CN111073919A - Method for preparing (S) -2- (3, 4-difluorophenyl) ethylene oxide - Google Patents
Method for preparing (S) -2- (3, 4-difluorophenyl) ethylene oxide Download PDFInfo
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- CN111073919A CN111073919A CN201911265308.8A CN201911265308A CN111073919A CN 111073919 A CN111073919 A CN 111073919A CN 201911265308 A CN201911265308 A CN 201911265308A CN 111073919 A CN111073919 A CN 111073919A
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- Prior art keywords
- difluorophenyl
- ala
- gly
- ketoreductase
- leu
- Prior art date
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- UNJRFWWCCAHSRB-MRVPVSSYSA-N (2s)-2-(3,4-difluorophenyl)oxirane Chemical compound C1=C(F)C(F)=CC=C1[C@@H]1OC1 UNJRFWWCCAHSRB-MRVPVSSYSA-N 0.000 title claims abstract description 19
- 238000000034 method Methods 0.000 title claims abstract description 17
- 101001110310 Lentilactobacillus kefiri NADP-dependent (R)-specific alcohol dehydrogenase Proteins 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- VMEDAWUIKFAFJQ-UHFFFAOYSA-N 2-chloro-1-(3,4-difluorophenyl)ethanone Chemical compound FC1=CC=C(C(=O)CCl)C=C1F VMEDAWUIKFAFJQ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 102000004190 Enzymes Human genes 0.000 claims abstract description 9
- 238000006476 reductive cyclization reaction Methods 0.000 claims abstract 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 108090000790 Enzymes Proteins 0.000 claims description 7
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 claims description 7
- 239000011347 resin Substances 0.000 claims description 7
- 229920005989 resin Polymers 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 6
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 claims description 4
- 239000008055 phosphate buffer solution Substances 0.000 claims description 4
- 150000001450 anions Chemical class 0.000 claims description 3
- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical group NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 2
- 125000000129 anionic group Chemical group 0.000 claims description 2
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 3
- PYEJQVYISBUGDU-UHFFFAOYSA-N 2-(3,4-difluorophenyl)cyclopropane-1-carboxamide Chemical compound NC(=O)C1CC1C1=CC=C(F)C(F)=C1 PYEJQVYISBUGDU-UHFFFAOYSA-N 0.000 abstract description 2
- 239000007787 solid Substances 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 14
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 229960002528 ticagrelor Drugs 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 4
- 241001468191 Lactobacillus kefiri Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- RYOLLNVCYSUXCP-MRVPVSSYSA-N (1s)-2-chloro-1-(3,4-difluorophenyl)ethanol Chemical compound ClC[C@@H](O)C1=CC=C(F)C(F)=C1 RYOLLNVCYSUXCP-MRVPVSSYSA-N 0.000 description 2
- 102000005751 Alcohol Oxidoreductases Human genes 0.000 description 2
- 108010031132 Alcohol Oxidoreductases Proteins 0.000 description 2
- QSDKBRMVXSWAQE-BFHQHQDPSA-N Gly-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN QSDKBRMVXSWAQE-BFHQHQDPSA-N 0.000 description 2
- 108010079364 N-glycylalanine Proteins 0.000 description 2
- HFZNNDWPHBRNPV-KZVJFYERSA-N Pro-Ala-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O HFZNNDWPHBRNPV-KZVJFYERSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 2
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 2
- 229960000723 ampicillin Drugs 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000002210 biocatalytic effect Effects 0.000 description 2
- 239000005515 coenzyme Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Chemical compound NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 2
- 108010050848 glycylleucine Proteins 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- BRPMXFSTKXXNHF-IUCAKERBSA-N (2s)-1-[2-[[(2s)-pyrrolidine-2-carbonyl]amino]acetyl]pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H]1NCCC1 BRPMXFSTKXXNHF-IUCAKERBSA-N 0.000 description 1
- VWWKKDNCCLAGRM-GVXVVHGQSA-N (2s)-2-[[2-[[(2s)-2-[[(2s)-2-amino-4-methylpentanoyl]amino]propanoyl]amino]acetyl]amino]-3-methylbutanoic acid Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O VWWKKDNCCLAGRM-GVXVVHGQSA-N 0.000 description 1
- RYOLLNVCYSUXCP-UHFFFAOYSA-N 2-chloro-1-(3,4-difluorophenyl)ethanol Chemical compound ClCC(O)C1=CC=C(F)C(F)=C1 RYOLLNVCYSUXCP-UHFFFAOYSA-N 0.000 description 1
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- RLMISHABBKUNFO-WHFBIAKZSA-N Ala-Ala-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O RLMISHABBKUNFO-WHFBIAKZSA-N 0.000 description 1
- LGQPPBQRUBVTIF-JBDRJPRFSA-N Ala-Ala-Ile Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LGQPPBQRUBVTIF-JBDRJPRFSA-N 0.000 description 1
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 1
- VGPWRRFOPXVGOH-BYPYZUCNSA-N Ala-Gly-Gly Chemical compound C[C@H](N)C(=O)NCC(=O)NCC(O)=O VGPWRRFOPXVGOH-BYPYZUCNSA-N 0.000 description 1
- MQIGTEQXYCRLGK-BQBZGAKWSA-N Ala-Gly-Pro Chemical compound C[C@H](N)C(=O)NCC(=O)N1CCC[C@H]1C(O)=O MQIGTEQXYCRLGK-BQBZGAKWSA-N 0.000 description 1
- OBVSBEYOMDWLRJ-BFHQHQDPSA-N Ala-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N OBVSBEYOMDWLRJ-BFHQHQDPSA-N 0.000 description 1
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 1
- YHBDGLZYNIARKJ-GUBZILKMSA-N Ala-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N YHBDGLZYNIARKJ-GUBZILKMSA-N 0.000 description 1
- DCVYRWFAMZFSDA-ZLUOBGJFSA-N Ala-Ser-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O DCVYRWFAMZFSDA-ZLUOBGJFSA-N 0.000 description 1
- IOFVWPYSRSCWHI-JXUBOQSCSA-N Ala-Thr-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C)N IOFVWPYSRSCWHI-JXUBOQSCSA-N 0.000 description 1
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- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
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Abstract
The invention discloses a method for preparing ticagrelor intermediate (S) -2- (3, 4-difluorophenyl) ethylene oxide by a one-step enzyme method. And (S) -2- (3, 4-difluorophenyl) oxirane is obtained by reductive cyclization of 2-chloro-1- (3, 4-difluorophenyl) ethanone by ketoreductase under alkaline conditions. The invention adopts liquid-solid three-phase reaction to obtain the target product in one step, has simple operation and mild reaction condition and is suitable for industrial production.
Description
The technical field is as follows:
the invention belongs to the field of biological pharmacy, and particularly relates to a method for preparing ticagrelor intermediate (S) -2- (3, 4-difluorophenyl) ethylene oxide by a one-step enzyme method.
Background art:
ticagrelor (Ticagrelor), trade name brilina, chemical name (1S,2S,3R,5S) -3- [7- [ [ (1R,2S) -2- (3, 4-difluorophenyl) cyclopropyl ] amino ] -5-propylthio-triazolo [4,5-d ] pyrimidin-3-yl ] -5- (2-hydroxyethoxy) -1, 2-cyclopentanediol, formula I. Ticagrelor is a novel medicine for treating acute coronary syndrome, which is developed and developed by Aslicon pharmaceutical company, and the PLATO research shows that the curative effect of the Ticagrelor is obviously superior to that of clopidogrel, so the Ticagrelor is listed as a first-line recommendation by a plurality of guidelines at home and abroad.
Wherein, (S) -2- (3, 4-difluorophenyl) ethylene oxide (formula II) is used as one of key intermediates for preparing ticagrelor, and the improvement of the preparation method is always important work in the field of synthesis process of ticagrelor intermediates because the chiral center has a unique structure.
The (S) -2- (3, 4-difluorophenyl) oxirane is mostly reported to be prepared by at least two steps of reactions by using 2-chloro-1- (3, 4-difluorophenyl) ethanone as a starting material.
Patent WO2008018822 discloses the reduction of carbonyl groups in 2-chloro-1- (3, 4-difluorophenyl) ethanone to chiral hydroxyl groups using (S) -diphenylprolinol as a chiral catalyst, followed by epoxidation to produce (S) -2- (3, 4-difluorophenyl) oxirane, the route being shown in Scheme 1.
Patent CN105671099 discloses a biocatalytic preparation method, the specific route is shown in Scheme 2. The method comprises the steps of firstly, using carbonyl reductase to catalyze and reduce a substrate into (S) -2-chloro-1- (3, 4-difluorophenyl) ethanol, then stirring and epoxidizing the substrate in a sodium hydroxide or potassium hydroxide solution to generate a target product, extracting the target product by using methyl tert-butyl ether to obtain a crude product, and then, still needing column chromatography purification, which is not suitable for industrial production application.
Patent CN106906249 discloses a biocatalytic preparation method, and the specific route is shown in Scheme 3. The method comprises the steps of firstly, catalyzing and reducing a substrate into 2-chloro-1- (3, 4-difluorophenyl) ethanol by carbonyl reductase, and then stirring in toluene and sodium hydroxide (or potassium hydroxide) solution to obtain a target product.
The invention content is as follows:
the invention aims to provide a new technical scheme for preparing (S) -2- (3, 4-difluorophenyl) ethylene oxide by improved one-step enzymatic catalysis in the prior art.
The technical scheme adopted by the invention is as follows:
under the alkaline condition, 2-chloro-1- (3, 4-difluorophenyl) ethanone is subjected to one-step reduction cyclization in the presence of ketoreductase, cofactor and anion resin to obtain (S) -2- (3, 4-difluorophenyl) oxirane.
Further, adding 2-chloro-1- (3, 4-difluorophenyl) ethanone, ketoreductase, cofactor and anion resin into a mixed solution consisting of phosphate buffer solution, methyl tert-butyl ether and isopropanol, stirring for reaction, filtering, extracting and distilling to obtain (S) -2- (3, 4-difluorophenyl) oxirane.
Furthermore, the amino acid sequence of the ketoreductase is shown as SEQ ID No. 1.
Further, the ketoreductase is ketoreductase enzyme powder or whole cells or cell disruption solution containing the ketoreductase, preferably ketoreductase enzyme powder.
Furthermore, the ketoreductase is a mutant derived from Lactobacillus kefir, and is obtained by screening a mutant library of the ketoreductase of Lactobacillus kefir. The wild-type ketoreductase enzyme derived from Lactobacillus kefir is under accession number WP-054768785.1 at NCBI.
Further, the cofactor is selected from NAD+、NADH、NADP+And NADPH or a combination thereof, preferably NADP+。
Further, the anionic resin is selected from 201 × 7, D201, D202, D213, WDA-OH, D318, preferably D201.
Further, the pH value of the phosphate buffer solution is 8.0-10.0, and the preferable pH value is 9.0.
The invention has the beneficial effects that: the method adopts liquid-solid three-phase reaction, takes 2-chloro-1- (3, 4-difluorophenyl) ethanone as a substrate, does not need unstable intermediate (S) -2-chloro-1- (3, 4-difluorophenyl) ethanol, prepares the product (S) -2- (3, 4-difluorophenyl) ethylene oxide in one step, has simple operation, mild reaction conditions, high yield and good optical purity, and is suitable for industrial production.
Drawings
FIG. 1 Infrared Spectrum of the product of example 2
FIG. 2 HPLC chromatogram for purity of product of example 2
FIG. 3 chiral purity HPLC chromatogram of the product of example 2
FIG. 4 chiral purity HPLC chromatogram of the product of example 3
Detailed Description
The technical content of the present invention is further described below with reference to specific examples for better understanding of the content of the present invention, but the scope of the present invention is not limited thereto.
EXAMPLE 1 preparation of ketoreductase
A genetically engineered bacterium (vector pET21a, host cell E.Coli BL21(DE3)) containing a gene encoding ketoreductase (SEQ ID No.1) was inoculated into 5mL of an LB tube medium containing ampicillin for activated culture (culture at 37 ℃ for 12 hours), the activated culture was transferred to 400mL of an LB liquid medium containing ampicillin in an amount of 1%, OD was cultured at 37 ℃ to 0.6 to 0.8, and IPTG (final concentration of 0.1mM) was added for induced culture at 25 ℃ for 16 hours. Centrifuging to collect thallus to obtain ketoreductase cell, re-suspending thallus with 40mL phosphate buffer solution (10mM, pH 7.5), ultrasonic crushing in ice water bath for 15min, centrifuging to collect supernatant, pre-freezing at-20 deg.C, vacuum freeze drying for 48 hr, and grinding to obtain recombinant ketoreductase enzyme powder.
EXAMPLE 2 preparation of (S) -2- (3, 4-difluorophenyl) oxirane
Methyl tert-butyl ether (500mL), 0.05M phosphate buffer (300mL) at pH 9.0, isopropanol (100g) and substrate 2-chloro-1- (3, 4-difluorophenyl) ethanone (200g) were added to the reaction vessel, and after stirring well, ketoreductase enzyme powder (20g), coenzyme NADP (60mg) and D201 resin were added, and the reaction was magnetically stirred at 25 ℃ for 12 hours while monitoring the progress of the reaction by TLC. After the reaction, the mixture is filtered, the filtrate is kept stand and layered, an organic phase is collected, an aqueous phase is extracted twice by using 100mL of 2 methyl tert-butyl ether, the organic phase and the aqueous phase are combined, dried by anhydrous sodium sulfate and dried by decompression and spin-drying, and 155.7g of (S) -2- (3, 4-difluorophenyl) ethylene oxide is obtained, and the ee value of an S-type product is 99.99%. The infrared spectrum of the product is shown in figure 1, the HPLC spectrum of the product purity is shown in figure 2, and the HPLC spectrum of the product chiral purity is shown in figure 3.
EXAMPLE 3 preparation of (S) -2- (3, 4-difluorophenyl) oxirane
Methyl tert-butyl ether (2.5L), 0.05M phosphate buffer (2.5L) at pH 10.0, isopropanol (1kg) and substrate 2-chloro-1- (3, 4-difluorophenyl) ethanone (2kg) were added to the reaction vessel, and after stirring well, ketoreductase enzyme powder (500g), coenzyme NADP (600mg) and D201 resin were added, and the reaction was magnetically stirred at 25 ℃ for 20h while monitoring the progress of the reaction by TLC. Filtering after the reaction is finished, standing and layering the filtrate, collecting an organic phase, extracting the water phase twice by using 100mL of 2 methyl tert-butyl ether, combining the organic phase and the organic phase, drying by using anhydrous sodium sulfate, and performing reduced pressure spin-drying to obtain 1.52kg of (S) -2- (3, 4-difluorophenyl) ethylene oxide, wherein the ee value of the S-type product is 99.99%. The chiral purity HPLC chromatogram of the product is shown in figure 4.
Sequence listing
<110> Shang Ke biomedical (Shanghai) Co., Ltd
<120> a method for preparing (S) -2- (3, 4-difluorophenyl) oxirane
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<170>SIPOSequenceListing 1.0
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Met Thr Ala Ala Leu Leu Gly Leu Val Ala Ile Val Thr Gly Gly Thr
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Leu Gly Ile Gly Leu Ala Ile Ala Ala Leu Pro Val Gly Gly Gly Ala
20 25 30
Leu Val Val Ile Thr Gly Ala His Ala Ala Val Gly Gly Leu Ala Ala
35 40 45
Leu Ser Ile Gly Gly Thr Ala Val Ile Ala Pro Val Gly His Ala Ala
50 55 60
Ser Ala Gly Ala Gly Thr Thr Leu Leu Pro Ala Thr Thr Gly Gly Ala
65 70 75 80
Pro Gly Pro Val Thr Thr Val Val Ala Ala Ala Gly Ile Pro Leu Thr
85 90 95
Leu Ser Val Gly Ala Thr Thr Thr Gly Gly Thr Ala Leu Leu Leu Ser
100 105 110
Val Ala Leu Ala Gly Val Pro Pro Gly Thr Ala Leu Gly Ile Gly Ala
115 120 125
Met Leu Ala Leu Gly Leu Gly Ala Ser Ile Ile Ala Met Ser Ser Ile
130 135 140
Gly Gly Leu Val Gly Ala Pro Thr Gly Gly Ala Thr Ala Ala Ser Leu
145 150 155 160
Gly Ala Val Ala Ile Met Ser Leu Ser Ala Ala Leu Ala Cys Ala Leu
165 170 175
Leu Ala Thr Ala Val Ala Val Ala Thr Val His Pro Gly Thr Ile Leu
180 185 190
Thr Pro Leu Val Ala Ala Leu Gly Gly Ala Gly Gly Met Met Ser Gly
195 200 205
Ala Thr Leu Thr Pro Met Gly His Ile Gly Gly Pro Ala Ala Ile Ala
210 215 220
Thr Ile Cys Val Thr Leu Ala Ser Ala Gly Ser Leu Pro Ala Thr Gly
225 230 235 240
Ala Gly Pro Val Val Ala Gly Gly Thr Thr Ala Gly
245 250
Claims (6)
1. A method for preparing (S) -2- (3, 4-difluorophenyl) oxirane is characterized in that under alkaline conditions, 2-chloro-1- (3, 4-difluorophenyl) ethanone is subjected to one-step reductive cyclization in the presence of ketoreductase, cofactor and anion resin to obtain (S) -2- (3, 4-difluorophenyl) oxirane.
2. The method according to claim 1, wherein the reaction is carried out in a mixed solvent of a phosphate buffer solution having a pH of 8.0 to 10.0 and methyl t-butyl ether and isopropyl alcohol.
3. The method of claim 1, wherein the ketoreductase has an amino acid sequence shown in SEQ ID No. 1.
4. The method of claim 1, wherein the ketoreductase is ketoreductase enzyme powder or whole cells or cell debris containing the ketoreductase.
5. The method of claim 1, wherein the cofactor is selected from NAD+、NADH、NADP+And NADPH or a combination thereof.
6. The method of claim 1, wherein the anionic resin is selected from the group consisting of 201 x 7, D201, D202, D213, WDA-OH, D318.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105671099A (en) * | 2016-01-26 | 2016-06-15 | 中国科学院成都生物研究所 | Method for preparing optical pure difluorophenyl ethylene oxide |
| CN107686447A (en) * | 2017-08-25 | 2018-02-13 | 许昌恒生制药有限公司 | A kind of preparation method of ticagrelor intermediate |
| US20180312483A1 (en) * | 2015-06-25 | 2018-11-01 | Central Glass Company, Limited | Method for Industrial Production of Optically Active Fluoroalkyl Ethylene Oxide |
| CN109423484A (en) * | 2017-09-04 | 2019-03-05 | 尚科生物医药（上海）有限公司 | A kind of ketoreductase and its in the chloro- 1-(3,4- difluorophenyl of preparation (S) -2-) application on ethyl alcohol |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180312483A1 (en) * | 2015-06-25 | 2018-11-01 | Central Glass Company, Limited | Method for Industrial Production of Optically Active Fluoroalkyl Ethylene Oxide |
| CN105671099A (en) * | 2016-01-26 | 2016-06-15 | 中国科学院成都生物研究所 | Method for preparing optical pure difluorophenyl ethylene oxide |
| CN107686447A (en) * | 2017-08-25 | 2018-02-13 | 许昌恒生制药有限公司 | A kind of preparation method of ticagrelor intermediate |
| CN109423484A (en) * | 2017-09-04 | 2019-03-05 | 尚科生物医药（上海）有限公司 | A kind of ketoreductase and its in the chloro- 1-(3,4- difluorophenyl of preparation (S) -2-) application on ethyl alcohol |
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