CN102766072A - Method for preparing atorvastatin calcium chiral side chain - Google Patents
Method for preparing atorvastatin calcium chiral side chain Download PDFInfo
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- CN102766072A CN102766072A CN2012102781514A CN201210278151A CN102766072A CN 102766072 A CN102766072 A CN 102766072A CN 2012102781514 A CN2012102781514 A CN 2012102781514A CN 201210278151 A CN201210278151 A CN 201210278151A CN 102766072 A CN102766072 A CN 102766072A
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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 suppressor factor of novel HMG-CoA reductase enzyme, and the medicine of reduce fat efficiently is because it has the advantage of high-efficiency low-toxicity spinoff; Extremely people's favor, so this medicine prospect is extremely wide.
The synthetic route of atorvastatincalcuim chiral side chain compd B is following in the prior art:
Wherein the chemical name of compd A is: (R)-and 4-cyano-3-hydroxy ethyl n-butyrate; The chemical name of compd B is: (R)-and 6-cyanic acid-5-hydroxyl-3-carbonyl-hecanoic acid t-butyl ester.
Prior art is when preparing а-lithium for tert.-butyl acetate; Earlier metallic lithium and the reaction of alpha-brominated normal butane are obtained n-Butyl Lithium; N-Butyl Lithium and Diisopropylamine reaction obtain N-Lithiodiisopropylamide (being also referred to as LDA); At last tert.-butyl acetate is added drop-wise among the LDA, reaction obtains а-lithium for tert.-butyl acetate, and reaction process is comparatively complicated.
There is following shortcoming in above-mentioned technology: metallic lithium (precious metal) and the higher raw materials of price such as alpha-brominated normal butane and Diisopropylamine are adopted in (1); Directly cause cost very high; Wherein, Metallic lithium price per ton is about 400,000 yuan, and alpha-brominated normal butane price per ton is about 2.5 ten thousand, and Diisopropylamine price per ton is about 30,000; (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 adopt liquid nitrogen to cool off, because in the cooling use of liquid nitrogen; Nitrogen after the gasification (tail gas) temperature is extremely low, is difficult to again recycle, and has caused the cryogenic energy utilization efficient of this raw material very low; Liquid nitrogen consumption in use is very big, 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; When (4) 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
Problem to the prior art existence; The objective of the invention is to design provides a kind of technical scheme for preparing the method for atorvastatincalcuim chiral side chain; This method is simple to operate; And can improve the yield of product, avoid the use of the high liquid nitrogen raw material of energy consumption when preparing, reach the effect of energy-saving and emission-reduction.
Described a kind of method for preparing the atorvastatincalcuim chiral side chain is characterized in that comprising following process step:
1) under the nitrogen protection, tert.-butyl acetate and highly basic are joined in the toluene for 1:1～1.15 in molar ratio, slowly be warming up to 105～110 ℃, stirring reaction was incubated 2～4 hours after 3～7 hours, obtained а-sodium for tert.-butyl acetate;
2) above-mentioned material is cooled to-30～0 ℃ through conventional freezer; In above-mentioned material, drip the mixing solutions that contains compd A and THF again; The mol ratio of described compd A and the original add-on of tert.-butyl acetate is 0.3～0.5:1, and the weight ratio of described THF and compd A is 1.0～2.0, drips in 0.5～2 hour to accomplish; Be incubated 2～4 hours then, obtain compd B;
The reaction formula of above-mentioned reaction is following:
Described a kind of method for preparing the atorvastatincalcuim chiral side chain is characterized in that tert.-butyl acetate and highly basic join in the toluene for 1:1.05～1.12 in molar ratio in the described step 1).
Described a kind of method for preparing the atorvastatincalcuim chiral side chain is characterized in that the mol ratio of tert.-butyl acetate and toluene is 1:8～10 in the described step 1).
Described a kind of method for preparing the atorvastatincalcuim chiral side chain is characterized in that being warming up to 106～108 ℃ in the described step 1), and stirring reaction was incubated 3～4 hours after 4～6 hours.
Described a kind of method for preparing the atorvastatincalcuim chiral side chain is characterized in that highly basic is sodium or sodium hydride in the described step 1).
Described a kind of method for preparing the atorvastatincalcuim chiral side chain is characterized in that described step 2) in material be cooled to-20～-10 ℃ through conventional freezer.
Described a kind of method for preparing the atorvastatincalcuim chiral side chain is characterized in that described step 2) in material be cooled to-10～0 ℃ through conventional freezer.
Described a kind of 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.
Described a kind of method for preparing the atorvastatincalcuim chiral side chain is characterized in that described step 2) middle dropping completion in 1～1.5 hour.
Above-mentioned a kind of method for preparing the atorvastatincalcuim chiral side chain; Adopt sodium Metal 99.5 or sodium hydride alternative metals lithium; In toluene solvant, prepare а-sodium for tert.-butyl acetate by sodium Metal 99.5 or sodium hydride with tert.-butyl acetate, again-30～0 ℃ down and the compd A condensation obtain compd B.Compared with prior art, the present invention has following beneficial effect: 1) reactions step is simple, and is 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/THF system, improved transformation efficiency, and helped solvent recuperation more; 4) improved temperature of reaction, the present invention only need reach the purpose of energy-saving and emission-reduction, and also reduce production cost through conventional refrigerator cooling instead of liquid nitrogen cooling; 5) because reactant is comparatively single, transformation efficiency is high, makes that waste water component of the present invention is fairly simple, and sodium-chlor and some organic constituents are only arranged, and can handle through ordinary methods such as desalination rectifying, has significantly reduced cost recovery.
Embodiment
Further specify the present invention below in conjunction with specific embodiment.
The chemical name of compd A is among the present invention: (R)-4-cyano-3-hydroxy ethyl n-butyrate, chemical formula is:
;
The chemical name of compd B is: (R)-6-cyanic acid-5-hydroxyl-3-carbonyl-hecanoic acid t-butyl ester, chemical formula is:
; A and compd B are currently available products.
Embodiment 1
1) under the nitrogen protection, 1mol tert.-butyl acetate and 1mol sodium Metal 99.5 are joined in the 8mol toluene, slowly be warming up to 108 ℃, stirring reaction was incubated 3 hours after 5 hours, obtained а-sodium for tert.-butyl acetate;
2) above-mentioned material is cooled to-10 ℃ through conventional freezer, in above-mentioned material, drips the mixing solutions that contains 0.4mol compd A and 75ml THF again, drip in 1 hour and accomplish, be incubated 2 hours then, obtain compd B;
3) under nitrogen protection, controlled temperature is under 0～-10 ℃, and successively the Hydrogen chloride of Dropwise 5 0ml ethanol and 1000ml 1M slowly in the above-mentioned material adds the back standing demix; Water layer adds the 350ml extracted in toluene once again, merges organic layer, uses 250ml saturated aqueous common salt washed twice at every turn; With organic layer-0.095～-0.099Mpa under, controlled temperature is concentrated into the dried red oil 88.2g that obtains in 50 ℃; Be compd B, purity 93.4%, yield 90.7%.
Embodiment 2
1) under the nitrogen protection, 1mol tert.-butyl acetate and 1.15mol sodium hydride are joined in the 10mol toluene, slowly be warming up to 105 ℃, stirring reaction was incubated 4 hours after 7 hours, obtained а-sodium for tert.-butyl acetate;
2) above-mentioned material is cooled to 0 ℃ through conventional freezer, in above-mentioned material, drips the mixing solutions that contains 0.3mol compd A and 70ml THF again, drip in 0.5 hour and accomplish, be incubated 4 hours then, obtain compd B;
3) controlled temperature is under 0～-10 ℃, and successively the Hydrogen chloride of Dropwise 5 0ml ethanol and 1150ml 1M slowly in the above-mentioned material adds the back standing demix; Water layer adds the 250ml extracted in toluene once again, merges organic layer, uses 250ml saturated aqueous common salt washed twice at every turn; With organic layer-0.095～-0.099Mpa under, controlled temperature is concentrated into the dried red oil 66.8g that obtains in 50 ℃; Be compd B, purity 91.9%, yield 90.1%.
Embodiment 3
1) under the nitrogen protection, 1mol tert.-butyl acetate and 1.1mol sodium hydride are joined in the 9mol toluene, slowly be warming up to 110 ℃, stirring reaction was incubated 2 hours after 3 hours, obtained а-sodium for tert.-butyl acetate;
2) above-mentioned material is cooled to-25 ℃ through conventional freezer, in above-mentioned material, drips the mixing solutions that contains 0.5mol compd A and 110ml THF again, drip in 2 hours and accomplish, be incubated 3 hours then, obtain compd B;
3) controlled temperature successively slowly drips in above-mentioned material under 0～-10 ℃, and the Hydrogen chloride of 50ml ethanol and 1100ml 1M adds the back standing demix; Water layer adds the 400ml extracted in toluene once again, merges organic layer, uses 320ml saturated aqueous common salt washed twice at every turn; With organic layer-0.095～-0.099Mpa under, controlled temperature is concentrated into the dried red oil 110.8g that obtains in 50 ℃; Be compd B, purity 92.7%, yield 90.5%.
Embodiment 4
1) under the nitrogen protection, 1mol tert.-butyl acetate and 1.05mol sodium Metal 99.5 are joined in the 8.5mol toluene, slowly be warming up to 106 ℃, stirring reaction was incubated 3.5 hours after 6.5 hours, obtained а-sodium for tert.-butyl acetate;
2) above-mentioned material is cooled to-30 ℃ through conventional freezer; In above-mentioned material, drip the mixing solutions that contains 0.45mol compd A and 85ml THF again; Dropping was accomplished in 1.5 hours, was incubated 3.5 hours again, obtained like the said compd B of formula II;
3) controlled temperature is under 0～-10 ℃, and successively the Hydrogen chloride of Dropwise 5 0ml ethanol and 1050ml 1M slowly in the above-mentioned material adds the back standing demix; Water layer adds the 350ml extracted in toluene once again, merges organic layer, uses 350ml saturated aqueous common salt washed twice at every turn; With organic layer-0.095～-0.099Mpa under, controlled temperature is concentrated into the dried red oil 103.4g that obtains in 50 ℃; Be compd B, purity 91.7%, yield 91.2%.
Embodiment 5
1) under the nitrogen protection, 1mol tert.-butyl acetate and 1.12mol sodium Metal 99.5 are joined in the 9mol toluene, slowly be warming up to 110 ℃, stirring reaction was incubated 3.5 hours after 6 hours, obtained а-sodium for tert.-butyl acetate;
2) above-mentioned material is cooled to-15 ℃ through conventional freezer, in above-mentioned material, drips the mixing solutions that contains 0.35mol compd A and 110ml THF again, drip in 1 hour and accomplish, be incubated 3.5 hours then, obtain compd B;
3) controlled temperature is under 0～-10 ℃, and successively the Hydrogen chloride of Dropwise 5 0ml ethanol and 1120ml 1M slowly in the above-mentioned material adds the back standing demix; Water layer adds the 350ml extracted in toluene once again, merges organic layer, uses 350ml saturated aqueous common salt washed twice at every turn; With organic layer-0.095～-0.099Mpa under, controlled temperature is concentrated into the dried red oil 80.4g that obtains in 50 ℃; Be compd B, purity 90.7%, yield 91.8%.
Claims (9)
1. method for preparing the atorvastatincalcuim chiral side chain is characterized in that comprising following process step:
1) under the nitrogen protection, tert.-butyl acetate and highly basic are joined in the toluene for 1:1～1.15 in molar ratio, slowly be warming up to 105～110 ℃, stirring reaction was incubated 2～4 hours after 3～7 hours, obtained а-sodium for tert.-butyl acetate;
2) above-mentioned material is cooled to-30～0 ℃ through conventional freezer; In above-mentioned material, drip the mixing solutions that contains compd A and THF again; The mol ratio of described compd A and the original add-on of tert.-butyl acetate is 0.3～0.5:1, and the weight ratio of described THF and compd A is 1.0～2.0, drips in 0.5～2 hour to accomplish; Be incubated 2～4 hours then, obtain compd B;
The reaction formula of above-mentioned reaction is following:
2. a kind of method for preparing the atorvastatincalcuim chiral side chain as claimed in claim 1 is characterized in that tert.-butyl acetate and highly basic join in the toluene for 1:1.05～1.12 in molar ratio in the described step 1).
3. a kind of method for preparing the atorvastatincalcuim chiral side chain as claimed in claim 1 is characterized in that the mol ratio of tert.-butyl acetate and toluene is 1:8～10 in the described step 1).
4. a kind of method for preparing the atorvastatincalcuim chiral side chain as claimed in claim 1 is characterized in that being warming up to 106～108 ℃ in the described step 1), and stirring reaction was incubated 3～4 hours after 4～6 hours.
5. a kind of method for preparing the atorvastatincalcuim chiral side chain as claimed in claim 1 is characterized in that highly basic is sodium or sodium hydride in the described step 1).
6. a kind of method for preparing the atorvastatincalcuim chiral side chain as claimed in claim 1 is characterized in that described step 2) in material be cooled to-20～-10 ℃ through conventional freezer.
7. a kind of method for preparing the atorvastatincalcuim chiral side chain as claimed in claim 1 is characterized in that described step 2) in material be cooled to-10～0 ℃ through conventional freezer.
8. a kind of method for preparing the atorvastatincalcuim chiral side chain as claimed in claim 1 is characterized in that described step 2) in compd A and tert.-butyl acetate mol ratio be 0.35～0.45:1.
9. a kind of method for preparing the atorvastatincalcuim chiral side chain as claimed in claim 1 is characterized in that described step 2) middle dropping completion in 1～1.5 hour.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105461593A (en) * | 2015-12-31 | 2016-04-06 | 江西科苑生物药业有限公司 | Continuous preparing method for 6-cyano-5-hydroxyl-3-oxohexanoate tert-butyl ester |
| CN108033899A (en) * | 2017-12-06 | 2018-05-15 | 浙江科技学院 | The preparation method of one kind (R) -6- cyano group -5- hydroxyl -3- carbonyl hecanoic acid t-butyl esters |
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 |
-
2012
- 2012-08-07 CN CN 201210278151 patent/CN102766072B/en active Active
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 |
|---|
| 《中国优秀硕士学位论文全文数据库工程科技I辑》 20110228 付翁 高位阻beta-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: "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》, 28 February 2011 (2011-02-28) * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105461593A (en) * | 2015-12-31 | 2016-04-06 | 江西科苑生物药业有限公司 | Continuous preparing method for 6-cyano-5-hydroxyl-3-oxohexanoate tert-butyl ester |
| CN108033899A (en) * | 2017-12-06 | 2018-05-15 | 浙江科技学院 | The preparation method of one kind (R) -6- cyano group -5- hydroxyl -3- carbonyl hecanoic acid t-butyl esters |
| 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 |
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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. |