Fluorine atom substituted alpha-deuterated chiral alcohol compound as well as enzyme catalysis preparation method and application thereof

Abstract

The invention provides a fluorine atom substituted alpha-deuterated chiral alcohol compound which has a structure as shown in a formula (I) or a formula (II). The fluoro-alpha-deuterated chiral alcohol provided by the invention is prepared by using deuterated isopropanol as a deuterium source and carbonyl reductase as a catalyst through a reduction reaction of a fluoroketone compound, and the method has the advantages of mild reaction conditions, environmental friendliness, high conversion rate, high deuterated rate, high enantioselectivity, wide substrate universality and the like, and can be used for preparing the fluoro-alpha-deuterated chiral alcohol. The fluoro alpha-deuterated chiral alcohol provided by the invention can be used as a synthetic intermediate for preparing deuterated drug active molecules, and has a very strong industrial application prospect. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of the preparation of fluorine atom-substituted α-deuterated chiral alcohol compounds, and relates to a fluorine atom-substituted α-deuterated chiral alcohol compound, a preparation method and an application thereof, in particular to a fluorine atom-substituted α-deuterated chiral alcohol compound, an enzyme-catalyzed preparation method and an application thereof. Background Art

[0002] Carbonyl reductases (CRs) can catalyze a series of carbonyl compounds to carry out asymmetric reduction reactions. When catalyzing the reduction reaction, they require coenzymes nicotinamide adenine dinucleotide or nicotinamide adenine dinucleotide phosphate (NAD(P)H) as hydrogen or electron carriers. There are also a small number of CRs that use tetrahydroxyacetone alcohol or pyrroloquinoline quinone (PQQ) (Xia X.L., European Food Research and Technology, 2015, 241(4): 479-485; Zheng Y., Food Science and Biotechnology, 2015, 24(1): 133-140) as coenzymes to complete the catalytic reaction. When CRs catalyze the asymmetric reduction reaction of carbonyl compounds, they generally follow the sequential mechanism: first, the enzyme binds to the coenzyme to form an enzyme-coenzyme complex; then the enzyme-coenzyme complex binds to the substrate; the hydrogen on the coenzyme is transferred to the carbonyl substrate, attacking and adding hydrogen from the re-face or si-face of the substrate to generate the corresponding R-configuration or S-configuration chiral alcohol, and at the same time, the reduced coenzyme NAD(P)H becomes the oxidized coenzyme NAD(P) + ; the product is released from the enzyme-coenzyme complex; finally, the enzyme is separated from the oxidized coenzyme to complete the catalytic reaction (Musa M.M., Catalysis Science and Technology, 2011, 1(8): 1311-1323; Itoh N., Applied Microbiology and Biotechnology, 2014, 98(9): 3889-3904).

[0003] Fluorinated carbonyl compounds and the optically active alcohols obtained by their reduction are widely used as important synthetic intermediates in the chemical and pharmaceutical fields. Affected by factors such as the high electronegativity, small volume of fluorine atoms, and high C-F bond energy, fluorinated compounds have unique physical, chemical, and biological characteristics. Introducing fluorinated groups into organic molecules can change the acidity, polarity, and reactivity of the parent compound, improve chemical and metabolic stability, and increase lipophilicity and bioavailability. Many drugs and bioactive molecules contain fluorine atom groups. Among various fluorinated compounds, chiral alcohols are a class of organic molecules that deserve special attention and are widely used in fields such as drugs, organic materials, and fine chemicals. For example, crizotinib (for treating non-small cell lung cancer (NSCLC) with abnormal anaplastic lymphoma kinase (ALK) gene expression) (John W., Organic Process Research & Development 2018, 22, 1289-1293.), Fluoroartemisinin (an antimalarial drug) (Sculptoreanu A., Journal of Pharmacology and Experimental Therapeutics, 2004, 310(1): 159-168.), LX-1031 (a tryptophan 5-hydroxylase inhibitor) (Camilleri M., Neurogastroenterology and Motility, 2011, 23(3): 193-200.), Efavirenz (an HIV reverse transcriptase inhibitor), Telotristat (LP-778902, a tryptophan hydroxylase inhibitor) (Benavent M., Endocrine-Related Cancer, 2018, 25(3): 309-322.), the human neurokinin-1 (NK-1) receptor blocker aprepitant, fosaprepitant, BTMPA (Huang Z.S., Organic Process Research & Development 2014, 18, 1137-1141), etc.

[0004] Deuterated compounds have attracted attention due to their unique physical and chemical properties (Schaffenberger M., ChemSusChem., 2008, 1(5): 431-436.; Krumbiegel P., Isotopes in Environmental and Health Studies, 2011, 47(1): 1-17.). Compared with the C-H bond, the C-D bond has a higher bond energy and is difficult to break. Therefore, the use of C-D bonds in drug molecules can, to a certain extent, reduce the metabolic rate of drugs. Deuteration modification at the metabolic sites of drug molecules may have certain positive effects, such as improving drug pharmacokinetics, increasing active metabolites, reducing toxic by-products, inhibiting the conversion between chiral drug isomers and drug-drug interactions, etc. Fluorine-containing chiral alcohols are important structural units of drugs and bioactive molecules and have important reference significance in drug design and development. In addition, deuterated molecules are widely used in compound detection, compound tracking, and changing compound properties. Especially, introducing deuterium atoms into drugs will improve the pharmacokinetics, pharmacodynamics of drugs or reduce drug metabolic toxicity by changing the drug metabolism rate and pathway.

[0005] Currently, the preparation of fluorine-containing chiral alcohols mainly uses transition metal-catalyzed methods with hydrogen as a reducing agent and chiral ligands added for stereocontrol. However, this type of method has problems such as expensive metal catalysts / chiral ligands, harsh reaction conditions, and high risk factors (Org. Chem. Front., 2021, 8, 3705-3711).

[0006] Therefore, how to develop a more suitable method for preparing fluorine atom-substituted α-deuterated chiral alcohol compounds has become one of the focuses widely concerned by many forward-looking researchers in this field and has important scientific significance and application value. Summary of the Invention

[0007] In view of this, the technical problem to be solved by the present invention is to provide a fluorine atom-substituted α-deuterated chiral alcohol compound, its preparation method and application, especially a fluorine atom-substituted α-deuterated chiral alcohol compound and its enzyme-catalyzed preparation method. The present invention uses enzyme-catalyzed reactions to prepare fluorine-containing chiral alcohols, which have the advantages of mild conditions, green sustainability, safety and high efficiency.

[0008] The present invention provides a fluorine atom-substituted α-deuterated chiral alcohol compound, which has a structure shown in formula (I) or formula (II); the chiral center configuration of the α-deuterated chiral alcohol compound is selected from the R configuration or the S configuration. Compared with the prior art, the present invention particularly designs a class of fluorine atom-substituted α-deuterated chiral alcohol compounds with specific structures and elements. The present invention uses deuterated isopropanol as a deuterium source, a carbonyl reductase as a catalyst, and prepares a fluorinated α-deuterated chiral alcohol by a reduction reaction of a fluorinated ketone compound. This method has the advantages of mild reaction conditions, environmental friendliness, high conversion rate, high deuteration rate, high enantioselectivity, and broad substrate generality. The fluorinated α-deuterated chiral alcohol provided by the present invention can be used as a synthetic intermediate for the preparation of deuterated drug active molecules, and has strong industrial application prospects. The novel fluorine atom-substituted α-deuterated chiral alcohol compound designed by the present invention is an optically pure fluorine atom-substituted α-deuterated chiral alcohol compound, which can be used as a drug itself or as a core structural unit for drug synthesis for drug activity screening.

[0009] The present invention adopts an enzyme-catalyzed reaction with mild reaction conditions. Compared with the transition metal-catalyzed method, it does not require harsh reaction conditions such as high temperature and high pressure, reducing energy consumption and equipment requirements; moreover, it is environmentally friendly. As a catalyst, the enzyme has biodegradability, and the reagents used in the reaction process are relatively environmentally friendly, meeting the concept of green chemistry; at the same time, it has broad substrate generality and can be used for the reduction reactions of various fluorinated carbonyl compounds to prepare fluorinated α-deuterated chiral alcohol compounds with different structures, providing more choices for drug synthesis.

[0010] Experimental results show that the preparation method provided by the present invention has a high conversion rate, a high deuteration rate, and can obtain a target product with high enantioselectivity. The conversion rate can reach 96% - 99%, the deuteration rate can reach 96% - 99%, and the enantiomeric excess value (ee) can reach 97% - 99%. Description of the Drawings

[0011] Figure 1 It is the 19F NMR spectrum of the product prepared in Example 30 of the present invention;

[0012] Figure 2 It is the 13C NMR spectrum of the product prepared in Example 30 of the present invention;

[0013] Figure 3 It is the 1H NMR spectrum (S configuration) of the product prepared in Example 30 of the present invention;

[0014] Figure 4 It is the 1H NMR spectrum (R configuration) of the product prepared in Example 30 of the present invention;

[0015] Figure 5 It is the liquid chromatography diagram of the product prepared in Example 30 of the present invention and its corresponding data;

[0016] Figure 6 1H NMR spectrum of the product prepared in Example 31 of the present invention (R configuration);

[0017] Figure 7 19F NMR spectrum of the product prepared in Example 31 of the present invention;

[0018] Figure 8 13C NMR spectrum of the product prepared in Example 31 of the present invention;

[0019] Figure 9 19F NMR spectrum of the product prepared in Example 31 of the present invention (S configuration);

[0020] Figure 10 Liquid chromatography diagram of the product prepared in Example 31 of the present invention and its corresponding data. Detailed implementation manners

[0021] To further understand the present invention, the preferred implementation manners of the present invention will be described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the invention.

[0022] There are no special restrictions on the sources of all raw materials of the present invention, and they can be purchased on the market or prepared by conventional methods well-known to those skilled in the art.

[0023] There are no special restrictions on the purity of the raw materials used in the present invention. The present invention preferably uses analytical pure or conventional purity in the field of α-deuterated chiral alcohol compounds.

[0024] All raw materials of the present invention, their trade names and abbreviations are all conventional trade names and abbreviations in the art, and each trade name and abbreviation is clear and definite in the field of its related uses. Those skilled in the art can purchase or prepare them by conventional methods according to the trade name, abbreviation and corresponding uses.

[0025] All processes of the present invention, their abbreviations are all conventional abbreviations in the art, and each abbreviation is clear and definite in the field of its related uses. Those skilled in the art can understand their conventional process steps according to the abbreviations.

[0026] The present invention provides a fluorine atom-substituted α-deuterated chiral alcohol compound having a structure shown in formula (I) or formula (II):

[0027]

[0028] Among them, the Rf substituent is selected from trifluoromethyl, difluoromethyl or monofluoromethyl; the R substituent is selected from aromatic groups, alkyl groups or alkenyl groups;

[0029] Ar f The substituent is selected from an aromatic group substituted with a fluorine atom; Me is a methyl group;

[0030] The chiral center configuration of the α-deuterated chiral alcohol compound is selected from the R configuration or the S configuration.

[0031] In the present invention, the R substituent is selected from an aromatic group, an alkyl group or an alkenyl group, and more preferably an aromatic group.

[0032] In the present invention, the α-deuterated chiral alcohol compound substituted with a fluorine atom having the structure shown in formula (I) is specifically preferably the structure shown in formula (I-1) to formula (I-35):

[0033]

[0034]

[0035] In the present invention, the α-deuterated chiral alcohol compound substituted with a fluorine atom having the structure shown in formula (II) is specifically preferably the structure shown in formula (II-1) to formula (II-9):

[0036]

[0037] The present invention provides a method for preparing an α-deuterated chiral alcohol compound substituted with a fluorine atom according to any one of the above technical solutions, comprising the following steps:

[0038] After mixing a fluorine-containing carbonyl compound, a carbonyl reductase catalyst, deuterated isopropanol, a cofactor, a buffer solution and a cosolvent, an enzymatic reduction reaction is carried out, and then aftertreatment is carried out to obtain an α-deuterated chiral alcohol compound substituted with a fluorine atom;

[0039] The fluorine-containing carbonyl compound has the structure shown in formula (III) or formula (IV):

[0040]

[0041] When the fluorine-containing carbonyl compound is a compound having the structure shown in formula (III), an α-deuterated chiral alcohol compound having the structure shown in formula (I) is prepared;

[0042] When the fluorine-containing carbonyl compound is a compound having the structure shown in formula (IV), an α-deuterated chiral alcohol compound having the structure shown in formula (II) is prepared.

[0043] In the present invention, the carbonyl reductase catalyst preferably comprises one or more of AaADH derived from Aromatoleum aromaticum EbN1, DrADH derived from Devosia riboflavina, LkADH derived from Lactobacillus kefiri DSM 20587, LzADH derived from Lactobacillus zymae DSM 19395, and RasADH derived from Ralstonia sp. DSM 6428, and more preferably is AaADH derived from Aromatoleum aromaticum EbN1, DrADH derived from Devosia riboflavina, LkADH derived from Lactobacillus kefiri DSM 20587, LzADH derived from Lactobacillus zymae DSM 19395, or RasADH derived from Ralstonia sp. DSM 6428.

[0044] In the present invention, the deuterated isopropanol preferably comprises 2-monodeuterated isopropanol and / or octadeuterated isopropanol, and more preferably is 2-monodeuterated isopropanol or octadeuterated isopropanol.

[0045] In the present invention, the cofactor preferably comprises nicotinamide adenine dinucleotide phosphate and / or nicotinamide adenine dinucleotide, and more preferably is nicotinamide adenine dinucleotide phosphate or nicotinamide adenine dinucleotide.

[0046] In the present invention, the buffer solution preferably comprises one or more of KH2PO4 / K2HPO4, NaH2PO4 / Na2HPO4, and Tris-HCl, and more preferably is KH2PO4 / K2HPO4, NaH2PO4 / Na2HPO4, or Tris-HCl.

[0047] In the present invention, the cosolvent preferably comprises one or more of tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, ether, and dimethyl sulfoxide, and more preferably is tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, ether, or dimethyl sulfoxide.

[0048] In the present invention, after mixing, the concentration of the fluorine-containing carbonyl compound is preferably 0.01 - 0.5 mmol / mL, more preferably 0.1 - 0.4 mmol / mL, and even more preferably 0.2 - 0.3 mmol / mL.

[0049] In the present invention, after the mixing, the concentration of the carbonyl reductase catalyst is preferably 1 to 40 mg / mL, more preferably 6 to 35 mg / mL, still more preferably 11 to 30 mg / mL, and even more preferably 16 to 25 mg / mL.

[0050] In the present invention, after the mixing, the volume ratio of deuterated isopropanol is preferably 1.5% (v / v) to 5% (v / v), more preferably 2.0% (v / v) to 4.5% (v / v), still more preferably 2.5% (v / v) to 4.0% (v / v), and even more preferably 3.0% (v / v) to 3.5% (v / v).

[0051] In the present invention, after the mixing, the concentration of the cofactor dosage is preferably 0.05 to 0.40 mM / mL, more preferably 0.1 to 0.35 mM / mL, still more preferably 0.15 to 0.3 mM / mL, and even more preferably 0.2 to 0.25 mM / mL.

[0052] In the present invention, after the mixing, the volume ratio of the cosolvent is preferably 4% (v / v) to 10% (v / v), more preferably 6% (v / v) to 9% (v / v), still more preferably 7% (v / v) to 8% (v / v).

[0053] In the present invention, the temperature of the enzymatic reduction reaction is preferably 15 to 70 °C, more preferably 25 to 60 °C, still more preferably 35 to 50 °C.

[0054] In the present invention, the time of the enzymatic reduction reaction is preferably 1 to 24 hours, more preferably 6 to 19 hours, still more preferably 11 to 14 hours.

[0055] In the present invention, the post-treatment preferably includes one or more steps of extraction, concentration, and chromatography purification, and more preferably multiple steps of extraction, concentration, and chromatography purification.

[0056] The present invention provides the use of the fluorine atom-substituted α-deuterated chiral alcohol compound according to any one of the above technical solutions or the fluorine atom-substituted α-deuterated chiral alcohol compound prepared by the preparation method according to any one of the above technical solutions in medicine, drug synthesis, or drug activity screening.

[0057] The present invention provides a fluorine atom-substituted α-deuterated chiral alcohol compound having a structure shown in formula (VI) or formula (VII):

[0058]

[0059] Among them, the Rf substituent is selected from trifluoromethyl, difluoromethyl, or monofluoromethyl; the R substituent is selected from an aromatic group, an alkyl group, or an alkenyl group;

[0060] Ar f The substituent is selected from an aromatic group substituted by a fluorine atom; Me is a methyl group;

[0061] The configuration of the chiral center of the α-deuterated chiral alcohol compound is selected from the R configuration or the S configuration.

[0062] The present invention provides the use of the α-deuterated chiral alcohol compound substituted by a fluorine atom as described in the above technical solution in drug screening.

[0063] In the present invention, the α-deuterated chiral alcohol compound substituted by a fluorine atom is specifically an inhibitor of the α-deuterated chiral alcohol compound substituted by a fluorine atom.

[0064] In the present invention, the said use preferably includes that itself or its derivatives can be further used as active molecules in drug screening.

[0065] In order to complete and refine the overall technical solution of the present invention, better ensure the structure and properties of the α-deuterated chiral alcohol compound substituted by a fluorine atom, and further improve the efficiency of the preparation method of the α-deuterated chiral alcohol compound substituted by a fluorine atom, the above-mentioned α-deuterated chiral alcohol compound substituted by a fluorine atom, its preparation method by enzymatic catalysis, and the application may specifically include the following content:

[0066] A class of α-deuterated chiral alcohol compounds substituted by a fluorine atom has the following chemical structure:

[0067]

[0068] Among them, the Rf substituent is selected from trifluoromethyl, difluoromethyl, monofluoromethyl, and Ar f The substituent is selected from an aromatic group substituted by a fluorine atom, and the configuration of the chiral center of the compound is selected from the R configuration or the S configuration.

[0069] Specifically, for the preparation method of the said Compound I or II, using the fluorine-containing carbonyl compound III or IV as the raw material, using a carbonyl reductase as the catalyst and deuterated isopropanol as the deuterium source, adding cofactors, buffer solutions, and cosolvents, after complete reaction at a certain temperature, through extraction and separation, the α-deuterated chiral alcohol compound I or II substituted by a fluorine atom is obtained. The reaction equation is as shown below:

[0070]

[0071] Specifically, the carbonyl reductase is selected from any one of AaADH (Genbank: CAI07428.1) from Aromatoleum aromaticum EbN1, DrADH (Genbank: BD450088.1) from Devosia riboflavina, LkADH (AY267012.1) from Lactobacillus kefiri DSM 20587, LzADH (KRL08675.1) from Lactobacillus zymae DSM19395, and RasADH from Ralstonia sp. DSM 6428.

[0072] Specifically, the cofactor is selected from any one of nicotinamide adenine dinucleotide phosphate (NADP) and nicotinamide adenine dinucleotide (NAD).

[0073] Specifically, the deuterated isopropanol is selected from 2-monodeuterated isopropanol (D- i PrOH), octa-deuterated isopropanol (d8- i Any one of PrOD).

[0074] Specifically, the buffer solution is selected from any one of KH2PO4 / K2HPO4 (pH 5.8-8.0), NaH2PO4 / Na2HPO4 (pH 5.8-8.0), and Tris-HCl (pH 7.1-8.9).

[0075] Specifically, the co-solvent is selected from any one of tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide (DMF), ether, and dimethyl sulfoxide (DMSO).

[0076] Specifically, in the enzyme-catalyzed reduction reaction, the concentration of substrate III or IV is any one of 0.01 mmol / mL to 0.5 mmol / mL, the amount of carbonyl reductase is any one of 1 mg / mL to 40 mg / mL, the amount of cofactor is any one of 0.05 mM / mL to 0.40 mM / mL, the amount of deuterated isopropanol is any one of 1.5% (v / v) to 5% (v / v), and the volume ratio of the cosolvent is any one of 4% (v / v) to 10% (v / v).

[0077] Specifically, the enzyme-catalyzed reduction reaction has a reaction temperature of any temperature between 15°C and 70°C, and a reaction time of any time between 1 hour and 24 hours; after the reaction is completed, an organic compound separation and purification method is used to extract, concentrate, and purify by silica gel column chromatography to obtain the target product.

[0078] Specifically, for the use of Compound I or II, nucleophilic substitution reaction of Compound I or II with amino acid derivative V can yield deuterium atom-substituted TPH (tryptophan 5-hydroxylase) inhibitors VI or VII, which themselves or their derivatives can be used as active molecules for further drug screening. The specific reaction equation is as follows:

[0079]

[0080] Specifically, the fluorine-containing α-deuterated chiral alcohol compounds (I, II, VI, VII) preferably have one of the following structural formulas:

[0081]

[0082]

[0083] The present invention provides a novel fluorine atom-substituted α-deuterated chiral alcohol compound and its preparation method. The obtained target compound is an optically pure fluorine atom-substituted α-deuterated chiral alcohol compound, which can be used as a drug itself or as a core structural unit for drug synthesis for drug activity screening.

[0084] The above content of the present invention provides a fluorine atom-substituted α-deuterated chiral alcohol compound, its enzyme-catalyzed preparation method and application. A class of fluorine atom-substituted α-deuterated chiral alcohol compounds with specific structures and elements are specially designed in the present invention. Using deuterated isopropanol as the deuterium source, carbonyl reductase as the catalyst, fluorinated ketone compounds are subjected to a reduction reaction to prepare fluorinated α-deuterated chiral alcohols. This method has the advantages of mild reaction conditions, environmental friendliness, high conversion rate, high deuteration rate, high enantioselectivity and wide substrate generality. The fluorinated α-deuterated chiral alcohols provided by the present invention can be used as synthetic intermediates for the preparation of deuterated drug active molecules and have strong industrial application prospects. The novel fluorine atom-substituted α-deuterated chiral alcohol compounds designed in the present invention are optically pure fluorine atom-substituted α-deuterated chiral alcohol compounds, which can be used as drugs themselves or as core structural units for drug synthesis for drug activity screening.

[0085] The present invention uses an enzyme-catalyzed reaction with mild reaction conditions. Compared with the transition metal-catalyzed method, it does not require harsh reaction conditions such as high temperature and high pressure, reducing energy consumption and equipment requirements; moreover, it is environmentally friendly. Enzymes as catalysts have biodegradability, and the reagents used in the reaction process are relatively environmentally friendly, meeting the concept of green chemistry; at the same time, it has wide substrate generality and can be used for the reduction reactions of various fluorinated carbonyl compounds to prepare fluorinated α-deuterated chiral alcohol compounds with different structures, providing more choices for drug synthesis.

[0086] The experimental results show that the preparation method provided by the present invention has high conversion rate, high deuteration rate, and can obtain the target product with high enantioselectivity. The conversion rate can reach 96% - 99%, the deuteration rate can reach 96% - 99%, and the enantiomeric excess value (ee) can reach 97% - 99%.

[0087] To further illustrate the present invention, the following describes in detail a fluorine atom-substituted α-deuterated chiral alcohol compound provided by the present invention, its preparation method, and its application in combination with embodiments. However, it should be understood that these embodiments are implemented on the premise of the technical solution of the present invention, and give detailed implementation manners and specific operation processes, only to further illustrate the features and advantages of the present invention, rather than a limitation on the claims of the present invention. The protection scope of the present invention is not limited to the following embodiments either.

[0088] Example 1: 2,2,2-Trifluoro-1-(m-tolyl)ethane-1-d-1-ol

[0089]

[0090] Table 1 Reaction parameters in Example 1

[0091]

[0092] Add a buffer solution (K2HPO4 / KH2PO4, pH = 7.4) to the reaction tube, add the carbonyl reductase AaADH lysate to the system, and then sequentially add deuterated isopropanol (D- i PrOH, 1.1% v), cofactor nicotinamide adenine dinucleotide phosphate (NADP + , 10 mM, 10 μL, 1% mol), cosolvent DMSO (50 μL, 5% v), and the reaction starting material 2,2,2-trifluoro-1-(m-tolyl)ethan-1-one. Place it in a metal bath at 30 °C and shake the reaction at 1000 rpm for 24 hours. Extract with ethyl acetate (2 X 1 mL), combine the organic phases and dry with anhydrous MgSO4, and perform column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain the target product 2,2,2-trifluoro-1-(m-tolyl)ethane-1-d-1-ol (I-1(R)). 99% conv., >99% ee, 98% D; [α] D 20 = -28.4 (c 1.0, CHCl3); HPLC [Daicel Chirapak OJ-H, n-Hex∶i-PrOH = 95∶5, 1 mL / min, 210 nm UV detector, t R = 13.328 min (major) and t S= 17.857 min (minor); 1 1H NMR (400 MHz, CDCl3) δ 7.32 - 7.19 (m, 4H), 2.66 (s, 1H), 2.37 (s, 3H); 19 19F NMR (376 MHz, CDCl3) δ -78.31; 13 13C NMR (101 MHz, CDCl3) δ 138.6, 134.0, 130.4, 128.6, 128.2, 124.7, 124.4 (q, J = 282.0 Hz), 73.3 - 71.7 (m), 21.3; HRMS (ESI) m / z [M+Na] + calcd for C9H8DF3ONa + 214.0566, found 214.0569.

[0093] Add buffer solution (K2HPO4 / KH2PO4, pH = 7.4) to the reaction tube, add the carbonyl reductase DrADH lysate to the system, and then sequentially add deuterated isopropanol (D- i PrOH, 1.1% v), cofactor nicotinamide adenine dinucleotide phosphate (NADP + , 10 mM, 10 μL, 1% mol), cosolvent DMSO (50 μL, 5% v) and reaction starting material 2,2,2-trifluoro-1-(m-tolyl)ethan-1-one, place it in a metal bath at 30 °C, shake the reaction at 1000 rpm for 24 hours, extract with ethyl acetate (2X1 mL), combine the organic phases and dry with anhydrous MgSO4, column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain the target product 2,2,2-trifluoro-1-(m-tolyl)ethan-1-d-1-ol (I-1(S)). colorless oil; 99% conv., >99% ee, 98% D; [α] D 20 = 26.8 (c 1.0, CHCl3); HPLC [Daicel Chirapak OJ-H, n-Hex∶i-PrOH = 95∶5, 1 mL / min, 210 nm UV detector, t R = 13.637 min (minor) and t S = 17.404 min (major); 1 1H NMR (400 MHz, CDCl3) 1 1H NMR (400 MHz, CDCl3) δ 7.32 - 7.19 (m, 4H), 2.64 (s, 1H), 2.37 (s, 3H).

[0094] Example 2: (2,2,2-Trifluoro-1)-(4-methoxyphenyl)ethane-1-d-1-ol

[0095]

[0096] Using a method similar to Experiment 1 and the carbonyl reductase AaADH, the target product (2,2,2-Trifluoro-1)-(4-methoxyphenyl)ethane-1-d-1-ol (I-2(R)) was obtained. 99% conv., >99% ee, 98% D; [α] D 20 = -33.2 (c 1.0, CHCl3); HPLC [Daicel Chirapak OJ-H, n-Hex∶i-PrOH = 95∶5, 1 mL / min, 210 nm UV detector, t R = 32.758 min (major) and t S = 36.089 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.4 Hz, 2H), 6.92 - 6.87 (m, 2H), 3.79 (s, 3H), 3.01 (s, 1H); 19 19F NMR (376 MHz, CDCl3) δ -78.56; 13 13C NMR (101 MHz, CDCl3) δ 160.5, 128.9, 126.2, 124.4 (q, J = 281.9 Hz), 114.2, 72.7 - 71.6 (m), 55.4; HRMS (ESI) m / z [M+Na] + calcd for C9H8DF3O2Na + 230.0515, found 230.0514.

[0097] Using a method similar to Experiment 1 and the carbonyl reductase DrADH, the target product (2,2,2-Trifluoro-1)-(4-methoxyphenyl)ethane-1-d-1-ol (I-2(S)) was obtained. 99% conv., >99% ee, 98% D; [α] D 20 = 33.8 (c 1.0, CHCl3); HPLC [Daicel Chirapak OJ-H, n-Hex∶i-PrOH = 95∶5, 1 mL / min, 210 nm UV detector, t R = 32.919 min (minor) and t S= 36.302 min (major); 1 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.3 Hz, 2H), 6.93 - 6.87 (m, 2H), 3.79 (s, 3H), 2.95 (s, 1H).

[0098] Example 3: 1-(3-chlorophenyl)-2,2,2-trifluoroethane-1-d-1-ol

[0099]

[0100] Using a method similar to Experiment 1 and carbonyl reductase AaADH, the target product 1-(3-chlorophenyl)-2,2,2-trifluoroethane-1-d-1-ol (I-3(R)) was obtained. 97% conv., 98% ee, 98% D; [α] D 20 = -18.1 (c 0.4, CHCl3); HPLC [Daicel Chirapak OJ-H, n-Hex∶i-PrOH = 95∶5, 1 mL / min, 210 nm UV detector, t R = 11.103 min (major) and t S = 13.641 min (minor); 1 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.41 - 7.32 (m, 3H), 2.67 (s, 1H); 19 19F NMR (376 MHz, CDCl3) δ -78.43; 13 13C NMR (101 MHz, CDCl3) δ 135.7, 134.7, 130.0, 129.9, 127.7, 125.7, 124.1 (q, J = 282.1 Hz), 72.9 - 71.1 (m); HRMS (ESI) m / z [M+Na] + calcd for C8H5DClF3ONa + 234.0019, found 234.0014.

[0101] Using a method similar to Experiment 1 and carbonyl reductase DrADH, the target product 1-(3-chlorophenyl)-2,2,2-trifluoroethane-1-d-1-ol (I-3(S)) was obtained. colorless oil; 99% conv., >99% ee, 97% D; [α] D 20= 9.3 (c 0.2, CHCl3); HPLC [Daicel Chirapak OJ-H, n-Hex∶i-PrOH = 95∶5, 1 mL / min, 210 nm UV detector, t R = 11.180 min (minor) and t S = 13.918 min (major)]; 1 1H NMR (600 MHz, CDCl3) δ 7.50 (s, 1H), 7.42 - 7.32 (m, 3H), 2.63 (s, 1H).

[0102] Example 4: 2,2,2-Trifluoro-1-(4-nitrophenyl)ethan-1-d-1-ol

[0103]

[0104] Using a method similar to that of Experiment 1 and the carbonyl reductase AaADH, the target compound 2,2,2-trifluoro-1-(4-nitrophenyl)ethan-1-d-1-ol (I-4(R)) was obtained. 99% conv., 98% ee, 98% D; [α] D 20 = -26.8 (c 1.0, MeOH); HPLC [Daicel Chirapak OJ-H, n-Hex∶i-PrOH = 90∶10, 1 mL / min, 210 nm UV detector, t R = 14.430 min (major) and t S = 16.809 min (minor)]; 1 1H NMR (400 MHz, DMSO-d6) δ 8.30 - 8.24 (m, 2H), 7.79 (d, J = 8.5 Hz, 2H), 7.19 (s, 1H); 19 19F NMR (376 MHz, DMSO-d6) δ -76.74; 13 13C NMR (101 MHz, DMSO-d6) δ 147.9, 143.0, 129.0, 124.7 (q, J = 283.2 Hz), 123.3, 70.3 - 68.6 (m); HRMS (ESI) m / z [M + H] + calcd for C8H6DF3NO3 + 223.0440, found 223.0433.

[0105] Using a method similar to Experiment 1 and employing carbonyl reductase DrADH, the target compound 2,2,2-trifluoro-1-(4-nitrophenyl)ethan-1-d-1-ol (I-4(S)) was obtained. 99% conv., 99% ee, 98% D; [α] D 20 = 26.8 (c 1.0, MeOH); HPLC [Daicel Chirapak OJ-H, n-Hex∶i-PrOH = 90∶10, 1 mL / min, 210 nm UV detector, t R = 14.374 min (minor) and t S = 16.671 min (major)]; 1 H NMR (400 MHz, DMSO-d6) δ 8.30 - 8.24 (m, 2H), 7.79 (d, J = 8.5 Hz, 2H), 7.19 (s, 1H).

[0106] Example 5: 4-(2,2,2-Trifluoro-1-hydroxyethyl-1-d)benzonitrile

[0107]

[0108] Using a method similar to Experiment 1 and employing carbonyl reductase AaADH, the target compound 4-(2,2,2-trifluoro-1-hydroxyethyl-1-d)benzonitrile (I-5(R)) was obtained. 96% conv., 99% ee, 97% D; [α] D 20 = -30.7 (c 0.4, MeOH); HPLC [Daicel Chirapak OJ-H, n-Hex∶i-PrOH = 90∶10, 1 mL / min, 210 nm UV detector, t R = 15.616 min (major) and t S = 18.350 min (minor)]; 1 H NMR (400 MHz, DMSO-d6) δ 7.92 - 7.86 (m, 2H), 7.70 (d, J = 8.0 Hz, 3H), 7.10 (s, 1H); 19 F NMR (376 MHz, DMSO-d6) δ -76.69; 13 C NMR (101 MHz, DMSO-d6) δ 141.2, 132.2, 128.6, 124.7 (q, J = 283.1 Hz), 118.5, 111.8, 70.4 - 68.8 (m); HRMS (ESI) m / z [M+Na] +Calculated for C9H5DF3NONa + 225.0362, found 225.0365.

[0109] Using a method similar to Experiment 1 and the carbonyl reductase DrADH, the target compound 4-(2,2,2-trifluoro-1-hydroxyethyl-1-d)benzonitrile (I-5(S)) was obtained. 99% conv., >99% ee, 98% D; [α] D 20 = 33.2 (c 0.4, MeOH); HPLC [Daicel Chirapak OJ-H, n-Hex∶i-PrOH = 90∶10, 1 mL / min, 210 nm UV detector, t R = 15.763 min (minor) and t S = 18.055 min (major)]; 1 1H NMR (400 MHz, DMSO-d6) δ 7.92 - 7.86 (m, 3H), 7.70 (d, J = 8.1 Hz, 3H), 7.10 (s, 1H).

[0110] Example 6: 1-([1,1′-Biphenyl]-4-yl)-2,2,2-trifluoroethane-1-d-1-ol

[0111]

[0112] Using a method similar to Experiment 1 and the carbonyl reductase AaADH, the target compound 1-([1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethane-1-d-1-ol (I-6(R)) was obtained. White solid: M.p.: 122 - 124 °C; R f = 0.26 (PE / EtOAc = 10∶1), purified by column chromatography on silica gel (PE / EtOAc = 10∶1); 96% conv., >99% ee, 98% D; [α] D 20 = -26.2 (c 1.0, CHCl3); HPLC [Daicel Chirapak OJ-H, n-Hex∶i-PrOH = 90∶10, 1 mL / min, 254 nm UV detector, t R = 20.041 min (major) and t S = 26.155 min (minor)]; 11H NMR (400 MHz, CDCl3) δ 7.59 (dd, J = 14.7, 7.8 Hz, 4H), 7.51 (d, J = 8.1 Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 2.73 (s, 1H); 19 19F NMR (376 MHz, CDCl3) 19 19F NMR (376 MHz, CDCl3) δ -78.23; 13 13C NMR (101 MHz, CDCl3) δ 142.7, 140.5, 132.9, 129.0, 128.0, 127.8, 127.5, 127.3, 124.4 (q, J = 282.1 Hz), 72.9 - 72.0 (m); HRMS (ESI) m / z [M+H] + calcd for C 14 H 11 DF3O + 254.0903, found 254.0905.

[0113] Using a method similar to that of Experiment 1 and the carbonyl reductase DrADH, the target compound 1-([1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethane-1-d-1-ol (I-6(S)) was obtained. 96% conv., >99% ee, 98% D; [α] D 20 = 26.4 (c 1.0, CHCl3); HPLC [Daicel Chirapak OJ-H, n-Hex∶i-PrOH = 90∶10, 1 mL / min, 254 nm UV detector, t R = 20.824 min (minor) and t S = 25.315 min (major)]; 1 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, J = 14.6, 7.8 Hz, 4H), 7.51 (d, J = 8.1 Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 2.74 (s, 1H).

[0114] Example 7: (E)-1,1,1-Trifluoro-4-phenylbut-3-en-2-d-2-ol

[0115]

[0116] Using a method similar to Experiment 1 and the carbonyl reductase AaADH, the target compound (R,E)-1,1,1-trifluoro-4-phenylbut-3-en-2-d-2-ol (I-7(R)) was obtained. 96% conv., >99% ee, 98% D; [α] D 20 = -10.4 (c 0.8, CHCl3); HPLC [Daicel Chirapak OJ-H, n-Hex∶i-PrOH = 95∶5, 1 mL / min, 254 nm UV detector, t R = 15.240 min (major) and t S = 18.462 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 6.8 Hz, 3H), 7.31 (q, J = 7.9, 7.1 Hz, 5H), 6.81 (d, J = 16.0 Hz, 1H), 6.17 (d, J = 16.0 Hz, 1H), 2.84 (s, 1H); 19 19F NMR (376 MHz, CDCl3) δ -78.99; 13 13C NMR (101 MHz, CDCl3) δ 136.6, 135.4, 128.9, 128.9, 127.0, 124.4 (q, J = 281.9 Hz), 120.6 (d, J = 1.9 Hz), 72.2 - 70.6 (m); HRMS (ESI) m / z [M+H] + calcd for C 10 H9DF3O + 204.0746, found 204.0747.

[0117] Using a method similar to Experiment 1 and the carbonyl reductase DrADH, the target compound (S,E)-1,1,1-trifluoro-4-phenylbut-3-en-2-d-2-ol (I-7(S)) was obtained. 99% conv., >99% ee, 98% D; [α] D 20 = 10.2 (c 1.0, CHCl3); HPLC [Daicel Chirapak OJ-H, n-Hex∶i-PrOH = 95∶5, 1 mL / min, 254 nm UV detector, t R = 15.264 min (minor) and t S = 18.287 min (major)]; 11H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 7.0 Hz, 3H), 7.31 (q, J = 7.8, 7.1 Hz, 4H), 6.80 (d, J = 16.0 Hz, 1H), 6.16 (d, J = 16.0 Hz, 1H), 2.89 (s, 1H).

[0118] Example 8: (E)-1,1,1-Trifluoro-4-(4-methoxyphenyl)but-3-en-2-d-2-ol

[0119]

[0120] Using a method similar to that of Experiment 1 and carbonyl reductase AaADH, the target compound (R,E)-1,1,1-trifluoro-4-(4-methoxyphenyl)but-3-en-2-d-2-ol (I-8(R)) was obtained. 99% conv., >99% ee, 98% D; [α] D 20 = -24.4 (c 1.0, CHCl3); HPLC [Daicel Chirapak OJ-H, n-Hex∶i-PrOH = 80∶20, 1 mL / min, 254 nm UV detector, t R = 10.834 min (major) and t S = 14.208 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 7.36 - 7.30 (m, 2H), 6.89 - 6.84 (m, 2H), 6.76 (d, J = 15.9 Hz, 1H), 6.04 (d, J = 15.9 Hz, 1H), 3.81 (s, 3H), 2.59 (s, 1H); 19 19F NMR (376 MHz, CDCl3) δ -79.12; 13 13C NMR (101 MHz, CDCl3) δ 160.1, 136.2, 128.3, 128.3, 124.5 (q, J = 281.9 Hz), 118.4 (d, J = 1.9 Hz), 114.3, 72.4 - 70.8 (m), 55.4; HRMS (ESI) m / z [M+H] + calcd for C 11 H 11 DF3O2 + 234.0847, found 234.0844.

[0121] Using a method similar to that in Experiment 1 and the carbonyl reductase DrADH, the target compound (S,E)-1,1,1-trifluoro-4-(4-methoxyphenyl)but-3-en-2-d-2-ol (I-8(S)) was obtained. 99% conv., >99% ee, 98% D; [α] D 20 = 23.8 (c 1.0, CHCl3); HPLC [Daicel Chirapak OJ-H, n-Hex∶i-PrOH = 80∶20, 1 mL / min, 254 nm UV detector, t R = 10.874 min (minor) and t S = 14.092 min (major)]; 1 1H NMR (400 MHz, CDCl3) δ 7.37 - 7.30 (m, 2H), 6.89 - 6.83 (m, 2H), 6.76 (d, J = 15.9 Hz, 1H), 6.04 (d, J = 15.9 Hz, 1H), 3.81 (s, 3H), 2.59 (s, 1H).

[0122] Example 9: (E)-1,1,1-trifluoro-4-(4-fluorophenyl)but-3-en-2-d-2-ol

[0123]

[0124] Using a method similar to that in Experiment 1 and the carbonyl reductase AaADH, the target compound (R,E)-1,1,1-trifluoro-4-(4-fluorophenyl)but-3-en-2-d-2-ol (I-9(R)) was obtained. 99% conv., >99% ee, 98% D; [α] D 20 = -7.0 (c 1.0, CHCl3); HPLC [Daicel Chirapak OJ-H, n-Hex∶i-PrOH = 95∶5, 1 mL / min, 254 nm UV detector, t R = 15.352 min (major) and t S = 17.307 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 8.6, 5.4 Hz, 2H), 7.01 (t, J = 8.6 Hz, 2H), 6.78 (d, J = 16.0 Hz, 1H), 6.09 (d, J = 16.0 Hz, 1H), 3.03 (s, 1H); 1919F NMR (376 MHz, CDCl3) δ -79.07, -112.50--112.60 (m); 13 13C NMR (101 MHz, CDCl3) δ 163.1 (d, J = 248.5 Hz), 135.4, 131.7 (d, J = 3.4 Hz), 128.7 (d, J = 8.2 Hz), 124.4 (q, J = 281.9 Hz), 120.4 (t, J = 2.0 Hz), 115.8 (d, J = 21.7 Hz), 72.1-70.5 (m); HRMS (ESI) m / z + calcd for C 10 H7DF4ONa + 244.0471, found 244.0470.

[0125] Using a method similar to that of Experiment 1 and the carbonyl reductase DrADH, the target compound (S, E)-1,1,1-trifluoro-4-(4-fluorophenyl)but-3-en-2-d-2-ol (I-9(S)) was obtained. 99% conv., >99% ee, 98% D; [α] D 20 = 6.0 (c 1.0, CHCl3); HPLC [Daicel Chirapak OJ-H, n-Hex∶i-PrOH = 95∶5, 1 mL / min, 254 nm UV detector, t R = 15.436 min (minor) and t S = 17.164 min (major)]; 1 1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 8.6, 5.4 Hz, 2H), 7.01 (t, J = 8.6 Hz, 2H), 6.78 (d, J = 16.0 Hz, 1H), 6.09 (d, J = 16.0 Hz, 1H), 3.04 (s, 1H).

[0126] Example 10: 3-(3-chlorophenyl)-1,1,1-trifluoropropan-2-d-2-ol

[0127]

[0128] Using a method similar to that of Experiment 1 and the carbonyl reductase AaADH, the target compound (R)-3-(3-chlorophenyl)-1,1,1-trifluoropropan-2-d-2-ol (I-10(R)) was obtained. 99% conv., >99% ee, 96% D; [α] D 20= 41.8 (c 0.8, CHCl3); HPLC [Daicel Chirapak IB, n-Hex∶i-PrOH = 95∶5, 0.8 mL / min, 210 nm UV detector, t R = 7.585 min (major) and t S = 10.733 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 5.0 Hz, 3H), 7.18 - 7.12 (m, 1H), 3.01 (d, J = 14.3 Hz, 1H), 2.83 (d, J = 14.3 Hz, 1H), 2.17 (s, 1H); 19 19F NMR (376 MHz, CDCl3) δ -79.75; 13 13C NMR (101 MHz, CDCl3) δ 138.0, 134.7, 130.1, 129.7, 127.8, 127.6, 124.9 (q, J = 282.1 Hz), 71.8 - 70.3 (m), 35.8 (q, J = 1.9 Hz); HRMS (ESI) m / z [M+K] + calcd for C9H7DClF3OK + 263.9915, found 263.9907.

[0129] Using a method similar to that in Experiment 1 and the carbonyl reductase DrADH, the target compound (S)-3-(3-chlorophenyl)-1,1,1-trifluoropropan-2-d-2-ol (I-10(S)) was obtained. 99% conv., >99% ee, 96% D; [α] D 20 = -42.8 (c 1.0, CHCl3); HPLC [Daicel Chirapak IB, n-Hex∶i-PrOH = 95∶5, 0.8 mL / min, 210 nm UV detector, t R = 7.601 min (minor) and t S = 10.867 min (major)]; 1 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 4.4 Hz, 3H), 7.17 - 7.11 (m, 1H), 3.00 (d, J = 14.3 Hz, 1H), 2.81 (d, J = 14.3 Hz, 1H), 2.24 (s, 1H).

[0130] Example 11: 1,1,1-Trifluoro-4-(p-tolyl)butan-2-d-2-ol

[0131]

[0132] Using a method similar to that of Experiment 1 and the carbonyl reductase AaADH, the target compound 1,1,1-trifluoro-4-(p-tolyl)butan-2-d-2-ol (I-11(R)) was obtained. 99% conv., >99% ee, 98% D; [α] D 20 = 37.8 (c 1.0, CHCl3); HPLC [Daicel Chirapak IB, n-Hex∶i-PrOH = 97∶3, 1 mL / min, 210 nm UV detector, t S = 11.371 min (minor) and t R = 12.013 min (major)]; 1 H NMR (400 MHz, CDCl3) δ 7.14 - 7.06 (m, 4H), 2.91 - 2.81 (m, 1H), 2.74 - 2.64 (m, 1H), 2.32 (s, 3H), 2.22 (s, 1H), 2.03 - 1.85 (m, 2H); 19 FNMR (376 MHz, CDCl3) δ -79.93; 13 C NMR (101 MHz, CDCl3) δ 137.4, 136.0, 129.5, 128.5, 125.4 (q, J = 281.8 Hz), 70.1 - 68.6 (m), 31.1, 30.5, 21.1; HRMS (ESI) m / z [M+Na] + calcd for C 11 H 12 DF3ONa + 242.0879, found 242.0881.

[0133] Using a method similar to that of Experiment 1 and the carbonyl reductase DrADH, the target compound 1,1,1-trifluoro-4-(p-tolyl)butan-2-d-2-ol (I-11(S)) was obtained. 99% conv., >99% ee, 98% D; [α] D 20 = -35.8 (c 1.0, CHCl3); HPLC [Daicel Chirapak IB, n-Hex∶i-PrOH = 97∶3, 1 mL / min, 210 nm UV detector, t S = 11.357 min (major) and t R= 12.005 min (minor)); 1 1H NMR (400 MHz, CDCl3) δ 7.15 - 7.05 (m, 4H), 2.91 - 2.80 (m, 1H), 2.74 - 2.63 (m, 1H), 2.32 (s, 3H), 2.25 (s, 1H), 2.03 - 1.84 (m, 2H).

[0134] Example 12: 2,2 - Difluoro - 1 - (p - tolyl)ethan - 1 - d - 1 - ol

[0135]

[0136] Using a method similar to Experiment 1, with the carbonyl reductase AaADH, the target compound 2,2 - difluoro - 1 - (p - tolyl)ethan - 1 - d - 1 - ol (I - 12(R)) was obtained. 99% conv.; >99% ee; 99% D; [α] D 20 = - 21.0 (c 1.0, CHCl3); HPLC [Daicel Chirapak OJ - H, n - hexane∶iso - propanol = 95∶5, 1.0 mL / min, 210 nm UV detector, t R = 26.072 min (major) and t S = 29.064 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 5.74 (t, J = 56.0 Hz, 1H), 2.43 (s, 1H), 2.36 (s, 3H); 19 19F NMR (376 MHz, CDCl3) δ - 127.59 (dd, J = 55.9, 4.7 Hz); 13 13C NMR (151 MHz, CDCl3) δ 139.0, 133.0 (t, J = 3.3 Hz), 129.4, 127.1, 115.9 (t, J = 245.2 Hz), 73.6 - 72.6 (m), 21.2; HRMS (ESI) m / z [M + H] + calcd for C9H 10 DF2O + 174.0840, found 174.0845.

[0137] Using a method similar to that in Experiment 1 and the carbonyl reductase DrADH, the target compound 2,2-difluoro-1-(p-tolyl)ethan-1-d-1-ol (I-12(S)) was obtained. 99% conv.; >99% ee; 99% D; [α] D 20 = 21.4 (c 1.0, CHCl3); HPLC [Daicel Chirapak OJ-H, n-hexane∶iso-propanol = 95∶5, 1.0 mL / min, t R = 26.092 min (minor) and t S = 28.416 min (major)]; 1 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 5.74 (t, J = 56.0 Hz, 1H), 2.43 (s, 1H), 2.36 (s, 3H); 19 19F NMR (376 MHz, CDCl3) δ -127.59 (dd, J = 55.9, 4.7 Hz).

[0138] Example 13: 2,2-Difluoro-1-(4-methoxyphenyl)ethan-1-d-1-ol

[0139]

[0140] Using a method similar to that in Experiment 1 and the carbonyl reductase AaADH, the target compound 2,2-difluoro-1-(4-methoxyphenyl)ethan-1-d-1-ol (I-13(R)) was obtained. 99% conv., >99% ee, 99% D; [α] D 25 = -21.6 (c 1.1, CH2Cl2); HPLC [Daicel Chirapak IC, n-hexane∶iso-propanol = 98∶2, 1.0 mL / min, 220 nm UV detector, t R = 15.205 min (major)]; 1 1H NMR (500 MHz, CDCl3) δ 7.35 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 5.75 (t, J = 56.1 Hz, 1H), 3.82 (s, 3H), 2.32 (s, 1H); 19 19F NMR (470 MHz, CDCl3) δ -127.62 (d, J = 55.5 Hz); 1313C NMR (126 MHz, CDCl3) δ 160.6, 129.0, 128.6 (t, J = 3.2 Hz), 116.4 (t, J = 245.0 Hz), 114.6, 74.8 - 70.5 (m), 55.8; HRMS (ESI) m / z [M+Na] + calcd for C9H9DF2O2Na + 212.0609, found 212.0605

[0141] Using a method similar to that of Experiment 1, the target compound 2,2-difluoro-1-(4-methoxyphenyl)ethan-1-d-1-ol (I-13(S)) was obtained by using carbonyl reductase DrADH. 99% conv., >99% ee, 98% D. D 25 α = 18.1 (c 0.8, CH2Cl2); HPLC [Daicel Chirapak IC, n-hexane∶iso-propanol = 98∶2, 1.0 mL / min, 220 nm UV detector, t S = 19.266 min (major); 1 1H NMR (500 MHz, CDCl3) δ 7.34 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 5.74 (t, J = 56.1 Hz, 1H), 3.82 (s, 3H), 2.42 (s, 1H); 19 19F NMR (470 MHz, CDCl3) δ -127.69 (dd, J = 55.9, 5.6 Hz).

[0142] Example 14: 1-(4-Chlorophenyl)-2,2-difluoroethan-1-d-1-ol

[0143]

[0144] Using a method similar to that of Experiment 1, the target compound 1-(4-chlorophenyl)-2,2-difluoroethan-1-d-1-ol (I-14(R)) was obtained by using carbonyl reductase AaADH. 99% conv., >99% ee, 99% D; α D 25 = -26.9 (c 0.7, CH2Cl2); HPLC [Daicel Chirapak OJ-H, n-hexane∶iso-propanol = 98∶2, 1.0 mL / min, 220 nm UV detector, t R = 56.560 min (major);1 1H NMR (500 MHz, CDCl3) δ 7.42 - 7.34 (m, 4H), 5.73 (t, J = 55.8 Hz, 1H), 2.55 (s, 1H); 19 19F NMR (470 MHz, CDCl3) δ -127.76 (dd, J = 55.7, 18.4 Hz); 13 13C NMR (126 MHz, CDCl3) δ 135.6, 134.7, 129.5, 129.0, 116.1 (t, J = 245.7 Hz), 75.0 - 69.9 (m); HRMS (ESI) m / z [M+H] + calcd for C8H7DClF2O + 194.0295, found 194.0290.

[0145] Using a method similar to that of Experiment 1 and the carbonyl reductase DrADH, the target compound 1-(4-chlorophenyl)-2,2-difluoroethan-1-d-1-ol (I-14(S)) was obtained. 99% conv., >99% ee, 98% D; [α] D 25 = 25.3 (c 1.1, CH2Cl2); HPLC [Daicel Chirapak IC, n-hexane∶iso-propanol = 98∶2, 1.0 mL / min, 220 nm UV detector, t S = 59.465 min (major)]; 1 1H NMR (500 MHz, CDCl3) δ 7.38 (d, J = 2.3 Hz, 4H), 5.73 (t, J = 55.9 Hz, 1H), 2.48 (s, 1H); 19 19F NMR (470 MHz, CDCl3) δ -127.76 (dd, J = 56.1, 24.2 Hz).

[0146] Example 15: 2,2-Difluoro-1-(4-nitrophenyl)ethan-1-d-1-ol

[0147]

[0148] Using a method similar to that of Experiment 1 and the carbonyl reductase AaADH, the target compound 2,2-difluoro-1-(4-nitrophenyl)ethan-1-d-1-ol (I-15(R)) was obtained. 99% conv., 99% ee, 97% D; [α] D 25= -32.6 (c 0.8, CH2Cl2); HPLC [Daicel Chirapak IC, n - hexane∶iso - propanol = 95∶5, 0.7 mL / min, 220 nm UV detector, t R = 14.641 min (major) and t S = 15.409 min (minor)]; 1 1H NMR (500 MHz, CDCl3) δ 9.06 - 7.95 (m, 2H), 7.64 (dd, J = 8.7, 2.1 Hz, 2H), 5.77 (t, J = 55.6 Hz, 1H), 2.86 (s, 1H); 19 19F NMR (470 MHz, CDCl3) δ - 124.38--129.40 (m); 13 13C NMR (126 MHz, CDCl3) δ 147.3, 141.4 (d, J = 4.1 Hz), 127.1, 122.7, 114.1 (t, J = 246.5 Hz), 74.1 - 66.2 (m); HRMS (ESI) m / z [M + Na] + calcd for C8H6D F2NO3Na + 227.0354, found 227.0354.

[0149] Using a method similar to that in Experiment 1, with carbonyl reductase DrADH, the target compound 2,2 - difluoro - 1 - (4 - nitrophenyl)ethan - 1 - d - 1 - ol (I - 15(S)) was obtained. 99% conv., 99% ee, 98% D; [α] D 25 = 28 (c 0.9, CH2Cl2); HPLC [Daicel Chirapak IC, n - hexane∶iso - propanol = 95∶5, 0.7 mL / min, 220 nm UV detector, t R = 14.143 min (minor) and t S = 15.055 min (major)]; 1 1H NMR (500 MHz, CDCl3) δ 8.25 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.9 Hz, 2H), 5.78 (t, J = 55.7 Hz, 1H), 2.83 (s, 1H); 19 19F NMR (470 MHz, CDCl3) δ - 124.76--129.14 (m).

[0150] Example 16: 4-(2,2-difluoro-1-hydroxyethyl-1-d)benzonitrile

[0151]

[0152] Using a method similar to that in Experiment 1 and the carbonyl reductase AaADH, the target compound 4-(2,2-difluoro-1-hydroxyethyl-1-d)benzonitrile (I-16(R)) was obtained. 99% conv., 99% ee, 98% D; [α] D 25 = -26.1 (c 1.0, CH2Cl2); HPLC [Daicel Chirapak IC, n-hexane∶iso-propanol = 97∶3, 1.0 mL / min, 220 nm UV detector, t R = 24.806 min (major) and t S = 27.584 min (minor)]; 1 1H NMR (500 MHz, CDCl3) δ 7.68 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 5.75 (t, J = 55.7 Hz, 1H), 2.98 (s, 1H); 19 19F NMR (470 MHz, CDCl3) δ -123.22--129.71 (m); 13 13C NMR (126 MHz, CDCl3) δ 141.7 (dd, J = 4.1, 1.9 Hz), 132.8, 128.5, 119.0, 115.7 (t, J = 246.3 Hz), 112.9, 74.5-71.5 (m); HRMS (ESI) m / z [M+H] + calcd for C9H8DF2NO + 185.0637, found 185.0633.

[0153] Using a method similar to that in Experiment 1 and the carbonyl reductase DrADH, the target compound 4-(2,2-difluoro-1-hydroxyethyl-1-d)benzonitrile (I-16(S)) was obtained. 99% conv., >99% ee, 98% D; [α] D 25 = 26.0 (c 0.9, CH2Cl2); HPLC [Daicel Chirapak IC, n-hexane∶iso-propanol = 95∶5, 0.5 mL / min, 220 nm UV detector, t S = 26.094 min (major)]; 11H NMR (500 MHz, CDCl3) δ 7.77 - 7.61 (m, 2H), 7.57 (d, J = 8.2 Hz, 2H), 5.76 (t, J = 55.7 Hz, 1H), 3.18 (s, 1H); 19 19F NMR (470 MHz, CDCl3) δ -126.00--128.84 (m).

[0154] Example 17: 1-([1,1'-Biphenyl]-4-yl)-2,2-difluoroethan-1-d-1-ol

[0155]

[0156] Using a method similar to Experiment 1 and the carbonyl reductase AaADH, the target compound 1-([1,1'-biphenyl]-4-yl)-2,2-difluoroethan-1-d-1-ol (I-17(R)) was obtained. 99% conv., >99% ee, 97% D; [α] D 20 = -14.3 (c 1.5, CH2Cl2); HPLC [Daicel Chirapak IC, n-hexane∶iso-propanol = 95∶5, 0.5 mL / min, 220 nm UV detector, t R = 7.483 min (major) and t S = 8.267 min (minor)]; 1 1H NMR (500 MHz, CDCl3) δ 7.74 - 7.58 (m, 4H), 7.56 - 7.45 (m, 4H), 7.44 - 7.36 (m, 1H), 5.83 (t, J = 55.9 Hz, 1H), 2.61 (s, 1H); 19 19F NMR (470 MHz, CDCl3) δ -127.54 (dd, J = 55.8, 15.5 Hz); 13 13C NMR (126 MHz, CDCl3) δ 142.5, 141.0, 135.3 (t, J = 3.3 Hz), 129.4, 128.2, 128.1, 128.0, 127.7, 116.3 (t, J = 245.5 Hz), 73.6 (dt, J = 46.3, 23.6 Hz); HRMS (ESI) m / z [M+H] + calcd for C 14 H 12 DF2O + 236.0997, found 236.0994.

[0157] Using a method similar to Experiment 1 and the carbonyl reductase DrADH, the target compound 1-([1,1′-biphenyl]-4-yl)-2,2-difluoroethan-1-d-1-ol (I-17(S)) was obtained. 99% conv., >99% ee, 98% D; [α] D 20 = 15 (c 1.4, CH2Cl2); HPLC [Daicel Chirapak IC, n-hexane∶iso-propanol = 95∶5, 0.5 mL / min, 220 nm UV detector, t R = 7.265 min (minor) and t S = 8.393 min (major)]; 1 1H NMR (500 MHz, CDCl3) δ 8.26 - 7.57 (m, 4H), 7.49 (dd, J = 20.0, 8.1 Hz, 4H), 7.43 - 7.35 (m, 1H), 5.83 (t, J = 55.9 Hz, 1H), 2.61 (s, 1H); 19 19F NMR (470 MHz, CDCl3) δ -127.54 (dd, J = 56.1, 14.9 Hz).

[0158] Example 18: 2,2-Difluoro-1-(pyridin-3-yl)ethan-1-d-1-ol

[0159]

[0160] Using a method similar to Experiment 1 and the carbonyl reductase AaADH, the target compound 2,2-difluoro-1-(pyridin-3-yl)ethan-1-d-1-ol (I-18(R)) was obtained. 99% conv., >99% ee, 98% D; [α] D 20 = -21.3 (c 0.7, CHCl3); HPLC [Daicel Chirapak IC, n-hexane∶iso-propanol = 95∶5, 1.0 mL / min, 220 nm UV detector, t R = 29.317 min (major)]; 1 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J = 2.2 Hz, 1H), 8.39 (dd, J = 5.0, 1.7 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.52 (s, 1H), 7.31 (ddd, J = 8.1, 5.0, 0.9 Hz, 1H), 5.77 (t, J = 55.8 Hz, 1H); 1919F NMR (470 MHz, CDCl3) δ -124.43--129.73 (m); 13 13C NMR (126 MHz, CDCl3) δ 148.4, 147.6, 136.4, 134.5 - 131.3 (m), 124.0, 115.6 (t, J = 245.9 Hz), 70.4 (dt, J = 46.5, 24.0 Hz); HRMS (ESI) m / z + calcd for C9H8DF2NO + 161.0637, found 161.0637.

[0161] Using a method similar to that of Experiment 1 and the carbonyl reductase DrADH, the target compound 2,2-difluoro-1-(pyridin-3-yl)ethan-1-d-1-ol (I-18(S)) was obtained. 99% conv., >99% ee, 97% D; [α] D 20 = 19.1 (c 0.9, CHCl3); HPLC [Daicel Chirapak IC, n-hexane∶iso-propanol = 95∶5, 1.0 mL / min, 220 nm UV detector, t S = 27.345 min (major)]; 1 1H NMR (500 MHz, CDCl3) δ 8.88 - 8.37 (m, 2H), 7.81 (d, J = 8.0 Hz, 1H), 7.32 (dd, J = 7.9, 4.8 Hz, 1H), 5.78 (t, J = 55.8 Hz, 1H), 2.59 (s, 1H); 19 19F NMR (470 MHz, CDCl3) δ -125.11--129.61 (m).

[0162] Example 19: 2,2-Difluoro-1-(thiophen-2-yl)ethan-1-d-1-ol

[0163]

[0164] Using a method similar to that of Experiment 1 and the carbonyl reductase AaADH, the target compound 2,2-difluoro-1-(thiophen-2-yl)ethan-1-d-1-ol (I-19(R)) was obtained. 99% conv.; >99% ee; 99% D; [α] D 20= -12.2 (c 0.5, CHCl3); HPLC [Daicel Chirapak OJ-H, n-hexane∶iso-propanol = 90∶10, 1.0 mL / min, 210 nm UV detector, t R = 16.930 min (major) and t S = 20.497 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 7.37 (dd, J = 5.0, 1.2 Hz, 1H), 7.14 (d, J = 3.3 Hz, 1H), 7.04 (dd, J = 5.1, 3.6 Hz, 1H), 5.82 (t, J = 55.8 Hz, 1H), 2.60 (s, 1H); 13 13C NMR (101 MHz, CDCl3) δ 138.3 (t, J = 3.5 Hz), 127.2, 126.7, 126.6, 115.1 (t, J = 245.9 Hz), 70.2 - 69.1 (m); 19 19F NMR (376 MHz, CDCl3) δ -127.50 (dd, J = 55.8, 11.8 Hz); HRMS (ESI) m / z [M+H] + calcd for C6H6DF2OS + 166.0248, found 166.0253.

[0165] Using a method similar to that in Experiment 1, the target compound 2,2-difluoro-1-(thiophen-2-yl)ethan-1-d-1-ol (I-19(S)) was obtained using the carbonyl reductase DrADH. 99% conv.; >99% ee; 98% D; [α] D 20 = 8.3 (c 0.4, CHCl3); HPLC [Daicel Chirapak OJ-H, n-hexane∶iso-propanol = 90∶10, 1.0 mL / min, 210 nm UV detector, t R = 16.875 min (minor) and t S = 19.955 min (major)]; 1 1H NMR (400 MHz, CDCl3) δ 7.37 (dd, J = 5.1, 1.2 Hz, 1H), 7.14 (d, J = 3.0 Hz, 1H), 7.05 (dd, J = 5.1, 3.6 Hz, 1H), 5.82 (t, J = 55.8 Hz, 1H), 2.58 (s, 1H).

[0166] Example 20: 1,1-difluoro-4-phenylbutan-2-d-2-ol

[0167]

[0168] Using a method similar to that in Experiment 1 and the carbonyl reductase AaADH, the target compound 1,1-difluoro-4-phenylbutan-2-d-2-ol (I-20(R)) was obtained. 99% conv., 99% ee, 97% D; [α] D 20 = 36.1 (c 1.4, CH2Cl2); HPLC [Daicel Chirapak IC, n-hexane∶iso-propanol = 95∶5, 0.8 mL / min, 220 nm UV detector, t R = 16.210 min (major) and t S = 18.792 min (minor)]; 1 H NMR (500 MHz, CDCl3) δ 7.36 - 7.24 (m, 2H), 7.20 (dt, J = 6.4, 1.5 Hz, 3H), 5.59 (t, J = 56.1 Hz, 1H), 2.87 (ddd, J = 14.3, 9.3, 5.3 Hz, 1H), 2.72 (ddd, J = 13.9, 9.0, 7.5 Hz, 1H), 2.21 (s, 1H), 2.00 - 1.74 (m, 2H); 19 F NMR (470 MHz, CDCl3) δ -129.62 (d, J = 55.8 Hz); 13 C NMR (126 MHz, CDCl3) δ 139.9, 127.5, 127.4, 125.1, 115.3 (t, J = 243.6 Hz), 70.4 - 65.2 (m), 30.3 (t, J = 3.2 Hz), 29.8; HRMS (ESI) m / z [M+Na]+ calcd for C 10 H 11 DF2ONa + 210.0817, found 210.0811.

[0169] Using a method similar to that in Experiment 1 and the carbonyl reductase AaADH, the target compound 1,1-difluoro-4-phenylbutan-2-d-2-ol (I-20(S)) was obtained. 99% conv., >99% ee, 97% D; [α] D 20= -36.7 (c 1.5, CH2Cl2); HPLC [Daicel Chirapak IC, n - hexane∶iso - propanol = 95∶5, 0.8 mL / min, 220 nm UV detector, t R = 16.046 min (minor) and t S = 18.575 min (major)]; 1 1H NMR (500 MHz, CDCl3) δ 7.34 - 7.23 (m, 2H), 7.20 (dt, J = 7.4, 2.4 Hz, 3H), 5.58 (t, J = 56.0 Hz, 1H), 2.87 (ddd, J = 14.3, 9.3, 5.3 Hz, 1H), 2.71 (ddd, J = 13.9, 9.1, 7.6 Hz, 1H), 2.24 (s, 1H), 2.06 - 1.72 (m, 2H); 19 19F NMR (470 MHz, CDCl3) δ -129.60 (d, J = 55.8 Hz).

[0170] Example 21: 2 - fluoro - 1 - (p - tolyl)ethan - 1 - d - 1 - ol

[0171]

[0172] Using a method similar to Experiment 1 and the carbonyl reductase AaADH, the target compound 2 - fluoro - 1 - (p - tolyl)ethan - 1 - d - 1 - ol (I - 21(R)) was obtained. 99% conv., 98% ee, 97% D; [α] D 25 = -45.5 (c 1.8, CH2Cl2); HPLC [Daicel Chirapak IC, n - hexane∶iso - propanol = 95∶5, 1.0 mL / min, 220 nm UV detector, t R = 11.034 min (major) and t S = 12.041 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 7.8 Hz, 2H), 4.77 - 4.29 (m, 2H), 2.64 (s, 1H), 2.38 (s, 3H); 19 19F NMR (376 MHz, CDCl3) δ -220.50 (t, J = 47.7 Hz); 1313C NMR (101 MHz, CDCl3) δ 138.2, 135.4 (d, J = 8.1 Hz), 129.3, 126.3, 87.1 (d, J = 174.4 Hz), 73.8 - 67.6 (m), 21.1; HRMS (ESI) m / z [M+H] + calcd for C9H 11 DFO + 156.0935, found 156.0940

[0173] Using a method similar to that of Experiment 1 and the carbonyl reductase DrADH, the target compound 2-fluoro-1-(p-tolyl)ethan-1-d-1-ol (I-21(S)) was obtained. 99% conv., 99% ee, 99% D; [α] D 25 = 49.2 (c 1.0, CH2Cl2); HPLC [Daicel Chirapak IC, n-hexane∶iso-propanol = 95∶5, 1.0 mL / min, 220 nm UV detector, t R = 11.112 min (minor) and t S = 12.264 min (major)]; 1 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 4.67 - 4.31 (m, 2H), 2.56 (s, 1H), 2.38 (s, 3H); 19 19F NMR (376 MHz, CDCl3) δ -220.53 (t, J = 47.7 Hz).

[0174] Example 22: 2-Fluoro-1-(4-methoxyphenyl)ethan-1-d-1-ol

[0175]

[0176] Using a method similar to that of Experiment 1 and the carbonyl reductase AaADH, the target compound 2-fluoro-1-(4-methoxyphenyl)ethan-1-d-1-ol (I-22(R)) was obtained. 99% conv., 99% ee, 99% D; [α] D 25 = -53.3 (c 4.1, CH2Cl2); HPLC [Daicel Chirapak IC, n-hexane∶iso-propanol = 95∶5, 1.0 mL / min, 220 nm UV detector, t R= 17.877 min (major) and t S = 18.978 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 4.66 - 4.17 (m, 2H), 3.80 (s, 3H), 2.73 (s, 1H); 19 19F NMR (376 MHz, CDCl3) δ -220.21 (t, J = 47.7 Hz); 13 13C NMR (101 MHz, CDCl3) δ 159.7, 130.6, 127.7, 114.1, 87.1 (d, J = 174.7 Hz), 72.1 (q, J = 21.4 Hz), 55.4; HRMS (ESI) m / z [M+H] + calcd for C9H 11 DFO2 + 172.0884, found 172.0895.

[0177] Using a method similar to that in Experiment 1 and the carbonyl reductase DrADH, the target compound 2-fluoro-1-(4-methoxyphenyl)ethan-1-d-1-ol (I-22(S)) was obtained. 99% conv., 99% ee, 99% D; [α] D 25 = 50.5 (c 2.1, CH2Cl2); HPLC [Daicel Chirapak IC, n-hexane∶iso-propanol = 95∶5, 0.5 mL / min, 220 nm UV detector, t R = 17.876 min (minor) and t S = 19.604 min (major)]; 1 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 4.71 - 4.23 (m, 2H), 3.80 (s, 3H), 2.57 (s, 1H); 19 19F NMR (376 MHz, CDCl3) δ -220.25 (t, J = 47.8 Hz).

[0178] Example 23: 1-(4-Chlorophenyl)-2-fluoroethan-1-d-1-ol

[0179]

[0180] Using a method similar to that of Experiment 1 and employing carbonyl reductase AaADH, the target compound 1-(4-chlorophenyl)-2-fluoroethan-1-d-1-ol (I-23(R)) was obtained. 99% conv., 99% ee, 98% D; [α] D 25 = -41.6 (c 4.2, CH2Cl2); HPLC [Daicel Chirapak IC, n-hexane∶iso-propanol = 99∶1, 1.0 mL / min, 220 nm UV detector, t R = 14.215 min (major) and t S = 15.755 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 7.32 (q, J = 8.8 Hz, 4H), 4.41 (ddd, J = 47.8, 39.6, 9.6 Hz, 2H), 2.88 (s, 1H); 19 19F NMR (376 MHz, CDCl3) δ -221.26 (t, J = 47.3 Hz); 13 13C NMR (101 MHz, CDCl3) δ 137.2 (d, J = 7.9 Hz), 134.7, 129.3, 128.2, 87.3 (d, J = 174.8 Hz), 74.5 - 70.5 (m); HRMS (ESI) m / z [M+H] + calcd for C8H8DClFO + 176.0388, found 176.0380.

[0181] Using a method similar to that of Experiment 1 and employing carbonyl reductase DrADH, the target compound 1-(4-chlorophenyl)-2-fluoroethan-1-d-1-ol (I-23(S)) was obtained. 99% conv., >99% ee, 99% D; [α] D 25 = 39.9 (c 2.8, CH2Cl2); HPLC [Daicel Chirapak IC, n-hexane∶iso-propanol = 99∶1, 1.0 mL / min, 220 nm UV detector, t R = 13.339 min (minor) and t S = 16.194 min (major)]; 11H NMR (400 MHz, CDCl3) δ 7.39 - 7.29 (m, 4H), 4.42 (ddd, J = 48.3, 40.8, 9.6 Hz, 2H), 2.73 (s, 1H); 19 19F NMR (376 MHz, CDCl3) δ -221.28 (t, J = 47.7 Hz).

[0182] Example 24: 1-(4-Bromophenyl)-2-fluoroethan-1-d-1-ol

[0183]

[0184] Using a method similar to that in Experiment 1 and the carbonyl reductase AaADH, the target compound 1-(4-bromophenyl)-2-fluoroethan-1-d-1-ol (I-24(R)) was obtained. 99% conv., >99% ee, 98% D; [α] D 25 = -35.2 (c 4.2, CH2Cl2); HPLC [Daicel Chirapak ID, n-hexane∶iso-propanol = 99∶1, 1.0 mL / min, 220 nm UV detector, t R = 21.984 min (major); 1 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.5 Hz, 2H), 7.40 - 7.16 (m, 2H), 4.44 (ddd, J = 48.3, 41.8, 9.6 Hz, 2H), 2.71 (s, 1H); 19 19F NMR (376 MHz, CDCl3) δ -221.35 (t, J = 46.7 Hz); 13 13C NMR (101 MHz, CDCl3) δ 137.8 (d, J = 7.8 Hz), 132.2, 128.5, 122.8, 87.2 (d, J = 175.0 Hz), 74.8 - 70.8 (m); HRMS (ESI) m / z [M+Na] + calcd for C8H7DBrFONa + 241.9703, found 241.9712.

[0185] Using a method similar to that in Experiment 1 and the carbonyl reductase DrADH, the target compound 1-(4-bromophenyl)-2-fluoroethan-1-d-1-ol (I-24(S)) was obtained. 99% conv., >99% ee, 99% D; [α] D 25= 32.0 (c 5.9, CH2Cl2); HPLC [Daicel Chirapak ID, n-hexane∶iso-propanol = 99∶1, 1.0 mL / min, 220 nm UV detector, t R = 20.702 min (minor) and t S = 22.314 min (major)]; 1 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 4.43 (ddd, J = 48.2, 40.7, 9.6 Hz, 2H), 2.87 (s, 1H); 19 19F NMR (376 MHz, CDCl3) δ -221.28 (t, J = 47.7 Hz).

[0186] Example 25: 2-Fluoro-1-(4-(trifluoromethyl)phenyl)ethan-1-d-1-ol

[0187]

[0188] Using a method similar to Experiment 1 and the carbonyl reductase AaADH, the target compound 2-fluoro-1-(4-(trifluoromethyl)phenyl)ethan-1-d-1-ol (I-25(R)) was obtained. 99% conv., 98% ee, 98% D; [α] D 25 = -32.5 (c 3.5, CH2Cl2); HPLC [Daicel Chirapak OD-H, n-hexane∶iso-propanol = 99∶1, 1.0 mL / min, 220 nm UV detector, t R = 28.628 min (major) and t S = 31.501 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 4.65 - 4.19 (m, 2H), 2.75 (s, 1H); 19 19F NMR (376 MHz, CDCl3) δ -62.66, -222.10 (t, J = 47.9 Hz); 1313C NMR (101 MHz, CDCl3) δ 142.2 (d, J = 7.6 Hz), 130.6 (q, J = 32.5 Hz), 126.7, 125.6 (q, J = 3.9 Hz), 124.0 (q, J = 272.2 Hz), 86.7 (d, J = 174.9 Hz), 71.9 (td, J = 22.2, 20.1 Hz); HRMS (ESI) m / z [M+H] + calcd for C9H8DF4O + 210.0652, found 210.0652.

[0189] Using a method similar to that of Experiment 1 and the carbonyl reductase DrADH, the target compound 2-fluoro-1-(4-(trifluoromethyl)phenyl)ethan-1-d-1-ol (I-25(S)) was obtained. 99% conv., 99% ee, 98% D; [α] D 25 = 29.5 (c 2.5, CH2Cl2); HPLC [Daicel Chirapak OD-H, n-hexane∶iso-propanol = 99∶1, 1.0 mL / min, 220 nm UV detector, t R = 27.671 min (minor) and t S = 31.117 min (major)]; 1 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 4.73 - 4.24 (m, 2H), 2.82 (s, 1H); 19 19F NMR (376 MHz, CDCl3) δ -62.66, -222.08 (t, J = 46.3 Hz).

[0190] Example 26: 4-(2-Fluoro-1-hydroxyethyl-1-d)benzonitrile

[0191]

[0192] Using a method similar to that of Experiment 1 and the carbonyl reductase AaADH, the target compound 4-(2-fluoro-1-hydroxyethyl-1-d)benzonitrile (I-26(R)) was obtained. 99% conv., 99% ee, 99% D; [α] D 25= -44.9 (c 3.7, CH2Cl2); HPLC [Daicel Chirapak OD-H, n-hexane∶iso-propanol = 95∶5, 1.0 mL / min, 220 nm UV detector, t R = 32.093 min (major) and t S = 34.832 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 4.45 (td, J = 46.6, 9.6 Hz, 2H), 3.02 (s, 1H); 19 19F NMR (376 MHz, CDCl3) δ -222.73 (t, J = 47.3 Hz); 13 13C NMR (101 MHz, CDCl3) δ 143.6 (d, J = 7.4 Hz), 132.4, 127.1, 118.5, 112.2, 86.5 (d, J = 175.5 Hz), 71.8 (dd, J = 43.2, 21.6 Hz);

[0193] Using a method similar to that in Experiment 1, with carbonyl reductase DrADH, the target compound 4-(2-fluoro-1-hydroxyethyl-1-d)benzonitrile (I-26(S)) was obtained. 99% conv., >99% ee, 97% D; [α] D 25 = 49.4 (c 2.7, CH2Cl2); HPLC [Daicel Chirapak OD-H, n-hexane∶iso-propanol = 95∶5, 1.0 mL / min, 220 nm UV detector, t R = 33.425 min (minor) and t S = 34.594 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 4.46 (ddd, J = 49.7, 47.1, 9.6 Hz, 2H), 2.83 (s, 1H); 19 19F NMR (376 MHz, CDCl3) δ -222.72 (t, J = 47.0 Hz).

[0194] Example 27: 2-Fluoro-1-(4-nitrophenyl)ethan-1-d-1-ol

[0195]

[0196] Using a method similar to that in Experiment 1 and the carbonyl reductase AaADH, the target compound 2-fluoro-1-(4-nitrophenyl)ethan-1-d-1-ol (I-27(R)) was obtained. 99% conv., 99% ee, 98% D; [α] D 25 = -21.4 (c 0.7, CH2Cl2); HPLC [Daicel Chirapak OD-H, n-hexane∶iso-propanol = 95∶5, 1.0 mL / min, 220 nm UV detector, t R = 33.980 min (major) and t S = 36.780 min (minor)]; 1 H NMR (500 MHz, CDCl3) δ 8.35 - 8.11 (m, 2H), 7.84 - 7.41 (m, 2H), 4.70 - 4.33 (m, 2H), 2.67 (s, 1H); 19 F NMR (470 MHz, CDCl3) δ -222.87 (t, J = 45.9 Hz); 13 C NMR (101 MHz, CDCl3) δ 148.0, 145.3 (d, J = 7.4 Hz), 127.2, 123.8, 86.5 (d, J = 175.7 Hz), 72.1 (d, J = 20.6 Hz).

[0197] Using a method similar to that in Experiment 1 and the carbonyl reductase DrADH, the target compound 2-fluoro-1-(4-nitrophenyl)ethan-1-d-1-ol (I-27(S)) was obtained. 99% conv., 99% ee, 98% D; [α] D 25 = 16.2 (c 1.7, CH2Cl2); HPLC [Daicel Chirapak OD-H, n-hexane∶iso-propanol = 95∶5, 1.0 mL / min, 220 nm UV detector, t R = 32.906 min (major) and t S = 37.049 min (minor)]; 1 H NMR (500 MHz, CDCl3) δ 8.25 (d, J = 8.9 Hz, 2H), 7.60 (d, J = 8.9 Hz, 2H), 4.65 - 4.29 (m, 2H), 2.64 (s, 1H); 1919F NMR (470 MHz, CDCl3) δ -222.86 (t, J = 46.8 Hz).

[0198] Example 28: 2-Fluoro-1-(thiophen-2-yl)ethan-1-d-1-ol

[0199]

[0200] Using the same method as in Experiment 1 and carbonyl reductase AaADH, the target compound 2-fluoro-1-(thiophen-2-yl)ethan-1-d-1-ol (I-28(R)) was obtained. 90% conv., 97% ee, 98% D; [α] D 25 = -18.4 (c 1.8, CH2Cl2); HPLC [Daicel Chirapak IC, n-hexane∶iso-propanol = 95∶5, 1.0 mL / min, 220 nm UV detector, t S = 10.424 min (major) and t R = 11.391 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 7.31 (dd, J = 5.0, 1.3 Hz, 1H), 7.13 - 6.94 (m, 2H), 4.81 - 4.36 (m, 2H), 2.77 (s, 1H); 19 19F NMR (376 MHz, CDCl3) δ -221.19 (t, J = 47.3 Hz); 13 13C NMR (101 MHz, CDCl3) δ 141.5 (d, J = 8.3 Hz), 127.0, 125.5, 125.0, 86.5 (d, J = 175.2 Hz), 72.7 - 64.0 (m); HRMS (ESI) m / z [M + H] + calcd for C6H7DFOS + 148.0342, found 148.0345.

[0201] Using the same method as in Experiment 1 and carbonyl reductase DrADH, the target compound 2-fluoro-1-(thiophen-2-yl)ethan-1-d-1-ol (I-28(S)) was obtained. 91% conv., 99% ee, 97% D; [α] D 25= 24.6 (c 2.3, CH2Cl2); HPLC [Daicel Chirapak IC, n - hexane∶iso - propanol = 95∶5, 1.0 mL / min, 220 nm UV detector, t S = 10.483 min (minor) and t R = 11.995 min (major)]; 1 1H NMR (400 MHz, CDCl3) δ 7.31 (dd, J = 5.0, 1.3 Hz, 1H), 7.16 - 6.98 (m, 2H), 4.78 - 4.42 (m, 2H), 2.67 (s, 1H); 19 19F NMR (376 MHz, CDCl3) δ - 221.26 (t, J = 45.0 Hz).

[0202] Example 29: 1 - fluoro - 4 - phenylbutan - 2 - d - 2 - ol

[0203]

[0204] Using a method similar to Experiment 1 and the carbonyl reductase AaADH, the target compound 1 - fluoro - 4 - phenylbutan - 2 - d - 2 - ol (I - 29(R)) was obtained. 99% conv., 98% ee, 99% D; [α] D 25 = 20.9 (c 1.7, CH2Cl2); HPLC [Daicel Chirapak OD - H, n - hexane∶iso - propanol = 95∶5, 1.0 mL / min, 220 nm UV detector, t R = 19.464 min (major) and t S = 28.629 min (minor)]; 1 1H NMR (500 MHz, CDCl3) δ 7.39 - 7.30 (m, 2H), 7.24 (d, J = 7.4 Hz, 3H), 4.37 (ddd, J = 52.5, 47.5, 9.4 Hz, 2H), 3.08 - 2.68 (m, 2H), 2.38 (s, 1H), 1.79 (tdd, J = 13.8, 11.3, 7.6 Hz, 2H); 19 19F NMR (470 MHz, CDCl3) δ - 228.16 (t, J = 47.3 Hz); 1313C NMR (101 MHz, CDCl3) δ 141.5, 128.5, 128.5, 126.1, 86.9 (d, J = 168.8 Hz), 71.1 - 66.7 (m), 33.3 (d, J = 6.3 Hz), 31.5.

[0205] Using a method similar to Experiment 1, the target compound 1-fluoro-4-phenylbutan-2-d-2-ol (I-29(S)) was obtained using the carbonyl reductase DrADH. 99% conv., 99% ee, 96% D; [α] D 25 = -22.9 (c 2.4, CH2Cl2); HPLC [Daicel Chirapak OD-H, n-hexane∶iso-propanol = 95∶5, 1.0 mL / min, 220 nm UV detector, t R = 20.042 min (minor) and t S = 28.348 min (major)]; 1 1H NMR (500 MHz, CDCl3) δ 7.36 - 7.22 (m, 2H), 7.18 (d, J = 7.5 Hz, 3H), 4.30 (ddd, J = 49.4, 47.6, 9.6 Hz, 2H), 3.13 - 2.62 (m, 2H), 2.61 - 2.49 (m, 1H), 2.03 - 1.55 (m, 2H); 19 19F NMR (470 MHz, CDCl3) δ -227.97 (t, J = 47.7 Hz).

[0206] Example 30: 2,2,2-trifluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethan-1-d-1-ol

[0207]

[0208] Table 2 Reaction parameters in Example 30

[0209]

[0210] Add a buffer solution (K2HPO4 / KH2PO4, pH = 7.4) to a 250 mL conical flask, add the carbonyl reductase AaADH lysate to the system, and then sequentially add deuterated isopropanol (D- i PrOH), cofactor nicotinamide adenine dinucleotide phosphate (NADP +, 10 mM, 1% mol), co-solvent DMSO (5% v), and the reaction starting material 2,2,2-trifluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethan-1-one were placed in a shaker at 30 °C and reacted with shaking at 220 rpm for 40 h. The mixture was extracted with ethyl acetate (2 × 40 mL), the organic phases were combined and dried over anhydrous MgSO4, and column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 to 2 / 1) gave the target product (R)-2,2,2-trifluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethan-1-d-1-ol (I-30(R)). 73% yield; 97% ee; 98% D; [α] D 20 = -22.6 (c 1.0, CHCl3); HPLC [Daicel Chirapak OD-H, n-Hex∶i-PrOH = 95∶5, 1 mL / min, 254 nm UV detector, t R = 26.307 min (major) and t S = 38.095 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 7.62 - 7.56 (m, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.35 (t, J = 7.9 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.10 (t, J = 2.2 Hz, 1H), 6.90 (dd, J = 8.2, 2.0 Hz, 1H), 3.84 (s, 3H), 2.88 (s, 1H); 19 19F NMR (376 MHz, CDCl3) δ -78.19; 13 13C NMR (101 MHz, CDCl3) δ 160.1, 142.4, 142.0, 133.2, 130.0, 128.0, 127.5, 124.4 (q, J = 282.1 Hz), 119.9, 113.2, 113.1, 73.2 - 71.6 (m), 55.5; HRMS (ESI) m / z [M+H] + calcd for C 15 H 13 DF3O2 + 284.1008, found 284.1016.

[0211] In a 250 mL conical flask, a buffer solution (K2HPO4 / KH2PO4, pH = 7.4) was added, the carbonyl reductase DrADH lysate was added to the system, and then deuterated isopropanol (D- iPrOH), cofactor nicotinamide adenine dinucleotide phosphate (NADP + , 10 mM, 1% mol), cosolvent DMSO (5% v), and reaction starting material 2,2,2-trifluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethan-1-one were placed in a shaker at 30 °C and reacted with shaking at 220 rpm for 40 hours. The mixture was extracted with ethyl acetate (2 × 40 mL), the organic phases were combined and dried over anhydrous MgSO4, and column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) was used to obtain the target product (S)-2,2,2-trifluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethan-1-d-1-ol (I-30(S)). 69% yield; >99% ee; 98% D; [α] D 20 = 22.6 (c 1.0, CHCl3); HPLC [Daicel Chirapak OD-H, n-Hex∶i-PrOH = 95∶5, 1 mL / min, 254 nm UV detector, t R = 26.684 min (minor) and t S = 37.295 min (major)]; 1 1H NMR (400 MHz, CDCl3) δ 7.62 - 7.57 (m, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.35 (t, J = 7.9 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.10 (t, J = 2.1 Hz, 1H), 6.91 (dd, J = 8.2, 1.9 Hz, 1H), 3.84 (s, 3H), 2.84 (s, 1H).

[0212] See Figure 1 , Figure 1 , which is the 19F NMR spectrum of the product prepared in Example 30 of the present invention. See Figure 2 , Figure 2 , which is the 13C NMR spectrum of the product prepared in Example 30 of the present invention. See Figure 3 , Figure 3 , which is the 1H NMR spectrum (S configuration) of the product prepared in Example 30 of the present invention. See Figure 4 , Figure 4 , which is the 1H NMR spectrum (R configuration) of the product prepared in Example 30 of the present invention. See Figure 5 , Figure 5 , which is the HPLC chromatogram of the product prepared in Example 30 of the present invention and its corresponding data.

[0213] Example 31: 2,2,2-Trifluoro-1-(4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)ethan-1-d-1-ol

[0214]

[0215] Using a method similar to Experiment 30 and the carbonyl reductase AaADH, the target compound 2,2,2-trifluoro-1-(4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)ethan-1-d-1-ol (I-31(R)) was obtained. 86% yield; 99% ee; 98% D; [α] D 20 = -29.2 (c 0.5, MeOH); HPLC [Daicel Chirapak IA, n-Hex∶i-PrOH = 80∶20, 0.8 mL / min, 254 nm UV detector, t R = 16.340 min (major) and t R = 19.064 min (minor)]; 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.1 Hz, 2H), 6.94 (s, 1H), 3.27 (s, 3H); 19 F NMR (376 MHz, DMSO-d6) δ -76.69; 13 C NMR (101 MHz, DMSO-d6) δ 144.6, 139.8, 138.9, 136.3, 128.4, 127.7, 127.1, 125.1 (q, J = 282.9 Hz), 70.6 - 69.1 (m), 43.6; HRMS (ESI) m / z [M+Na] + calcd for C 15 H 12 DF3O3SNa + 354.0498, found 354.0499.

[0216] Using a method similar to Experiment 30 and the carbonyl reductase DrADH, the target compound 2,2,2-trifluoro-1-(4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)ethan-1-d-1-ol (I-31(S)) was obtained. 81% yield; >99% ee; 99% D; [α] D 20= 29.6 (c 0.5, MeOH); HPLC [Daicel Chirapak IA, n-Hex∶i-PrOH = 80∶20, 0.8 mL / min, 254 nm UV detector, t R = 16.742 min (minor) and t R = 19.352 min (major)]; 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 6.94 (s, 1H), 3.27 (s, 3H).

[0217] See Figure 6 , Figure 6 which is the 1H NMR spectrum (R configuration) of the product prepared in Example 31 of the present invention.

[0218] See Figure 7 , Figure 7 which is the 19F NMR spectrum of the product prepared in Example 31 of the present invention.

[0219] See Figure 8 , Figure 8 which is the 13C NMR spectrum of the product prepared in Example 31 of the present invention.

[0220] See Figure 9 , Figure 9 which is the 19F NMR spectrum (S configuration) of the product prepared in Example 31 of the present invention.

[0221] See Figure 10 , Figure 10 which is the HPLC chromatogram of the product prepared in Example 31 of the present invention and its corresponding data.

[0222] Example 32: 2,2-Difluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethan-1-d-1-ol

[0223]

[0224] Using a method similar to that in Experiment 30, the target compound 2,2-difluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethan-1-d-1-ol (I-32(R)) was obtained by using carbonyl reductase AaADH. 90% yield, 99% ee, 98% D; [α] D 20=-24.3 (c 1.6, DMSO); HPLC [Daicel Chirapak OD-H, n-hexane∶iso-Dropanol = 90∶10, 1.0 mL / min, 254 nm UV detector, t R = 15.836 min (major) and t S = 19.906 min (minor)]; 1 1H NMR (500 MHz, CDCl3) δ 7.63 (d, J = 7.9 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 7.9 Hz, 1H), 7.24 - 7.16 (m, 1H), 7.16 - 7.08 (m, 1H), 7.06 - 6.87 (m, 1H), 5.81 (t, J = 55.9 Hz, 1H), 3.87 (s, 3H), 2.48 (s, 1H); 19 19F NMR (470 MHz, CDCl3) δ -127.60 (dd, J = 55.7, 12.9 Hz); 13 13C NMR (126 MHz, CDCl3) δ 158.9, 140.9, 140.7, 133.9 (t, J = 3.2 Hz), 128.8, 126.5, 126.4, 118.6, 114.7 (t, J = 245.5 Hz), 111.9, 71.9 (p, J = 23.6 Hz), 54.3; HRMS (ESI) m / z [M+H] + calcd for C 15 H 14 D F2O2 + 266.1103, found 266.1106

[0225] Using a method similar to that in Experiment 30, the target compound 2,2-difluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethan-1-d-1-ol (I-32(S)) was obtained using the carbonyl reductase DrADH. 90% yield, 99% ee, 98% D; [α] D 20 = 25.6 (c 1.7, DMSO); HPLC [Daicel Chirapak OD-H, n-hexane∶iso-propanol = 90∶10, 1.0 mL / min, 254 nm UV detector, t R = 15.824 min (minor) and t S = 19.647 min (major)]; 11H NMR (500 MHz, CDCl3) δ 7.63 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.38 (t, J = 7.9 Hz, 1H), 7.19 (dd, J = 7.6, 1.6 Hz, 1H), 7.13 (t, J = 2.1 Hz, 1H), 6.93 (dd, J = 8.2, 2.6 Hz, 1H), 5.82 (t, J = 55.9 Hz, 1H), 3.87 (s, 3H), 2.57 (s, 1H). 19 19F NMR (470 MHz, CDCl3) δ -127.57 (dd, J = 55.9, 11.0 Hz).

[0226] Example 33: 2,2-Difluoro-1-(4'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)ethan-1-d-1-ol

[0227]

[0228] Using a method similar to that of Experiment 30 and carbonyl reductase AaADH (5 mL, 100 mg / mL), the target compound 2,2-difluoro-1-(4'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)ethan-1-d-1-ol (I-33(R)) was obtained. 76% yield, 99% ee, 99% D; [α] D 20 = -22.2 (c 1.6, DMSO); HPLC [Daicel Chirapak AD-H, n-hexane∶iso-propanol = 70∶30, 1.0 mL / min, 254 nm UV detector, t R = 12.115 min (major) and t S = 15.635 min (minor)]; 1 1H NMR (500 MHz, DMSO) δ 8.01 (d, J = 8.6 Hz, 2H), 7.98 - 7.92 (m, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H), 6.27 (s, 1H), 6.07 (t, J = 55.5 Hz, 1H), 3.26 (s, 3H); 19 19F NMR (470 MHz, DMSO) δ -127.20 (dd, J = 87.6, 55.5 Hz); 1313C NMR (126 MHz, DMSO) δ 145.2, 140.1, 138.8 (t, J = 2.9 Hz), 138.6, 128.7, 128.1, 128.1, 127.4, 116.8 (t, J = 243.9 Hz), 74.9 - 66.1 (m), 44.1; HRMS (ESI) m / z [M+H] + calcd for C 15 H 14 DF2O3S + 314.0773, found 314.0772.

[0229] Using a method similar to that in Experiment 30, with carbonyl reductase DrADH (5 mL, 100 mg / mL), the target compound 2,2-difluoro-1-(4'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)ethan-1-d-1-ol (I-33(S)) was obtained. 83% yield, 99% ee, 98% D; [α] D 20 = 23.0 (c 1.7, DMSO); HPLC [Daicel Chirapak AD-H, n-hexane∶iso-propanol = 70∶30, 1.0 mL / min, 254 nm UV detector, t R = 12.358 min (minor) and t S = 13.768 min (major)]; 1 1H NMR (500 MHz, DMSO) δ 8.02 (d, J = 8.3 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 6.27 (s, 0H), 6.08 (t, J = 55.4 Hz, 0H), 3.27 (s, 1H); 19 19F NMR (470 MHz, DMSO) δ -127.23 (dd, J = 84.7, 55.5 Hz).

[0230] Example 34: 2-Fluoro-1-(3'-methoxy-[1,1'-biphenyl]-4-yl)ethan-1-d-1-ol

[0231]

[0232] Using a method similar to Experiment 30 and the carbonyl reductase AaADH, the target compound 2-fluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethan-1-d-1-ol (I-34(R)) was obtained. 96% yield, 99% ee, 98% D; [α] D 25 = -36.7 (c 5.9, CH2Cl2); HPLC [Daicel Chirapak AD-H, n-hexane∶iso-propanol = 90∶10, 0.4 mL / min, 220 nm UV detector, t R = 38.956 min (major) and t S = 40.942 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 7.37 (t, J = 8.0 Hz, 1H), 7.18 (dt, J = 7.7, 1.3 Hz, 1H), 7.13 (t, J = 2.1 Hz, 1H), 6.92 (dd, J = 8.3, 2.6 Hz, 1H), 4.71 - 4.33 (m, 2H), 3.87 (s, 3H), 2.76 (s, 1H); 19 19F NMR (376 MHz, CDCl3) δ -220.94 (t, J = 47.3 Hz); 13 13C NMR (126 MHz, CDCl3) δ 160.1, 142.2, 141.3, 137.4 (d, J = 7.8 Hz), 130.0, 127.5, 126.9, 119.7, 112.9 (d, J = 13.8 Hz), 87.2 (d, J = 174.6 Hz), 72.9 - 71.7 (m), 55.4; HRMS (ESI) m / z [M+H] + calcd for C 15 H 15 DFO2 + 248.1197, found 248.1206.

[0233] Using a method similar to Experiment 30 and the carbonyl reductase DrADH, the target compound 2-fluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethan-1-d-1-ol (I-34(S)) was obtained. 93% yield, 98% ee, 98% D; [α] D 25= 34.6 (c 4.9, CH2Cl2); HPLC [Daicel Chirapak AD-H, n-hexane∶iso-propanol = 90∶10, 0.4 mL / min, 220 nm UV detector, t R = 38.083 min (minor) and t S = 39.986 min (major)]; 1 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 7.37 (t, J = 7.9 Hz, 1H), 7.23 - 7.15 (m, 1H), 7.15 - 7.08 (m, 1H), 6.91 (ddd, J = 8.2, 2.6, 1.0 Hz, 1H), 4.73 - 4.29 (m, 2H), 3.87 (s, 3H), 2.57 (s, 1H); 19 19F NMR (376 MHz, CDCl3) δ -221.04 (t, J = 47.3 Hz).

[0234] Example 35: 2-Fluoro-1-(4'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)ethan-1-d-1-ol

[0235]

[0236] Using a method similar to that of Experiment 30 and the carbonyl reductase AaADH, the target compound 2-fluoro-1-(4'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)ethan-1-d-1-ol (I-35(R)) was obtained. 71% yield, 99% ee, 99% D; [α] D 25 = -34.6 (c 1.9, CH2Cl2); HPLC [Daicel Chirapak IC, n-hexane∶iso-propanol = 75∶25, 1.0 mL / min, 220 nm UV detector, t R = 129.436 min (major)] 1 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 4.78 - 4.11 (m, 2H), 3.09 (s, 3H), 2.65 (s, 1H); 1919F NMR (470 MHz, CDCl3) δ -222.29 (t, J = 47.7 Hz); 13 13C NMR (101 MHz, CDCl3) δ 146.1, 139.3 (d, J = 18.0 Hz), 138.9 (d, J = 7.7 Hz), 128.0, 127.9, 127.6, 127.1, 86.9 (d, J = 175.0 Hz), 72.1 (dd, J = 43.0, 21.1 Hz), 44.6; HRMS (ESI) m / z + calcd for C 15 H 15 DFO3S + 296.0867, found 296.0869.

[0237] Using a method similar to that in Experiment 30 and the carbonyl reductase DrADH, the target compound 2-fluoro-1-(4'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)ethan-1-d-1-ol (I-35(S)) was obtained. 75% yield, >99% ee, 98% D; [α] D 25 = 30.9 (c 1.0, CH2Cl2); HPLC [Daicel Chirapak IC, n-hexane∶iso-propanol = 75∶25, 1.0 mL / min, 220 nm UV detector, t S = 144.183 min (major)]; 1 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 4.68 - 4.28 (m, 2H), 3.09 (s, 3H), 2.71 (s, 1H); 19 19F NMR (470 MHz, CDCl3) δ -222.27 (t, J = 47.7 Hz).

[0238] Example 36: 1-(3,5-Bis(trifluoromethyl)phenyl)ethan-1-d-1-ol

[0239]

[0240] Table 3 Reaction parameters in Example 36

[0241]

[0242] Add buffer solution (K2HPO4 / KH2PO4, pH = 7.4) to the reaction tube, add the carbonyl reductase AaADH lysate to the system, and then sequentially add deuterated isopropanol (D- i PrOH, 1.1% v), cofactor nicotinamide adenine dinucleotide phosphate (NADP + , 10 mM, 15 μL, 1.5% mol), cosolvent DMSO (50 μL, 5% v) and reaction starting material 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one, place it in a metal bath at 30 °C, shake the reaction at 1000 rpm for 24 hours, extract with ethyl acetate (2×1 mL), combine the organic phases and dry with anhydrous MgSO4, and perform column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain the target product (S)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-d-1-ol (II-1(S)). 99% conv., >99% ee, 98% D; [α] D 20 = -27.8 (c 5.7, CH2Cl2); HPLC [Daicel Chirapak OJ-H, n-hexane∶iso-Dropanol = 100∶0, 0.4 mL / min, 254 nm UV detector, t R = 29.779 min (minor) and t S = 32.594 min (major)]; 1 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 2H), 7.79 (s, 1H), 1.96 (s, 1H), 1.54 (s, 3H); 19 19F NMR (376 MHz, CDCl3) δ -62.85; 13 13C NMR (101 MHz, CDCl3) δ 148.1, 131.8 (q, J = 33.4 Hz), 128.3 - 118.5 (m), 125.6 (d, J = 4.0 Hz), 121.3 (q, J = 3.7 Hz), 72.9 - 62.9 (m), 25.40; HRMS (ESI) m / z [M+H] + calcd for C 10 H8DF6O + 260.0578, found 260.0627.

[0243] Add buffer solution (K2HPO4 / KH2PO4, pH = 7.4) to the reaction tube, add the carbonyl reductase DrADH lysate to the system, and then sequentially add deuterated isopropanol (D- iPrOH, 1.1% v), cofactor nicotinamide adenine dinucleotide phosphate (NADP + , 10 mM, 15 μL, 1.5% mol), cosolvent DMSO (50 μL, 5% v) and reaction starting material 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one were placed in a metal bath at 30 °C and shaken at 1000 rpm for 24 h. The mixture was extracted with ethyl acetate (2 × 1 mL), the organic phases were combined and dried over anhydrous MgSO4, and column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) gave the target product (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-d-1-ol (II-1(R)). 99% conv., >99% ee, 98% D; [α] D 20 = 28.2 (c 5.0, CH2Cl2); HPLC [Daicel Chirapak OJ-H, n-hexane∶iso-propanol = 100∶0, 0.4 mL / min, 220 nm UV detector, t R = 30.975 min (major) and t S = 32.309 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.79 (s, 1H), 1.96 (s, 0H), 1.54 (s, 2H); 19 19F NMR (376 MHz, CDCl3) δ -62.85.

[0244] Example 37: 1-(4-(Trifluoromethyl)phenyl)ethan-1-d-1-ol

[0245]

[0246] Using a method similar to Experiment 36, the target compound 1-(4-(trifluoromethyl)phenyl)ethan-1-d-1-ol (II-2(S)) was obtained using carbonyl reductase AaADH. 99% conv., >99% ee, 97% D; [α] D 25 = -32.1 (c 1.0, CH2Cl2); HPLC [Daicel Chirapak OJ-H, n-hexane∶iso-propanol = 99∶1, 1.0 mL / min, 210 nm UV detector, t R = 26.067 min (minor) and t S = 23.107 min (major)]; 11H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.3 Hz, 2H), 1.83 (s, 1H), 1.51 (s, 3H); 19 19F NMR (376 MHz, CDCl3) δ -62.46; 13 13C NMR (101 MHz, CDCl3) δ 149.6, 129.6 (q, J = 32.3 Hz), 125.6, 125.4 (q, J = 3.9 Hz), 124.2 (q, J = 272.0 Hz), 71.0 - 65.5 (m), 25.1; HRMS (ESI) m / z [M+H] + calcd for C9H9DF3O + 192.0746, found 192.0753.

[0247] Using a method similar to Experiment 36 and the carbonyl reductase DrADH, the target compound 1-(4-(trifluoromethyl)phenyl)ethan-1-d-1-ol (II-2(R)) was obtained. 99% conv., >99% ee, 99% D; [α] D 25 = 31.6 (c 1.0, CH2Cl2); HPLC [Daicel Chirapak OJ-H, n-hexane∶iso-propanol = 99∶1, 1.0 mL / min, 210 nm UV detector, t R = 24.430 min (major) and t S = 22.398 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.3 Hz, 2H), 1.87 (s, 1H), 1.50 (s, 3H); 19 19F NMR (376 MHz, CDCl3) δ -62.46.

[0248] Example 38: 1-(6-(Trifluoromethyl)pyridin-3-yl)ethan-1-d-1-ol

[0249]

[0250] Using a method similar to Experiment 36 and the carbonyl reductase AaADH, the target compound 1-(6-(trifluoromethyl)pyridin-3-yl)ethan-1-d-1-ol (II-3(S)) was obtained. 99% conv., 99% ee, 96% D; [α] D 25= -54.3 (c 2.5, CH2Cl2); HPLC [Daicel Chirapak IC, n-hexane∶iso-Dropanol = 95∶5, 1.0 mL / min, 254 nm UV detector, t R = 12.395 min (minor) and t S = 13.328 min (major)]; 1 H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 7.92 (d, J = 10.4 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 1.96 (s, 1H), 1.55 (s, 3H); 19 FNMR (376 MHz, CDCl3) δ -67.80; 13 C NMR (101 MHz, CDCl3) δ 147.6, 147.2 (q, J = 34.8 Hz), 144.2, 134.4, 121.5 (q, J = 274.0 Hz), 120.3 (q, J = 2.8 Hz), 69.4 - 62.9 (m), 25.3; HRMS (ESI) m / z [M+H] + calcd for C8H8DF3NO + 193.0699, found 193.0704.

[0251] Using a method similar to Experiment 36, with carbonyl reductase DrADH, the target compound 1-(6-(trifluoromethyl)pyridin-3-yl)ethane-1-d-1-ol (II-3(R)) was obtained. 99% conv., 98% ee, 96% D; [α] D 25 = 50.5 (c 2.5, CH2Cl2); HPLC [Daicel Chirapak IC, n-hexane∶iso-propanol = 95∶5, 1.0 mL / min, 254 nm UV detector, t R = 12.184 min (major) and t S = 13.337 min (minor)]; 1 H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 2.16 (s, 1H), 1.54 (s, 3H); 19 FNMR (376 MHz, CDCl3) δ -67.78.

[0252] Example 39: 1-(3,4-difluorophenyl)ethan-1-d-1-ol

[0253]

[0254] Using a method similar to that of Experiment 36 and the carbonyl reductase AaADH, the target compound 1-(3,4-difluorophenyl)ethan-1-d-1-ol (II-4(S)) was obtained. 87% conv., 99% ee, 96% D; [α] D 25 = -29.3 (c 3.6, CH2Cl2); HPLC [Daicel Chirapak IC, n-hexane∶iso-propanol = 99∶1, 1.0 mL / min, 220 nm UV detector, t R = 15.834 min (minor) and t S = 14.238 min (major)]; 1 1H NMR (400 MHz, CDCl3) δ 7.24 - 7.17 (m, 1H), 7.16 - 7.03 (m, 2H), 1.81 (s, 1H), 1.46 (s, 3H); 19 19F NMR (376 MHz, CDCl3) δ -137.56, -139.97; 13 13C NMR (101 MHz, CDCl3) δ 150.3 (dd, J = 248.0, 12.8 Hz), 147.6 (dd, J = 247.2, 12.8 Hz), 135.1 (d, J = 10.3 Hz), 124.2 (dd, J = 6.6, 4.4 Hz), 121.2 (t, J = 3.5 Hz), 115.9 (d, J = 16.9 Hz), 65.0 - 62.21 (m), 23.9; HRMS (ESI) m / z [M+Na] + calcd for C8H7DF2ONa + 182.0504, found 182.0507.

[0255] Using a method similar to that of Experiment 36 and the carbonyl reductase DrADH, the target compound 1-(3,4-difluorophenyl)ethan-1-d-1-ol (II-4(R)) was obtained. 99% conv., 99% ee, 98% D; [α] D 25= 34.9 (c 3.2, CH2Cl2); HPLC [Daicel Chirapak IC, n - hexane∶iso - propanol = 99∶1, 1.0 mL / min, 220 nm UV detector, t R = 16.041 min (major) and t S = 14.526 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 7.24 - 7.14 (m, 1H), 7.15 - 6.98 (m, 2H), 2.13 (s, 1H), 1.44 (s, 3H), 19 19F NMR (376 MHz, CDCl3) δ - 137.59, - 140.03.

[0256] Example 40: 1 - (3,5 - difluorophenyl)ethan - 1 - d - 1 - ol

[0257]

[0258] Using a method similar to that of Experiment 36, the target compound 1 - (3,5 - difluorophenyl)ethan - 1 - d - 1 - ol (II - 5(S)) was obtained using the carbonyl reductase AaADH. 99% conv. > 99% ee, 96% D; [α] D 25 = - 36.2 (c 1.2, CH2Cl2); HPLC [Daicel Chirapak OJ - H, n - hexane∶iso - propanol = 99∶1, 1.0 mL / min, 210 nm UV detector, t R = 21.973 min (minor) and t S = 18.581 min (major)]; 1 1H NMR (400 MHz, CDCl3) δ 6.99 - 6.81 (m, 2H), 6.70 (td, J = 6.5, 3.3 Hz, 1H), 1.88 (s, 1H), 1.47 (s, 3H); 19 19F NMR (376 MHz, CDCl3) δ - 109.58; 13 13C NMR (101 MHz, CDCl3) δ 163.1 (dd, J = 248.3, 12.5 Hz), 149.9 (t, J = 8.3 Hz), 121.3 - 105.7 (m), 102.5 (t, J = 25.5 Hz), 71.2 - 58.9 (m), 25.0; HRMS (ESI) m / z [M + Na] +Calculated for C8H7DF2ONa + 182.0504, found 182.0500.

[0259] Using a method similar to Experiment 36, the target compound 1-(3,5-difluorophenyl)ethan-1-d-1-ol (II-5(R)) was obtained using the carbonyl reductase DrADH. 99% conv., >99% ee, 99% D; [α] D 25 = 34.5 (c 1.2, CH2Cl2); HPLC [Daicel Chirapak OJ-H, n-hexane∶iso-propanol = 99∶1, 1.0 mL / min, 210 nm UV detector, t R = 20.163 min (major) and t S = 18.160 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 6.89 (dd, J = 8.4, 2.4 Hz, 2H), 6.69 (tt, J = 8.9, 2.3 Hz, 1H), 1.93 (s, 1H), 1.46 (s, 3H); 19 19F NMR (376 MHz, CDCl3) δ -109.58.

[0260] Example 41: 1-(2,4-difluorophenyl)ethan-1-d-1-ol

[0261]

[0262] Using a method similar to Experiment 36, the target compound 1-(2,4-difluorophenyl)ethan-1-d-1-ol (II-6(S)) was obtained using the carbonyl reductase AaADH. 99% conv., 99% ee, 95% D; [α] D 25 = -40.3 (c 2.7, CH2Cl2); HPLC [Daicel Chirapak OJ-H, n-hexane∶iso-propanol = 99∶1, 1.0 mL / min, 210 nm UV detector, t R = 12.593 min (minor) and t S = 13.874 min (major)]; 11H NMR (400 MHz, CDCl3) δ 7.45 (td, J = 8.6, 6.5 Hz, 1H), 6.87 (tdd, J = 8.4, 2.6, 1.3 Hz, 1H), 6.77 (ddd, J = 11.4, 8.9, 2.6 Hz, 1H), 2.00 (s, 1H), 1.48 (s, 3H).; 19 19F NMR (376 MHz, CDCl3) δ -112.01, -116.16; 13 13C NMR (101 MHz, CDCl3) δ 162.1 (dd, J = 248.0, 12.1 Hz), 158.4 (d, J = 11.7 Hz), 128.6 (dd, J = 13.8, 3.9 Hz), 127.6 (dd, J = 9.5, 6.2 Hz), 111.3 (dd, J = 20.9, 3.7 Hz), 103.7 (t, J = 25.7 Hz), 71.9 - 53.3 (m), 24.0; HRMS (ESI) m / z [M+H] + calcd for C8H8DF2O + 160.0684, found 160.0681.

[0263] Using a method similar to that in Experiment 36 and the carbonyl reductase DrADH, the target compound 1-(2,4-difluorophenyl)ethan-1-d-1-ol (II-6(R)) was obtained. 99% conv., 98% ee, 96% D; [α] D 25 = 45.8 (c 1.2, CH2Cl2); HPLC [Daicel Chirapak OJ-H, n-hexane∶iso-propanol = 99∶1, 1.0 mL / min, 220 nm UV detector, t R = 12.616 min (major) and t S = 13.937 min (minor)]; 1 1H NMR (400 MHz, CDCl3) δ 7.46 (td, J = 8.5, 6.5 Hz, 1H), 6.98 - 6.81 (m, 1H), 6.77 (ddd, J = 11.4, 8.8, 2.5 Hz, 1H), 1.93 (s, 1H), 1.49 (s, 3H); 19 19F NMR (376 MHz, CDCl3) δ -112.00, -116.18.

[0264] Example 42: 1-(3,4,5-trifluorophenyl)ethan-1-d-1-ol

[0265]

[0266] Using a method similar to Experiment 36, the target compound 1-(3,4,5-trifluorophenyl)ethan-1-d-1-ol (II-7(S)) was obtained by using carbonyl reductase AaADH. 99% conv., 98% ee, 96% D; [α] D 25 = -33.9 (c 3.2, CH2Cl2); HPLC [Daicel Chirapak AD-H, n-hexane∶iso-propanol = 99∶1, 1.0 mL / min, 210 nm UV detector, t R = 16.050 min (minor) and t S = 17.626 min (major)]; 1 1H NMR (400 MHz, CDCl3) δ 7.09 - 6.90 (m, 2H), 2.00 (s, 1H), 1.44 (s, 3H); 19 19F NMR (376 MHz, CDCl3) δ -134.05, -162.40; 13 13C NMR (101 MHz, CDCl3) δ 151.2 (ddd, J = 250.2, 10.1, 3.9 Hz), 142.1 (td, J = 6.6, 4.4 Hz), 138.7 (dt, J = 250.5, 15.6 Hz), 119.1 - 102.91 (m), 72.5 - 63.6 (m), 25.0; HRMS (ESI) m / z [M+Na] + calcd for C8H6DF3ONa + 200.0410, found 200.0411.

[0267] Example 43: 1-(2,3,4,5-tetrafluorophenyl)ethan-1-d-1-ol

[0268]

[0269] Using a method similar to Experiment 36, the target compound 1-(2,3,4,5-tetrafluorophenyl)ethan-1-d-1-ol (II-8(S)) was obtained by using carbonyl reductase AaADH. 99% conv., 98% ee, 98% D; [α] D 25= -35.9 (c 1.6, CH2Cl2); HPLC [Daicel Chirapak OJ-H, n-hexane∶iso-propanol = 99∶1, 1.0 mL / min, 220 nm UV detector, t R = 12.478 min (minor) and t S = 14.510 min (major)]; 1 1H NMR (400 MHz, CDCl3) δ 7.15 (tdt, J = 8.4, 6.0, 2.6 Hz, 1H), 2.09 (s, 1H), 1.47 (s, 3H); 19 19F NMR (376 MHz, CDCl3) δ -138.85, -145.82, -156.10, -157.66; 13 13C NMR (101 MHz, CDCl3) δ 147.2 (dddd, J = 246.9, 9.9, 3.6, 2.2 Hz), 144.1 (ddd, J = 244.3, 10.5, 4.4 Hz), 141.2 (dddd, J = 97.6, 15.8, 12.5, 3.5 Hz), 138.7 (dddd, J = 96.8, 16.5, 12.5, 3.7 Hz), 129.2 (dt, J = 12.8, 4.8 Hz), 107.7 (dt, J = 20.5, 4.0 Hz), 64.7 - 62.3 (m), 23.9; HRMS (ESI) m / z [M+H] + calcd for C8H6DF4O + 196.0496, found 196.0483.

[0270] Using a method similar to Experiment 36, the target compound 1-(2,3,4,5-tetrafluorophenyl)ethan-1-d-1-ol (II-8(R)) was obtained using the carbonyl reductase DrADH. 99% conv., 99% ee, 96% D; [α] D 25 = 30.3 (c 2.0, CH2Cl2); HPLC [Daicel Chirapak OJ-H, n-hexane∶iso-propanol = 99∶1, 1.0 mL / min, 210 nm UV detector, t R = 12.955 min (major) and t S = 14.575 min (minor)]; 11H NMR (400 MHz, CDCl3) δ 7.20 - 7.08 (m, 1H), 2.17 (s, 1H), 1.47 (s, 3H); 19 19F NMR (376 MHz, CDCl3) δ -138.83, -145.86, -156.13, -157.65.

[0271] Example 44: 1-(Perfluorophenyl)ethan-1-d-1-ol

[0272]

[0273] Using the same method as in Experiment 36, the target compound 1-(perfluorophenyl)ethan-1-d-1-ol (II-9(S)) was obtained by using carbonyl reductase AaADH. 99% conv., 98% ee, 99% D; [α] D 25 = -6.3 (c 1.7, CH2Cl2); HPLC [Daicel Chirapak OJ-H, n-hexane∶iso-propanol = 100∶0, 1.0 mL / min, 220 nm UV detector, t R = 22.884 min (minor) and t S = 28.028 min (major)]; 1 1H NMR (400 MHz, CDCl3) δ 2.38 (s, 1H), 1.63 (s, 3H); 19 19F NMR (376 MHz, CDCl3) δ -144.77, -155.66, -162.02; 13 13C NMR (101 MHz, CDCl3) δ 144.6 (dddt, J = 247.9, 12.6, 8.5, 4.0 Hz), 140.5 (dtt, J = 253.5, 13.4, 5.4 Hz), 139.0 - 136.0 (m), 123.1 - 108.3 (m), 68.7 - 57.3 (m), 22.8; HRMS (ESI) m / z [M+H] + calcd for C8H5DF5O + 214.0401, found 214.0410.

[0274] Using the same method as in Experiment 36, the target compound 1-(perfluorophenyl)ethan-1-d-1-ol (II-9(R)) was obtained by using carbonyl reductase DrADH. 99% conv., 99% ee, 97% D; [α] D 25= 6.3 (c 1.5, CH2Cl2); HPLC [Daicel Chirapak OJ-H, n-hexane∶iso-propanol = 100∶0, 1.0 mL / min, 220 nm UV detector, t R = 23.132 min (major) and t S = 27.858 min (minor)]; 1 1H NMR (500 MHz, CDCl3) δ 2.35 (s, 1H), 1.62 (s, 3H); 19 19F NMR (470 MHz, CDCl3) δ -144.75, -155.67, -162.05.

[0275] Example 45: (2S)-3-(4-(2-Amino-6-(1-(2,2,2-trifluoro-1-(3'-methoxy-[1,1'-biphenyl]-4-ethoxy)ethyl)-1-d)pyrimidin-4-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid

[0276]

[0277] In a dry 25 mL Schlenk reaction flask, add 2,2,2-difluoro-1-(3'-methoxy-[1,1'-biphenyl]-4-yl)ethan-1-d-1-ol (0.24 mmol, 67 mg), cesium carbonate (0.7 mmol, 247.0 mg), 18-crown-6 (0.04 mmol, 10.6 mg), displace argon three times, add 1.5 mL of 1,4-dioxane to the system, heat to 100 °C. In another dry reaction flask, add 3-(4-(2-amino-6-chloropyrimidin-4-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (0.2 mmol, 78.6 mg), dissolve it with 0.5 mL of 1,4-dioxane, slowly drip it into the reaction system, stir at 100 °C for 16 - 24 hours. After TLC detection shows that the reaction is complete and the raw materials have completely disappeared, cool to 30 °C, add 1.5 mL of water, then add di-tert-butyl dicarbonate (0.03 mmol, 6.55 mg) and continue to stir for 2 hours. Subsequently, adjust the pH to 2 - 3 with 1 M HCl and extract with ethyl acetate (3 X 5 ml). Combine the organic phases and dry with anhydrous Na2SO4. Column chromatography (eluent: DCM / MeOH = 20 / 1 to 5 / 1) can obtain the target product (2S)-3-(4-(2-amino-6-(1-(2,2,2-trifluoro-1-(3'-methoxy-[1,1'-biphenyl]-4-ethoxy)ethyl)-1-d)pyrimidin-4-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid, 55 mg, with a yield of 43%.

[0278] 1 1H NMR (500 MHz, DMSO) δ 8.13 (s, 2H), 8.04 (s, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.63 - 7.55 (m, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.36 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 7.6 Hz, 2H), 6.64 (s, 1H), 6.57 (s, 1H), 6.15 (s, 1H), 3.82 (s, 1H), 3.09 (dd, J = 13.4, 5.2 Hz, 1H), 3.03 - 2.91 (m, 1H), 3.85 (s, 3H), 1.33 (s, 9H); 19 19F NMR (470 MHz, DMSO) δ -75.57.

[0279] Example 46: (2S)-3-(4-(2-Amino-6-(1-(3,5-bis(trifluoromethyl)phenyl)ethoxy-1-d)pyrimidin-4-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid

[0280]

[0281] In a dry 25 mL Schlenk reaction flask, add 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-d-1-ol (0.24 mmol, 62 mg), cesium carbonate (0.7 mmol, 247.0 mg), 18-crown-6 (0.04 mmol, 10.6 mg), displace argon three times, add 1.5 mL of 1,4-dioxane to the system, heat to 100 °C. In another dry reaction flask, add 3-(4-(2-amino-6-chloropyrimidin-4-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (0.2 mmol, 78.6 mg), dissolve it with 0.5 mL of 1,4-dioxane, slowly drip it into the reaction system, stir at 100 °C for 16 - 24 hours. After TLC detection shows that the reaction is complete and the raw materials have completely disappeared, cool down to 30 °C, add 1.5 mL of water, then add di-tert-butyl dicarbonate (0.03 mmol, 6.55 mg) and continue to stir for 2 hours. Subsequently, adjust the pH to 2 - 3 with 1 M HCl and extract with ethyl acetate (3 × 5 mL). Combine the organic phases and dry with anhydrous Na2SO4. Column chromatography (eluent: DCM / MeOH = 20 / 1 to 5 / 1) can obtain the target product (2S)-3-(4-(2-amino-6-(1-(3,5-bis(trifluoromethyl)phenyl)ethoxy-1-d)pyrimidin-4-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid, 65 mg, with a yield of 53%.

[0282] 11H NMR (500 MHz, DMSO) δ 8.13 (s, 2H), 8.04 (s, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 7.6 Hz, 2H), 6.64 (s, 1H), 6.57 (s, 1H), 6.15 (s, 1H), 3.82 (s, 1H), 3.09 (dd, J = 13.4, 5.2 Hz, 1H), 3.03 - 2.91 (m, 1H), 1.65 (s, 3H), 1.33 (s, 9H); 19 19F NMR (470 MHz, DMSO) δ -61.17. The above has introduced in detail a fluorine atom-substituted α-deuterated chiral alcohol compound and its method for enzymatic catalysis preparation and application. Specific examples are used in this article to elaborate on the principle and implementation manner of the present invention. The description of the above examples is only used to help understand the method and its core idea of the present invention, including the best mode, and also enables any person skilled in the art to practice the present invention, including implementing any combined method. It should be pointed out that for those of ordinary skill in the art in this technical field, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention. The protection scope of this invention patent is defined by the claims and may include other embodiments that can be conceived by those skilled in the art. If these other embodiments have structural elements that are not different from the literal description of the claims, or if they include equivalent structural elements that have no substantial difference from the literal description of the claims, then these other embodiments should also be included within the scope of the claims.

Claims

1. A fluorine-substituted α-deuterated chiral alcohol compound, characterized in that: Having a structure as shown in formula (I) or formula (II): Among them, R f The substituent is selected from trifluoromethyl, difluoromethyl or monofluoromethyl; the R substituent is selected from aromatic groups, alkyl groups or alkenyl groups; Ar f The substituent is selected from aromatic groups substituted with fluorine atoms; Me is methyl; The chiral center configuration of the α-deuterated chiral alcohol compound is selected from R configuration or S configuration.

2. The fluorine atom-substituted α-deuterated chiral alcohol compound according to claim 1, characterized in that: The fluorine-atom-substituted α-deuterated chiral alcohol compound having a structure as shown in formula (I) is specifically a structure shown in formula (I-1) to formula (I-35):

3. The fluorine atom-substituted α-deuterated chiral alcohol compound according to claim 1, characterized in that: The fluorine-atom-substituted α-deuterated chiral alcohol compound having a structure as shown in formula (II) is specifically a structure shown in formula (II-1) to formula (II-9):

4. A method for preparing a fluorine-substituted α-deuterated chiral alcohol compound according to any one of claims 1 to 3, characterized in that: The following steps are involved: A fluorine-containing carbonyl compound, a carbonyl reductase catalyst, deuterated isopropanol, a cofactor, a buffer solution and a cosolvent are mixed and subjected to an enzyme-catalyzed reduction reaction, followed by post-treatment to obtain an α-deuterated chiral alcohol compound substituted with a fluorine atom; The fluorine-containing carbonyl compound has a structure as shown in formula (III) or formula (IV): When the fluorine-containing carbonyl compound is a compound of the structure shown in formula (III), an α-deuterated chiral alcohol compound of the structure shown in formula (I) is prepared; When the fluorine-containing carbonyl compound is a compound with a structure shown in formula (IV), an α-deuterated chiral alcohol compound with a structure shown in formula (II) is prepared.

5. The preparation method according to claim 4, characterized in that: The carbonyl reductase catalyst includes one or more of AaADH from Aromatoleum aromaticum EbN1, DrADH from Devosia riboflavina, LkADH from Lactobacillus kefiri DSM 20587, LzADH from Lactobacillus zymae DSM 19395, and RasADH from Ralstonia sp. DSM 6428; The deuterated isopropanol includes 2-monodeuterated isopropanol and / or octadeuterated isopropanol; The cofactors include nicotinamide adenine dinucleotide phosphate and / or nicotinamide adenine dinucleotide; The buffer solution includes one or more of KH2PO4 / K2HPO4, NaH2PO4 / Na2HPO4, and Tris-HCl; The co-solvent includes one or more of tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, ether and dimethyl sulfoxide.

6. The preparation method according to claim 4, characterized in that: After the mixing, the concentration of the fluorine-containing carbonyl compound is 0.01 to 0.5 mmol / mL; After the mixing, the concentration of the carbonyl reductase catalyst is 1 to 40 mg / mL; After the mixing, the volume ratio of deuterated isopropanol is 1.5% (v / v) to 5% (v / v); After the mixing, the concentration of the cofactor is 0.05-0.40 mM / mL; After the mixing, the volume ratio of the co-solvent is 4% (v / v) to 10% (v / v).

7. The preparation method according to claim 4, characterized in that: The temperature of the enzyme catalyzed reduction reaction is 15 to 70°C; The enzyme catalyzed reduction reaction time is 1 to 24 hours; The post-treatment includes one or more steps of extraction, concentration and chromatography purification.

8. Use of the fluorine atom substituted α-deuterated chiral alcohol compound according to any one of claims 1 to 3 or the fluorine atom substituted α-deuterated chiral alcohol compound prepared by the preparation method according to any one of claims 4 to 7 in drugs, drug synthesis or drug activity screening.

9. A fluorine-substituted α-deuterated chiral alcohol compound, characterized in that: Having a structure as shown in formula (VI) or formula (VII): Among them, R f The substituent is selected from trifluoromethyl, difluoromethyl or monofluoromethyl; the R substituent is selected from aromatic groups, alkyl groups or alkenyl groups; Ar f The substituent is selected from aromatic groups substituted with fluorine atoms; Me is methyl; The chiral center configuration of the α-deuterated chiral alcohol compound is selected from R configuration or S configuration.

10. Use of the fluorine atom-substituted α-deuterated chiral alcohol compound according to claim 9 in drug screening.

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