CN114540321B - Preparation method of R-2-sulfonyl-1-phenylethanol derivative - Google Patents

Preparation method of R-2-sulfonyl-1-phenylethanol derivative Download PDF

Info

Publication number
CN114540321B
CN114540321B CN202210102497.2A CN202210102497A CN114540321B CN 114540321 B CN114540321 B CN 114540321B CN 202210102497 A CN202210102497 A CN 202210102497A CN 114540321 B CN114540321 B CN 114540321B
Authority
CN
China
Prior art keywords
sulfonyl
ketoreductase
phenylethanol
compound
biocatalyst
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202210102497.2A
Other languages
Chinese (zh)
Other versions
CN114540321A (en
Inventor
游松
秦斌
张文鹤
郭继阳
高晓
钱东
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenyang Pharmaceutical University
Original Assignee
Shenyang Pharmaceutical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenyang Pharmaceutical University filed Critical Shenyang Pharmaceutical University
Priority to CN202210102497.2A priority Critical patent/CN114540321B/en
Publication of CN114540321A publication Critical patent/CN114540321A/en
Application granted granted Critical
Publication of CN114540321B publication Critical patent/CN114540321B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/0004—Oxidoreductases (1.)
    • C12N9/0006—Oxidoreductases (1.) acting on CH-OH groups as donors (1.1)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P11/00—Preparation of sulfur-containing organic compounds
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/002—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by oxidation/reduction reactions
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y101/00—Oxidoreductases acting on the CH-OH group of donors (1.1)
    • C12Y101/01—Oxidoreductases acting on the CH-OH group of donors (1.1) with NAD+ or NADP+ as acceptor (1.1.1)
    • C12Y101/01002—Alcohol dehydrogenase (NADP+) (1.1.1.2), i.e. aldehyde reductase
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y101/00—Oxidoreductases acting on the CH-OH group of donors (1.1)
    • C12Y101/01—Oxidoreductases acting on the CH-OH group of donors (1.1) with NAD+ or NADP+ as acceptor (1.1.1)
    • C12Y101/01047—Glucose 1-dehydrogenase (1.1.1.47)
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Analytical Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a preparation method of an R-2-sulfonyl-1-phenylethanol derivative, belonging to the fields of synthesis of pharmaceutical chemical intermediates and biotechnology. The invention takes 2-sulfonyl-1-phenyl ethyl ketone compound as an initial substrate, R-selective ketoreductase (R-KRED) from lactobacillus fermentum (Lactobacillus fermentum) as a chiral biocatalyst, and Glucose Dehydrogenase (GDH) from bacillus subtilis (Bacillus subtilis) as a circulating cofactor NDAPH, so that substrate carbonyl is asymmetrically reduced, and R-product alcohol is obtained; the amino acid sequence of the ketoreductase is shown as SEQ ID NO. 1. The invention utilizes the biocatalyst, has mild reaction conditions, avoids the use of transition metal catalysis and complex chiral ligands, is green and environment-friendly, has high substrate loading capacity and high conversion rate and stereoselectivity, and is beneficial to large-scale industrial production.

Description

Preparation method of R-2-sulfonyl-1-phenylethanol derivative
Technical Field
The invention belongs to the field of synthesis of pharmaceutical chemical intermediates and the field of biotechnology, and relates to a preparation method of an R-2-sulfonyl-1-phenylethanol derivative.
Background
Chiral 2-sulfonyl-1-phenylethanols are useful components in organic chemistry and have been widely used in the synthesis of pharmaceutical molecules and biologically active compounds, such as gamma-butenolide, gamma-butyrolactone, 2, 5-disubstituted tetrahydrofurandelta-valerolactone. Meanwhile, the compound can be used as a drug intermediate for synthesizing drugs.
Thus, over the last two decades, several methods of synthesizing these compounds have been developed, such as asymmetric conjugated boration of α, β -unsaturated sulfones and asymmetric reduction of β -ketosulfones, including borane reduction, transition metal catalyzed asymmetric hydrogenation, and asymmetric transfer hydrogenation. However, the popularity of these processes is often plagued by high pressure conditions, the use of complex chiral ligand catalysts or heavy metal contamination.
Ketoreductase (KRED), also known as carbonyl reductase or alcohol dehydrogenase, enzymes that stereoselectively reduce prochiral ketones to chiral secondary alcohols using reduced Nicotinamide Adenine Dinucleotide Phosphate (NADPH) or reduced Nicotinamide Adenine Dinucleotide (NADH) as a hydrogen donor. With the rapid development of protein engineering, including site-directed saturation mutagenesis and random mutagenesis, tailored KREDs have become the catalyst of choice for ketone reduction by many pharmaceutical companies and are increasingly being used for the synthesis of key chiral alcohol intermediates for pharmaceuticals such as montelukast sodium and atorvastatin calcium. Ketoreductase as a biocatalyst not only has the advantages of high stereoselectivity and high catalytic efficiency, but also compares to the chemocatalytic method: can react in aqueous solution, and the reaction condition is mild; the enzyme is easy to prepare and degradable, and is green and environment-friendly; and no metal or complex ligand catalyst is needed to be added, thus being beneficial to the subsequent product purification.
Disclosure of Invention
The invention provides a preparation method of an R-2-sulfonyl-1-phenylethanol derivative aiming at the defects in the existing chemical catalysis method. 2-sulfonyl-1-phenyl ethyl ketone compound is used as an initial substrate, R-selective ketoreductase (R-KRED) from lactobacillus fermentum (Lactobacillus fermentum) is used as a chiral biocatalyst, glucose Dehydrogenase (GDH) from bacillus subtilis (Bacillus subtilis) is used as a circulating cofactor NDAP, and carbonyl of the substrate is asymmetrically reduced, so that R-type product alcohol is obtained. The invention utilizes the biocatalyst, has mild reaction conditions, avoids the use of transition metal catalysis and complex chiral ligands, is green and environment-friendly, has high substrate loading capacity and high conversion rate and stereoselectivity, and is beneficial to large-scale industrial production.
The method comprises the following steps ofBiocatalysts, including ketoreductase, glucose dehydrogenase, NADP + Or NAD + Glucose, the amino acid sequence of the ketoreductase is shown as SEQ ID NO. 1.
Further, in the above technical solution, the ketoreductase: glucose dehydrogenase: NADP (NADP) + Or NAD + : glucose is 0.02-40g/L:0.02-40g/L:0-0.5mmol:6-200g/L.
Namely, the dosage of the ketoreductase is 0.02-40g/L (freeze-dried cells), the dosage of the glucose dehydrogenase is 0.02-40g/L (freeze-dried cells), the dosage of NADP+ is 0-0.5mmol and the dosage of the glucose is 6-200g/L.
The application of the biocatalyst in preparing the R-2-sulfonyl-1-phenylethanol derivative by catalysis takes the 2-sulfonyl-1-phenylethanone derivative as an initial substrate, and under the action of the biocatalyst, carbonyl of the substrate is asymmetrically reduced into hydroxyl to obtain the R-2-sulfonyl-1-phenylethanol derivative.
Further, in the above technical scheme, the structural formula of the 2-sulfonyl-1-phenylethanone derivative is shown in formula A, and the structural formula of the R-2-sulfonyl-1-phenylethanol derivative is shown in formula B;
wherein R is 1 Is a mono-or polysubstituted C1-C4 alkyl, or C1-C4 alkoxy, or halogen; r is R 2 Is C1-C4 alkyl or phenyl.
Further, in the above technical scheme, the pH value of the catalytic reaction is 5.5-8. Preferably 7.0.
Further, in the technical scheme, the temperature of the catalytic reaction is 28-45 ℃. Preferably 30 ℃.
Further, in the above technical scheme, the concentration of the substrate is 0.5-200g/L.
Further, in the above technical scheme, the 2-sulfonyl-1-phenylethanone derivative is selected from any one of the following:
a biocatalytic preparation method of R-2-sulfonyl-1-phenylethanol derivatives comprises the following steps:
asymmetrically reducing a structural compound shown in a formula A into an R-2-sulfonyl-1-phenylethanol derivative in a buffer salt solution by catalyzing with R-type ketoreductase, and catalyzing cofactor NADPH in a reaction system by glucose dehydrogenase;
wherein the structural compound R shown in the formula A 1 Is a mono-or polysubstituted C1-C4 alkyl, C1-C4 alkoxy, or halogen;
R 2 is C1-C4 alkyl or phenyl.
The buffer salt solution is selected from phosphate, sodium citrate and phosphate, preferably phosphate.
The biocatalysis preparation method of the R-2-sulfonyl-1-phenylethanol derivative has the advantages of mild reaction conditions, environment friendliness, high enantiomer selectivity of the product and the like.
Drawings
FIG. 1 is a chiral HPLC detection chart of R-2-methanesulfonyl-1-phenylethanol derivatives synthesized in example 4 of the present invention; a is a racemic 2-methylsulfonyl-1- (3-ethoxy-4-methoxyphenyl) ethanol standard substance control; b is R-2-methylsulfonyl-1- (3-ethoxy-4-methoxyphenyl) ethanol.
FIG. 2 is a chiral HPLC analysis of R-2-methanesulfonyl-1-phenylethanol derivatives synthesized in example 5 of the present invention. A is a racemic 2-methylsulfonyl-1-phenylethanol standard substance control; b is R-2-methylsulfonyl-1-phenylethanol.
FIG. 3 is a chiral HPLC analysis of the R-2-methanesulfonyl-1-phenylethanol derivative synthesized in example 6 of the present invention. A is a racemic 2-methylsulfonyl-1- (4-methylphenyl) ethanol standard substance control; b is R-2-methylsulfonyl-1- (4-methylphenyl) ethanol.
FIG. 4 is a chiral HPLC analysis of the R-2-methanesulfonyl-1-phenylethanol derivative synthesized in example 7 of the present invention. A is a racemic 2-methylsulfonyl-1- (3-methoxyphenyl) ethanol standard substance control; b is R-2-methylsulfonyl-1- (3-methoxyphenyl) ethanol.
FIG. 5 is a chiral HPLC analysis of R-2-methanesulfonyl-1-phenylethanol derivatives synthesized in example 8 of the present invention. A is a racemic 2-methylsulfonyl-1- (4-methoxyphenyl) ethanol standard substance control; b is R-2-methylsulfonyl-1- (4-methoxyphenyl) ethanol.
FIG. 6 is a chiral HPLC analysis of the R-2-methanesulfonyl-1-phenylethanol derivative synthesized in example 9 of the present invention. A is a racemic 2-methylsulfonyl-1- (4-fluorophenyl) ethanol standard substance control; b is R-2-methylsulfonyl-1- (4-fluorophenyl) ethanol.
FIG. 7 is a chiral HPLC analysis of R-2-methanesulfonyl-1-phenylethanol derivatives synthesized in example 10 of the present invention. A is a racemic 2-methylsulfonyl-1- (3-chlorophenyl) ethanol standard substance control; b is R-2-methylsulfonyl-1- (3-chlorophenyl) ethanol.
FIG. 8 is a chiral HPLC analysis of R-2-methanesulfonyl-1-phenylethanol derivatives synthesized in example 11 of the present invention. A is a racemic 2-methylsulfonyl-1- (4-chlorophenyl) ethanol standard substance control; b is R-2-methylsulfonyl-1- (4-chlorophenyl) ethanol.
FIG. 9 is a chiral HPLC analysis of R-2-methanesulfonyl-1-phenylethanol derivatives synthesized in example 12 of the present invention. A is a racemic 2-methylsulfonyl-1- (4-bromophenyl) ethanol standard substance control; b is R-2-methylsulfonyl-1- (4-bromophenyl) ethanol.
FIG. 10 is a chiral HPLC analysis of R-2-methanesulfonyl-1-phenylethanol derivatives synthesized in example 13 of the present invention. A is a racemic 2-benzenesulfonyl-1-phenylethanol standard substance control; b is R-2-benzenesulfonyl-1-phenylethanol.
FIG. 11 is a chiral HPLC analysis of R-2-methanesulfonyl-1-phenylethanol derivatives synthesized in example 14 of the present invention. A is a racemic 2-benzenesulfonyl-1- (4-methylphenyl) ethanol standard substance control; b is R-2-benzenesulfonyl-1- (4-methylphenyl) ethanol.
FIG. 12 is a chiral HPLC analysis of R-2-methanesulfonyl-1-phenylethanol derivatives synthesized in example 15 of the present invention. A is a racemic 2-benzenesulfonyl-1- (2-methoxyphenyl) ethanol standard substance control; b is R-2-benzenesulfonyl-1- (2-methoxyphenyl) ethanol.
FIG. 13 is a chiral HPLC analysis of R-2-methanesulfonyl-1-phenylethanol derivatives synthesized in example 16 of the present invention. A is a racemic 2-benzenesulfonyl-1- (3-methoxyphenyl) ethanol standard substance control; b is R-2-benzenesulfonyl-1- (3-methoxyphenyl) ethanol.
FIG. 14 is a chiral HPLC analysis of R-2-methanesulfonyl-1-phenylethanol derivatives synthesized in example 17 of the present invention. A is a racemic 2-benzenesulfonyl-1- (4-methoxyphenyl) ethanol standard substance control; b is R-2-benzenesulfonyl-1- (4-methoxyphenyl) ethanol.
FIG. 15 is a chiral HPLC analysis of R-2-methanesulfonyl-1-phenylethanol derivatives synthesized in example 18 of the present invention. A is a racemic 2-benzenesulfonyl-1- (4-fluorophenyl) ethanol standard substance control; b is R-2-benzenesulfonyl-1- (4-fluorophenyl) ethanol.
FIG. 16 is a chiral HPLC analysis of R-2-methanesulfonyl-1-phenylethanol derivatives synthesized in example 19 of the present invention. A is a racemic 2-benzenesulfonyl-1- (3-chlorophenyl) ethanol standard substance control; b is R-2-benzenesulfonyl-1- (3-chlorophenyl) ethanol.
FIG. 17 is a chiral HPLC analysis of R-2-methanesulfonyl-1-phenylethanol derivatives synthesized in example 20 of the present invention. A is a racemic 2-benzenesulfonyl-1- (4-chlorophenyl) ethanol standard substance control; b is R-2-benzenesulfonyl-1- (4-chlorophenyl) ethanol.
FIG. 18 is a chiral HPLC analysis of R-2-methanesulfonyl-1-phenylethanol derivatives synthesized in example 21 of the present invention. A is a racemic 2-benzenesulfonyl-1- (4-bromophenyl) ethanol standard control; b is R-2-benzenesulfonyl-1- (4-bromophenyl) ethanol.
Detailed Description
The technical scheme of the present invention will be further specifically described by means of specific examples, but the present invention is not limited to these examples.
The invention prepares the compound R-2-methylsulfonyl-1-phenylethanol derivative of the formula B by asymmetric reduction of the compound of the formula A by ketoreductase. And circulating cofactor NADPH by glucose dehydrogenase and glucose action:
wherein R is 1 Is a mono-or polysubstituted C1-C4 alkyl, C1-C4 alkoxy, or halogen;
R 2 is C1-C4 alkyl or phenyl.
LB medium: 0.5% yeast extract, 1% peptone and 1% sodium chloride (e.g. by preparing solid medium, adding 1.5% agar before sterilizing), and autoclaving at 115℃for 30min.
As an optimal implementation procedure, only ketoreductase with the amino acid sequence shown in SEQ ID NO.1 is selected for specific implementation.
Example 1 specific culture preparation of ketoreductase:
1mL of recombinant escherichia coli BL21 (DE 3) overnight culture solution containing ketoreductase gene is added into 100mL of LB culture medium, and the culture is carried out at 30 ℃ and 220rpm until OD600 is 0.8-1; the expression of ketoreductase was then induced by the addition of the inducer IPTG (final concentration of 0.1 mM) at 18℃for 12h at 220 rpm. Finally, after centrifugation at 3000rpm for 10min, the supernatant was discarded and the wet bacterial pellet containing ketoreductase was collected. The amino acid sequence of the ketoreductase is shown as SEQ ID NO. 1.
Example 2 specific culture preparation of glucose dehydrogenase:
1mL of a recombinant E.coli BL21 (DE 3) overnight broth containing a glucose dehydrogenase gene (NCBI database number: WP_ 044161863.1) was added to 100mL of LB medium, and cultured at 30℃and 220rpm until OD600 was 0.8-1; the inducer IPTG (final concentration of 0.1 mM) was then added to induce expression of glucose dehydrogenase and induction was carried out at 18℃for 12h at 220 rpm. Finally, after centrifugation at 3000rpm for 10min, the supernatant was discarded to collect a wet cell pellet containing glucose dehydrogenase.
Example 3 cell disruption crude enzyme solution was prepared:
4g of ketoreductase wet bacterial sediment (example 1) and 0.8g of glucose dehydrogenase wet bacterial sediment (example 2) are respectively taken, 20mL 100mM pH 7.0 sodium phosphate buffer solution is added to resuspend bacterial bodies, ultrasonic crushing is carried out in an ice-water bath under the conditions that the power is 55 percent, the ultrasonic treatment is carried out for 5s at intervals of 5s, after ultrasonic treatment is carried out for 10min, centrifugal treatment is carried out for 5min at 12000rpm, and the supernatant is taken to obtain crude enzyme mixed solution containing glucose dehydrogenase and ketoreductase.
EXAMPLE 4 biocatalytic preparation of the Apremilast chiral alcohol intermediate (R) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethanol
0.01mmol of substrate ketone (compound 1 a) was taken, and 50. Mu.L of dimethyl sulfoxide was added to dissolve the substrate sufficiently; adding the crude enzyme mixture obtained in example 3 to give a reaction volume of 950. Mu.L; finally, 4mg of NADPH (reduced nicotinamide adenine dinucleotide phosphate) and 8mg of glucose were added and reacted at 30 ℃. After 12 hours of reaction, the sample was taken to detect the substrate and the product until the reaction was completed. The solvent was distilled off under reduced pressure after extraction with ethyl acetate three times, and the conversion of the product alcohol compound 1b was >99% by HPLC and the ee value was 99.2%.
Example 5
Substantially the same as in example 4, except that: the substrate ketone used was 2-methanesulfonyl-1-phenylethanone (compound 2 a), and compound 2b was prepared with a conversion of >99% and an ee value of 94%.
Example 6
Substantially the same as in example 4, except that: the substrate ketone used was 2-methanesulfonyl-1- (4-methylphenyl) ethanone (compound 3 a), which gave compound 3b with a conversion of >99% and an ee value of 96.7%.
Example 7
Substantially the same as in example 4, except that: the substrate ketone used was 2-methanesulfonyl-1- (3-methoxyphenyl) ethanone (compound 4 a), which gave compound 4b with a conversion of >99% and an ee value of 99.7%.
Example 8
Substantially the same as in example 4, except that: the substrate ketone used was 2-methanesulfonyl-1- (4-methoxyphenyl) ethanone (compound 5 a), and compound 5b was prepared with a conversion of 80% and an ee value of 99.7%.
Example 9
Substantially the same as in example 4, except that: the substrate ketone used was 2-methanesulfonyl-1- (4-fluorophenyl) ethanone (compound 6 a), which gave compound 6b having a conversion of 80% and an ee value of 99.7%.
Example 10
Substantially the same as in example 4, except that: the substrate ketone used was 2-methanesulfonyl-1- (3-chlorophenyl) ethanone (compound 7 a), and compound 7b was prepared at a conversion of 99% and an ee value of 98.5%.
Example 11
Substantially the same as in example 4, except that: the substrate ketone used was 2-methanesulfonyl-1- (4-chlorophenyl) ethanone (compound 8 a), and compound 8b was prepared at a conversion of 99% and an ee value of 99.9%.
Example 12
Substantially the same as in example 4, except that: the substrate ketone used was 2-methanesulfonyl-1- (4-bromophenyl) ethanone (compound 9 a), which gave compound 9b with a conversion of 99% and an ee value of 99.9%.
Example 13
Substantially the same as in example 4, except that: the substrate ketone used was 2-benzenesulfonyl-1-phenylethanone (compound 10 a), and compound 10b was prepared with a conversion of 97.8% and an ee value of 94.3%.
Example 14
Substantially the same as in example 4, except that: the substrate ketone used was 2-benzenesulfonyl-1- (4-methylphenyl) ethanone (compound 11 a), which gave compound 11b as a 99.4% conversion with an ee value of 98.7%.
Example 15
Substantially the same as in example 4, except that: the substrate ketone used was 2-benzenesulfonyl-1- (2-methoxyphenyl) ethanone (compound 12 a) to give compound 12b with a conversion of 12.7% and an ee value of 91.2%.
Example 16
Substantially the same as in example 4, except that: the substrate ketone used was 2-benzenesulfonyl-1- (3-methoxyphenyl) ethanone (compound 13 a), and compound 13b was prepared with a conversion of 98.6% and an ee value of 93.0%.
Example 17
Substantially the same as in example 4, except that: the substrate ketone used was 2-benzenesulfonyl-1- (4-methoxyphenyl) ethanone (compound 14 a) to give compound 14b with a conversion of 73.9% and an ee value of 94.3%.
Example 18
Substantially the same as in example 4, except that: the substrate ketone used was 2-benzenesulfonyl-1- (4-fluorophenyl) ethanone (compound 15 a), and compound 15b was prepared with a conversion of 99% and an ee value of 96.0%.
Example 19
Substantially the same as in example 4, except that: the substrate ketone used was 2-benzenesulfonyl-1- (3-chlorophenyl) ethanone (compound 16 a), which gave compound 16b as a 99% conversion with an ee value of 78.9%.
Example 20
Substantially the same as in example 4, except that: the substrate ketone used was 2-benzenesulfonyl-1- (4-chlorophenyl) ethanone (compound 17 a), which gave compound 17b as 97.7% conversion and an ee value of 95.1%.
Example 21
Substantially the same as in example 4, except that: the substrate ketone used was 2-benzenesulfonyl-1- (4-bromophenyl) ethanone (compound 18 a), which gave compound 18b with a conversion of 98.6% and an ee value of 94.2%.
SEQUENCE LISTING
<110> university of Shenyang pharmacy
<120> a process for preparing R-2-sulfonyl-1-phenylethanol derivatives
<130> 2022
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 247
<212> PRT
<213> Ketone reductase (R-KRED)
<400> 1
Met Gly Gln Phe Asp Asn Lys Val Ala Leu Val Thr Gly Gly Thr Lys
1 5 10 15
Gly Ile Gly Leu Ala Ile Ala Glu Leu Phe Leu Lys Glu Gly Ala Lys
20 25 30
Gly Val Ala Phe Thr Gly Arg His Glu Asp Glu Gly Lys Ala Val Gln
35 40 45
Glu Arg Leu Gly Glu Arg Ser Leu Phe Ile Thr Gln Asp Val Ser Lys
50 55 60
Glu Glu Asp Trp Gln Asn Ala Thr Lys Ala Val Val Glu Lys Phe Gly
65 70 75 80
Gln Leu Asp Ala Ile Val Asn Asn Ala Gly Ile Gly Thr Pro Leu Gly
85 90 95
Ile Glu Glu Met Thr Leu Asp His Trp Asn Arg Glu Ile Ala Ile Asp
100 105 110
Leu Thr Gly Thr Met Leu Gly Cys Lys Tyr Gly Val Lys Ala Met Lys
115 120 125
Glu His Gly Gly Ala Ile Val Asn Ile Ser Ser Ile Ile Gly Met Ile
130 135 140
Gly Asp Pro Thr Val Pro Ala Tyr Asn Ala Ala Lys Gly Gly Val Arg
145 150 155 160
Leu Leu Thr Lys Ser Val Ala Leu Glu Cys Ala Glu Lys Gly Tyr Ala
165 170 175
Ile Arg Val Asn Ser Ile Tyr Pro Gly Ala Ile Ala Thr Pro Leu Ile
180 185 190
Asp His Leu Asp Asp Ala Thr Lys Gln Phe Tyr Ile Asp Lys His Pro
195 200 205
Met Gly Arg Leu Gly Lys Pro Glu Glu Val Ala Lys Met Ala Val Phe
210 215 220
Val Ala Ser Asp Gly Ala Ser Phe Ser Thr Gly Ser Glu Phe Val Val
225 230 235 240
Asp Gly Gly Tyr Thr Ala Gln
245

Claims (7)

1. A biocatalyst comprising a ketoreductase, a glucose dehydrogenase, NADP + Or NAD + Glucose, the amino acid sequence of the ketoreductase is shown as SEQ ID NO. 1.
2. The biocatalyst of claim 1, wherein the ketoreductase: glucose dehydrogenase: NADP (NADP) + Or NAD + : glucose is 0.02-40g/L:0.02-40g/L:0-0.5mmol:6-200g/L.
3. The application of the biocatalyst according to claim 1 or 2 in the catalytic preparation of R-2-sulfonyl-1-phenylethanol derivatives, characterized in that 2-sulfonyl-1-phenylethanol derivatives are used as starting substrates, and under the action of the biocatalyst, carbonyl groups of the substrates are asymmetrically reduced into hydroxyl groups to obtain R-2-sulfonyl-1-phenylethanol derivatives;
the structural formula of the 2-sulfonyl-1-phenylethanone derivative is shown as a formula A, and the structural formula of the R-2-sulfonyl-1-phenylethanol derivative is shown as a formula B;
wherein R is 1 Is a mono-or polysubstituted C1-C4 alkyl, or C1-C4 alkoxy, or halogen; r is R 2 Is C1-C4 alkyl or phenyl.
4. Use according to claim 3, characterized in that the pH of the catalytic reaction is 5.5-8.
5. Use according to claim 3, characterized in that the temperature of the catalytic reaction is 28-45 ℃.
6. Use according to claim 3, characterized in that the substrate concentration is 0.5-200g/L.
7. Use according to claim 3, characterized in that the 2-sulfonyl-1-phenylethanone derivative is selected from any one of the following:
CN202210102497.2A 2022-01-27 2022-01-27 Preparation method of R-2-sulfonyl-1-phenylethanol derivative Active CN114540321B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210102497.2A CN114540321B (en) 2022-01-27 2022-01-27 Preparation method of R-2-sulfonyl-1-phenylethanol derivative

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210102497.2A CN114540321B (en) 2022-01-27 2022-01-27 Preparation method of R-2-sulfonyl-1-phenylethanol derivative

Publications (2)

Publication Number Publication Date
CN114540321A CN114540321A (en) 2022-05-27
CN114540321B true CN114540321B (en) 2024-04-02

Family

ID=81672938

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210102497.2A Active CN114540321B (en) 2022-01-27 2022-01-27 Preparation method of R-2-sulfonyl-1-phenylethanol derivative

Country Status (1)

Country Link
CN (1) CN114540321B (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109652463A (en) * 2018-12-12 2019-04-19 浙江大学 A method of using Perakine reductase synthesis of chiral alcohol
CN110283799A (en) * 2019-05-07 2019-09-27 沈阳药科大学 Aldehyde ketone reductase BsAKR (YvgN) and its mutant and application
CN111057725A (en) * 2019-07-01 2020-04-24 上海弈柯莱生物医药科技有限公司 Application of ketoreductase in preparation of (S) -1, 1-di (4-fluorophenyl) -2-propanol and preparation
CN113583988A (en) * 2020-04-30 2021-11-02 沈阳药科大学 Amino acid dehydrogenase mutant and application thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109652463A (en) * 2018-12-12 2019-04-19 浙江大学 A method of using Perakine reductase synthesis of chiral alcohol
CN110283799A (en) * 2019-05-07 2019-09-27 沈阳药科大学 Aldehyde ketone reductase BsAKR (YvgN) and its mutant and application
CN111057725A (en) * 2019-07-01 2020-04-24 上海弈柯莱生物医药科技有限公司 Application of ketoreductase in preparation of (S) -1, 1-di (4-fluorophenyl) -2-propanol and preparation
CN113583988A (en) * 2020-04-30 2021-11-02 沈阳药科大学 Amino acid dehydrogenase mutant and application thereof

Also Published As

Publication number Publication date
CN114540321A (en) 2022-05-27

Similar Documents

Publication Publication Date Title
KR101354546B1 (en) Oxidoreductases for the stereoselective reduction of keto compounds
KR20060030478A (en) Oxidoreductase from pichia capsulata
Kratzer et al. Whole-cell bioreduction of aromatic α-keto esters using Candida tenuis xylose reductase and Candida boidinii formate dehydrogenase co-expressed in Escherichia coli
CN109468291B (en) Carbonyl reductase EbSDR8 mutant and construction method and application thereof
Liu et al. Large‐scale synthesis of tert‐butyl (3R, 5S)‐6‐chloro‐3, 5‐dihydroxyhexanoate by a stereoselective carbonyl reductase with high substrate concentration and product yield
CN105274160B (en) Method for preparing (S) -N-boc-3-hydroxypiperidine by enzymatic asymmetric reduction
Bai et al. Facile synthesis of (−)‐vibo‐quercitol from maltodextrin via an in vitro synthetic enzymatic biosystem
CN111454998B (en) Biological preparation method of chiral hydroxy acid ester
ES2365159T3 (en) PROCEDURE FOR ENANTIOSELECTIVE ENZYMATIC REDUCTION OF KEY CODES.
CN113355367B (en) Application of ketoacid reductase in synthesis of chiral aromatic 2-hydroxy acid
CN111996176A (en) Carbonyl reductase mutant and application thereof
CN114540321B (en) Preparation method of R-2-sulfonyl-1-phenylethanol derivative
WO2014075438A1 (en) Method for biological preparation of 6-cyano-(3r,5r)- dihydroxyhexanoic-tert-butyl-acetate
Asako et al. Biocatalytic production of (S)-4-bromo-3-hydroxybutyrate and structurally related chemicals and their applications
CN114277006B (en) Alcohol dehydrogenase and application thereof in synthesis of chiral heterocyclic alcohol
CN114908129B (en) Dehydrogenase for the preparation of (R) -4-chloro-3-hydroxybutyric acid ethyl ester
Chen et al. Efficient synthesis of Ibrutinib chiral intermediate in high space-time yield by recombinant E. coli co-expressing alcohol dehydrogenase and glucose dehydrogenase
US9045780B2 (en) Process for the stereoselective enzymatic reduction of keto compounds
CN113151131B (en) Self-induction culture medium for producing isoeugenol monooxygenase and application thereof
US20230107679A1 (en) Method For Preparing (S)-1,2,3,4-Tetrahydroisoquinoline-1 Carboxylic Acid and Derivatives Thereof
CN109897872B (en) Enzymatic preparation of (2S, 3S) -N-t-butoxycarbonyl-3-amino-1-chloro-2-hydroxy-4-phenylbutane
Wei et al. Marked improvement in the asymmetric reduction of 2-hydroxyacetophenone with mut-AcCR in a biphasic system
CN114875106B (en) Method for generating (S) -2-methylcyclohexanone by utilizing alkene reductase in micro-flow field
CN114774491B (en) Method for preparing (2S, 3R) -2- (phthalimidomethyl) -3-hydroxybutyrate
CN112442523B (en) Method for preparing (R) -1,2,3, 4-tetrahydroisoquinoline-1-formic acid and derivatives thereof by enzymatic resolution

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant