CN103012240A - Preparation method of atorvastatin calcium - Google Patents
Preparation method of atorvastatin calcium Download PDFInfo
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- CN103012240A CN103012240A CN2012105676505A CN201210567650A CN103012240A CN 103012240 A CN103012240 A CN 103012240A CN 2012105676505 A CN2012105676505 A CN 2012105676505A CN 201210567650 A CN201210567650 A CN 201210567650A CN 103012240 A CN103012240 A CN 103012240A
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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 the synthetic field of medicine, specifically, relate to a kind of preparation method of blood lipid-lowering medicine atorvastatincalcuim.
Background technology
The chemistry of atorvastatincalcuim is called (3R; 5R)-and 7-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-(aniline formyl radical)-pyrroles-1-yl]-3; 5-dihydroxy heptyl acid calcium salt (2: 1), commodity are called Lipitor (Lipitor), and structural formula is as follows:
There are endogenous and exogenous two kinds of approach in the source of cholesterol in the blood plasma.Exogenous cholesterol is mainly derived from food, thereby can control the intake of cholesterol by regulating diet; Endogenous cholesterol then is that reaction obtains through 26 steps take acetic acid as starting raw material at liver, 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 competitively the HMG-CoA reductase enzyme, thereby can the establishment endogenous cholesterol synthetic, all effective to primary hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia and mixed type hyperlipidemia etc., this medicine is also playing an important role aspect the generation that delays atherosclerosis, the acute cardiovascular and cerebrovascular diseases of minimizing simultaneously.
US Patent No. 4681893 has at first been reported ester synthesis in the racemize atorvastatin; in this route; take 2-bromo-para-fluorophenylacetic acid ethyl ester as starting raw material; through aminolysis; acidylate and hydrolysis reaction obtain 2-[N-isobutyryl-N-2-(1; the ethyl of 3-dioxolane-2-)] 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's propionic aldehyde; then this intermediate and methyl acetoacetate condensation under alkaline condition; with sodium borohydride and tri butyl boron reduction, obtain the atorvastatin lactone through hydrolysis and esterification.US Patent No. 5273995 has at first been 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's propionic aldehyde issues green hand's property aldol reaction in the diisopropylamine lithium effect, obtains chiral hydroxyl group pyrroles valerate.After transesterify, again with the tert.-butyl acetate condensation, then obtain product through asymmetric reduction, hydrolysis, salify.Above two patents all adopt 3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-anilino acyl group]-1H-pyrroles's propionic aldehyde is key intermediate, passes through aldol reaction again, then reduce, hydrolysis, salify obtain product.Adopt above-mentioned two kinds of methods to synthesize atorvastatincalcuim, finish pyrrole ring synthetic after, obtain in the dihydroxy heptyl ester side chain process through aldol reaction, use costliness and the dangerous reagent such as normal-butyl Lithium, sodium hydride, lithium diisopropyl amido, and under low temperature (78 ℃), anhydrous and oxygen-free condition, finish, reaction conditions is very harsh, and is very inconvenient in industrial production, and US5273995 wants the use aldol reaction twice in synthetic 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; the 4-dicarbonyl compound is hydrolyzed after the Paal-Knorr reaction generates pyrrole ring again and obtains key intermediate 3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-anilino acyl group]-1H-pyrroles's propionic aldehyde; then react under chiral catalyst DRI-5-phosphoric acid zymohexase catalysis with acetaldehyde; the product that generates obtains the atorvastatin lactone through the bromine oxidation again, and then hydrolysis and generate atorvastatincalcuim with the calcium acetate reaction.The method need to adopt expensive chiral catalyst and large usage quantity, improves and synthetic cost, and adopts bromine to make oxygenant, poisons larger to environment.
US5003080, US5097045, US5103024; US5124482; US5245047, US5280126, US5298627; WO0068221 and US5155251 disclose the another kind of synthetic method of atorvastatincalcuim: at first prepare 3 of chirality; then 5-dihydroxyl heptyl ester fragment reacts the atorvastatin that obtains with protecting group with Isosorbide-5-Nitrae-dicarbonyl compound through Paal-Knorr; then deprotection, salify obtains atorvastatincalcuim.US5929156, CN1190955, CN1190956, CN1351493, CN1379760, the patents such as CN1483022 have been reported again the preparation method of atorvastatin different crystal forms.
Summary of the invention
Technical problem to be solved by this invention provides a kind of preparation method of atorvastatincalcuim, and the method synthesis step is few, and agents useful for same is cheap, and operational safety is fit to large-scale commercial production.
In order to solve the problems of the technologies described above, the present invention takes following technical scheme:
A kind of preparation method of atorvastatincalcuim may further comprise the steps:
(a) 5-methyl-2-phenyl-1-(4-fluorophenyl)-3-(phenyl amine formyl radical)-Isosorbide-5-Nitrae-hexanedione and 2-(2-amine ethyl)-DOX react under protonic acid catalysis and generate intermediate (1):
Used protonic acid 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) obtains intermediate (2) with the concentrated hydrochloric acid effect:
(c) intermediate (2) and 1,3-two (three alkane siloxies)-1-alkoxyl group-1,3-butadiene obtains intermediate (3) through the Lewis acid catalyzed reaction in non-protonic solvent, temperature of reaction-60～-20 ℃:
Wherein, R is methyl or ethyl, R
1Be methyl, ethyl, propyl group or the tertiary butyl; Described Lewis acid is TiCl
4, AlCl
3, SrCl
4, ZnCl
2, BF
3Perhaps SbF
5Described non-protonic solvent is methylene dichloride, trichloromethane, tetrahydrofuran (THF), dioxane or ether;
(d) intermediate (3) obtains intermediate (4) through asymmetric catalytic hydrogenation in solvent, catalyst system therefor be CAS numbering 905709-79-7 Ru (R-C3-TunePhos) (acac)
2, solvent is the mixed solvent of methyl alcohol, ethanol or methyl alcohol and water, and temperature of reaction is 20-50 ℃, and hydrogen pressure is 20-50bar:
(e) intermediate (4) lactonizes in reflux in toluene, obtains intermediate (5)
(f) intermediate (5) with (R)-(+)-Alpha-Methyl benzylamine reaction obtains intermediate (6), obtains atorvastatincalcuim (6) with the solubility calcium reactant salt after intermediate (6) alkaline hydrolysis.
Preferably, in the described step (c), 1,3-two (three alkane siloxies)-1-alkoxyl group-1,3-butadiene is 1,3-two (three silyloxies)-1-methoxyl group-1, the 3-divinyl perhaps is 1,3-two (three silyloxies)-1-oxyethyl group-1, the 3-divinyl perhaps is 1,3-two (three silyloxies)-1-propoxy--1, the 3-divinyl, it perhaps is 1,3-two (three silyloxies)-1-tert.-butoxy-1,3-butadiene; Temperature of reaction is-50～-30 ℃.In the described step (d), temperature of reaction is 25 ℃, and hydrogen pressure is 30-35bar.
In the step (a), under nitrogen protection with 5-methyl-2-phenyl-1-(4-fluorophenyl)-3-(phenylamino formyl radical)-1,4-hexanedione and 2-(2-amine ethyl)-1, the 3-dioxolane adds in the tetrahydrofuran solvent, dropwise add PIVALIC ACID CRUDE (25), reflux is reacted complete rear decompression solvent is steamed, and gained solid volume ratio is that 1: 1 acetone and ethyl acetate recrystallization gets intermediate (1);
In the step (b), intermediate (1) is added in the methyl alcohol, dropwise add mass percent concentration and be 37% concentrated hydrochloric acid, stirring reaction under the room temperature, dropwise adding mass percent concentration at 0～5 ℃ is that 20% NaOH solution is regulated pH6～7, then adds methyl tertiary butyl ether and separates out solid, filters, washing, vacuum-drying gets intermediate (2); In the step (c), with intermediate (2) and described 1,3-two (three alkane siloxies)-1-alkoxyl group-1, the 3-divinyl adds in the described solvent, stirs and is cooled to described temperature, dropwise adds described catalyzer, react the phosphate buffer solution of complete rear adding pH=7, separatory after layering, the water layer dichloromethane extraction is through anhydrous MgSO
4Drying, filter, behind concentrated, the recrystallization intermediate (3); In the step (d), add methanol solvate in reactor, then add intermediate (3) and make its dissolving, the capping still passes into nitrogen flooding except the air in the reactor, then adds catalyzer Ru (R-C3-TunePhos) (acac)
2, the capping still slowly passes into hydrogen until hydrogen pressure is 30～35bar again, stir under room temperature and react, react the complete backward nitrogen flooding that wherein passes into except the hydrogen in the reactor, reaction solution is concentrated to get intermediate (4) crude product, behind the isopropanol-water recrystallization, get sterling; In the step (f), intermediate (6) is hydrolyzed in sodium hydroxide, generates atorvastatincalcuim with the calcium chloride reaction.
Beneficial effect of the present invention is, introduce dexterously 1,3-two (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's propionic aldehyde carries out condensation reaction and finishes the synthetic of target compound side chain committed step, the reagent price is low, reaction efficiency is high, and the operational safety performance is good; Asymmetric catalytic hydrogenation efficient is very high, and catalyzer can reclaim use, lactonizes and the salify step has succinctly been finished the synthetic of atorvastatincalcuim efficiently in conjunction with follow-up, so that whole technical process clean environment firendly is with low cost, is fit to large-scale commercial production.
Embodiment
The present invention will be further described below by specific embodiment.
Embodiment one:
(1) intermediate (1) is synthetic
Under nitrogen protection with 5-methyl-2-phenyl-1-(4-fluorophenyl)-3-(phenylamino formyl radical)-1; 4-hexanedione 418g (1mol); 2-(2-amine ethyl)-1; 3-dioxolane 140g (1.2mol) adds in the 1000mL tetrahydrofuran (THF); the PIVALIC ACID CRUDE (25) that dropwise adds equivalent, reflux 8h, decompression steams solvent; the gained solid gets intermediate (1) 359g, yield 72% with acetone and ethyl acetate (1: 1) recrystallization.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) intermediate (2) is synthetic
Intermediate (1) 300g (0.6mol) adds in the 1000mL methyl alcohol; dropwise add the 50mL37% concentrated hydrochloric acid; stir 3h under the room temperature, 0～5 ℃ dropwise adds 20%NaOH solution and regulates pH6～7, the methyl tertiary butyl ether of adding 1000mL under stirring; standing over night; there are a large amount of solids to separate out, filter, washing; vacuum-drying gets intermediate (2) (3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-aniline formyl radical]-1H-pyrroles's 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) intermediate (3) is synthetic
3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-aniline formyl radical]-1H-pyrroles's propionic aldehyde 200g (0.57mol) and 1,3-two (three silyloxies)-1-methoxyl group-1,3-butadiene 171g (0.66mol) add 1200mLCH
2Cl
2In, stir and be cooled to-50 ℃, dropwise add TiCl
410g (0.057mol) lasts approximately 2h, then slowly to room temperature, adds the phosphate buffer solution of 1000mLpH=7 in this thermotonus 6hr, layering, water layer 200mL washed with dichloromethane three times, combined dichloromethane layer, anhydrous MgSO
4Dried overnight is filtered, is concentrated to get intermediate (3) crude product, and sherwood oil-acetone recrystallization gets white powder solid 204g, yield 81%, m.p:66-68 ℃.
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，0H)，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) intermediate (4) is synthetic
Add 3L methyl alcohol in the 10L reactor, stir adding intermediate (3) 570g (1mol) and make its dissolving, the capping still passes into N
2Drive away the air in the reactor, then add catalyzer Ru (R-C3-TunePhos) (acac)
2400mg, the capping still slowly passes into hydrogen until hydrogen pressure is 30bar again, stirs in 25 ℃ of lower reaction 10h.Slowly remove reactor pressure, to wherein passing into N
2Drive away the hydrogen in the reactor, reaction solution is concentrated to get intermediate (4) crude product 549g.
(5) intermediate (5) is synthetic
Intermediate (4) crude product 50g is dissolved in the 400mL tetrahydrofuran (THF), slowly add 100mL1mol/LNaOH solution and at room temperature react 4h, decompression steams tetrahydrofuran (THF), add 100mL water, transfer pH=1-2 with 1mol/LHCl, (3 * 200mL) extract the combined ethyl acetate layer to ethyl acetate, the saturated common salt water washing, dry, filter, concentratedly to get light yellow oily liquid.Add 700mL toluene, reflux azeotropic dehydration 3h, cooling concentrates to get yellow oily liquid.Ethyl acetate-normal hexane recrystallization gets intermediate (5) 19.6g, yield 34%.LC-MS(m/z)：541(M+1)。
(6) atorvastatincalcuim is synthetic
Intermediate (5) 30g (0.055mol) adds (R)-(+)-Alpha-Methyl benzylamine (575mL, 4.45mol) in, stir under the room temperature and spend the night, add the 500mL methyl tertiary butyl ether, slowly add 500mL2mol/LHCl and 500mL water, tell organic layer, drying, filtration, the concentrated white powder solid 31g that to get, the gained solid gets intermediate (6) twice with ethyl acetate-normal hexane recrystallization, and HPLC shows d.e＞95%.
Intermediate (6) adds in the ethanol, slowly adds 80mL1mol/LNaOH solution, and reflux 10h, thin-layer chromatography show that feedstock conversion is complete, and decompression steams solvent, adds 500mL water, stirs to get colourless transparent solution, dropwise adds 1mol/LCaCl
2Solution 30mL stirs under the room temperature, is separated out by white solid gradually, continues reaction 1h, filter, and washing, vacuum-drying gets atorvastatincalcuim (2: 1) white powder solid, 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，7H0，6.85-7.45(m，13H0，9.50(s，1H)。LC-MS(m/z)：557(M-1)。
Embodiment two:
(1) intermediate (1) is synthetic
Under nitrogen protection with 5-methyl-2-phenyl-1-(4-fluorophenyl)-3-(phenylamino formyl radical)-1; 4-hexanedione 418g (1mol); 2-(2-amine ethyl)-1; 3-dioxolane 140g (1.2mol) adds in the 1000mL methyl tertiary butyl ether; the acetic acid that dropwise adds equivalent, reflux 8h, decompression steams solvent; the gained solid gets intermediate (1), yield 70% with acetone and ethyl acetate (1: 1) recrystallization.
(2) intermediate (2) is synthetic
Intermediate (1) 300g (0.6mol) adds in the 1000mL methyl alcohol; dropwise add the 50mL37% concentrated hydrochloric acid; stir 3h under the room temperature, 0～5 ℃ dropwise adds 20%NaOH solution and regulates pH6～7, the methyl tertiary butyl ether of adding 1000mL under stirring; standing over night; there are a large amount of solids to separate out, filter, washing; vacuum-drying gets intermediate (2) (3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-aniline formyl radical]-1H-pyrroles's propionic aldehyde) 245g, yield 90%.
(3) intermediate (3) is synthetic
3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-aniline formyl radical]-1H-pyrroles's propionic aldehyde 200g (0.57mol) and 1,3-two (three silyloxies)-1-oxyethyl group-1,3-butadiene 171g (0.66mol) add 1200mLCHCl
3In, stir and be cooled to-60 ℃, add gradually 0.057mol AlCl
3, last approximately 2h, then slowly to room temperature, add the phosphate buffer solution of 1000mLpH=7 in this thermotonus 6hr, layering, water layer 200mL washed with dichloromethane three times, combined dichloromethane layer, anhydrous MgSO
4Dried overnight is filtered, is concentrated to get intermediate (3) crude product, and sherwood oil-acetone recrystallization gets the white powder solid, yield 80%.
(4) intermediate (4) is synthetic
Add 3L ethanol in the 10L reactor, stir adding intermediate (3) 570g (1mol) and make its dissolving, the capping still passes into N
2Drive away the air in the reactor, then add catalyzer Ru (R-C3-TunePhos) (acac)
2400mg, the capping still slowly passes into hydrogen until hydrogen pressure is 20bar again, stirs in 20 ℃ of lower reaction 10h.Slowly remove reactor pressure, to wherein passing into N
2Drive away the hydrogen in the reactor, reaction solution is concentrated to get intermediate (4) crude product 540g.
(5) intermediate (5) is synthetic
Intermediate (4) crude product 50g is dissolved in the 400mL tetrahydrofuran (THF), slowly add 100mL1mol/LNaOH solution and at room temperature react 4h, decompression steams tetrahydrofuran (THF), add 100mL water, transfer pH=1-2 with 1mol/LHCl, (3 * 200mL) extract the combined ethyl acetate layer to ethyl acetate, the saturated common salt water washing, dry, filter, concentratedly to get light yellow oily liquid.Add 700mL toluene, reflux azeotropic dehydration 3h, cooling concentrates to get yellow oily liquid.Ethyl acetate-normal hexane recrystallization gets intermediate (5), yield 32%.
(6) atorvastatincalcuim is synthetic
Intermediate (5) 30g (0.055mol) adds (R)-(+)-Alpha-Methyl benzylamine (575mL, 4.45mol) in, stir under the room temperature and spend the night, add the 500mL methyl tertiary butyl ether, slowly add 500mL2mol/LHCl and 500mL water, tell organic layer, drying, filtration, the concentrated white powder solid 31g that to get, the gained solid gets intermediate (6) twice with ethyl acetate-normal hexane recrystallization, and HPLC shows d.e＞95%.
Intermediate (6) adds in the ethanol, slowly adds 80mL1mol/LKOH solution, and reflux 10h, thin-layer chromatography show that feedstock conversion is complete, and decompression steams solvent, adds 500mL water, stirs to get colourless transparent solution, dropwise adds 1mol/LCaNO
3Solution 30mL stirs under the room temperature, is separated out by white solid gradually, continues reaction 1h, filter, and washing, vacuum-drying gets atorvastatincalcuim (2: 1) white powder solid, yield: 80%.
Embodiment three:
(1) intermediate (1) is synthetic
Under nitrogen protection with 5-methyl-2-phenyl-1-(4-fluorophenyl)-3-(phenylamino formyl radical)-1; 4-hexanedione 418g (1mol); 2-(2-amine ethyl)-1; 3-dioxolane 140g (1.2mol) adds in the 1000mL dioxane; the formic acid (perhaps propionic acid, butyric acid) that dropwise adds equivalent, reflux 8h, decompression steams solvent; the gained solid gets intermediate (1), yield 73% with acetone and ethyl acetate (1: 1) recrystallization.
(2) intermediate (2) is synthetic
Intermediate (1) 300g (0.6mol) adds in the 1000mL methyl alcohol; dropwise add the 50mL37% concentrated hydrochloric acid; stir 3h under the room temperature, 0～5 ℃ dropwise adds 20%NaOH solution and regulates pH6～7, the methyl tertiary butyl ether of adding 1000mL under stirring; standing over night; there are a large amount of solids to separate out, filter, washing; vacuum-drying gets intermediate (2) (3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-aniline formyl radical]-1H-pyrroles's propionic aldehyde) 245g, yield 90%.
(3) intermediate (3) is synthetic
3-[2-(4-fluorophenyl)-5-sec.-propyl-3-phenyl-4-aniline formyl radical]-1H-pyrroles's propionic aldehyde 200g (0.57mol) and 1; 3-two (three silyloxies)-1-propoxy--1; (perhaps equivalent 1 for 3-divinyl 171g (0.66mol); 3-two (three silyloxies)-1-butoxy-1; the 3-divinyl) adds in the 1200mL tetrahydrofuran (THF) (perhaps dioxane, ether); stirring is cooled to-20 ℃, adds gradually 0.057mol SrCl
4(perhaps ZnCl
2, BF
3Perhaps SbF
5), last approximately 2h, then slowly to room temperature, add the phosphate buffer solution of 1000mLpH=7 in this thermotonus 6hr, layering, water layer 200mL washed with dichloromethane three times, combined dichloromethane layer, anhydrous MgSO
4Dried overnight is filtered, is concentrated to get intermediate (3) crude product, and sherwood oil-acetone recrystallization gets the white powder solid, yield 80%.
(4) intermediate (4) is synthetic
Add the mixture of 3L methyl alcohol and water in the 10L reactor, stir adding intermediate (3) 570g (1mol) and also makes its dissolving, the capping still passes into N
2Drive away the air in the reactor, then add catalyzer Ru (R-C3-TunePhos) (acac)
2400mg, the capping still slowly passes into hydrogen until hydrogen pressure is 35bar (perhaps 50bar) again, stirs in 50 ℃ of lower reaction 10h.Slowly remove reactor pressure, to wherein passing into N
2Drive away the hydrogen in the reactor, reaction solution is concentrated to get intermediate (4) crude product 545g.
(5) intermediate (5) is synthetic
Intermediate (4) crude product 50g is dissolved in the 400mL tetrahydrofuran (THF), slowly add 100mL1mol/LNaOH solution and at room temperature react 4h, decompression steams tetrahydrofuran (THF), add 100mL water, transfer pH=1-2 with 1mol/LHCl, (3 * 200mL) extract the combined ethyl acetate layer to ethyl acetate, the saturated common salt water washing, dry, filter, concentratedly to get light yellow oily liquid.Add 700mL toluene, reflux azeotropic dehydration 3h, cooling concentrates to get yellow oily liquid.Ethyl acetate-normal hexane recrystallization gets intermediate (5), yield 32%.
(6) atorvastatincalcuim is synthetic
Intermediate (5) 30g (0.055mol) adds (R)-(+)-Alpha-Methyl benzylamine (575mL, 4.45mol) in, stir under the room temperature and spend the night, add the 500mL methyl tertiary butyl ether, slowly add 500mL2mol/LHCl and 500mL water, tell organic layer, drying, filtration, the concentrated white powder solid 31g that to get, the gained solid gets intermediate (6) twice with ethyl acetate-normal hexane recrystallization, and HPLC shows d.e＞95%.
Intermediate (6) adds in the ethanol, slowly adds 80mL1mol/LKOH solution, and reflux 10h, thin-layer chromatography show that feedstock conversion is complete, and decompression steams solvent, adds 500mL water, stirs to get colourless transparent solution, dropwise adds 1mol/LCaCl
2Solution 30mL stirs under the room temperature, is separated out by white solid gradually, continues reaction 1h, filter, and washing, vacuum-drying gets atorvastatincalcuim (2: 1) white powder solid, yield: 80%.
Claims (5)
1. the preparation method of an atorvastatincalcuim may further comprise the steps:
(a) 5-methyl-2-phenyl-1-(4-fluorophenyl)-3-(phenyl amine formyl radical)-Isosorbide-5-Nitrae-hexanedione and 2-(2-amine ethyl)-DOX react under protonic acid catalysis and generate intermediate (1):
Used protonic acid 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) obtains intermediate (2) with the concentrated hydrochloric acid effect:
(c) intermediate (2) and 1,3-two (three alkane siloxies)-1-alkoxyl group-1,3-butadiene obtains intermediate (3) through the Lewis acid catalyzed reaction in non-protonic solvent, temperature of reaction-60～-20 ℃:
Wherein, R is methyl or ethyl, R
1Be methyl, ethyl, propyl group or the tertiary butyl; Described Lewis acid is TiCl
4, AlCl
3, SrCl
4, ZnCl
2, BF
3Or SbF
5Described non-protonic solvent is methylene dichloride, trichloromethane, tetrahydrofuran (THF), dioxane or ether;
(d) intermediate (3) obtains intermediate (4) through asymmetric catalytic hydrogenation in solvent, catalyst system therefor be CAS numbering 905709-79-7 Ru (R-C3-TunePhos) (acac)
2, solvent is the mixed solvent of methyl alcohol, ethanol or methyl alcohol and water, and temperature of reaction is 20-50 ℃, and hydrogen pressure is 20-50bar:
(e) intermediate (4) lactonizes in reflux in toluene, obtains intermediate (5):
(f) intermediate (5) with (R)-(+)-Alpha-Methyl benzylamine reaction obtains intermediate (6), obtains atorvastatincalcuim (6) with the solubility calcium reactant salt after intermediate (6) alkaline hydrolysis.
2. the preparation method of atorvastatincalcuim as claimed in claim 1, it is characterized in that, in the described step (c), 1,3-two (three alkane siloxies)-1-alkoxyl group-1, the 3-divinyl is 1,3-two (three silyloxies)-1-methoxyl group-1,3-divinyl, 1,3-two (three silyloxies)-1-oxyethyl group-1,3-butadiene, 1,3-two (three silyloxies)-1-propoxy--1,3-divinyl or 1,3-two (three silyloxies)-1-tert.-butoxy-1,3-butadiene; Temperature of reaction is-50～-30 ℃.
3. such as the preparation method of claim 1 or 2 described atorvastatincalcuims, it is characterized in that, in the described step (d), temperature of reaction is 25 ℃, and hydrogen pressure is 30-35bar.
4. the preparation method of atorvastatincalcuim as claimed in claim 3 is characterized in that, in the described step (e), intermediate (4) is hydrolyzed first, then lactonizes in reflux in toluene, obtains intermediate (5).
5. such as the preparation method of claim 1 or 2 described atorvastatincalcuims, it is characterized in that, in the described step (e), intermediate (4) is hydrolyzed first, then lactonizes in reflux in toluene, obtains intermediate (5).
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| CN103641764A (en) * | 2013-11-25 | 2014-03-19 | 李兴惠 | Pharmaceutical composition for regulating blood lipid |
| CN104311517A (en) * | 2014-10-17 | 2015-01-28 | 上海应用技术学院 | Polysubstituted phenanthrene ring statin lactone dehydrated compounds and application thereof |
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Cited By (3)
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| CN104311517A (en) * | 2014-10-17 | 2015-01-28 | 上海应用技术学院 | Polysubstituted phenanthrene ring statin lactone dehydrated compounds and application thereof |
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