CN103012240B - Preparation method of atorvastatin calcium - Google Patents
Preparation method of atorvastatin calcium Download PDFInfo
- Publication number
- CN103012240B CN103012240B CN201210567650.5A CN201210567650A CN103012240B CN 103012240 B CN103012240 B CN 103012240B CN 201210567650 A CN201210567650 A CN 201210567650A CN 103012240 B CN103012240 B CN 103012240B
- Authority
- CN
- China
- Prior art keywords
- reaction
- atorvastatincalcuim
- methyl
- acid
- bis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 0 CC(C)c1c(**)c(C(CC=C2)C=C2C2=ICI2)c(-c(cc2)ccc2F)[n]1CCC(C[C@](C1)O)OC1=O Chemical compound CC(C)c1c(**)c(C(CC=C2)C=C2C2=ICI2)c(-c(cc2)ccc2F)[n]1CCC(C[C@](C1)O)OC1=O 0.000 description 1
Abstract
The invention relates to a preparation method of atorvastatin calcium. The method comprises the steps that 5-methyl--2-benzene-1-(4-fluorophenyl)-3-(phenyl amine formyl)-1,4-hexanedione as a starting material, and subjected to cyclization, hydrolysis, aldol condensation, asymmetric hydrogenation, resolution and salifying reaction, and atorvastatin calcium is obtained. The method is short in synthetic route, rich in raw material source, easy and simple to operate and mild in reaction condition and has a good industrialization prospect.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, specifically, relate to a kind of preparation method of blood lipid-lowering medicine atorvastatincalcuim.
Background technology
Chemistry (the 3R by name of atorvastatincalcuim; 5R)-7-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-(aniline formyl radical)-pyrroles-1-base]-3; 5-dihydroxy heptyl acid calcium salt (2: 1); commodity are called Lipitor (Lipitor), and structural formula is as follows:
In blood plasma, there are endogenous and exogenous two kinds of approach in the source of cholesterol.Exogenous cholesterol is mainly derived from food, the intake thus by regulating diet can control cholesterol; Endogenous cholesterol is then be that starting raw material is obtained by reacting through 26 steps at liver with acetic acid, and wherein 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase enzyme is the rate-limiting enzyme in this building-up process.Atorvastatin can selectivity, suppress HMG-CoA reductase competitively, thus the synthesis of endogenous cholesterol can effectively be suppressed, all effective to primary hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia and mix type hyperlipidemia etc., simultaneously this medicine delaying atherosclerosis, reduce in the generation of acute cardiovascular and cerebrovascular diseases and also play an important role.
US Patent No. 4681893 first reported the synthesis of racemize atorvastatin lactone, in this route, with the bromo-para-fluorophenylacetic acid ethyl ester of 2-for starting raw material, through aminolysis, acidylate and hydrolysis reaction obtain 2-[N-isobutyryl-N-2-(1, 3-dioxolane-2-) ethyl] amino-para-fluorophenylacetic acid, then with the cyclization of N-3-diphenylprop alkynyl amide, then hydrolysis obtains key intermediate 3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-aniline formyl radical)]-1H-pyrroles propionic aldehyde, then this intermediate and methyl acetoacetate condensation in the basic conditions, with sodium borohydride and tri butyl boron reduction, atorvastatin lactone is obtained through hydrolysis and esterification.US Patent No. 5273995 first reported the preparation method of optical purity atorvastatincalcuim; namely use chiral acetate and intermediate 3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-aniline formyl radical]-1H-pyrroles propionic aldehyde to issue green hand's property aldol reaction in diisopropylamine lithium effect, obtain chiral hydroxyl group pyrroles valerate.After transesterify, then with tert.-butyl acetate condensation, then through asymmetric reduction, hydrolysis, salify obtain product.Above two patents all adopt 3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-anilino acyl group]-1H-pyrroles propionic aldehyde to be key intermediate, then through aldol reaction, then reduce, be hydrolyzed, salify obtains product.Adopt above-mentioned two kinds of methods synthesis atorvastatincalcuim, after completing pyrrole ring synthesis, obtain in dihydroxy heptyl ester side chain process through aldol reaction, use normal-butyl Lithium, sodium hydride, lithium diisopropyl amido etc. expensive and the reagent of danger, and to complete under low temperature (-78 DEG C), anhydrous and oxygen-free condition, reaction conditions is very harsh, very inconvenient in the industrial production, and US5273995 wants twice use aldol reaction in synthesis side chain process.
Chinese invention patent application CN101892276 discloses a kind of synthetic method of atorvastatincalcuim: 2-(2-amine ethyl)-1, 3-dioxolane and 1, 4-dicarbonyl compound is hydrolyzed again and obtains key intermediate 3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-anilino acyl group]-1H-pyrroles propionic aldehyde after Paal-Knorr reaction generates pyrrole ring, then react under the catalysis of chiral catalyst DRI-5-phosphate aldolase with acetaldehyde, the product generated obtains atorvastatin lactone through bromine oxidation again, and then hydrolysis react with calcium acetate and generate atorvastatincalcuim.The method needs to adopt expensive chiral catalyst and large usage quantity, improves and synthesis cost, and adopts bromine to make oxygenant, poison larger to environment.
US5003080, US5097045, US5103024; US5124482; US5245047, US5280126, US5298627; WO0068221 and US5155251 discloses the another kind of synthetic method of atorvastatincalcuim: first prepare 3 of chirality; 5-dihydroxyl heptyl ester fragment, is then obtained by reacting atorvastatin with protecting group with Isosorbide-5-Nitrae-dicarbonyl compound through Paal-Knorr; then deprotection, salify obtains atorvastatincalcuim.The patents such as US5929156, CN1190955, CN1190956, CN1351493, CN1379760, CN1483022 report again the preparation method of atorvastatin different crystal forms.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of preparation method of atorvastatincalcuim, and the method synthesis step is few, and agents useful for same is cheap, operational safety, is applicable to large-scale commercial production.
In order to solve the problems of the technologies described above, the present invention takes following technical scheme:
A preparation method for atorvastatincalcuim, comprises the following steps:
A () 5-methyl-2-phenyl-1-(4-fluorophenyl)-3-(phenylcarbamoyl)-Isosorbide-5-Nitrae-hexanedione and 2-(2-amine ethyl)-DOX generate intermediate (1) Protic Acid Catalyzed lower reaction:
Protonic acid used is formic acid, acetic acid, propionic acid, butyric acid or PIVALIC ACID CRUDE (25); Reaction solvent is methyl tertiary butyl ether, tetrahydrofuran (THF) or dioxane;
B () intermediate (1) and concentrated hydrochloric acid effect obtain intermediate (2):
C () intermediate (2) and 1,3-bis-(three alkane siloxies)-1-alkoxyl group-1,3-butadiene obtains intermediate (3) through Lewis acid catalyzed reaction, temperature of reaction-60 ~-20 DEG C in non-protonic solvent:
Wherein, R is methyl or ethyl, R
1for methyl, ethyl, propyl group or the tertiary butyl; Described Lewis acid is TiCl
4, AlCl
3, SrCl
4, ZnCl
2, BF
3or SbF
5; Described non-protonic solvent is methylene dichloride, trichloromethane, tetrahydrofuran (THF), dioxane or ether;
D () intermediate (3) obtains intermediate (4) through asymmetric catalytic hydrogenation in alcoholic solvent, used catalyst is Ru (R-C3-TunePhos) (acac) of CAS numbering 905709-79-7
2, reaction solvent is the mixed solvent of methyl alcohol, ethanol or methyl alcohol and water, and temperature of reaction is 20-50 DEG C, and hydrogen pressure is 20-50bar:
E () intermediate (4) lactonizes in reflux in toluene, obtain intermediate (5)
F () intermediate (5) and (R)-(+)-Alpha-Methyl benzylamine are obtained by reacting intermediate (6), be obtained by reacting atorvastatincalcuim (6) after intermediate (6) alkaline hydrolysis with soluble calcium salt.
Preferably, in described step (c), 1,3-bis-(three alkane siloxies)-1-alkoxyl group-1,3-butadiene is 1,3-bis-(three silyloxies)-1-methoxyl group-1,3-divinyl, or be 1,3-bis-(three silyloxies)-1-oxyethyl group-1,3-divinyl, or be 1,3-bis-(three silyloxies)-1-propoxy--1,3-divinyl, or be 1,3-bis-(three silyloxies)-1-tert.-butoxy-1,3-butadiene; Temperature of reaction is-50 ~-30 DEG C.In described step (d), temperature of reaction is 25 DEG C, and hydrogen pressure is 30-35bar.
In step (a), under nitrogen protection by 5-methyl-2-phenyl-1-(4-fluorophenyl)-3-(phenylcarbamoyl)-1,4-hexanedione and 2-(2-amine ethyl)-1,3-dioxolane adds in tetrahydrofuran solvent, dropwise add PIVALIC ACID CRUDE (25), reflux, reducing pressure after completion of the reaction steams solvent, gained solid volume ratio be 1: 1 acetone and ethyl acetate recrystallization obtain intermediate (1); In step (b), intermediate (1) is added in methyl alcohol, dropwise add the concentrated hydrochloric acid that mass percent concentration is 37%, stirred at ambient temperature reacts, dropwise add at 0 ~ 5 DEG C NaOH solution adjustment pH6 ~ 7 that mass percent concentration is 20%, then add methyl tertiary butyl ether and separate out solid, filter, washing, vacuum-drying obtains intermediate (2); In step (c), by intermediate (2) and described 1,3-bis-(three alkane siloxies)-1-alkoxyl group-1,3-divinyl adds in described solvent, stirs and is cooled to described temperature, dropwise add described catalyzer, add the phosphate buffer solution of pH=7 after completion of the reaction, separatory after layering, water layer dichloromethane extraction, through anhydrous MgSO
4drying, filter, after concentrated, recrystallization intermediate (3); In step (d), add methanol solvate in a kettle., then add intermediate (3) and make it dissolve, capping still passes into nitrogen flooding except the air in reactor, then adds catalyzer Ru (R-C3-TunePhos) (acac)
2, capping still again, slowly passes into hydrogen until hydrogen pressure is 30 ~ 35bar, stir and react under room temperature, pass into nitrogen flooding after completion of the reaction wherein except the hydrogen in reactor, reaction solution is concentrated and to obtain intermediate (4) crude product, after isopropanol-water recrystallization, obtain sterling; In step (f), intermediate (6) is hydrolyzed in sodium hydroxide, reacts generate atorvastatincalcuim with calcium chloride.
Beneficial effect of the present invention is, introduce 1 dexterously, 3-bis-(three alkane siloxies)-1-alkoxyl group-1,3-divinyl and intermediate 3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-anilino acyl group]-1H-pyrroles propionic aldehyde carry out the synthesis that condensation reaction completes target compound side chain committed step, reagent price is low, reaction efficiency is high, and operational safety performance is good; Asymmetric catalytic hydrogenation efficiency is very high, and catalyzer can reclaim use, succinctly completes the synthesis of atorvastatincalcuim efficiently, make whole technical process clean environment firendly in conjunction with follow-up lactonizing with salt-forming steps, with low cost, is applicable to large-scale commercial production.
Embodiment
Below by specific embodiment, the present invention will be further described.
Embodiment one:
(1) synthesis of intermediate (1)
Under nitrogen protection by 5-methyl-2-phenyl-1-(4-fluorophenyl)-3-(phenylcarbamoyl)-1; 4-hexanedione 418g (1mol); 2-(2-amine ethyl)-1; 3-dioxolane 140g (1.2mol) adds in 1000mL tetrahydrofuran (THF); dropwise add the PIVALIC ACID CRUDE (25) of equivalent; reflux 8h; solvent steams by decompression; gained solid acetone and ethyl acetate (1: 1) recrystallization obtains intermediate (1) 359g, yield 72%.Characterization data:
m.p：159-160℃。
1H NMR(CDCl
3，400MHz)δ：1.54(d，6H，J＝7Hz)，1.91(m，2H)，3.60(sep，1H，J＝7Hz)，3.7-4.1(m，6H)，4.74(t，1H，J＝4.3Hz)，7.0-7.3(m，15H)；LC-MS(m/z)：394(M+1)。
(2) synthesis of intermediate (2)
Intermediate (1) 300g (0.6mol) adds in 1000mL methyl alcohol; dropwise add 50mL37% concentrated hydrochloric acid; stirred at ambient temperature 3h; 0 ~ 5 DEG C dropwise adds 20%NaOH solution and regulates pH6 ~ 7; the methyl tertiary butyl ether of 1000mL is added under stirring; hold over night; a large amount of solid is had to separate out; filter; washing; vacuum-drying obtains intermediate (2) (3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-aniline formyl radical]-1H-pyrroles propionic aldehyde) 245g, yield 90%.
m.p：163-164℃。
1H NMR(CDCl
3，400MHz)δ：1.52(d，6H，J＝7Hz)，2.68(br，2H，J＝4Hz)，3.63(sep，1H，J＝7Hz)，4.27(br，2H，J＝4Hz)，6.86(br，1H)，7.0-7.2(m，14H)，9.60(s，1H)；LC-MS(m/z)：350(M+1)。
(3) synthesis of intermediate (3)
3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-aniline formyl radical]-1H-pyrroles propionic aldehyde 200g (0.57mol) and 1; 3-bis-(three silyloxies)-1-methoxyl group-1,3-butadiene 171g (0.66mol) adds 1200mLCH
2cl
2in, stir and be cooled to-50 DEG C, dropwise add TiCl
410g (0.057mol), lasts about 2h, then slow in room temperature in this thermotonus 6hr, adds the phosphate buffer solution of 1000mLpH=7, layering, water layer 200mL washed with dichloromethane three times, combined dichloromethane layer, anhydrous MgSO
4dried overnight, filter, concentrate to obtain intermediate (3) crude product, sherwood oil-acetone recrystallization obtains white powdery solids 204g, yield 81%, m.p:66-68 DEG C.
1H NMR(CDCl
3，400MHz)δ：1.4(s，3H)，1.53(dd，6H，J＝7.1Hz)，1.6(m，2H)，2.51(s，1H)，2.53(d，1H，J＝2Hz)，2.80(1H，OH)，3.31(s，2H)，3.60(sep，1H，J＝7.1Hz)，3.9-4.0(m，2H)，4.09-4.22(m，1H)，6.85(s，1H)，6.95-7.2(m，14H)。LC-MS(m/z)：466(M+1)。
(4) synthesis of intermediate (4)
In 10L reactor, add 3L methyl alcohol, stir and add intermediate (3) 570g (1mol) and make it dissolve, capping still passes into N
2drive away the air in reactor, then add catalyzer Ru (R-C3-TunePhos) (acac)
2400mg, again capping still, slowly pass into hydrogen until hydrogen pressure is 30bar, stir and react 10h at 25 DEG C.Slow releasing reactor pressure, passes into N wherein
2drive away the hydrogen in reactor, reaction solution is concentrated to obtain intermediate (4) crude product 549g.
(5) synthesis of intermediate (5)
Intermediate (4) crude product 50g is dissolved in 400mL tetrahydrofuran (THF), slowly add 100mL1mol/LNaOH solution and at room temperature react 4h, tetrahydrofuran (THF) steams by decompression, add 100mL water, adjust pH=1-2 with 1mol/LHCl, ethyl acetate (3 × 200mL) is extracted, combined ethyl acetate layer, saturated common salt water washing, dry, filter, concentratedly to obtain pale yellowish oil liquid.Add 700mL toluene, reflux azeotropic dehydration 3h, cooling, concentrate to obtain yellow oily liquid.Ethyl acetate-hexane recrystallization obtains intermediate (5) 19.6g, yield 34%.LC-MS(m/z)：541(M+1)。
(6) synthesis of atorvastatincalcuim
Intermediate (5) 30g (0.055mol) adds (R)-(+)-Alpha-Methyl benzylamine (575mL, 4.45mol) in, room temperature for overnight, add 500mL methyl tertiary butyl ether, slowly add 500mL2mol/LHCl and 500mL water, separate organic layer, dry, filter, concentratedly to obtain white powdery solids 31g, gained solid with ethyl acetate-twice, normal hexane recrystallization obtains intermediate (6), and HPLC shows d.e > 95%.
Intermediate (6) adds in ethanol, slowly adds 80mL1mol/LNaOH solution, reflux 10h, and thin-layer chromatography display feedstock conversion is complete, reduces pressure solvent to steam, and adds 500mL water, stirs to obtain colourless transparent solution, dropwise add 1mol/LCaCl
2solution 30mL, stirred at ambient temperature, is separated out by white solid gradually, and continue reaction 1h, filter, washing, vacuum-drying obtains atorvastatincalcuim (2: 1) white powdery solids, yield: 85%.m.p：176-177℃。
1HNMR(DMSO-d
6，400MHz)δ：1.20-1.68(m，4H)，1.35(d，J＝7.2Hz，6H)，1.75-2.10(m，2H)，3.18-4.10(m，7HO，6.85-7.45(m，13HO，9.50(s，1H)。LC-MS(m/z)：557(M-1)。
Embodiment two:
(1) synthesis of intermediate (1)
Under nitrogen protection by 5-methyl-2-phenyl-1-(4-fluorophenyl)-3-(phenylcarbamoyl)-1; 4-hexanedione 418g (1mol); 2-(2-amine ethyl)-1; 3-dioxolane 140g (1.2mol) adds in 1000mL methyl tertiary butyl ether; dropwise add the acetic acid of equivalent; reflux 8h; solvent steams by decompression; gained solid acetone and ethyl acetate (1: 1) recrystallization obtains intermediate (1), yield 70%.
(2) synthesis of intermediate (2)
Intermediate (1) 300g (0.6mol) adds in 1000mL methyl alcohol; dropwise add 50mL37% concentrated hydrochloric acid; stirred at ambient temperature 3h; 0 ~ 5 DEG C dropwise adds 20%NaOH solution and regulates pH6 ~ 7; the methyl tertiary butyl ether of 1000mL is added under stirring; hold over night; a large amount of solid is had to separate out; filter; washing; vacuum-drying obtains intermediate (2) (3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-aniline formyl radical]-1H-pyrroles propionic aldehyde) 245g, yield 90%.
(3) synthesis of intermediate (3)
3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-aniline formyl radical]-1H-pyrroles propionic aldehyde 200g (0.57mol) and 1; 3-bis-(three silyloxies)-1-oxyethyl group-1,3-butadiene 171g (0.66mol) adds 1200mLCHCl
3in, stir and be cooled to-60 DEG C, add 0.057mol AlCl gradually
3, last about 2h, then slow in room temperature in this thermotonus 6hr, add the phosphate buffer solution of 1000mLpH=7, layering, water layer 200mL washed with dichloromethane three times, combined dichloromethane layer, anhydrous MgSO
4dried overnight, filter, concentrate to obtain intermediate (3) crude product, sherwood oil-acetone recrystallization obtains white powdery solids, yield 80%.
(4) synthesis of intermediate (4)
In 10L reactor, add 3L ethanol, stir and add intermediate (3) 570g (1mol) and make it dissolve, capping still passes into N
2drive away the air in reactor, then add catalyzer Ru (R-C3-TunePhos) (acac)
2400mg, again capping still, slowly pass into hydrogen until hydrogen pressure is 20bar, stir and react 10h at 20 DEG C.Slow releasing reactor pressure, passes into N wherein
2drive away the hydrogen in reactor, reaction solution is concentrated to obtain intermediate (4) crude product 540g.
(5) synthesis of intermediate (5)
Intermediate (4) crude product 50g is dissolved in 400mL tetrahydrofuran (THF), slowly add 100mL1mol/LNaOH solution and at room temperature react 4h, tetrahydrofuran (THF) steams by decompression, add 100mL water, adjust pH=1-2 with 1mol/LHCl, ethyl acetate (3 × 200mL) is extracted, combined ethyl acetate layer, saturated common salt water washing, dry, filter, concentratedly to obtain pale yellowish oil liquid.Add 700mL toluene, reflux azeotropic dehydration 3h, cooling, concentrate to obtain yellow oily liquid.Ethyl acetate-hexane recrystallization obtains intermediate (5), yield 32%.
(6) synthesis of atorvastatincalcuim
Intermediate (5) 30g (0.055mol) adds (R)-(+)-Alpha-Methyl benzylamine (575mL, 4.45mol) in, room temperature for overnight, add 500mL methyl tertiary butyl ether, slowly add 500mL2mol/LHCl and 500mL water, separate organic layer, dry, filter, concentratedly to obtain white powdery solids 31g, gained solid with ethyl acetate-twice, normal hexane recrystallization obtains intermediate (6), and HPLC shows d.e > 95%.
Intermediate (6) adds in ethanol, slowly adds 80mL1mol/LKOH solution, reflux 10h, and thin-layer chromatography display feedstock conversion is complete, reduces pressure solvent to steam, and adds 500mL water, stirs to obtain colourless transparent solution, dropwise add 1mol/LCaNO
3solution 30mL, stirred at ambient temperature, is separated out by white solid gradually, and continue reaction 1h, filter, washing, vacuum-drying obtains atorvastatincalcuim (2: 1) white powdery solids, yield: 80%.
Embodiment three:
(1) synthesis of intermediate (1)
Under nitrogen protection by 5-methyl-2-phenyl-1-(4-fluorophenyl)-3-(phenylcarbamoyl)-1; 4-hexanedione 418g (1mol); 2-(2-amine ethyl)-1; 3-dioxolane 140g (1.2mol) adds in 1000mL dioxane; dropwise add the formic acid (or propionic acid, butyric acid) of equivalent; reflux 8h; solvent steams by decompression; gained solid acetone and ethyl acetate (1: 1) recrystallization obtains intermediate (1), yield 73%.
(2) synthesis of intermediate (2)
Intermediate (1) 300g (0.6mol) adds in 1000mL methyl alcohol; dropwise add 50mL37% concentrated hydrochloric acid; stirred at ambient temperature 3h; 0 ~ 5 DEG C dropwise adds 20%NaOH solution and regulates pH6 ~ 7; the methyl tertiary butyl ether of 1000mL is added under stirring; hold over night; a large amount of solid is had to separate out; filter; washing; vacuum-drying obtains intermediate (2) (3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-aniline formyl radical]-1H-pyrroles propionic aldehyde) 245g, yield 90%.
(3) synthesis of intermediate (3)
3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-aniline formyl radical]-1H-pyrroles propionic aldehyde 200g (0.57mol) and 1; 3-bis-(three silyloxies)-1-propoxy--1; 3-divinyl 171g (0.66mol) (or equivalent 1; 3-bis-(three silyloxies)-1-butoxy-1; 3-divinyl) add in 1200mL tetrahydrofuran (THF) (or dioxane, ether); stirring is cooled to-20 DEG C, adds 0.057mol SrCl gradually
4(or ZnCl
2, BF
3or SbF
5), last about 2h, then slow in room temperature in this thermotonus 6hr, add the phosphate buffer solution of 1000mLpH=7, layering, water layer 200mL washed with dichloromethane three times, combined dichloromethane layer, anhydrous MgSO
4dried overnight, filter, concentrate to obtain intermediate (3) crude product, sherwood oil-acetone recrystallization obtains white powdery solids, yield 80%.
(4) synthesis of intermediate (4)
In 10L reactor, add the mixture of 3L methyl alcohol and water, stir and add intermediate (3) 570g (1mol) and make it dissolve, capping still passes into N
2drive away the air in reactor, then add catalyzer Ru (R-C3-TunePhos) (acac)
2400mg, again capping still, slowly pass into hydrogen until hydrogen pressure is 35bar (or 50bar), stir and react 10h at 50 DEG C.Slow releasing reactor pressure, passes into N wherein
2drive away the hydrogen in reactor, reaction solution is concentrated to obtain intermediate (4) crude product 545g.
(5) synthesis of intermediate (5)
Intermediate (4) crude product 50g is dissolved in 400mL tetrahydrofuran (THF), slowly add 100mL1mol/LNaOH solution and at room temperature react 4h, tetrahydrofuran (THF) steams by decompression, add 100mL water, adjust pH=1-2 with 1mol/LHCl, ethyl acetate (3 × 200mL) is extracted, combined ethyl acetate layer, saturated common salt water washing, dry, filter, concentratedly to obtain pale yellowish oil liquid.Add 700mL toluene, reflux azeotropic dehydration 3h, cooling, concentrate to obtain yellow oily liquid.Ethyl acetate-hexane recrystallization obtains intermediate (5), yield 32%.
(6) synthesis of atorvastatincalcuim
Intermediate (5) 30g (0.055mol) adds (R)-(+)-Alpha-Methyl benzylamine (575mL, 4.45mol) in, room temperature for overnight, add 500mL methyl tertiary butyl ether, slowly add 500mL2mol/LHCl and 500mL water, separate organic layer, dry, filter, concentratedly to obtain white powdery solids 31g, gained solid with ethyl acetate-twice, normal hexane recrystallization obtains intermediate (6), and HPLC shows d.e > 95%.
Intermediate (6) adds in ethanol, slowly adds 80mL1mol/LKOH solution, reflux 10h, and thin-layer chromatography display feedstock conversion is complete, reduces pressure solvent to steam, and adds 500mL water, stirs to obtain colourless transparent solution, dropwise add 1mol/LCaCl
2solution 30mL, stirred at ambient temperature, is separated out by white solid gradually, and continue reaction 1h, filter, washing, vacuum-drying obtains atorvastatincalcuim (2: 1) white powdery solids, yield: 80%.
Claims (5)
1. a preparation method for atorvastatincalcuim, comprises the following steps:
A () 5-methyl-2-phenyl-1-(4-fluorophenyl)-3-(phenylcarbamoyl)-Isosorbide-5-Nitrae-hexanedione and 2-(2-amine ethyl)-DOX generate intermediate (1) Protic Acid Catalyzed lower reaction:
Protonic acid used is formic acid, acetic acid, propionic acid, butyric acid or PIVALIC ACID CRUDE (25); Reaction solvent is methyl tertiary butyl ether, tetrahydrofuran (THF) or dioxane;
B () intermediate (1) and concentrated hydrochloric acid effect obtain intermediate (2):
C () intermediate (2) and 1,3-bis-(three alkane siloxies)-1-alkoxyl group-1,3-butadiene obtains intermediate (3) through Lewis acid catalyzed reaction, temperature of reaction-60 ~-20 DEG C in non-protonic solvent:
Wherein, R is methyl or ethyl, R
1for methyl, ethyl, propyl group or the tertiary butyl; Described Lewis acid is TiCl
4, AlCl
3, SrCl
4, ZnCl
2, BF
3or SbF
5; Described non-protonic solvent is methylene dichloride, trichloromethane, tetrahydrofuran (THF), dioxane or ether;
D () intermediate (3) obtains intermediate (4) through asymmetric catalytic hydrogenation in a solvent, used catalyst is Ru (R-C3-TunePhos) (acac) of CAS numbering 905709-79-7
2, solvent is the mixed solvent of methyl alcohol, ethanol or methyl alcohol and water, and temperature of reaction is 20-50 DEG C, and hydrogen pressure is 20-50bar:
E () intermediate (4) lactonizes in reflux in toluene, obtain intermediate (5):
F () intermediate (5) and (R)-(+)-Alpha-Methyl benzylamine are obtained by reacting intermediate (6), be obtained by reacting atorvastatincalcuim (6) after intermediate (6) alkaline hydrolysis with soluble calcium salt
。
2. the preparation method of atorvastatincalcuim as claimed in claim 1, it is characterized in that, in described step (c), 1,3-bis-(three alkane siloxies)-1-alkoxyl group-1,3-divinyl is 1,3-bis-(three silyloxies)-1-methoxyl group-1,3-divinyl, 1,3-bis-(three silyloxies)-1-oxyethyl group-1,3-butadiene, 1,3-bis-(three silyloxies)-1-propoxy--1,3-divinyl or 1,3-bis-(three silyloxies)-1-tert.-butoxy-1,3-butadiene; Temperature of reaction is-50 ~-30 DEG C.
3. the preparation method of atorvastatincalcuim as described in claim 1 or 2, it is characterized in that, in described step (d), temperature of reaction is 25 DEG C, and hydrogen pressure is 30-35bar.
4. the preparation method of atorvastatincalcuim as claimed in claim 3, it is characterized in that, in described step (e), intermediate (4) is first hydrolyzed, and then lactonizes in reflux in toluene, obtains intermediate (5).
5. the preparation method of atorvastatincalcuim as described in claim 1 or 2, it is characterized in that, in described step (e), intermediate (4) is first hydrolyzed, and then lactonizes in reflux in toluene, obtains intermediate (5).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210567650.5A CN103012240B (en) | 2012-12-11 | 2012-12-11 | Preparation method of atorvastatin calcium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210567650.5A CN103012240B (en) | 2012-12-11 | 2012-12-11 | Preparation method of atorvastatin calcium |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103012240A CN103012240A (en) | 2013-04-03 |
| CN103012240B true CN103012240B (en) | 2015-05-27 |
Family
ID=47961403
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210567650.5A Expired - Fee Related CN103012240B (en) | 2012-12-11 | 2012-12-11 | Preparation method of atorvastatin calcium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103012240B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103641764B (en) * | 2013-11-25 | 2015-12-02 | 北京三泉医药技术有限公司 | The pharmaceutical composition of adjusting blood lipid |
| CN104311517B (en) * | 2014-10-17 | 2017-06-06 | 上海应用技术学院 | His statin lactone anhydro compounds and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4681893A (en) * | 1986-05-30 | 1987-07-21 | Warner-Lambert Company | Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis |
| US5273995A (en) * | 1989-07-21 | 1993-12-28 | Warner-Lambert Company | [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof |
| CN1765892A (en) * | 2005-11-16 | 2006-05-03 | 华东师范大学 | Orlistat preparation method |
| CN101805279A (en) * | 2010-01-22 | 2010-08-18 | 绍兴民生医药有限公司 | Preparation method of atorvastatin calcium |
| CN101892276A (en) * | 2010-06-12 | 2010-11-24 | 郝志艳 | Atorvastatin calcium compound and new method thereof |
-
2012
- 2012-12-11 CN CN201210567650.5A patent/CN103012240B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4681893A (en) * | 1986-05-30 | 1987-07-21 | Warner-Lambert Company | Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis |
| US5273995A (en) * | 1989-07-21 | 1993-12-28 | Warner-Lambert Company | [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof |
| CN1765892A (en) * | 2005-11-16 | 2006-05-03 | 华东师范大学 | Orlistat preparation method |
| CN101805279A (en) * | 2010-01-22 | 2010-08-18 | 绍兴民生医药有限公司 | Preparation method of atorvastatin calcium |
| CN101892276A (en) * | 2010-06-12 | 2010-11-24 | 郝志艳 | Atorvastatin calcium compound and new method thereof |
Non-Patent Citations (1)
| Title |
|---|
| Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran 2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus;Bruce D. Roth等;《J. Med. Chem.》;19910131;第34卷(第1期);第358-366页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103012240A (en) | 2013-04-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100208867B1 (en) | Diastereomer salt of optically active quinolinemevalonic acid | |
| EP1948598B1 (en) | Process for preparation of (3r, 5r)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt | |
| WO2002057274A1 (en) | A process for the synthesis of atorvastatin form v and phenylboronates as intermediate compounds | |
| CA2572149A1 (en) | Process for production of azulene derivatives and intermediates for the synthesis of the same | |
| US7812179B2 (en) | Process for the preparation of atorvastatin and intermediates | |
| CN103012240B (en) | Preparation method of atorvastatin calcium | |
| WO2007107276A2 (en) | Process for preparing c7 intermediates and their use in the preparation of n-substituted pyrrole derivatives | |
| KR100598079B1 (en) | Novel boronate esters | |
| KR101063146B1 (en) | Method for preparing pitavastatin intermediate and method for preparing pitavastatin hemicalcium salt | |
| KR100980379B1 (en) | Process for the preparation of optically active 5-hydroxy-3-oxoheptanoate derivatives | |
| WO2008103016A1 (en) | Atorvastatin intermediates and method for producing the same | |
| EP0583171B1 (en) | (3R,5S)-3,5,6-trihydroxyhexanoic acid derivatives and methods for their production | |
| Stach et al. | Synthesis of some impurities and/or degradation products of atorvastatin | |
| CN110698426B (en) | Method for preparing 1, 3-benzothiazole derivative by efficient catalysis of potassium tert-butoxide | |
| IL150881A (en) | Process for preparing quinolylacrylonitrile and intermediates therefor | |
| WO2007023503A1 (en) | A process for the preparation of fluvastatin sodium | |
| KR20090104253A (en) | Method for preparing atorvastatin, intermediate compounds used in the method and their preparation methods | |
| EP2245008B1 (en) | Method for the preparation of atorvastatin and intermediates used therein | |
| KR20170078033A (en) | Novel Statin intermediate, the preparation method of the same and the preparation method of Rosuvastatin using the same | |
| CN100352821C (en) | Rosuvastain calcium intermediate preparation method | |
| KR100613687B1 (en) | Process for preparation of atorvastatin | |
| KR100379939B1 (en) | Process for preparing [(3R,5R)/(3R,5S)]-3,5-dihydroxyhexanoic acid ester derivatives | |
| CN104163808B (en) | A kind of preparation method of 2-((4R, 6S)-6-substituent methyl-2-substituting group-1,3-dioxane-4-base) acetic ester | |
| WO2022075347A1 (en) | Method for producing octahydrothienoquinoline compound, and production intermediate of same | |
| KR20120059148A (en) | Process for preparing a chiral intermediate for the prepartion of pitavastatin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150527 Termination date: 20151211 |
|
| EXPY | Termination of patent right or utility model |