CN114478345A - Preparation method of (R) -2- (2, 5-difluorophenyl) pyrrolidine - Google Patents
Preparation method of (R) -2- (2, 5-difluorophenyl) pyrrolidine Download PDFInfo
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Abstract
The invention relates to a preparation method of (R) -2- (2, 5-difluorophenyl) pyrrolidine, which takes cheap 2, 5-difluorotoluene as a raw material and prepares the (R) -2- (2, 5-difluorophenyl) pyrrolidine efficiently through oxidation reaction, esterification reaction, nucleophilic substitution rearrangement and whole-cell biocatalysis.
Description
Technical Field
The invention belongs to the technical field of organic synthesis and biological enzyme catalysis, and particularly relates to a preparation method of (R) -2- (2, 5-difluorophenyl) pyrrolidine.
Background
The (R) -2- (2, 5-difluorophenyl) pyrrolidine is used as a medical intermediate with high added value, is used for synthesizing various anti-cancer drugs, and is mainly used as an intermediate of a new anti-cancer drug Raatinib at present. The larotinib is a novel TRK target fusion broad-spectrum anti-tumor novel medicine, and has oral administration and broad-spectrum characteristics. Clinical experiment results prove that the compound has lasting anti-tumor effect and good tolerance on 17 age-independent TRK-fused cancer patients, has little side effect and is the first choice of TRK gene mutation cancer patients. For the synthesis method of (R) -2- (2, 5-difluorophenyl) pyrrolidine, which is mainly chiral induction synthesis, very low temperature is often needed in the reaction of the type, and the result of chiral induction is worsened along with the increase of the temperature.
U.S. patent publication No. US2015/005280a1 discloses a process for preparing (R) -2- (2, 5-difluorophenyl) pyrrolidine, the reaction formula of which is as follows:
the CN112624950A chiral induction reaction is as follows:
in both patent methods, a chiral induction reagent (S) -2-tert-butyl sulfonamide is adopted to induce the synthesis of a chiral intermediate, and the reagent is expensive, has unpleasant odor, does not meet the existing environmental protection requirement and is difficult to be applied in a large scale; U.S. Pat. No. 3,2015/005280A 1 uses another expensive lithium triethylborohydride (LiBEt)3) The reduction of the tertiary butyl sulfenimide needs to be carried out at the temperature of minus 78 ℃, the final yield is only 36 percent, the production cost is extremely high, and the industrial production is difficult to realize totally; also, patent CN112624950A uses expensive raw materials of 2, 5-difluorobenzaldehyde and 2- (2-bromoethyl) -1, 3-dioxane, and needs a dangerous grignard reaction process, is difficult to realize safety, still has extremely high raw material production cost, and is difficult to scale up.
In CN108101820A, the synthesis is also performed by chiral induction, and the reaction mode of the method is as follows:
the first scheme is as follows:
scheme II:
according to the first and second methods, expensive chiral reagents are adopted to induce the synthesis of chiral intermediates, borane dimethyl sulfide is used, the method has unpleasant odor and does not meet the existing environmental protection requirements, a dangerous Grignard reaction process is required, the safety is difficult to realize, the large-scale application is difficult, the ee value obtained by induction is low, and the production cost is still extremely high.
The synthetic route protected by patent CN 109593803A is as follows:
compared with the prior art, the method has great improvement, but still needs a dangerous Grignard reaction process, the inventor verifies the step Grignard reaction, the yield is far from high, the generated defluorinated impurities are large and difficult to remove, the safety and the scale application are difficult to realize, and the method has great potential safety hazard under the current requirements of safety and environmental protection; besides, a large amount of acidic wastewater and high-salinity wastewater exist in the treatment process of the patent, so that the environmental protection cost is high, and the industrial application is still difficult to realize.
The present invention has been made in view of the above circumstances.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a preparation method of (R) -2- (2, 5-difluorophenyl) pyrrolidine, and the method has the advantages of cheap and easily-obtained raw materials, environmental friendliness, mild reaction conditions, simplicity in operation, low cost, high yield and the like.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for preparing (R) -2- (2, 5-difluorophenyl) pyrrolidine, said method comprising the steps of:
(1) dissolving 2, 5-difluorotoluene in an organic solvent A, adding an oxidant, stirring for reaction, adding water, washing for layering, and drying an organic phase to obtain a compound II, wherein the reaction equation is as follows:
(2) adding the compound II into an organic solvent B, stirring under the condition of a catalyst, carrying out heat preservation, carrying out suction filtration and drying to obtain a compound III, wherein the reaction equation is as follows:
(3) dissolving the compound III in an organic solvent C, reacting with N-substituted pyrrolidone under an alkaline reagent to obtain an intermediate compound V, directly adding an acidic reagent without purification, stirring for reaction, extracting, and drying to obtain an intermediate VI, wherein the reaction equation is as follows:
(4) dissolving the intermediate VI in an organic solvent D, adding a biological catalytic cell, NADP + and a buffer solution to perform asymmetric whole-cell catalytic reaction, carrying out salt-forming resolution on a resolution reagent in the organic solvent E by a chiral acid after the reaction is finished, and adjusting alkali to obtain a target compound VII, wherein the reaction equation is as follows:
wherein R is1Is C1-C9 alkyl, preferably, R1Is one of methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl, R2Is one of tert-butyloxycarbonyl, vinyl, benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl, trifluoroacetyl and trityl.
Further, the organic solvent A in the step (1) is one or more of dichloromethane, dichloroethane, tetrahydrofuran, dioxane, acetonitrile, ethyl acetate and dimethyl sulfoxide, and the oxidant is one or more of permanganate, dichromate, periodate, perchlorate, hydrogen peroxide, manganese dioxide, oxygen and persulfate.
Further, the organic solvent A is acetonitrile.
Further, the oxidizing agent is sodium persulfate.
Further, in the step (1), the reaction temperature is 0-70 ℃, and the reaction time is 1-6 hours.
Further, the reaction temperature was 60 ℃ and the reaction time was 4 hours.
Further, in the step (2), the organic solvent B is C1-C9 alcohol, preferably, the organic solvent B is methanol, ethanol, propanol, isopropanol, butanol or tert-butanol, and the catalyst is oxalyl chloride, thionyl chloride or sulfuric acid.
Further, the organic solvent B is methanol, and the catalyst is thionyl chloride.
Further, the reaction temperature in the step (2) is 0-90 ℃, and the reaction time is 2-12 h.
Further, the reaction temperature was 70 ℃ and the reaction time was 5 hours.
Further, in the step (3), the organic solvent C is one or more of methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, 1, 2-dichloroethane, 1, 4-dioxane, N-dimethylformamide and acetonitrile.
Further, the alkaline reagent is one or more of potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, n-butyl lithium and lithium diisopropylamide.
Further, the organic solvent C is acetonitrile, and the alkaline reagent is potassium tert-butoxide.
Further, the acidic reagent in the step (3) is one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid and substituted benzenesulfonic acid.
Further, the acidic reagent is hydrochloric acid.
Further, the reaction temperature after the acid reagent is added is 20-90 ℃, and the reaction time is 2-10 hours.
Further, the reaction temperature was 70 ℃ and the reaction time was 6 hours.
Further, the organic solvent D in step (4) is one of methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, 1, 2-dichloroethane, 1, 4-dioxane, N-dimethylformamide, and acetonitrile.
Further, the organic solvent D is ethanol.
Furthermore, the biocatalytic cell is recombinant escherichia coli co-expressing imine reductase and glucose dehydrogenase genes, and the buffer solution is potassium phosphate buffer solution containing Triton X-100.
Further, the biocatalytic system comprises a substrate, glucose, NADP +, recombinant Escherichia coli and a buffer solution.
Further, the imine reductase is a conventional imine reductase, and preferably is a codon-optimized imine reductase gene derived from Paenibacillus elgii, P.mulaginosus and other strains.
Further, the glucose dehydrogenase is NADP dependent glucose dehydrogenase, preferably codon-optimized glucose dehydrogenase gene derived from Bacillus subtilis, Thermoplasma acidophilum and other strains.
Furthermore, the recombinant Escherichia coli construction method is characterized in that an artificially synthesized imine reductase gene and a glucose dehydrogenase gene are simultaneously connected into pETDuet-1 plasmid and then transformed into E.coli BL21(DE 3). Further, in the step (4), the resolving agent is one of malic acid, tartaric acid derivatives, citric acid, tryptophan, proline, histidine, leucine, N-acetyl leucine, phenylalanine, cysteine and N-acetyl cysteine.
Further, the resolving agent is N-acetyl cysteine.
Further, the organic solvent E is one of methanol, ethanol, isopropanol, N-butanol, tert-butanol, ethyl acetate, dichloromethane, chloroform, 1, 2-dichloroethane, 1, 4-dioxane, N-dimethylformamide and acetonitrile.
Further, the organic solvent E is ethanol.
Further, the temperature of the asymmetric whole-cell enzyme catalytic reaction in the step (4) is 20-50 ℃, and the reaction time is 2-20 hours.
Furthermore, the temperature of the resolution reaction is 40-90 ℃, and the reaction time is 2-10 h.
Furthermore, the resolution reaction temperature is 60 ℃, and the reaction time is 3 hours. Compared with the prior art, the invention has the following beneficial effects:
the method takes cheap 2, 5-difluorotoluene as a raw material, and efficiently prepares the (R) -2- (2, 5-difluorophenyl) pyrrolidine through oxidation reaction, esterification reaction, nucleophilic substitution rearrangement and whole-cell biocatalysis.
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In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a nuclear magnetic spectrum of Compound II of example 1 of the present invention;
FIG. 2 is a methyl esterification NMR spectrum of Compound III of example 1 of the present invention;
FIG. 3 is a nuclear magnetic spectrum of Compound VI of example 1 of the present invention;
FIG. 4 is a nuclear magnetic spectrum of Compound VII in example 1 of the present invention;
FIG. 5 is an HPLC chromatogram of Compound VII in example 1 of the present invention;
FIG. 6 is a chiral HPLC chromatogram of compound VII in example 1 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the examples given herein without any inventive step, are within the scope of the present invention.
The chemical reactions involved in the preparation of (R) -2- (2, 5-difluorophenyl) pyrrolidine in the following examples are as follows:
example 1
The preparation method of (R) -2- (2, 5-difluorophenyl) pyrrolidine of this example includes the following steps:
(1) dissolving 2, 5-difluorotoluene in an organic solvent A, wherein the organic solvent A is acetonitrile, slowly adding sodium persulfate under the condition of heat preservation, monitoring by TLC (thin layer chromatography) under stirring until the reaction is complete, wherein the reaction temperature is 60 ℃, the reaction time is 4h, adding water, washing, layering, and drying the organic phase to obtain a compound II;
(2) adding the compound II into an organic solvent B, wherein the organic solvent B is methanol, slowly adding a catalyst under stirring, carrying out heat preservation and stirring reaction at 70 ℃ for 5h under the condition of the catalyst, after TLC detection reaction is finished, stirring, cooling, carrying out suction filtration to obtain a light yellow solid, carrying out forced air drying, and drying to obtain a compound III;
(3) dissolving a compound III in an organic solvent C, wherein the organic solvent C is acetonitrile, adding an alkaline reagent, the alkaline reagent is potassium tert-butoxide, reacting with N-substituted pyrrolidone under the alkaline reagent, monitoring by TLC that the compound III disappears, cooling to obtain an intermediate compound V, directly adding an acidic reagent without purification, stirring to react, adding the acidic reagent into the compound V, adjusting the reaction temperature to 70 ℃ after adding the acidic reagent, reacting for 6 hours, adjusting the alkali of an organic phase, spin-drying, extracting with dichloromethane, drying the organic phase obtained after extraction, and drying to obtain a light yellow oily compound VI;
(4) dissolving the intermediate VI in an organic solvent D, wherein the organic solvent D is ethanol, adding recombinant escherichia coli, glucose, NADP + and a buffer solution which are dissolved in a potassium phosphate buffer solution and co-express imine reductase and glucose dehydrogenase to perform asymmetric whole-cell catalytic reaction at the temperature of 30 ℃ for 18 h; the imine reductase is a conventional imine reductase, preferably a codon-optimized imine reductase gene derived from Paenibacillus elgii, and the glucose dehydrogenase is NADP-dependent glucose dehydrogenase, preferably a codon-optimized glucose dehydrogenase gene derived from Bacillus subtilis; the construction method of the recombinant Escherichia coli is that an artificially synthesized imine reductase gene and a glucose dehydrogenase gene are simultaneously connected into pETDuet-1 plasmid and then transformed into E.coli BL21(DE 3); sampling, detecting the ee value of a product by a derivatization method to judge the reaction progress, after the reaction is finished, adding dichloromethane for dissolving, washing, drying an organic phase to obtain an oily substance, directly adding the oily substance into an organic solvent E which is ethanol, adding a certain amount of a resolving agent D which is malic acid, heating, stirring, cooling, crystallizing, performing suction filtration to obtain a white solid, adding the solid into water, adjusting alkalinity, extracting with dichloromethane, drying and evaporating the organic phase to dryness to obtain a pale yellow oily substance VII, and detecting the ee value of the compound VII by the derivatization method HPLC to be more than 99.5%.
Example 2
The preparation method of (R) -2- (2, 5-difluorophenyl) pyrrolidine according to this example includes the following steps:
(1) dissolving 2, 5-difluorotoluene in an organic solvent A, slowly adding sodium persulfate under the condition of heat preservation, monitoring by TLC (thin layer chromatography) under stirring until the reaction is complete, wherein the reaction temperature is 25 ℃, the reaction time is 6 hours, adding water, washing and layering, and drying an organic phase to obtain a compound II;
(2) adding the compound II into an organic solvent B, wherein the organic solvent B is isopropanol, slowly adding a catalyst under stirring, carrying out heat preservation and stirring reaction on the catalyst which is oxalyl chloride under the condition of the catalyst, wherein the reaction temperature is 25 ℃, the reaction time is 10 hours, carrying out stirring cooling and suction filtration after TLC detection reaction is finished, obtaining a light yellow solid, carrying out forced air drying, and drying to obtain a compound III;
(3) dissolving a compound III in an organic solvent C, adding an alkaline reagent, wherein the organic solvent C is tert-butyl alcohol, reacting the compound III with N-substituted pyrrolidone under the alkaline reagent, monitoring by TLC (thin-layer chromatography) that the compound III disappears, cooling to obtain an intermediate compound V, directly adding an acidic reagent without purification, stirring to react, wherein the acidic reagent is sulfuric acid, the reaction temperature after adding the acidic reagent is 50 ℃, the reaction time is 10 hours, adjusting alkali for an organic phase, spin-drying, extracting with dichloromethane, drying an organic phase obtained after extraction, and drying to obtain a light yellow oily compound VI;
(4) dissolving the intermediate VI in an organic solvent D, wherein the organic solvent D is methanol, adding recombinant escherichia coli, glucose, NADP + and a buffer solution which are dissolved in a potassium phosphate buffer solution and co-express imine reductase and glucose dehydrogenase to perform asymmetric whole-cell catalytic reaction, wherein the reaction temperature is 25 ℃, the reaction time is 15h, the imine reductase is conventional imine reductase, preferably codon-optimized imine reductase gene derived from P.mulaginosus, the glucose dehydrogenase is NADP-dependent glucose dehydrogenase, preferably codon-optimized glucose dehydrogenase gene derived from Thermoplasma acidophilum; the construction method of the recombinant Escherichia coli is that an artificially synthesized imine reductase gene and a glucose dehydrogenase gene are simultaneously connected into pETDuet-1 plasmid and then transformed into E.coli BL21(DE 3); sampling, detecting the ee value of a product by a derivatization method to judge the reaction progress, after the reaction is finished, adding dichloromethane for dissolving, washing, drying an organic phase to obtain an oily substance, directly adding the oily substance into an organic solvent E which is isopropanol, adding a certain amount of N-acetylcysteine, heating to 80 ℃, stirring for reacting for 5 hours, cooling for crystallization, performing suction filtration to obtain a white solid, adding the solid into water, adjusting alkalinity, extracting with dichloromethane, drying and drying the organic phase to dryness to obtain a pale yellow oily substance VII, and detecting the ee value of the compound VII by a derivatization method HPLC to be more than 99.5%.
Test example 1
The nuclear magnetic spectrum of the compound II in the test example 1 is shown in figure 1, wherein 7-8 ppm is a characteristic peak of three hydrogen on a benzene ring, and 13.5ppm is a characteristic peak of carboxyl hydrogen; the methyl esterification nuclear magnetic spectrum of the compound III in the example 1 is shown in figure 2, wherein 7.0-7.5 ppm is a characteristic peak of three hydrogen on a benzene ring, and 3.8ppm is a characteristic peak of methyl ester methyl hydrogen; the nuclear magnetic spectrum of the compound VI in the example 1 is shown in figure 3, wherein 7.25-7.75 ppm is a characteristic peak of three hydrogen groups on a benzene ring, and 2.0-4.0 ppm is a characteristic peak of three methylene hydrogen groups of a pyrrole ring; the nuclear magnetic spectrum of the compound VII in the example 1 is shown in figure 4, wherein 7.0-7.5 ppm is a characteristic peak of three hydrogens on a benzene ring, 4.2ppm is a characteristic peak of a benzylic hydrogen connected with the benzene ring, 2.7ppm is a characteristic peak of an amino hydrogen, and in addition, three groups of methylene hydrogens of a pyrrole ring are characteristic peaks; an HPLC spectrogram of the compound VII in the example 1 is shown in fig. 5, the purity of the product is 99.9 percent, the single impurity content is less than 0.1 percent, and the product quality is far higher than that of the product obtained by other processes; the chiral HPLC chromatogram of compound VII in example 1 is shown in fig. 6, the required R-configuration purity is 99.82% at 6.8min, the S-isomer purity is 0.18% at 7.7min, and the total ee value is 99.64%, which is much greater than 98% in the prior art, and completely meets the control requirement of the existing pharmaceutical material reported quality specifications on isomer limit.
The inventors also conducted the above experiments on the above compounds prepared in other examples, and the results were substantially consistent and, due to the limited space, are not listed.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.
Claims (10)
1. A method for preparing (R) -2- (2, 5-difluorophenyl) pyrrolidine, comprising the following steps:
(1) dissolving 2, 5-difluorotoluene in an organic solvent A, adding an oxidant, stirring for reaction, adding water, washing for layering, and drying an organic phase to obtain a compound II, wherein the reaction equation is as follows:
(2) adding the compound II into an organic solvent B, stirring under the condition of a catalyst, carrying out heat preservation, carrying out suction filtration and drying to obtain a compound III, wherein the reaction equation is as follows:
(3) dissolving the compound III in an organic solvent C, reacting with N-substituted pyrrolidone under an alkaline reagent to obtain an intermediate compound V, directly adding an acidic reagent without purification, stirring for reaction, extracting, and drying to obtain an intermediate VI, wherein the reaction equation is as follows:
(4) dissolving the intermediate VI in an organic solvent D, adding a biological catalytic cell, NADP + and a buffer solution to perform asymmetric whole-cell catalytic reaction, carrying out salt formation resolution on a resolution reagent in the organic solvent E by a chiral acid after the reaction is finished, and adjusting alkali to obtain a target compound VII, wherein the reaction equation is as follows:
wherein R is1Is C1-C9 alkyl, preferably, R1Is one of methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl, R2Is one of tert-butyloxycarbonyl, vinyl, benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl, trifluoroacetyl and trityl.
2. The method for preparing (R) -2- (2, 5-difluorophenyl) pyrrolidine according to claim 1, wherein the organic solvent A in step (1) is one or more selected from dichloromethane, dichloroethane, tetrahydrofuran, dioxane, acetonitrile, ethyl acetate and dimethyl sulfoxide, and the oxidant is one or more selected from permanganate, dichromate, periodate, perchlorate, hydrogen peroxide, manganese dioxide, oxygen and persulfate.
3. The method for preparing (R) -2- (2, 5-difluorophenyl) pyrrolidine according to claim 1, wherein the reaction temperature in step (1) is 0-70 ℃ and the reaction time is 1-6 h.
4. The process for preparing (R) -2- (2, 5-difluorophenyl) pyrrolidine according to claim 1, wherein the organic solvent B in step (2) is C1-C9 alcohol, preferably, the organic solvent B is methanol, ethanol, propanol, isopropanol, butanol or tert-butanol, and the catalyst is oxalyl chloride, thionyl chloride or sulfuric acid.
5. The method for preparing (R) -2- (2, 5-difluorophenyl) pyrrolidine according to claim 1, wherein the reaction temperature in step (2) is 0-90 ℃ and the reaction time is 2-12 h.
6. The method for preparing (R) -2- (2, 5-difluorophenyl) pyrrolidine according to claim 1, wherein the organic solvent C in step (3) is one or more selected from methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, 1, 2-dichloroethane, 1, 4-dioxane, N-dimethylformamide, and acetonitrile, preferably, the alkaline reagent is one or more selected from potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, N-butyllithium, and lithium diisopropylamide.
7. The method for preparing (R) -2- (2, 5-difluorophenyl) pyrrolidine according to claim 1, wherein the acidic reagent in step (3) is one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid and substituted benzenesulfonic acid, preferably, the reaction temperature after the acidic reagent is added is 20-90 ℃ and the reaction time is 2-10 hours.
8. The method for preparing (R) -2- (2, 5-difluorophenyl) pyrrolidine according to claim 1, wherein the organic solvent D in step (4) is one of methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, 1, 2-dichloroethane, 1, 4-dioxane, N-dimethylformamide, and acetonitrile, preferably, the biocatalytic cell is a recombinant Escherichia coli coexpressing imine reductase and glucose dehydrogenase genes, and the buffer solution is potassium phosphate buffer solution containing TritonX-100.
9. The method for preparing (R) -2- (2, 5-difluorophenyl) pyrrolidine according to claim 1, wherein the resolving agent in step (4) is one of malic acid, tartaric acid derivative, citric acid, tryptophan, proline, histidine, leucine, N-acetyl leucine, phenylalanine, cysteine and N-acetyl cysteine, preferably, the organic solvent E is one of methanol, ethanol, isopropanol, N-butanol, tert-butanol, ethyl acetate, dichloromethane, chloroform, 1, 2-dichloroethane, 1, 4-dioxane, N-dimethylformamide and acetonitrile.
10. The preparation method of (R) -2- (2, 5-difluorophenyl) pyrrolidine according to claim 1, wherein the asymmetric whole-cell enzyme catalysis reaction temperature in step (4) is 20-50 ℃, the reaction time is 2-20 h, preferably, the resolution reaction temperature is 40-90 ℃, and the reaction time is 2-10 h.
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| CN115108957A (en) * | 2022-06-21 | 2022-09-27 | 深圳博瑞医药科技有限公司 | Synthesis method of chiral 2-phenylpyrrolidine |
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| CN115108957B (en) * | 2022-06-21 | 2023-12-29 | 深圳博瑞医药科技有限公司 | Synthesis method of chiral 2-phenylpyrrolidine |
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