CN1951901A - Process for producing simvastatin ammonium salt - Google Patents
Process for producing simvastatin ammonium salt Download PDFInfo
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- CN1951901A CN1951901A CN 200610123019 CN200610123019A CN1951901A CN 1951901 A CN1951901 A CN 1951901A CN 200610123019 CN200610123019 CN 200610123019 CN 200610123019 A CN200610123019 A CN 200610123019A CN 1951901 A CN1951901 A CN 1951901A
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- ammonium salt
- simvastatin
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Abstract
The invention discloses a preparing method of Simvastatin ammonium salt, which comprises the following steps: 1) dissolving Simvastatin acid in the benign solvent; stirring; 2) aerating ammonia gas slowly; stopping aerating ammonia gas until the pH value is alkaline; stirring; 3) condensing; stopping condensing until the crystal is evolved; stirring; 4) filtering; washing crystal through benign solvent as same as solvent in the step 1); obtaining wet product; 5) drying in the vacuum to obtain the product.
Description
Technical field
The present invention relates to a kind of preparation method of statins ammonium salt, particularly a kind of preparation method of simvastatin ammonium salt.
Background technology
Simvastatin (Simvastatin) is developed by Merck company, be to be the semi-synthetic HMG-CoA reductase inhibitor that forms of raw material with the lovastatin, these product were in Initial Public Offering in 1988, obtain drugs approved by FDA in December, 1991, is mainly used in treatment former generation hypercholesterolemia blood fat, hypertriglyceridemia and other hyperlipemias clinically.Activity is 4 times of Pravastatin in vivo, and effectively development that prevention of arterial is atherosis and heart trouble recurrence reduces the danger that non-deadly myocardial infarction and myocardial vascular form art again.International at present technology of producing Simvastatin mainly adopts following several routes:
1), Canadian Patent CA1199322 record: earlier with lovastatin lithium hydroxide hydrolysis; obtain triol acid; lactonize again and obtain lactone compound; protected silane 4-position hydroxyl optionally then; use 2 again; 2-dimethyl-butyryl chloride and its reaction are sloughed the protected silane base at last and are obtained Simvastatin.
2), U.S. Pat 4582915 records: react the sylvite that obtains lovastatin acid with lovastatin and potassium hydroxide, with n-Butyl Lithium and methyl iodide and the reaction of above-mentioned sylvite, on its side chain, methylate and obtain Simvastatin again.
3), Canadian Patent CA1287063 record: lovastatin and n-butylamine reaction are obtained amine salt, and recycle silicon alkane is protected the hydroxyl of 4-position, uses methyl iodide and alkali and its reaction again, sloughs protected silane at last and lactonizes and obtain Simvastatin.
All there is weak point in above-mentioned three routes in producing utilization, mainly be following some: 1. article one route causes side reaction to increase, its total recovery lower (about 40%) because the first step pyrohydrolysis time is grown (approximately needing 56 hours).2. the second route because not hydrolysis exists than large space sterically hindered side chain, only makes the lactone open loop, so side reaction is less, but has the incomplete problem that methylates, and total recovery is also undesirable.3. the 3rd route, in order to solve the incomplete problem that methylates that the second route exists, this patent is come catalysis with the tetramethyleneimine lithium as highly basic, this method can make the yield that methylates greater than more than 99%, but there is the problem identical: a with second technology, with the n-Butyl Lithium reaction, this compound is abnormally dangerous, makes to produce to have bigger potential safety hazard; There are multiple solvents such as THF, normal hexane, tetramethyleneimine in b in the methylation reaction system, make that solvent is difficult to reclaim, and produces bigger environmental hazard; C from the whole piece route, owing to used many expensive reagent, makes total cost of production higher; D, the final step cyclization has used toluene as solvent, and making the residual boundary much larger than the ICH regulation of toluene has also influenced the promotion and application of this kind.
The synthesis route of Canadian Patent CA1287063 can adopt following procedural representation:
Formula 1 formula 2 formulas 3
The ammonium salt that promptly utilizes simvastatin acid to prepare Simvastatin earlier obtains Simvastatin through ring-closure reaction then.Wherein, the detailed process of preparation ammonium salt is: add methyl alcohol in the ethyl acetate solution of simvastatin acid, temperature control is at 25～30 ℃, dripped the strong aqua methanol solution by 1: 3, separate out crystal after, leave standstill 30min, continue to drip the strong aqua methanol solution, after the strong aqua methanol solution adds, be cooled to-10 ℃ in 1 hour, 100rpm stirs 2h under-10 ℃ of temperature, filter, wash crystalline substance with 3: 5 ethyl acetate methanol solution, 40 ℃ of vacuum-drying 2h get simvastatin ammonium salt.
It partly is the synthetic route that adopts this patent that the technology of producing Simvastatin at home has, and still when above-mentioned ammonium salt prepared, the yield in this step was very low, and complicated operation, and major cause is that simvastatin acid has the part cyclization when dropping ammonia, can not all become ammonium salt; Be that crystallization is separated out in pure water simultaneously, ammonium salt is separated out not exclusively; Should the step react the mixed solvent that adopts ethyl acetate, second alcohol and water in addition, solvent can't reclaim, and does not have cost advantage and is unfavorable for environment protection.
Summary of the invention
The objective of the invention is to, a kind of preparation method of simvastatin ammonium salt is provided, ammonium salt prepares the low problem of link productive rate in the solution prior art.
The objective of the invention is to be achieved through the following technical solutions:
1), simvastatin acid is dissolved in the optimum solvent stirring;
2), feed ammonia, detecting pH value be alkalescence, stops logical ammonia, stirring;
3), concentrate, stop to concentrate after crystal to be had is separated out, stir;
4), filter, and use with step 1) in identical optimum solvent wash crystalline substance, product must wet;
5), vacuum-drying gets simvastatin ammonium salt.
In above-mentioned steps 1), 2), 3) in stirring all be under-15 ℃-15 ℃, to carry out.
In above-mentioned steps 1), 4) in optimum solvent be that carbochain is a kind of in the alcoholic solvent, DMF, ethyl acetate, methylene dichloride, chloroform, acetone of 1-5.
In above-mentioned steps 3) in the simmer down to concentrating under reduced pressure.
In above-mentioned steps 5) in vacuum drying temperature be 15 ℃-50 ℃.
This technology is dissolved in simvastatin acid in the optimum solvent earlier, feeds ammonia then, and detecting pH value is that alkalescence gets final product, reaction times is short, simple to operate, reacts completely, and side reaction such as the no cyclization of reaction, by condensing crystal, the product that remains in the solvent is few, the reaction yield height.
Specific embodiment
Embodiment one
8g is dissolved in the 120ml methanol solution with simvastatin acid (compound shown in the formula 1), 0 ℃ of following 200rpm stirs, and feeds ammonia about 5 minutes, and detecting pH value is alkalescence, stop logical ammonia, stir 10min, wait to stablize the back and stir half an hour, the following concentrating under reduced pressure of 35 degree, stop to concentrate after having crystal to separate out, 0 ℃ is stirred 2h down, filters, and washes crystalline substance with methanol solution.Get white wet product 10.76g, 35 ℃ of vacuum-dryings get simvastatin ammonium salt (compound shown in the formula 2) 8.04g, yield 96.9%.
Present method can be utilized following procedural representation.
Formula 1 formula 2
Embodiment two
8g is dissolved in the 100ml ethanolic soln with compound 1 (simvastatin acid),-15 ℃ of stirrings fed ammonia about 5 minutes, and detecting pH value is alkalescence, stop logical ammonia,-15 ℃ are stirred 5～10min, wait to stablize the back and stir half an hour, then at the following concentrating under reduced pressure of 50 degree, stop to concentrate after having crystal to separate out,-15 ℃ are stirred 1h, filter, and wash crystalline substance with the 10ml ethanolic soln.Get white wet product 12.54g, 15 ℃ of vacuum-dryings get simvastatin ammonium salt 8.10g, yield 97.6%.
Embodiment three
10g is dissolved in the 120ml chloroformic solution with compound 1 (simvastatin acid), 15 ℃ of stirrings fed ammonia about 10 minutes, and detecting pH value is alkalescence, stop logical ammonia, 15 ℃ are stirred 5～10min, wait to stablize the back and stir half an hour, then at 60 degree left and right sides concentrating under reduced pressure, stop to concentrate after having crystal to separate out, behind 15 ℃ of stirring 2h, filter, wash crystalline substance with the chloroformic solution of 10ml ice.Get white wet product 14.45g, 50 ℃ of vacuum-dryings get simvastatin ammonium salt 9.91g, yield 95.5%.
Embodiment four
8g is dissolved in the 120ml methanol solution with compound 1 (simvastatin acid),-10 ℃ are stirred down, slowly feed the about 5-10 of ammonia minute, and detecting pH value is alkalescence, stop logical ammonia,-10 ℃ are stirred 5～10min down, wait to stablize the back and stir half an hour, then at the following concentrating under reduced pressure of 35 degree, stop to concentrate after having crystal to separate out,-10 ℃ are stirred down to be placed on behind the 1h and spend the night in-10 ℃ of refrigerators, filter (employing press filtration) in second day, and the methanol solution with 10ml after freezing is washed crystalline substance.Get white wet product 10.63g, 35 ℃ of vacuum-dryings get simvastatin ammonium salt 8.16g, yield 98.3%.
Embodiment five
Present embodiment is that the test differing temps stirs the embodiment to the yield influence.
3100g is dissolved in the 3600ml chloroformic solution with compound 1 (simvastatin acid), divide three groups of A, B, C, getting 100 ℃, 85 ℃, 65 ℃, 50 ℃, 30 ℃, 15 ℃, 0 ℃ ,-15 ℃ ,-20 ℃ ,-30 ℃ temperature respectively for every group stirs, fed ammonia about 10 minutes, detecting pH value is alkalescence, stop logical ammonia, go to stir 5～10min with preceding relevant temperature, wait to stablize the back and stir half an hour, then at 60 degree left and right sides concentrating under reduced pressure, stop to concentrate after having crystal to separate out, stir 2h after, filter, wash crystalline substance with the chloroformic solution of 10ml ice.It is some to get white wet product, and 50 ℃ of vacuum-dryings get simvastatin ammonium salt, measures yield.
| Group | 100℃ | 85℃ | 65℃ | 50℃ | 30℃ | ?15℃ | 0℃ | -15℃ | -20℃ | -30℃ |
| A | ?63.2％ | 57.1％ | 70％ | 68.8％ | 84.4％ | 96.2％ | 98.5％ | 94.4％ | 85.4％ | 80.2％ |
| B | ?58.5％ | 59.3％ | 64.2％ | 63.3％ | 82.3％ | 95.7％ | 98.4％ | 92.5％ | 86.7％ | 79.9％ |
| C | ?64.4％ | 59.9％ | 60.3％ | 71.2％ | 86.2％ | 96.1％ | 97.7％ | 93.5％ | 83.0％ | 88.3％ |
Embodiment six
Present embodiment is the preparation method's of original Simvastatin embodiment, and the purpose in present specification is to be provided with in order to contrast effect of the present invention.
Add 45ml methyl alcohol in the about 200ml of the ethyl acetate solution of simvastatin acid 8g, temperature control drips 1: 3 strong aqua methanol solution 15ml at 25～30 ℃ among the 60min, after separating out crystal, leave standstill 30min, continue to drip the strong aqua methanol solution, after the strong aqua methanol solution added, 60min was cooled to-10 ℃, and 100rpm stirs 2h under-10 ℃ of temperature, filter, wash crystalline substance with 3: 5 ethyl acetate methanol solution 8ml, the heavy 12.5g of wet product, 40 vacuum-drying 2h, get simvastatin ammonium salt 7.1g, yield 85%.
The most important improvement of this technology is that the dropping ammonia with former technology changes the feeding ammonia into, makes side reactions such as the no cyclization of reaction; Though title of the present invention and embodiment are to be the preparation technology that example is introduced ammonium salt with the Simvastatin, actual formula of is that the preparation of the ammonium salt of formula 4 also is fall into protection scope of the present invention.General formula is that the ammonium salt of formula 4 gets final product to such an extent that general formula is to get statin compound shown in the formula 5 by ring-closure reaction.
Formula 4 formulas 5
R in the formula
1, R
2, R
3, R
4=H, OH, halogen or alkyl, aromatic base and derivative thereof.Described optimum reaction solvent protection domain comprises: carbochain is the alcoholic solvent of 1-5, THF, DMF, ethyl acetate, methylene dichloride, chloroform, acetone and other organic solvent.Range of reaction temperature is-20 ℃～50 ℃.
Claims (5)
1, a kind of preparation method of simvastatin ammonium salt, it comprises the steps:
1), simvastatin acid is dissolved in the optimum solvent stirring;
2), feed ammonia, detecting pH value be alkalescence, stops logical ammonia, stirring;
3), concentrate, stop to concentrate after crystal to be had is separated out, stir;
4), filter, and use with step 1) in identical optimum solvent wash crystalline substance, product must wet;
5), vacuum-drying gets simvastatin ammonium salt.
2, the preparation method of simvastatin ammonium salt according to claim 1 is characterized in that, in above-mentioned steps 1), 2), 3) in stirring all be under-15 ℃-15 ℃, to carry out.
3, the preparation method of simvastatin ammonium salt according to claim 1 and 2 is characterized in that, in above-mentioned steps 1), 4) in optimum solvent be that carbochain is a kind of in the alcoholic solvent, DMF, ethyl acetate, methylene dichloride, chloroform, acetone of 1-5.
4, the preparation method of simvastatin ammonium salt according to claim 1 and 2 is characterized in that, in above-mentioned steps 3) in the simmer down to concentrating under reduced pressure.
5, the preparation method of simvastatin ammonium salt according to claim 1 and 2 is characterized in that, in above-mentioned steps 5) in the exsiccant temperature be 15 ℃-50 ℃.
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| CNB2006101230190A CN100441562C (en) | 2006-10-26 | 2006-10-26 | Process for producing simvastatin ammonium salt |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101575287A (en) * | 2008-05-09 | 2009-11-11 | 上海医药工业研究院 | Synthesizing method of simvastatin ammonium salt, midbody used thereby and preparation method thereof |
| CN103254076A (en) * | 2008-05-09 | 2013-08-21 | 上海医药工业研究院 | Synthesis method for simvastatin ammonium salt, used intermediate and preparation methods for both |
| CN103787881A (en) * | 2013-11-22 | 2014-05-14 | 成都摩尔生物医药有限公司 | Simvastatin ammonium salt |
| CN102690254B (en) * | 2008-05-09 | 2014-06-04 | 上海医药工业研究院 | Simvastatin ammonium salt intermediates and preparation methods thereof |
-
2006
- 2006-10-26 CN CNB2006101230190A patent/CN100441562C/en active Active
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101575287A (en) * | 2008-05-09 | 2009-11-11 | 上海医药工业研究院 | Synthesizing method of simvastatin ammonium salt, midbody used thereby and preparation method thereof |
| CN101575287B (en) * | 2008-05-09 | 2013-04-03 | 上海医药工业研究院 | Synthesizing method of simvastatin ammonium salt, midbody used thereby and preparation method thereof |
| CN103254076A (en) * | 2008-05-09 | 2013-08-21 | 上海医药工业研究院 | Synthesis method for simvastatin ammonium salt, used intermediate and preparation methods for both |
| CN102690254B (en) * | 2008-05-09 | 2014-06-04 | 上海医药工业研究院 | Simvastatin ammonium salt intermediates and preparation methods thereof |
| CN103787881A (en) * | 2013-11-22 | 2014-05-14 | 成都摩尔生物医药有限公司 | Simvastatin ammonium salt |
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| CN100441562C (en) | 2008-12-10 |
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Assignee: Xinbeijiang Pharmaceutical Co., Ltd., Lizhu Group Assignor: Lizhu Medicine Group Co., Ltd. Contract fulfillment period: 2009.1.31 to 2019.1.31 contract change Contract record no.: 2009990000348 Denomination of invention: Process for producing simvastatin ammonium salt Granted publication date: 20081210 License type: Exclusive license Record date: 2009.4.21 |
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Free format text: EXCLUSIVE LICENSE; TIME LIMIT OF IMPLEMENTING CONTACT: 2009.1.31 TO 2019.1.31; CHANGE OF CONTRACT Name of requester: LIVZON GROUP XINBEI JIANG PHARMACY STOCK CO., LTD. Effective date: 20090421 |