CN102311376A - Preparation process of atorvastatin calcium - Google Patents
Preparation process of atorvastatin calcium Download PDFInfo
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- CN102311376A CN102311376A CN2010102112304A CN201010211230A CN102311376A CN 102311376 A CN102311376 A CN 102311376A CN 2010102112304 A CN2010102112304 A CN 2010102112304A CN 201010211230 A CN201010211230 A CN 201010211230A CN 102311376 A CN102311376 A CN 102311376A
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Abstract
The invention provides a preparation process of atorvastatin calcium, which is characterized by being divided into two steps when preparing a condensation compound (4R-cis)-1,1-dimethyl ethyl-6-[2-[2-(4-fluorophenyl)-5-(1-methyl ethyl)-3-phenyl-4-[(phenyl amino)-carbonyl]-1H-pyrrole-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate: 1), adding (4R-cis)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-tertbutyl acetate (called ATS-9 for short) into a mixed solvent of n-heptane, tetrahydrofuran and toluene to react with pivalic acid; and 2), adding 4-fluorine-alpha-[2-methyl-1-oxygen-propyl]-gamma-oxo-N,beta-diphenyl phenyl butyramide (called M-4 for short) and rising the temperature for reaction. The invention has the advantage of capability of greatly improving the yield of the intermediate condensation compound and is more in favor of industrialized production.
Description
Technical field
The invention belongs to chemosynthesis, particularly a kind of preparation technology of atorvastatincalcuim.
Background technology
Atorvastatin is selectivity, the competitive inhibitor of HMG-CoA reductase enzyme; Thereby syntheticly reduce SUV and lipoprotein levels in the blood plasma, and through increasing picked-up and the metabolism of liver DL acceptor that cell shows with enhancing LDL through what suppress HMG-CoA reductase enzyme and SUV in the liver.(4R-cis)-1 wherein; 1-dimethyl ethyl-6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenyl amino)-carbonyl]-1H-pyrroles-1-yl] ethyl]-2; 2-dimethyl--1; 3-diox-4-acetic ester (abbreviating condenses down as) is its important midbody; The preparation technology that condenses is commonly used at present adds (4R-cis) 6-aminoethyl-2 in the mixed solvent that normal heptane, THF, toluene are formed, 2-dimethyl--1,3-dioxane-4-tert.-butyl acetate (being called for short ATS-9 down), trimethylacetic acid, 4-fluoro-α-[2-methyl isophthalic acid-oxygen propyl group]-γ-oxo-N; β-diphenyl benzene yulocrotine (being called for short M-4 down), reaction under reflux temperature.Because structure one end of reactant A TS-9 is-NH
2, the other end is-COO-C-that the two id reaction takes place with this understanding easily generates acid amides, produces impurity, causes the condenses yield to reduce simultaneously, at present basically at 55-60%.
Summary of the invention
Technical problem to be solved by this invention provides a kind of preparation technology of atorvastatincalcuim, when the preparation condenses, can avoid the id reaction of ATS-9.
The preparation technology of a kind of atorvastatincalcuim of the present invention; By condenses (4R-cis)-1; 1-dimethyl ethyl-6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenyl amino)-carbonyl]-1H-pyrroles-1-yl] ethyl]-2,2-dimethyl--1,3-diox-4-acetic ester forms sodium salt through hydrolysis; Add lime acetate again and make, the preparation that it is characterized in that condenses in two steps:
The first step adds (4R-cis)-6-aminoethyl-2 earlier in the mixed solvent that normal heptane, THF, toluene are formed, 2-dimethyl--1,3-dioxane-4-tert.-butyl acetate (being called for short ATS-9) and trimethylacetic acid reaction;
Second step added 4-fluoro-α-[2-methyl isophthalic acid-oxygen propyl group]-γ-oxo-N again, β-diphenyl benzene yulocrotine (being called for short M-4), temperature reaction.
The present invention during condenses, adds trimethylacetic acid in preparation earlier, to structure one end of ATS-9-NH
2Protect.
The first step temperature of reaction is 40-75 ℃, and the second step reaction temperature is 85-92 ℃.
First step reaction times: 0.5-2 hour, second step reaction time: the 20-24 hour.
Technology provided by the invention can make the condenses yield improve greatly, on average can reach 70-75%, also can significantly reduce impurity, reduces cost, and improves the quality, and more helps suitability for industrialized production.
Embodiment
Embodiment 1:
In the 2L reaction flask, adding normal heptane 600ml, THF 200ml, toluene 200ml stir adding trimethylacetic acid 14.6g down, are warming up to 40 ℃, then, add 60.1g ATS-9, and 40 ℃ were reacted 1 hour.Add 83.5gM-4 again, heat up 85 ℃, reacted 24 hours.Reaction finishes, and is evaporated to no cut and steams, and adds ETHYLE ACETATE 500ml dissolving; Respectively with saturated sodium bicarbonate solution 100ml and saturated common salt aqueous solution 100ml washing; Added the 50g anhydrous sodium sulfate drying 2 hours, reclaim under reduced pressure ETHYLE ACETATE is concentrated into no cut and steams.Add Virahol 500ml dissolving, be evaporated to no cut and steam; Repetitive operation 2 times.Add the dissolving of 550ml Virahol, drip water 400ml, drip and finish, reduce to 25～30 ℃, suction filtration, 300ml Virahol-water mixed liquid washing leaching cake.Drying under reduced pressure is to constant weight.Get 93g, yield 71%.
Embodiment 2:
In the 2L reaction flask, adding normal heptane 600ml, tetrahydrochysene furan 200ml, toluene 200ml stir adding trimethylacetic acid 14.6g down, are warming up to 40 ℃, then, add 60.1g ATS-9, and 55 ℃ were reacted 2 hours.Add 83.5gM-4 again, heat up 90 ℃, reacted 24 hours.Reaction finishes, and is evaporated to no cut and steams, and adds ETHYLE ACETATE 500ml dissolving; Respectively with saturated sodium bicarbonate solution 100ml and saturated common salt aqueous solution 100ml washing; Added the 50g anhydrous sodium sulfate drying 2 hours, reclaim under reduced pressure ETHYLE ACETATE is concentrated into no cut and steams.Add Virahol 500ml dissolving, be evaporated to no cut and steam; Repetitive operation 2 times.Add the dissolving of 550ml Virahol, drip water 400ml, drip and finish, reduce to 25～30 ℃, suction filtration, 300ml Virahol-water mixed liquid washing leaching cake.Drying under reduced pressure is to constant weight.Get 95g, yield 72.5%.
Embodiment 3:
In the 2L reaction flask, adding normal heptane 600ml, tetrahydrochysene furan 200ml, toluene 200ml stir adding trimethylacetic acid 14.6g down, are warming up to 40 ℃, then, add 60.1g ATS-9, and 75 ℃ were reacted 0.5 hour.Add 83.5gM-4 again, heat up 92 ℃, reacted 20 hours.Reaction finishes, and is evaporated to no cut and steams, and adds ETHYLE ACETATE 500ml dissolving; Respectively with saturated sodium bicarbonate solution 100ml and saturated common salt aqueous solution 100ml washing; Added the 50g anhydrous sodium sulfate drying 2 hours, reclaim under reduced pressure ETHYLE ACETATE is concentrated into no cut and steams.Add Virahol 500ml dissolving, be evaporated to no cut and steam; Repetitive operation 2 times.Add the dissolving of 550ml Virahol, drip water 400ml, drip and finish, reduce to 25～30 ℃, suction filtration, 300ml Virahol-water mixed liquid washing leaching cake.Drying under reduced pressure is to constant weight.Get 98g, yield 74.8%.
Claims (3)
1. the preparation technology of an atorvastatincalcuim; By condenses (4R-cis)-1; 1-dimethyl ethyl-6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenyl amino)-carbonyl]-1H-pyrroles-1-yl] ethyl]-2,2-dimethyl--1,3-diox-4-acetic ester forms sodium salt through hydrolysis; Add lime acetate again and make, the preparation that it is characterized in that condenses in two steps:
The first step adds (4R-cis)-6-aminoethyl-2 earlier in the mixed solvent that normal heptane, THF, toluene are formed, 2-dimethyl--1,3-dioxane-4-tert.-butyl acetate and trimethylacetic acid reaction;
In second step, add 4-fluoro-α-[2-methyl isophthalic acid-oxygen propyl group]-γ-oxo-N again, β-diphenyl benzene yulocrotine, temperature reaction.
2. preparation technology according to claim 1 is characterized in that the first step temperature of reaction is 40-75 ℃, and the second step temperature of reaction is 85-92 ℃.
3. preparation technology according to claim 1 is characterized in that the first step reaction times: 0.5-2 hour, second reaction times: the 20-24 hour step.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010211230 CN102311376B (en) | 2010-06-29 | 2010-06-29 | Preparation process of atorvastatin calcium |
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| CN 201010211230 CN102311376B (en) | 2010-06-29 | 2010-06-29 | Preparation process of atorvastatin calcium |
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| CN102311376A true CN102311376A (en) | 2012-01-11 |
| CN102311376B CN102311376B (en) | 2013-01-02 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109232354A (en) * | 2018-10-09 | 2019-01-18 | 河南师范大学 | A kind of preparation method of high purity atorvastatin calcium raw material drug |
| CN109232353A (en) * | 2018-10-09 | 2019-01-18 | 河南师范大学 | A kind of preparation method of Atorvastatin calcium condensation product |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1749248A (en) * | 2005-08-15 | 2006-03-22 | 浙江新东港药业股份有限公司 | Process for preparing high purity atorvastatin calcium |
| WO2009023260A2 (en) * | 2007-08-15 | 2009-02-19 | Teva Pharmaceutical Industries Ltd. | An improved process for synthesis of pyrrole derivative, an intermediate for atorvastatin |
| US20090216029A1 (en) * | 2005-09-16 | 2009-08-27 | Yatendra Kumar | Process for the production of atorvastatin calcium in amorphous form |
-
2010
- 2010-06-29 CN CN 201010211230 patent/CN102311376B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1749248A (en) * | 2005-08-15 | 2006-03-22 | 浙江新东港药业股份有限公司 | Process for preparing high purity atorvastatin calcium |
| US20090216029A1 (en) * | 2005-09-16 | 2009-08-27 | Yatendra Kumar | Process for the production of atorvastatin calcium in amorphous form |
| WO2009023260A2 (en) * | 2007-08-15 | 2009-02-19 | Teva Pharmaceutical Industries Ltd. | An improved process for synthesis of pyrrole derivative, an intermediate for atorvastatin |
Non-Patent Citations (1)
| Title |
|---|
| KELVIN L. BAUMANN,ET AL.: "The Convergent Synthesis of CI-981,an Optically Active, Highly Potent,Tissue Selective Inhibitor of HMG-CoA Reductase", 《TCNAHEDRON LETTERS》, vol. 33, no. 17, 31 December 1992 (1992-12-31), pages 2283 - 2284, XP002143555, DOI: doi:10.1016/S0040-4039(00)74190-6 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109232354A (en) * | 2018-10-09 | 2019-01-18 | 河南师范大学 | A kind of preparation method of high purity atorvastatin calcium raw material drug |
| CN109232353A (en) * | 2018-10-09 | 2019-01-18 | 河南师范大学 | A kind of preparation method of Atorvastatin calcium condensation product |
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| CN102311376B (en) | 2013-01-02 |
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