CN102965403A - Biological preparation method of tert-butyl(3R,5S)-6-chloro-3,5-dihydroxyhexanoate - Google Patents
Biological preparation method of tert-butyl(3R,5S)-6-chloro-3,5-dihydroxyhexanoate Download PDFInfo
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Abstract
The invention discloses a biological preparation method of tert-butyl(3R,5S)-6-chloro-3,5-dihydroxyhexanoate. According to the method, tert-butyl(S)-6-chloro-5-carbonyl-3-carbonyhexanoate is used as a substrate; and a reduction reaction of the substrate takes place in the presence of a biocatalyst, a co-factor and a hydrogen donor to generate tert-butyl(3R,5S)-6-chloro-3,5-dihydroxyhexanoate, wherein the biocatalyst is recombinant ketoreductase, the co-factor is NAD/NADH or NADP/NADPH, the hydrogen donor is isopropyl alcohol, and the reduction reaction takes place in an aqueous phase buffer solution with pH of 6.0-9.0. According to the invention, by adopting recombinant ketoreductase, the problems of enzyme deactivation, difficulty in product extract and the like caused by adding auxiliary glucose dehydrogenase and glucose are avoided; and through the improved technology, the reaction conditions are mild, the reaction efficiency is improved, and the operation is convenient.
Description
Technical field:
The invention belongs to bio-pharmaceuticals and Green Chemistry field, be specifically related to a kind of (3R, 5S)-6-chloro-3, the biological preparation method of 5-dihydroxyl hecanoic acid t-butyl ester.
Background technology:
Utilize the biological enzyme agent to prepare chirality pharmaceutical intermediate compound, important application is arranged in medicine industry.Producing in the world decreasing cholesterol statins salable, namely in the research of hydroxymethyl glutaryl CoA (HMG-CoA) reductase inhibitor compounds, the production stage of its chiral side chain is most critical.Wherein, attempting preparation key intermediate (3R, 5S)-6-chloro-3, in the research of 5-dihydroxyl hecanoic acid t-butyl ester, utilize reductase enzyme to obtain target product, become the object of chemistry and pharmaceutical industry circle primary study with the characteristics of its high-level efficiency, highly selective from (the S)-6-chloro-5-carbonyl-3-hydroxycaproic acid tert-butyl ester one step reduction.
At disclosed preparation (3R, 5S)-6-chloro-3, in the method for 5-dihydroxyl hecanoic acid t-butyl ester, the reaction conditions of chemical reduction method often needs low temperature (such as-70 ℃), and inflammable boranes compound participates in, very dangerous and be difficult to practical (Angew. Chem. Int. Ed. 2000,39:4306-4307).Comparatively speaking, the application conditions of biological process is gentleer, therefore also more practical and environmental protection.For example US Patent No. 2008/0248539 A1 discloses ketoreductase and the mutant strain reduction method production (3R thereof that a kind of utilization comes from yeast saccharomyces cerevisiae (Saccharomyces cerevisiae), 5S)-and 6-chloro-3, the method for 5-dihydroxyl hecanoic acid t-butyl ester.In order to realize the original position circulation of coenzyme, this patent has adopted adds auxiliary Hexose phosphate dehydrogenase and the method for glucose.Although the method has many advantages than chemical method, but its coenzyme circulating system can produce the gluconic acid with the product equivalent, in order to keep the pH of reaction system, the alkali that needs to add equivalent neutralizes, not only affect process economy and the Atom economy of reaction, the acid that produces in the reaction system and the alkali of interpolation also may produce certain impact to enzyme activity, are not the optimal selection of this route.
This patent discloses a kind of improved ketoreductase production (3R that utilizes, 5S)-and 6-chloro-3, the method for 5-dihydroxyl hecanoic acid t-butyl ester has not only been avoided the variety of problems that exists in the chemical method, also biological process is carried out rational improvement, had important industrial application value.
Summary of the invention:
The object of the present invention is to provide a kind of improved (3R, 5S)-6-chloro-3, the biological preparation method of 5-dihydroxyl hecanoic acid t-butyl ester.
For solving above technical problem, the present invention adopts following technical scheme:
A kind of (3R, 5S)-6-chloro-3, the biological preparation method of 5-dihydroxyl hecanoic acid t-butyl ester, it is take (S)-6-chloro-5-carbonyl-3-hydroxycaproic acid tert-butyl ester as substrate, this substrate is at biological catalyst, the reduction reaction occurs under the existence of cofactor and hydrogen donor generate (3R, 5S)-6-chloro-3,5-dihydroxyl hecanoic acid t-butyl ester, described biological catalyst is the restructuring ketoreductase, the preparation method of described restructuring ketoreductase is: the recombination bacillus coli list colony inoculation that will contain the ketoreductase gene is received in the liquid LB substratum of mycin resistance to containing card, in 35 ~ 40 ℃ of lower shaking table activation 8 ~ 12 hours, the culture that obtains after the activation is inoculated into contains card and receive in the liquid LB substratum of mycin resistance, in 35 ~ 40 ℃ of lower shaking table enlarged culturing, be cultured to the OD600 value and reach at 0.6 ~ 0.8 o'clock, add inductor, cultivated 8 ~ 12 hours in 25 ~ 33 ℃ of lower continuation, centrifugal, the collecting precipitation thing, add phosphate buffered saline buffer and get suspension, suspension was placed the ice-water bath ultrasonication 8 ~ 12 minutes, centrifugal again, supernatant liquor pre-freeze to temperature is down to-10 ~-25 ℃, and then freeze-drying 24 ~ 48 hours, namely get the restructuring ketoreductase of lyophilized powder, described restructuring ketoreductase can be acetone with iso-propanol conversion, described cofactor is NAD/NADH or NADP/NADPH, described hydrogen donor is Virahol, and described reduction reaction is carried out in pH is 6.0 ~ 9.0 water damping fluid.
In the reaction system when reaction is initial, the restructuring ketoreductase with (S)-mass percent of 6-chloro-5-carbonyl-3-hydroxycaproic acid tert-butyl ester is 2 ~ 4%, cofactor with (S)-mass percent of 6-chloro-5-carbonyl-3-hydroxycaproic acid tert-butyl ester is 0.05 ~ 0.2%, the amount of substance per-cent of relatively described (the S)-6-of described Virahol chloro-5-carbonyl-3-hydroxycaproic acid tert-butyl ester is 100 ~ 150%.
Described inductor is isopropyl-β-D-thiogalactoside(IPTG) (IPTG) or lactose.
Described cofactor is NAD/NADH.
Described water damping fluid is phosphate buffered saline buffer, Tris-HCl buffered soln or trolamine hydrochloric acid buffered soln.
Described reduction reaction is carried out in pH is 8.0 water damping fluid.
Described preparation method's implementation process is as follows: add successively substrate (S)-6-chloro-5-carbonyl-3-hydroxycaproic acid tert-butyl ester in reaction vessel, Virahol, described water damping fluid, stir, continue to add restructuring ketoreductase and cofactor, under 25 ~ 45 ℃, stirring reaction, utilize HPLC-MS detection reaction process, when rate to be transformed reaches 90 ~ 99%, add ethyl acetate and repeatedly extract, merge organic phase and evaporate and slough solvent, namely get (3R, 5S)-6-chloro-3 5-dihydroxyl hecanoic acid t-butyl ester product.
According to the present invention, except the restructuring ketoreductase, all the other raw materials all can be commercially available by general channel.
Beneficial effect of the present invention is:
The inventive method is by adopting the ketoreductase of restructuring, avoided extracting the problems such as difficulty because adding make enzyme deactivation and the product that auxiliary Hexose phosphate dehydrogenase and glucose causes; And the employing modified processing route, so that reaction conditions is gentle, reaction efficiency improves, and is easy and simple to handle.
Description of drawings:
Accompanying drawing 1 is that transformation efficiency is with the pH variation diagram.
Embodiment:
Reaction formula of the present invention is as follows:
The following examples can make the present invention of professional and technical personnel's comprehend, but do not limit the present invention in any way.
Embodiment one: restructuring ketoreductase enzyme powder shaking flask production technique
The recombination bacillus coli list bacterium colony that will contain the ketoreductase gene is from the glycerine pipe or transform plating and contain card to 4 mL and receive the liquid LB substratum of resistance and activate spend the night (37 ℃, 200 rpm).Contain card and receive the liquid LB substratum of resistance with 1/100 inoculum size, 100 mL that transfer from overnight culture, 37 ℃, 200 rpm shaking culture to OD600 value reach 0.6-0.8, add IPTG 0.5 mM and continue overnight incubation in 30 ℃.Centrifugal collecting cell is with 10 mL phosphate buffered saline buffers (2 mM, pH 7.0) suspension cell.Cell suspending liquid placed the ice bath ultrasonic disruption 10 minutes.Centrifugal, supernatant liquor pre-freeze is spent the night.The ketoreductase powder obtains recombinating behind the freeze-drying 48h.
Embodiment two: the checking of cofactor regeneration system
Get restructuring ketoreductase enzyme powder 1 mg, add 1 mL phosphate buffer soln (pH 7.0,50 mM), Virahol 0.01 mL, NAD 15 mg are in 5 mL centrifuge tubes, 30 ℃ of constant temperature water bath magnetic agitation 1 min add 1 mL n-butyl acetate extraction, gas chromatographic analysis.Detected result shows has acetone to generate, and Virahol is converted, and is 10.5% according to the calculated by peak area transformation efficiency.
Embodiment three: the reaction monitoring method
Adopt the HPLC-MS detection method to measure (S)-6-chloro-5-carbonyl-3-hydroxycaproic acid tert-butyl ester to (3R, 5S)-6-chloro-3, the conversion of 5-dihydroxyl hecanoic acid t-butyl ester.Sample preparation: get different time points reaction solution 50 μ L, add methyl alcohol 950 μ L, behind the mixing with 0.45 μ m filtering with microporous membrane, sample detection (sample size 1 μ L) then.Chromatographic condition is: chromatographic column SB-C18 2.1 * 50 mm, 3.5 μ m, mobile phase A water (0.1%HCOOH)-B acetonitrile, flow velocity 0.3 mL/min, 0-5 min 32%B.Mass spectrum condition dry gas flow velocity 12 L/min, sheath atmospheric pressure 40 PSI, 350 ℃ of dry gas temperature, capillary voltage 3500 V, detecting pattern are positive ion mode.Detect ion 181.1,183.1,185.1,203.1,205.1,237.1,239.1, (S)-6-chloro-5-carbonyl-3-hydroxycaproic acid tert-butyl ester retention time 3.8 min, (3R, 5S)-6-chloro-3,5-dihydroxyl hecanoic acid t-butyl ester retention time 2.6 min.
Embodiment four: the pH condition optimizing
Get restructuring ketoreductase enzyme powder 10 mg, add 10 mL phosphate buffer solns (100 mM, pH is respectively 6.0,6.5,7.0,7.5,8.0,8.5), substrate 1 g, Virahol 0.65 mL, NAD 5 mg, in 50 mL centrifuge tubes, 35
oC constant temperature water bath magnetic agitation 5 hours is got 0.1 mL and is added 1 mL methyl alcohol cancellation reaction, and HPLC-MS analyzes, and as shown in Figure 1, transformation efficiency is respectively 39.1%, 49.8%, and 51.0%, 54.2%, 60.3%, 57.2%.According to this result, the damping fluid of choosing specification and be pH 8.0 is as most preferably.
Embodiment five: gram level preparation technology
In 100 mL there-necked flasks, add successively 5 g (S)-6-chloro-5-carbonyl-3-hydroxycaproic acid tert-butyl ester, 3.75 the mL Virahol, 42 mL phosphate buffer solns (pH 8.0) stir, add afterwards 0.2 g restructuring ketoreductase lyophilized powder, NAD
+5 mg, 30 ℃ of lower 800 rpm magnetic agitation begin clock reaction, sampling HPLC-MS analysis monitoring reaction process, react 24 h after, transformation efficiency〉99%, product steric configuration purity (d.e.)〉99%.
Embodiment six: hectogram level preparation technology
In reactor, add successively 500 g (S)-6-chloro-5-carbonyl-3-hydroxycaproic acid tert-butyl ester, 375 mL Virahols, 4.2 L phosphate buffer solns (pH 8.0,100 mM) stir, and add afterwards 20 g restructuring ketoreductase lyophilized powder, NAD
+0.5 g, 30 ℃ of lower mechanical stirring begin clock reaction, sampling HPLC-MS analysis monitoring reaction process, react 24 h after, transformation efficiency〉99%, product steric configuration purity (d.e.)〉99%.After reaction finishes, add equal-volume ethyl acetate extraction twice, solvent is sloughed in merging organic phase and evaporation, obtains product 490 ~ 500 g.
Above-described embodiment only is explanation technical conceive of the present invention and characteristics, and its purpose is to allow the personage who is familiar with technique can understand content of the present invention and according to this enforcement, can not limit protection scope of the present invention with this.All equivalences that spirit is done according to the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (7)
1. (3R, 5S)-6-chloro-3, the biological preparation method of 5-dihydroxyl hecanoic acid t-butyl ester, it is take (S)-6-chloro-5-carbonyl-3-hydroxycaproic acid tert-butyl ester as substrate, this substrate is at biological catalyst, the reduction reaction occurs under the existence of cofactor and hydrogen donor generate (3R, 5S)-6-chloro-3,5-dihydroxyl hecanoic acid t-butyl ester, it is characterized in that: described biological catalyst is the restructuring ketoreductase, the preparation method of described restructuring ketoreductase is: the recombination bacillus coli list colony inoculation that will contain the ketoreductase gene is received in the liquid LB substratum of mycin resistance to containing card, in 35 ~ 40 ℃ of lower shaking table activation 8 ~ 12 hours, the culture that obtains after the activation is inoculated into contains card and receive in the liquid LB substratum of mycin resistance, in 35 ~ 40 ℃ of lower shaking table enlarged culturing, be cultured to the OD600 value and reach at 0.6 ~ 0.8 o'clock, add inductor, cultivated 8 ~ 12 hours in 25 ~ 33 ℃ of lower continuation, centrifugal, the collecting precipitation thing, add phosphate buffered saline buffer and get suspension, suspension was placed the ice-water bath ultrasonication 8 ~ 12 minutes, centrifugal again, supernatant liquor pre-freeze to temperature is down to-10 ~-25 ℃, and then freeze-drying 24 ~ 48 hours, namely get the restructuring ketoreductase of lyophilized powder, described restructuring ketoreductase can be acetone with iso-propanol conversion, described cofactor is NAD/NADH or NADP/NADPH, described hydrogen donor is Virahol, and described reduction reaction is carried out in pH is 6.0 ~ 9.0 water damping fluid.
2. (3R according to claim 1,5S)-6-chloro-3, the biological preparation method of 5-dihydroxyl hecanoic acid t-butyl ester, it is characterized in that: in the reaction system when reaction is initial, the restructuring ketoreductase with (S)-mass percent of 6-chloro-5-carbonyl-3-hydroxycaproic acid tert-butyl ester is 2 ~ 4%, cofactor with (S)-mass percent of 6-chloro-5-carbonyl-3-hydroxycaproic acid tert-butyl ester is 0.05 ~ 0.2%, the amount of substance per-cent of relatively described (the S)-6-of described Virahol chloro-5-carbonyl-3-hydroxycaproic acid tert-butyl ester is 100 ~ 150%.
3. (3R, 5S) according to claim 1-6-chloro-3, and the biological preparation method of 5-dihydroxyl hecanoic acid t-butyl ester is characterized in that: described inductor is isopropyl-β-D-thiogalactoside(IPTG) or lactose.
4. (3R, 5S) according to claim 1-6-chloro-3, and the biological preparation method of 5-dihydroxyl hecanoic acid t-butyl ester is characterized in that: described cofactor is NAD/NADH.
5. (3R, 5S) according to claim 1-6-chloro-3, and the biological preparation method of 5-dihydroxyl hecanoic acid t-butyl ester is characterized in that: described water damping fluid is phosphate buffered saline buffer, Tris-HCl buffered soln or trolamine hydrochloric acid buffered soln.
6. (3R, 5S) according to claim 1-6-chloro-3, and the biological preparation method of 5-dihydroxyl hecanoic acid t-butyl ester is characterized in that: described reduction reaction is carried out in pH is 8.0 water damping fluid.
7. (3R according to claim 1 and 2,5S)-6-chloro-3, the biological preparation method of 5-dihydroxyl hecanoic acid t-butyl ester, it is characterized in that: described preparation method's implementation process is as follows: add successively substrate (S)-6-chloro-5-carbonyl-3-hydroxycaproic acid tert-butyl ester in reaction vessel, Virahol, described water damping fluid, stir, continue to add restructuring ketoreductase and cofactor, under 25 ~ 45 ℃, stirring reaction utilizes HPLC-MS detection reaction process, when rate to be transformed reaches 90 ~ 99%, add ethyl acetate and repeatedly extract, merge organic phase and evaporate and slough solvent, namely get (3R, 5S)-and 6-chloro-3,5-dihydroxyl hecanoic acid t-butyl ester product.
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| CN2012104656330A CN102965403A (en) | 2012-11-19 | 2012-11-19 | Biological preparation method of tert-butyl(3R,5S)-6-chloro-3,5-dihydroxyhexanoate |
| PCT/CN2013/077099 WO2014075439A1 (en) | 2012-11-19 | 2013-06-09 | Method for biological preparation of (3r,5s)-6-chloro-3,5-dihydroxyhexanoic-tert-butyl-acetate |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103276027A (en) * | 2013-05-10 | 2013-09-04 | 苏州汉酶生物技术有限公司 | Method for biologically preparing chiral N-protective pipradrol |
| WO2014075439A1 (en) * | 2012-11-19 | 2014-05-22 | 苏州汉酶生物技术有限公司 | Method for biological preparation of (3r,5s)-6-chloro-3,5-dihydroxyhexanoic-tert-butyl-acetate |
| CN104327039A (en) * | 2014-10-20 | 2015-02-04 | 张家港市信谊化工有限公司 | Preparation method of rosuvastatin intermediate |
| CN104342460A (en) * | 2013-08-09 | 2015-02-11 | 南京朗恩生物科技有限公司 | Method for preparing statin side chain intermediate by means of whole-cell catalysis |
| CN104372039A (en) * | 2013-08-12 | 2015-02-25 | 南京朗恩生物科技有限公司 | Two-enzyme method for preparing rosuvastatin intermediates with branched chains |
| CN104726506A (en) * | 2015-03-17 | 2015-06-24 | 苏州汉酶生物技术有限公司 | Preparation method of tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate |
| CN106011094A (en) * | 2016-07-27 | 2016-10-12 | 苏州汉酶生物技术有限公司 | Engineered ketoreductase polypeptide and method for preparing (3R, 5S)-6-chloro-3, 5-dihydroxy caproic acid tert-butyl ester by using same |
| US11999757B2 (en) | 2017-11-01 | 2024-06-04 | Melinta Subsidiary Corp. | Synthesis of boronate ester derivatives and uses thereof |
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| CN103276027A (en) * | 2013-05-10 | 2013-09-04 | 苏州汉酶生物技术有限公司 | Method for biologically preparing chiral N-protective pipradrol |
| CN104342460A (en) * | 2013-08-09 | 2015-02-11 | 南京朗恩生物科技有限公司 | Method for preparing statin side chain intermediate by means of whole-cell catalysis |
| CN104342460B (en) * | 2013-08-09 | 2018-03-16 | 南京朗恩生物科技有限公司 | A kind of method that statin side chain intermediate is prepared using whole-cell catalytic |
| CN104372039A (en) * | 2013-08-12 | 2015-02-25 | 南京朗恩生物科技有限公司 | Two-enzyme method for preparing rosuvastatin intermediates with branched chains |
| CN104327039A (en) * | 2014-10-20 | 2015-02-04 | 张家港市信谊化工有限公司 | Preparation method of rosuvastatin intermediate |
| CN104726506A (en) * | 2015-03-17 | 2015-06-24 | 苏州汉酶生物技术有限公司 | Preparation method of tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate |
| CN106011094A (en) * | 2016-07-27 | 2016-10-12 | 苏州汉酶生物技术有限公司 | Engineered ketoreductase polypeptide and method for preparing (3R, 5S)-6-chloro-3, 5-dihydroxy caproic acid tert-butyl ester by using same |
| CN106011094B (en) * | 2016-07-27 | 2020-11-03 | 苏州汉酶生物技术有限公司 | Engineered ketoreductase polypeptide and method for preparing (3R,5S) -6-chloro-3, 5-dyhydroxyl hexanoic acid tert-butyl ester by using same |
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