CN102876744B - Method for performing bio-enzyme catalytic synthesis for (2S,3S)-valnoctamide - Google Patents
Method for performing bio-enzyme catalytic synthesis for (2S,3S)-valnoctamide Download PDFInfo
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Abstract
The invention discloses a method for performing bio-enzyme catalytic synthesis for (2S,3S)-valnoctamide. According to the method, the (2S,3S)-valnoctamide is prepared by taking (3S)-methyl valeric acid which is readily available as a starting raw material and taking asymmetric catalytic hydrolysis reaction in presence of a bio-enzyme as a key step. According to the method, a key intermediate is prepared in high selectivity by utilizing the asymmetric catalytic hydrolysis reaction in presence of the bio-enzyme, so that the (2S,3S)-valnoctamide with high optical purity is prepared, and the purity of the (2S,3S)-valnoctamide accords with the standard of medicines. A process is simple, easy and convenient to operate, low in cost and high in total yield and has a bright industrial application prospect.
Description
Technical field
The present invention relates to a kind of biological enzyme synthetic method for the treatment of epilepsy new drug (2S, 3S)-valnoctamide, belong to medical technical field.
Background technology
In at present numerous antiepileptic drugs, valproic acid (Valproic Acid, VPA) is that clinical application is wide, curative effect is high and good first-selected, the broad-spectrum medicinal of security.Although the use of valproic acid exists very important side effect, as pregnant women can make the incidence of neonatal neural tube defect significantly improve after taking, its global sales volume is still larger, and its sales volume in 2006 reaches 2,000,000,000 dollars.Therefore by valproic acid research find the more surrogate of high reactivity and the low side effect of low toxicity and become study hotspot all the time.
One of valproic acid analogue has valnoctamide, and it,, as a kind of sedative hypnotics, is widely used.In valnoctamide chemical structural formula, contain two chiral carbon atoms, what sell in the market is the mixture of its four isomer, i.e. the mixture of (S, S) type, (R, R) type, (S, R) type and (R, S) type.1997, the Israel one report document Clin. Pharmacol. Ther. of research group 1997,61,442-449 adopt chirality gas phase post from four isomer of valnoctamide by (S, S) type isomer is successfully separated, research shows that (S, S) type valnoctamide is that (2S, 3S)-valnoctamide has high activity and selectivity to anti-epileptic.
Israel research group is in the document Tetrahedron:Asym. 1999 of report in 1999,10, the 841st, (the 2S that the ILE of take is committed step as starting raw material, the reaction of Evans asymmetric alkylation, the synthetic route of 3S)-valnoctamide, totally 8 step reactions, overall yield is about 1%, and reaction scheme is as follows:
The synthetic route of above-mentioned Israel research group, the ILE raw material adopting is expensive, and subsequent technique separation method is very complicated, is difficult to use in production in enormous quantities.
U.S. Neurocrine Biosciences, Inc. drugmaker disclosed to take Myers asymmetric alkylation reaction be committed step (Org. Process Res. Dev. 2009,13,463.), further synthesize the synthetic route that obtains (2S, 3S)-valnoctamide.It is higher that this synthesis technique has overall yield, and raw material is cheap, simple to operate, product purity high, and can be amplified to very reliably kg level, reaction scheme is as follows:
At above-mentioned U.S. Neurocrine Biosciences, Inc. in the synthesis technique of drugmaker, chiral auxiliary group Pseudoephedrine used is the strict chemical of controlling, in actual industrial production, can run into a lot of troubles, as manufacturer needs extra approval, the transportation of its raw material and the destruction of waste material of drugs management board, also need a lot of extra formalities etc., production cost first mate is increased.
Therefore, a production cost is low, and (2S, 3S)-valnoctamide production technique that productive rate is higher and simple to operate will have very large pushing effect for its application in anti-epileptic and other side field.
Summary of the invention
Defect in view of above-mentioned prior art existence, the object of the invention is to propose a kind of (2S, 3S)-valnoctamide biological enzyme synthetic method, it is gordian technique that the method be take very popular biological enzyme in current Green Chemistry, there is route short, productive rate is high, and starting material are cheap easily and the feature such as environmentally friendly, meets the aim of Green Chemistry.It is simple that the inventive method also has operational path, and feature easy and simple to handle does not have complicated last handling process, and this makes the present invention have good prospects for commercial application.
Object of the present invention will be achieved by the following technical programs:
(2S, 3S)-valnoctamide biological enzyme synthetic method, comprising: step 1, take (3S)-methylvaleric acid as starting raw material, and through esterification, make (3S)-methylvaleric acid ethyl ester; Step 2, (3S)-methylvaleric acid ethyl ester that step 1 is made obtains (3S)-3-methyl-2-ethyl Valeric acid ethylester via alkylated reaction; Step 3, (3S)-3-methyl-2-ethyl Valeric acid ethylester that step 2 is made adopts biological enzyme to carry out stereoselectivity catalyzed reaction and makes intermediate (2S, 3S)-3-methyl-2-ethyl valeric acid; Step 4, the process acylation reaction that step 3 is made makes (2S, 3S)-valnoctamide.Its synthetic route is as follows:
Preferably, above-mentioned (2S, 3S)-valnoctamide biological enzyme synthetic method, wherein: described step 3 comprises: the potassium primary phosphate/dipotassium hydrogen phosphate buffered soln that is first 6-9 by pH value is warming up to 25 ℃-75 ℃, to it, drop into (3S)-3-methyl-2-ethyl Valeric acid ethylester and lipase, wherein the quality of lipase be (3S)-3-methyl-2-ethyl Valeric acid ethylester quality 0.05-0.5 doubly, regulating the pH value of reaction solution is 4-9,20 ℃-60 ℃ of temperature of reaction, under the condition in 1 day-5 days reaction times, make (2S, 3S)-3-methyl-2-ethyl valeric acid.
Preferably, above-mentioned (2S, 3S)-valnoctamide biological enzyme synthetic method, wherein: the lipase in described step 3 is any one in Pseudomonas fluorescens lipase or Burkholderia cepacia lipase.
Preferably, above-mentioned (2S, 3S)-valnoctamide biological enzyme synthetic method, wherein: the pH value of the potassium primary phosphate/dipotassium hydrogen phosphate buffered soln in described step 3 is 6.5-7.5.
Preferably, above-mentioned (2S, 3S)-valnoctamide biological enzyme synthetic method, wherein: the potassium primary phosphate/dipotassium hydrogen phosphate buffered soln in described step 3 is warming up to 30 ℃-50 ℃.
Preferably, above-mentioned (2S, 3S)-valnoctamide biological enzyme synthetic method, wherein: the temperature of reaction in described step 3 is 32 ℃-36 ℃.
Preferably, above-mentioned (2S, 3S)-valnoctamide biological enzyme synthetic method, wherein: the reacting liquid pH value in described step 3 is 7.0-7.1.
The present invention has following beneficial effect:
1. by utilizing hydrolysis (3S)-3-methyl-2-ethyl Valeric acid ethylester of enzyme asymmetric catalysis, highly selective, thereby be prepared into the key intermediate (2S of optical purity > 95 ﹪, 3S)-3-methyl-2-ethyl valeric acid, further make (optical purity > 99 ﹪) individual isomer (2S of high-optical-purity, 3S)-valnoctamide, makes its purity meet the drug standard.
2. (the 3S)-methylvaleric acid cheap and easy to get of take is starting raw material, through four-step reaction step, synthesizes and obtains (2S, 3S)-valnoctamide, and its operational path is simple, easy and simple to handle, cost is low, has good prospects for commercial application.
3. adopt the rational highway route design of the present invention, make the overall yield of its end product higher, in its overall yield of (3S)-methylvaleric acid > 20%.
Embodiment
Below by specific embodiment, method of the present invention is described, but the present invention is not limited thereto.Experimental technique described in following embodiment, if no special instructions, is ordinary method; Described reagent and material, if no special instructions, all can obtain from commercial channels.
Embodiment:
The preparation of 1.1 (3S)-methylvaleric acid ethyl esters
In the ethanolic soln of 11.6kg (3S)-methylvaleric acid, drip the vitriol oil, be heated to 78 ℃, after spending the night, boil off excessive ethanol, after being dissolved in to sherwood oil, residuum uses saturated common salt water washing, remove the colourless liquid 13.4kg that obtains (3S)-methylvaleric acid ethyl ester after petroleum ether solvent, productive rate 93%.
1H-NMR?（300MHz，CDCl3）δ?4.08?(q,?3H),?2.32?(dd,?J=6.0?Hz,?1H);?2.10?(dd,?J=8.2?Hz,1H);?1.95–1.76?(m,?1H);?1.43–1.09?(m,?5H);?0.91?(d,?J=6.7?Hz,?3H);?0.85?(t,?J=7.5?Hz,?3H)。
The preparation of 1.2 (3S)-3-methyl-2-ethyl Valeric acid ethylesters
7.2kg (3S)-methylvaleric acid ethyl ester is dissolved in 72kg ethanol, add 3.5kg sodium ethylate, be warming up to 70 ℃ of left and right, sodium ethylate all dissolves, drip 5.6kg monobromethane, during dropping, start to reflux, dripping off refluxes keeps temperature 70 C reaction 3h, be chilled to room temperature, filter out solid, slough most of ethanol, add a small amount of water to make the dissolution of solid in solution, add ethyl acetate extraction, branch vibration layer, anhydrous sodium sulfate drying organic layer, except desolventizing, residual liquid rectifying, obtain (3S)-3-methyl-2-ethyl Valeric acid ethylester colourless transparent liquid 5.3kg, productive rate 62%.
1H-NMR（300MHz，CDCl3）δ?4.13?(q,?3H),?2.19–2.08?(m,?1H);?1.69–1.28?(m,?4H);?1.22–1.05?(m,?3H);?0.91–0.80?(m,?9H)。
The preparation of 1.3 (2S, 3S)-3-methyl-2-ethyl valeric acid
To clean 50L reactor, add 28L water, 1.35kg potassium primary phosphate, 3.75kg tri-water dipotassium hydrogen phosphates, are mixed with 30L, potassium primary phosphate/dipotassium hydrogen phosphate buffered soln of pH=7.1,45 ℃ of recirculated waters are heated.Then add 2.2kg (2RS, 3S)-3-methyl-2-ethyl Valeric acid ethylester and 450g Pseudomonas fluorescens lipase or Burkholderia cepacia lipase, use plum Teller pH self-operated regulator to add 1M potassium hydroxide solution adjust pH to 7.0-7.1, be controlled at 34 ± 2 ℃ of temperature.In 1 day-5 days reaction times, after reaction finishes, add concentrated hydrochloric acid and regulate pH value to 2.5, adding methyl tertiary butyl ether and diatomite in reaction solution again, after stirring 1h, removes solid, and the water in filtrate extracts with methyl tertiary butyl ether, merges organic phase.Organic phase extracts 3 times with 10% sodium hydroxide solution.Merge water, concentrated hydrochloric acid adjust pH to 2, petroleum ether extraction 3 times.Merge organic phase, except desolventizing, residual liquid rectifying, obtain (2S, 3S)-3-methyl-2-ethyl valeric acid colourless transparent liquid 1.0kg, productive rate 45%.Chirality gas phase is determined optical purity of products >95%.
1H-NMR?（300MHz，CDCl3）?δ?2.24-2.17?(m,?1H);?1.70–1.46?(m,?4H);?1.25–1.15?(m,?1H);?0.95-87?(m,?9H)。
The preparation of 1.4 (2S, 3S)-valnoctamide
1kg (2S, 3S)-3-methyl-2-ethyl valeric acid is joined in 1.1kg sulfur oxychloride, and then the liquid of gained join in advance and be cooled in the ammoniacal liquor of 3.5kg28% of-10 ℃, 20 ℃ of temperature of reaction, in 6 hours reaction times, then filters and obtain solid.Used ethyl acetate and sherwood oil recrystallization to obtain white solid 0.8kg, 80% productive rate.Chirality gas phase is determined optical purity of products >99%.
1H-NMR?（300MHz，CDCl3）?δ?5.53?(s,?1H);?5.39?(s,?1H);?1.89–1.84?(m,?1H);?1.64–1.47?(m,?4H);?1.25–1.10?(m,?1H);?1.00–0.86?(m,?9H)。
A kind of (2S, 3S)-valnoctamide biological enzyme synthetic method of the present embodiment, has following beneficial effect:
1. by utilizing hydrolysis (3S)-3-methyl-2-ethyl Valeric acid ethylester of enzyme asymmetric catalysis, highly selective, thereby be prepared into the key intermediate (2S of optical purity > 95 ﹪, 3S)-3-methyl-2-ethyl valeric acid, further make (optical purity > 99 ﹪) individual isomer (2S of high-optical-purity, 3S)-valnoctamide, makes its purity meet the drug standard.
2. (the 3S)-methylvaleric acid cheap and easy to get of take is starting raw material, through four-step reaction step, synthesizes and obtains (2S, 3S)-valnoctamide, and its operational path is simple, easy and simple to handle, cost is low, has good prospects for commercial application.
3. adopt the rational highway route design of the present invention, make the overall yield of its end product higher, in its overall yield of (3S)-methylvaleric acid > 20%.
The present invention still has numerous embodiments, and all employing equivalents or equivalent transformation and all technical schemes of forming, within all dropping on protection scope of the present invention.
Claims (2)
1. (2S, 3S)-valnoctamide biological enzyme synthetic method, is characterized in that: step 1, take (3S)-methylvaleric acid as starting raw material, and through esterification, make (3S)-methylvaleric acid ethyl ester; Step 2, (3S)-methylvaleric acid ethyl ester that step 1 is made obtains (3S)-3-methyl-2-ethyl Valeric acid ethylester via alkylated reaction; Step 3, (3S)-3-methyl-2-ethyl Valeric acid ethylester that step 2 is made adopts biological enzyme to carry out stereoselectivity catalyzed reaction and makes intermediate (2S, 3S)-3-methyl-2-ethyl valeric acid; Step 4, (2S, the 3S) that step 3 is made-3-methyl-2-ethyl valeric acid makes (2S, 3S)-valnoctamide through acylation reaction; Described step 3 comprises: the potassium primary phosphate/dipotassium hydrogen phosphate buffered soln that is first 6.5-7.5 by pH value is warming up to 30 ℃-50 ℃, to it, drop into (3S)-3-methyl-2-ethyl Valeric acid ethylester and lipase, regulating the pH value of reaction solution is 7.0-7.1,32 ℃-38 ℃ of temperature of reaction, under the condition in 1 day-5 days reaction times, make (2S, 3S)-3-methyl-2-ethyl valeric acid; Wherein, described lipase is any one in Pseudomonas fluorescens lipase and Burkholderia cepacia lipase.
2. (2S, 3S) according to claim 1-valnoctamide biological enzyme synthetic method, is characterized in that: the 0.05-0.5 of the quality that the quality of described lipase is (3S)-3-methyl-2-ethyl Valeric acid ethylester doubly.
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| WO2006119060A1 (en) * | 2005-04-29 | 2006-11-09 | E. I. Du Pont De Nemours And Company | Enzymatic production of peracids using perhydrolytic enzymes |
| CN101045936A (en) * | 2007-03-27 | 2007-10-03 | 吉林大学 | Process of preparing chiral fatty alcohol with acid anhydride as acry radical donor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2006119060A1 (en) * | 2005-04-29 | 2006-11-09 | E. I. Du Pont De Nemours And Company | Enzymatic production of peracids using perhydrolytic enzymes |
| CN101045936A (en) * | 2007-03-27 | 2007-10-03 | 吉林大学 | Process of preparing chiral fatty alcohol with acid anhydride as acry radical donor |
Non-Patent Citations (2)
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| 假单胞菌脂肪酶的研究进展;张搏等;《生物技术通报》;20071231;52-57 * |
| 张搏等.假单胞菌脂肪酶的研究进展.《生物技术通报》.2007,52-57. |
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