CN102766072B - Method for preparing atorvastatin calcium chiral side chain - Google Patents
Method for preparing atorvastatin calcium chiral side chain Download PDFInfo
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Abstract
The invention provides a method for preparing an atorvastatin calcium chiral side chain and belongs to the technical field of drug organic synthesis. The method includes the following steps: 1) under the protection of nitrogen, tertiary butyl acetate and strong base are added in methylbenzene according to molar ratio of 1:1-1.15, temperature rises to 105-110 DEG C slowly, stirring and reaction are performed for 3-7 hours, and thermal insulation is performed for 2-4 hours to obtain a-sodium tert-butyl acetate; and 2) the a-sodium tert-butyl acetate is cooled to the temperature of -30-0 DEG C through a conventional refrigerator, a mixed solution containing compound A and tetrahydrofuran is added in the a-sodium tert-butyl acetate in dropwise mode, molar ratio of original addition of the compound A and the tertiary butyl acetate is 0.3-0.5:1, weight ratio of the tetrahydrofuran and the compound A is 1.0-2.0, dropwide addition is finished in 0.5-2 hours, thermal insulation is performed for 2-4 hours, and a compound B is obtained. The method for preparing the atorvastatin calcium chiral side chain is simple to operate, can improve product yield, avoids liquid nitrogen raw materials which are extremely high in energy consumption during preparation, and achieves effects of energy conservation and emission reduction.
Description
Technical field
The invention belongs to the medicine technical field of organic synthesis, be specifically related to a kind of method for preparing the atorvastatincalcuim chiral side chain.
Background technology
Atorvastatincalcuim is the medicine of former of pharmacy giant Pfizer, this medicine is a kind of inhibitor of novel HMG-CoA reductase enzyme, can reduce efficiently the medicine of blood fat, because it has advantages of the high-efficiency low-toxicity side effect, extremely people's favor, so this medicine prospect is extremely wide.
In prior art, the synthetic route of atorvastatincalcuim chiral side chain compd B is as follows:
Wherein the chemical name of compd A is: (R)-4-cyano-3-hydroxy ethyl butyrate; The chemical name of compd B is: (R)-6-cyano group-5-hydroxyl-3-carbonyl-hecanoic acid t-butyl ester.
Prior art is when preparing а-lithium for tert.-butyl acetate, first metallic lithium and the reaction of alpha-brominated normal butane are obtained to n-Butyl Lithium, n-Butyl Lithium and Diisopropylamine reaction obtain N-Lithiodiisopropylamide (also referred to as LDA), finally tert.-butyl acetate is added drop-wise in LDA, reaction obtains а-lithium for tert.-butyl acetate, and reaction process is comparatively complicated.
There is following shortcoming in above-mentioned technology: (1) adopts metallic lithium (precious metal) and the higher raw materials of price such as alpha-brominated normal butane and Diisopropylamine, directly cause cost very high, wherein, metallic lithium price per ton is 400,000 yuan of left and right, alpha-brominated normal butane price per ton is in 2.5 ten thousand left and right, and Diisopropylamine price per ton is in 30,000 left and right; (2) n-Butyl Lithium is in industrialization process, to having relatively high expectations of equipment and production control; (3) when preparing а-lithium for tert.-butyl acetate, require temperature of reaction at-50～-70 ℃, so low temperature need to adopt liquid nitrogen cooling, and in the cooling use procedure due to liquid nitrogen, the nitrogen after gasification (tail gas) temperature is extremely low, be difficult to again recycle, caused the cryogenic energy utilization efficiency of this raw material very low, in use liquid nitrogen consumption is very large, causes energy consumption very high, in addition, in use, liquid nitrogen accounts for more than 10% of compd B cost, and production cost is high; (4) while adopting LDA to prepare, can produce the waste water of complicated pollution factors such as much containing Diisopropylamine hydrochloride, lithiumbromide, lithium chloride and organism, improve the subsequent recovery processing cost.
Summary of the invention
The problem existed for prior art, the object of the invention is to design a kind of technical scheme for preparing the method for atorvastatincalcuim chiral side chain is provided, the method is simple to operate, and can improve the yield of product, avoid using the high liquid nitrogen raw material of energy consumption while preparing, reach the effect of energy-saving and emission-reduction.
A kind of described method for preparing the atorvastatincalcuim chiral side chain is characterized in that comprising following processing step:
1) under nitrogen protection, tert.-butyl acetate and highly basic are joined in toluene for 1:1～1.15 in molar ratio, slowly be warming up to 105～110 ℃, stirring reaction, after 3～7 hours, is incubated 2～4 hours, obtains а-sodium for tert.-butyl acetate;
2) above-mentioned material is cooled to-30～0 ℃ by conventional freezer, drip again the mixing solutions that contains compd A and tetrahydrofuran (THF) in above-mentioned material, the mol ratio of described compd A and the original add-on of tert.-butyl acetate is 0.3～0.5:1, the weight ratio of described tetrahydrofuran (THF) and compd A is 1.0～2.0, dropping completed in 0.5～2 hour, then be incubated 2～4 hours, obtain compd B;
The reaction formula of above-mentioned reaction is as follows:
。
A kind of described method for preparing the atorvastatincalcuim chiral side chain, is characterized in that in described step 1) that tert.-butyl acetate and highly basic join in toluene for 1:1.05～1.12 in molar ratio.
A kind of described method for preparing the atorvastatincalcuim chiral side chain, is characterized in that in described step 1), the mol ratio of tert.-butyl acetate and toluene is 1:8～10.
A kind of described method for preparing the atorvastatincalcuim chiral side chain, is characterized in that in described step 1) being warming up to 106～108 ℃, and stirring reaction, after 4～6 hours, is incubated 3～4 hours.
A kind of described method for preparing the atorvastatincalcuim chiral side chain, is characterized in that in described step 1), highly basic is sodium or sodium hydride.
A kind of described method for preparing the atorvastatincalcuim chiral side chain, is characterized in that described step 2) in material be cooled to-20～-10 ℃ by conventional freezer.
A kind of described method for preparing the atorvastatincalcuim chiral side chain, is characterized in that described step 2) in material be cooled to-10～0 ℃ by conventional freezer.
A kind of described method for preparing the atorvastatincalcuim chiral side chain, is characterized in that described step 2) in compd A and tert.-butyl acetate mol ratio be 0.35～0.45:1.
A kind of described method for preparing the atorvastatincalcuim chiral side chain, is characterized in that described step 2) in drip and to complete in 1～1.5 hour.
A kind of above-mentioned method for preparing the atorvastatincalcuim chiral side chain, adopt sodium Metal 99.5 or sodium hydride alternative metals lithium, prepare а-sodium for tert.-butyl acetate with tert.-butyl acetate by sodium Metal 99.5 or sodium hydride in toluene solvant, then obtain compd B with the compd A condensation under-30～0 ℃.Compared with prior art, the present invention has following beneficial effect: 1) reactions steps is simple, easy to operate, is easy to control; 2) preparation а-sodium for the tert.-butyl acetate process in, do not re-use alpha-brominated normal butane and Diisopropylamine, and sodium Metal 99.5 or sodium hydride alternative metals lithium, the price of sodium Metal 99.5 and sodium hydride is 1.2 ten thousand and 2.5 ten thousand per ton, has obviously reduced production cost; 3) optimized reaction solvent, adopted toluene/Tetrahydrofuran System, improved transformation efficiency, and more be conducive to solvent recuperation; 4) improved temperature of reaction, the present invention only need, by conventional refrigerator cooling instead of liquid nitrogen cooling, reach the purpose of energy-saving and emission-reduction, and also reduce production cost; 5) because reactant is comparatively single, transformation efficiency is high, makes waste water Component comparison of the present invention simple, and sodium-chlor and some organic constituents are only arranged, and by ordinary methods such as desalination rectifying, can process, and has significantly reduced cost recovery.
Embodiment
Further illustrate the present invention below in conjunction with specific embodiment.
In the present invention, the chemical name of compd A is: (R)-4-cyano-3-hydroxy ethyl butyrate, and chemical formula is:
;
The chemical name of compd B is: (R)-6-cyano group-5-hydroxyl-3-carbonyl-hecanoic acid t-butyl ester, and chemical formula is:
; A and compd B are currently available products.
Embodiment 1
1) under nitrogen protection, 1mol tert.-butyl acetate and 1mol sodium Metal 99.5 are joined in 8mol toluene, slowly be warming up to 108 ℃, stirring reaction, after 5 hours, is incubated 3 hours, obtains а-sodium for tert.-butyl acetate;
2) above-mentioned material is cooled to-10 ℃ by conventional freezer, then drips the mixing solutions that contains 0.4mol compd A and 75ml tetrahydrofuran (THF) in above-mentioned material, drip and completed in 1 hour, then be incubated 2 hours, obtain compd B;
3), under nitrogen protection, control temperature under 0～-10 ℃, successively toward the dilute hydrochloric acid that slowly drips 50ml ethanol and 1000ml 1M in above-mentioned material; add rear stratification; water layer adds the extraction of 350ml toluene once again, merges organic layer, uses 250ml saturated aqueous common salt washed twice at every turn; by organic layer-0.095～-0.099Mpa under; control temperature in 50 ℃, be concentrated into the dry red oil 88.2g that obtains, be compd B; purity 93.4%, yield 90.7%.
Embodiment 2
1) under nitrogen protection, 1mol tert.-butyl acetate and 1.15mol sodium hydride are joined in 10mol toluene, slowly be warming up to 105 ℃, stirring reaction, after 7 hours, is incubated 4 hours, obtains а-sodium for tert.-butyl acetate;
2) above-mentioned material is cooled to 0 ℃ by conventional freezer, then drips the mixing solutions that contains 0.3mol compd A and 70ml tetrahydrofuran (THF) in above-mentioned material, drip and completed in 0.5 hour, then be incubated 4 hours, obtain compd B;
3) control temperature under 0～-10 ℃, successively, toward the dilute hydrochloric acid that slowly drips 50ml ethanol and 1150ml 1M in above-mentioned material, add rear stratification, water layer adds 250ml toluene to extract once again, merge organic layer, each by 250ml saturated aqueous common salt washed twice, by organic layer-0.095～-0.099Mpa under, control temperature in 50 ℃, be concentrated into the dry red oil 66.8g that obtains, be compd B, purity 91.9%, yield 90.1%.
Embodiment 3
1) under nitrogen protection, 1mol tert.-butyl acetate and 1.1mol sodium hydride are joined in 9mol toluene, slowly be warming up to 110 ℃, stirring reaction, after 3 hours, is incubated 2 hours, obtains а-sodium for tert.-butyl acetate;
2) above-mentioned material is cooled to-25 ℃ by conventional freezer, then drips the mixing solutions that contains 0.5mol compd A and 110ml tetrahydrofuran (THF) in above-mentioned material, drip and completed in 2 hours, then be incubated 3 hours, obtain compd B;
3) control temperature under 0～-10 ℃, successively in above-mentioned material, slowly drip the dilute hydrochloric acid of 50ml ethanol and 1100ml 1M, add rear stratification, water layer adds the extraction of 400ml toluene once again, merges organic layer, uses 320ml saturated aqueous common salt washed twice at every turn, by organic layer-0.095～-0.099Mpa under, control temperature in 50 ℃, be concentrated into the dry red oil 110.8g that obtains, be compd B, purity 92.7%, yield 90.5%.
Embodiment 4
1) under nitrogen protection, 1mol tert.-butyl acetate and 1.05mol sodium Metal 99.5 are joined in 8.5mol toluene, slowly be warming up to 106 ℃, stirring reaction, after 6.5 hours, is incubated 3.5 hours, obtains а-sodium for tert.-butyl acetate;
2) above-mentioned material is cooled to-30 ℃ by conventional freezer, drip again the mixing solutions that contains 0.45mol compd A and 85ml tetrahydrofuran (THF) in above-mentioned material, dropping completed in 1.5 hours, then was incubated 3.5 hours, obtained as compd B as described in formula II;
3) control temperature under 0～-10 ℃, successively, toward the dilute hydrochloric acid that slowly drips 50ml ethanol and 1050ml 1M in above-mentioned material, add rear stratification, water layer adds 350ml toluene to extract once again, merge organic layer, each by 350ml saturated aqueous common salt washed twice, by organic layer-0.095～-0.099Mpa under, control temperature in 50 ℃, be concentrated into the dry red oil 103.4g that obtains, be compd B, purity 91.7%, yield 91.2%.
Embodiment 5
1) under nitrogen protection, 1mol tert.-butyl acetate and 1.12mol sodium Metal 99.5 are joined in 9mol toluene, slowly be warming up to 110 ℃, stirring reaction, after 6 hours, is incubated 3.5 hours, obtains а-sodium for tert.-butyl acetate;
2) above-mentioned material is cooled to-15 ℃ by conventional freezer, then drips the mixing solutions that contains 0.35mol compd A and 110ml tetrahydrofuran (THF) in above-mentioned material, drip and completed in 1 hour, then be incubated 3.5 hours, obtain compd B;
3) control temperature under 0～-10 ℃, successively, toward the dilute hydrochloric acid that slowly drips 50ml ethanol and 1120ml 1M in above-mentioned material, add rear stratification, water layer adds 350ml toluene to extract once again, merge organic layer, each by 350ml saturated aqueous common salt washed twice, by organic layer-0.095～-0.099Mpa under, control temperature in 50 ℃, be concentrated into the dry red oil 80.4g that obtains, be compd B, purity 90.7%, yield 91.8%.
Claims (5)
1. a method for preparing the atorvastatincalcuim chiral side chain is characterized in that comprising following processing step:
1) under nitrogen protection, tert.-butyl acetate and highly basic are joined in toluene for 1:1～1.15 in molar ratio, described highly basic is sodium or sodium hydride, slowly be warming up to 105～110 ℃, after stirring reaction 3～7 hours, be incubated 2～4 hours, obtain а-sodium for tert.-butyl acetate;
2) above-mentioned material is cooled to-20～-10 ℃ by conventional freezer, drip again the mixing solutions that contains compd A and tetrahydrofuran (THF) in above-mentioned material, the mol ratio of described compd A and the original add-on of tert.-butyl acetate is 0.35～0.45:1, the weight ratio of described tetrahydrofuran (THF) and compd A is 1.0～2.0, dropping completed in 0.5～2 hour, then be incubated 2～4 hours, obtain compd B;
The reaction formula of above-mentioned reaction is as follows:
2. a kind of method for preparing the atorvastatincalcuim chiral side chain as claimed in claim 1, is characterized in that in described step 1) that tert.-butyl acetate and highly basic join in toluene for 1:1.05～1.12 in molar ratio.
3. a kind of method for preparing the atorvastatincalcuim chiral side chain as claimed in claim 1, is characterized in that in described step 1), the mol ratio of tert.-butyl acetate and toluene is 1:8～10.
4. a kind of method for preparing the atorvastatincalcuim chiral side chain as claimed in claim 1, is characterized in that in described step 1) being warming up to 106～108 ℃, and stirring reaction, after 4～6 hours, is incubated 3～4 hours.
5. a kind of method for preparing the atorvastatincalcuim chiral side chain as claimed in claim 1, is characterized in that described step 2) in drip and to complete in 1～1.5 hour.
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| CN105461593B (en) * | 2015-12-31 | 2018-02-27 | 江西科苑生物药业有限公司 | A kind of continuous preparation method of the oxo hecanoic acid t-butyl ester of 6 cyano group, 5 hydroxyl 3 |
| CN108033899B (en) * | 2017-12-06 | 2020-04-10 | 浙江科技学院 | Preparation method of (R) -6-cyano-5-hydroxy-3-carbonyl hexanoate tert-butyl ester |
Citations (3)
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|---|---|---|---|---|
| US5155251A (en) * | 1991-10-11 | 1992-10-13 | Warner-Lambert Company | Process for the synthesis of (5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate |
| CN1337940A (en) * | 1999-02-03 | 2002-02-27 | 三星精密化学株式会社 | A process for preparing (R)-4-cyano-3-hydroxybutyric acid ester |
| WO2005026107A1 (en) * | 2003-09-18 | 2005-03-24 | Biocon Limited | Novel process for the preparation of tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5155251A (en) * | 1991-10-11 | 1992-10-13 | Warner-Lambert Company | Process for the synthesis of (5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate |
| CN1337940A (en) * | 1999-02-03 | 2002-02-27 | 三星精密化学株式会社 | A process for preparing (R)-4-cyano-3-hydroxybutyric acid ester |
| WO2005026107A1 (en) * | 2003-09-18 | 2005-03-24 | Biocon Limited | Novel process for the preparation of tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate |
Non-Patent Citations (2)
| Title |
|---|
| 付翁.高位阻β-二酮萃取剂的制备及其对氨性溶液中铜和锌萃取性能的研究.《中国优秀硕士学位论文全文数据库工程科技I辑》.2011, |
| 高位阻β-二酮萃取剂的制备及其对氨性溶液中铜和锌萃取性能的研究;付翁;《中国优秀硕士学位论文全文数据库工程科技I辑》;20110228;29 * |
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Address after: 317016, Zhejiang, Taizhou City, chemical medicine base, near the sea (Du Qiao), East China Sea, four Avenue, No. 6 Patentee after: Zhejiang macro yuan pharmaceutical Limited by Share Ltd Address before: 317016, Zhejiang, Taizhou City, chemical medicine base, near the sea (Du Qiao), East China Sea, four Avenue, No. 6 Patentee before: Zhejiang Hongyuan Pharmaceutical Co., Ltd. |