, be incubated and slowly be warmed up to room temperature after 4 hours, stirred overnight at room temperature, HPLC follows the tracks of reaction, after raw material reaction is complete, remove by filter insolubles, add 200ml water, then add the 100ml dichloromethane extraction, organic layer 100ml water washing, dry, remove solvent under reduced pressure and obtain oily matter, be directly used in the next step.
add the 430ml dehydrated alcohol in above-mentioned oily matter, after stirring and dissolving, add the hydrochloric acid of 150ml 10%, stirring at room 24 hours, filter, cold ethanol rinsing for filter cake, and vacuum-drying, obtain the 45.0g pale solid, two step yields 65%.
by 30.6g (3R, 5S)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-sulfonyl methane amido) pyrimidine-5-yl]-3, 5-dihydroxyl-6(E)-heptene acyl-((S)-1-phenyl-ethyl) amine is dissolved in the mixed solvent of 500ml water and dehydrated alcohol 1:1, add 16.0g sodium hydroxide, be warmed up to 60 degree reactions, the HPCL monitoring reaction, after raw material disappears, slightly cooling, remove most of ethanol under reduced pressure, add part water, control total Water in the 350ml left and right, then with the extraction of 200ml methyl tertiary butyl ether, organic layer is abandoned it, between the salt acid for adjusting pH value to 2 of water layer use 1Mol～3, water layer extracts 3 times by 200 mL ethyl acetate, merge organic layer, concentrating under reduced pressure obtains the acid of 24.8g Rosuvastatin, productive rate 98.4%.
the acid of 4.8g Rosuvastatin is dissolved in 50mL toluene, heating, reflux water-dividing is after 1 hour, slightly cold, removes toluene under reduced pressure and obtains 4.6g Rosuvastain statin lactone, yield 98%.
the acid of 4.8g Rosuvastatin is dissolved in 20mL ethanol, drips 10mL 1Mol sodium hydroxide solution, drip and finish, after reacting half an hour, lyophilize obtains 5.0g Rosuvastatin sodium salt, yield 99%.
5.0g Rosuvastatin sodium salt is dissolved in 20mL water, adds the 20mL ethyl acetate, then drip 1Mol hydrochloric acid, to pH=2～3, adjust and finish, separate organic layer, water extracts by the 20mL ethyl acetate, merge organic layer, concentrating under reduced pressure obtains the acid of 4.6g Rosuvastatin, yield 96%.
4.6g Rosuvastain statin lactone is dissolved in the 20mL medicinal alcohol, drips 10mL 1Mol sodium hydroxide solution, drip and finish, be warmed up to 45 degree, be incubated one hour, after removing most of solvent under reduced pressure, lyophilize obtains 4.8g Rosuvastatin sodium salt, yield 97%.
embodiment 2.
a kind ofly prepare the intermediate that dihydroxy acid HMG CoA reductase inhibitor is used, general formula is 
, wherein X1 is trimethylsiloxy group; X2 is hydrogen; X3 is hydrogen, and Y is dimethyl phosphate, is (S)-4-trimethylsiloxy group-2-carbonyl 5-((R)-(1-phenyl-B carbonyl amine)-amyl group dimethyl phosphate.Chemical formula is 
.
the method for preparing this intermediate:
drop into hmds lithium 800ml in the 2L there-necked flask, tetrahydrofuran (THF) 200ml, nitrogen protection, stir cooling, when temperature reaches-78 degree when following, start to drip methyl-phosphoric acid dimethyl ester 190g, control below temperature-78 degree, drip off half an hour, then be incubated 2 hours below-78 degree, then start to drip the tetrahydrofuran solution (110g is dissolved in tetrahydrofuran (THF) 280ml) of (S)-N-benzyl-3-trimethylsiloxy group-4-methoxycarbonyl butyramide, in the dropping process, control below temperature-78 degree, approximately within 1 hour, drip off, then insulation reaction is 2.5 hours, insulation is finished and is started to drip Glacial acetic acid 89g, in the dropping process, control below temperature-78 degree, approximately within 1 hour, drip off, then be warmed up to the 10-30 degree, add acetic acid acetic acid 400ml, water 400ml, stir 5 minutes, stratification, organic phase is washed three times with saturated aqueous common salt 300ml respectively, once with the 300ml washing finally, organic layer is concentrated into without cut in the 50-60 degree, obtain yellow liquid: 120-125g.
the method of utilizing this intermediate to prepare dihydroxy acid HMG CoA reductase inhibitor is:
by 42.5 g 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-formaldehyde, 100g(S)-4-trimethylsiloxy group-2-oxo-5-(benzamido group carbonyl)-amyl group dimethyl phosphate joins in (9:1) mixing solutions of 500mL methylene dichloride and Virahol successively, then add 70g salt of wormwood in batches, stirred overnight at room temperature, HPLC follows the tracks of reaction, after raw material reaction is complete, remove by filter insolubles, add 200mL water, then add the 100mL dichloromethane extraction, organic layer 100mL water washing, dry, remove solvent under reduced pressure and obtain oily matter.
add the 430mL dehydrated alcohol in oily matter, after stirring and dissolving, add the phosphoric acid solution of 100mL 1M, stirring at room 24 hours, then add saturated sodium bicarbonate cancellation reaction, adds the ethyl acetate extraction, and the organic layer concentrating under reduced pressure, obtain the 38g pale solid.
under the noble gas protection, by 35.0g (R)-7-[4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-methoxycarbonyl-2-(N-methyl-N-sulfonyl methane amido)-pyrimidine-5-yl]-3-hydroxyl-5-carbonyl-6(E)-after heptene acyl benzylamine is dissolved in the anhydrous THF of 150ml, add the 50ml anhydrous methanol, after being cooled to-78 degree, drip 70g 10% triethyl-boron solution, drip off rear insulation 2 hours, then add the 3.0g sodium borohydride in batches, timing insulation 3 hours, add 10ml Glacial acetic acid cancellation reaction, then be warmed up to room temperature, remove solvent under reduced pressure and obtain oily matter, add the 200ml acetic acid ethyl dissolution, organic phase is washed with 50ml, dry, remove solvent under reduced pressure, and use the t-butyl methyl ether recrystallization, obtain the 34.4g pale solid, yield 95%.
by 29.8g (3R, 5S)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-sulfonyl methane amido) pyrimidine-5-yl]-3, 5-dihydroxyl-6(E)-heptene acyl benzylamine is dissolved in the mixed solvent of 500ml water and dehydrated alcohol 1:1, add 16.0g sodium hydroxide, be warmed up to 60 degree reactions, the HPCL monitoring reaction, after raw material disappears, slightly cooling, remove most of ethanol under reduced pressure, add part water, control total Water in the 350ml left and right, then with the extraction of 200ml methyl tertiary butyl ether, organic layer is abandoned it, drip 0.4g/ml calcium acetate solution 6ml in water layer, drip Bi Baowen 2 hours, filter, 100ml purified water washing for filter cake, dry 12 hours of normal pressure 40-50 degree, obtain the 23.0g rosuvastain calcium, productive rate 81%.
by 30.6g (3R, 5S)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-sulfonyl methane amido) pyrimidine-5-yl]-3, 5-dihydroxyl-6(E)-heptene acyl-((S)-1-phenyl-ethyl) amine is dissolved in the mixed solvent of 500ml water and dehydrated alcohol 1:1, add 16.0g sodium hydroxide, be warmed up to 60 degree reactions, the HPCL monitoring reaction, after raw material disappears, slightly cooling, remove most of ethanol under reduced pressure, add part water, control total Water in the 350ml left and right, then with the extraction of 200ml methyl tertiary butyl ether, organic layer is abandoned it, between the salt acid for adjusting pH value to 2 of water layer use 1Mol～3, water layer extracts 3 times by 200 mL ethyl acetate, merge organic layer, concentrating under reduced pressure obtains the acid of 24.8g Rosuvastatin, productive rate 98.4%.
the acid of 4.8g Rosuvastatin is dissolved in 50mL toluene, heating, reflux water-dividing is after 1 hour, slightly cold, removes toluene under reduced pressure and obtains 4.6g Rosuvastain statin lactone, yield 98%.
the acid of 4.8g Rosuvastatin is dissolved in 20mL ethanol, drips 10mL 1Mol sodium hydroxide solution, drip and finish, after reacting half an hour, lyophilize obtains 5.0g Rosuvastatin sodium salt, yield 99%.
5.0g Rosuvastatin sodium salt is dissolved in 20mL water, adds the 20mL ethyl acetate, then drip 1Mol hydrochloric acid, to pH=2～3, adjust and finish, separate organic layer, water extracts by the 20mL ethyl acetate, merge organic layer, concentrating under reduced pressure obtains the acid of 4.6g Rosuvastatin, yield 96%.
4.6g Rosuvastain statin lactone is dissolved in the 20mL medicinal alcohol, drips 10mL 1Mol sodium hydroxide solution, drip and finish, be warmed up to 45 degree, be incubated one hour, after removing most of solvent under reduced pressure, lyophilize obtains 4.8g Rosuvastatin sodium salt, yield 97%.
3. 1 kinds of embodiment prepare the intermediate that dihydroxy acid HMG CoA reductase inhibitor is used, and general formula is 
, wherein X1 is tert-butyldimethylsilane base (TBS); X2 is methyl; X3 is hydrogen, and Y is the p diethylaminobenzoic acid ester group, is (R)-4-tertiary butyl dimethyl Si base-2-carbonyl-5-((R)-(1-phenyl-B carbonyl amine)-amyl group phosphoric acid second methyl esters.Chemical formula is 
.
the method for preparing this intermediate:
drop into n-Butyl Lithium 800ml in the 2L there-necked flask, tetrahydrofuran (THF) 200ml, nitrogen protection, stir cooling, when temperature reaches-78 degree when following, start to drip methyl acid phosphate diethyl ester 200g, control below temperature-78 degree, drip off about half an hour, then be incubated 2 hours below-78 degree, then start to drip (3S, the tetrahydrofuran solution (110g is dissolved in tetrahydrofuran (THF) 280ml) of 1 ' R)-N-(1 '-phenylethyl)-3-tertiary butyl dimethyl Si base-4-methoxycarbonyl butyramide, in the dropping process, control below temperature-78 degree, approximately within 1 hour, drip off, then insulation reaction is 2.5 hours, be incubated and start to drip Glacial acetic acid 89g, in the dropping process, control below temperature-78 degree, approximately within 1 hour, drip off, then be warmed up to 10 degree-30 degree, add ethyl acetate 400ml, water 400ml, stir 5 minutes, stratification, organic layer is washed three times with saturated aqueous common salt 300ml respectively, once with the 300ml washing finally, organic layer is concentrated into without cut in the 50-60 degree, obtain yellow liquid 140-150g, for intermediate.
the method of utilizing this intermediate to prepare dihydroxy acid HMG CoA reductase inhibitor is:
by 58 g [2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl]-3-formaldehyde, 100g(R)-4-tertiary butyl dimethyl Si base-2-carbonyl 5-((R)-(1-phenyl-B carbonyl amine)-amyl group dimethyl phosphate joins in the mixing solutions of 500ml methylene dichloride and Virahol ((9:1) volume ratio content ratio) successively, then add the 70g cesium carbonate in batches, stirred overnight at room temperature, HPLC follows the tracks of reaction, after raw material reaction is complete, add the 200ml shrend reaction of going out, then use the 100ml dichloromethane extraction, organic layer 100ml water washing, dry, remove solvent under reduced pressure and obtain oily matter, be directly used in the next step.
add the 100ml acetonitrile in above-mentioned oily matter, after stirring and dissolving, the phosphoric acid solution that adds 100ml 1M, stirring at room 24 hours, then add saturated sodium bicarbonate cancellation reaction, with the extraction of 400mL ethyl acetate, organic layer obtains the spumescence solid after removing solvent under reduced pressure, 70.7g pale solid, two step yields 68%.
under the noble gas protection, by 36.8g(R)-the 7-[4-(4-fluorophenyl)-2-cyclopropyl quinoline-3-yl]-3-hydroxyl-5-oxo-6(E)-after the heptene acyl-((S)-1-phenyl-ethyl) amine is dissolved in the anhydrous THF of 150ml, add the 50ml anhydrous methanol, after being cooled to-78 degree, drip 70g 10% triethyl-boron solution, drip off rear insulation 2 hours, then add the 3.4g sodium borohydride in batches, timing insulation 3 hours, add 10ml Glacial acetic acid cancellation reaction, then be warmed up to room temperature, remove solvent under reduced pressure and obtain oily matter, add the 200ml acetic acid ethyl dissolution, organic phase is washed with 50ml, dry, remove solvent under reduced pressure, and use the t-butyl methyl ether recrystallization, obtain the 35.3g pale solid, yield 96%.
by 5g (3R, 5S)-7-[4-(4-fluorophenyl)-2-cyclopropyl quinoline-3-yl]-3, 5-dihydroxyl-6(E)-heptene acyl-((S)-1-phenyl-ethyl) amine is dissolved in the mixed solvent of 250ml water and dehydrated alcohol 1:1, add 8.0g sodium hydroxide, be warmed up to 60 degree reactions, the HPCL monitoring reaction, after raw material disappears, slightly cooling, remove most of ethanol under reduced pressure, add part water, control total Water in the 350ml left and right, then with the extraction of 200ml methyl tertiary butyl ether, organic layer is abandoned it, drip 0.4g/ml calcium acetate solution 6ml in water layer, drip Bi Baowen 2 hours, filter, 100ml purified water washing for filter cake, dry 12 hours of normal pressure 40-50 degree, obtain the 4.4g rosuvastain calcium, productive rate 85%.
by 5g (3R, 5S)-7-[4-(4-fluorophenyl)-2-cyclopropyl quinoline-3-yl]-3, 5-dihydroxyl-6(E)-heptene acyl-((S)-1-phenyl-ethyl) amine is dissolved in the mixed solvent of 250ml water and dehydrated alcohol 1:1, add 8.0g sodium hydroxide, be warmed up to 60 degree reactions, the HPCL monitoring reaction, after raw material disappears, slightly cooling, remove most of ethanol under reduced pressure, add part water, control total Water in the 350ml left and right, then with the extraction of 200ml methyl tertiary butyl ether, organic layer is abandoned it, between the salt acid for adjusting pH value to 2 of water layer use 1Mol～3, then by 200 mL ethyl acetate, extract 3 times, merge organic layer, concentrating under reduced pressure obtains the acid of 3.9g pitavastatin, productive rate 97.0%.
the acid of 4.2g pitavastatin is dissolved in 50mL toluene, heating, reflux water-dividing is after 1 hour, slightly cold, removes toluene under reduced pressure and obtains 4.0g Rosuvastain statin lactone, yield 99%.
the acid of 4.2g Rosuvastatin is dissolved in 20mL ethanol, drips 10mL 1Mol sodium hydroxide solution, drip and finish, after reacting half an hour, lyophilize obtains 4.4g Rosuvastatin sodium salt, yield 100%.
4.4g pitavastatin sodium salt is dissolved in 20mL water, adds the 20mL ethyl acetate, then drip 1Mol hydrochloric acid, to pH=2～3, adjust and finish, separate organic layer, water extracts by the 20mL ethyl acetate, merges organic layer, and concentrating under reduced pressure obtains the 4.1g pitavastatin, yield 98%.
4.0g pitavastatin lactone is dissolved in the 20mL medicinal alcohol, drips 10mL 1Mol sodium hydroxide solution, drip and finish, be warmed up to 45 degree, be incubated one hour, after removing most of solvent under reduced pressure, lyophilize obtains 4.4g pitavastatin sodium salt, yield 100%.
Claims (9)
1. one kind prepares the intermediate that dihydroxy acid HMG CoA reductase inhibitor is used, and general formula is
, wherein X1 is hydroxyl protecting group; X2 is hydrogen or the alkyl that contains a C atom to seven a C atom; X3 is hydrogen or one or more substituting group, alkanoyloxy, halogen, nitro, cyano group or trifluoromethyl that substituting group is selected from alkyl, the hydroxyl that contains a C atom to seven a C atom, the alkoxyl group that contains a C atom to seven a C atom, contains two C atoms to eight C atom; Y is phosphoric acid ester or alkyl phosphonium salt.
2. a kind of intermediate that dihydroxy acid HMG CoA reductase inhibitor is used for preparing according to claim 1, it is characterized in that: described X1 is hydrogen, tertiary butyl dimethylsilyl (TBS), tert-butyl diphenyl silylation (TBDPS), TMS (TMS), THP trtrahydropyranyl (THP) or 1-ethoxyethyl group (E.E); Described X2 is hydrogen or methyl; Described X3 is hydrogen; Described Y is dimethyl phosphate base, p diethylaminobenzoic acid ester group.
3. a kind of intermediate that dihydroxy acid HMG CoA reductase inhibitor is used for preparing according to claim 2, it is characterized in that: described X1 is tertiary butyl dimethylsilyl or TMS, described X2 is methyl or hydrogen.
4. the method for the intermediate that preparation is used as dihydroxy acid HMG CoA reductase inhibitor as described in arbitrary claim in claim 1-3, the steps include:
I. by methyl phosphorodithioate
or methyl trialkyl halogenation phosphine
form corresponding inner salt with the metallization alkane reaction;
Ii. the inner salt obtained is reacted and obtains preparing the intermediate that dihydroxy acid HMG CoA reductase inhibitor is used with compound c; The general formula of compound c is
;
Wherein X4 and X5 independently represent the alkyl that contains a C atom to seven a C atom of the alkyl or phenyl replacement that contains a C atom to seven a C atom; X6, X7 and X8 independently represent unsubstituted or are selected from the phenyl that following one or more substituting groups replace: alkyl, the hydroxyl that contains a C atom to seven a C atom, the alkoxyl group that contains a C atom to seven a C atom, the alkanoyloxy, halogen, nitro, cyano group and the trifluoromethyl that contain two C atoms to eight C atom; Hal
-represent halide anions.
5. the method for preparing the intermediate that dihydroxy acid HMG CoA reductase inhibitor uses according to claim 4, is characterized in that: described X4 and X5 preferable methyl; The preferred n-Butyl Lithium of described metallization alkane (n-BuLi), isobutyl-lithium (s-BuLi), tert-butyl lithium (BuLi), two (TMS) Lithamide (LiHMDS) or di-isopropyl nitrogen lithium.
6. one kind is utilized the described intermediate of arbitrary claim in claim 1-3 to prepare dihydroxy acid HMG CoA reductase inhibitor (general formula
) or the method for its salt or its lactone, it is characterized in that, the method is:
A. intermediate is converted into to Verbindung, the general formula of Verbindung is
, wherein Y1 representation hydroxy or protected hydroxyl, Y2 is hydroxyl or protected hydroxyl, Y3 represents hydrogen, and Y1 and Y2 form cis two alcohol configurations; Or wherein represent together with Y2-O-Alk-O-of Y1 and Alk are the alkylidene group that contains a C atom to seven a C atom, Y3 represents hydrogen, and Y1 and Y2 form cis two alcohol configurations;
B. Verbindung, with aldehyde R-CH=O, wittig is occurred to and react, form compound g, the general formula of compound g is
, wherein R is selected from following cyclic group
C. described compound g is removed to hydroxyl protecting group, obtain compound h, the general formula of compound h is
;
D. compound h is obtained to reaction mixture by the strong lye solution, wherein highly basic is preferably the alkali metal hydroxide that comprises sodium hydroxide or calcium hydroxide;
E. the reaction mixture of step D gained is separated, obtain the mixture that product is dihydroxy acid HMG CoA reductase inhibitor and salt and lactone;
F. by conventional method for transformation, by three kinds of Substance Transformations in mixture, be dihydroxy acid HMG CoA reductase inhibitor or its salt or its lactone;
The method or be:
A. intermediate, with aldehyde R-CH=O, wittig is occurred to and react, form compound g, the general formula of compound g is
, wherein Y2 represents the oxo base together with Y3, Y1 represents protected hydroxyl; Wherein R is selected from following cyclic group
B. by removing hydroxyl protecting group, described compound g is converted into to compound i, then described compound i is reduced to compound h, wherein compound i general formula is
, the general formula of compound h is
;
C. compound h is obtained to reaction mixture by the strong lye solution, wherein highly basic is the alkali metal hydroxide that comprises sodium hydroxide or calcium hydroxide;
D. the reaction mixture of step c gained is separated, obtain the mixture that product is dihydroxy acid HMG CoA reductase inhibitor and salt and lactone;
E. by conventional method for transformation, transfer three kinds of materials in mixture to dihydroxy acid HMG CoA reductase inhibitor or its salt or its lactone.
7. the method for preparing dihydroxy acid HMG CoA reductase inhibitor or its salt or its lactone according to claim 6, is characterized in that: in described steps A, transform and comprise reduction and protect two steps.
8. the method for preparing dihydroxy acid HMG CoA reductase inhibitor or its salt or its lactone according to claim 6, it is characterized in that: described R is
or
.
9. the method for preparing dihydroxy acid HMG CoA reductase inhibitor or its salt or its lactone according to claim 6, it is characterized in that: described Alk is 1,1-dimethylated methylene base.
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|---|---|---|---|---|
| CN104529908A (en) * | 2014-12-12 | 2015-04-22 | 浙江京新药业股份有限公司 | Method for preparing rosuvastatin calcium |
| CN105481838A (en) * | 2015-11-18 | 2016-04-13 | 北京万全德众医药生物技术有限公司 | Method for preparing pitavastatin lactone impurity |
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Application publication date: 20130911 |