Synthetic method for preparing alpha-point-selective deuterated alcohol by catalyzing high-point selective hydrogen-deuterium exchange reaction of alcohol

Abstract

The application relates to a high-point-selectivity hydrogen-deuterium exchange reaction of alcohol compounds catalyzed by a supported transition metal catalyst to prepare alpha-point-selectivity deuterated alcohol. The key to the success of the reaction is to develop a supported heterogeneous transition metal catalyst, and to realize the reaction of alcohol and deuterium water to synthesize deuterated alcohol. Through the investigation of different catalysts, simple and easily obtained alcohol compounds are efficiently and high-point-selectivity converted into high-value-added deuterated alcohol compounds.

Description

Technical Field

[0001] This invention relates to a synthetic method for preparing α-point-selective deuterated alcohols by high-point-selectivity hydrogen-deuterium exchange reaction of alcohols catalyzed by a supported catalyst. Background Technology

[0002] Since April 2017, when the U.S. Food and Drug Administration (FDA) approved the world's first deuterated drug, deuterated bubenazine tablets... With the market launch of deuterated drugs, people are becoming increasingly interested in their research and development. Compared with H atoms, D atoms have a larger radius, lower lipophilicity, shorter CD bonds than CH bonds, lower vibrational stretching frequencies and ground state energies, and require higher free energy for bond breaking (the difference between the two is 1.2–1.5 kcal / mol). They are more stable than CH bonds and are less prone to chemical or metabolic enzyme cleavage. (Reference: Journal of Medicinal Chemistry, 2014, 57(9): 3595-3611.) When the drug-active site is replaced by a CD bond with a CH bond, the drug oxidation metabolism becomes relatively slow due to the kinetic isotope effect, thus resulting in a longer duration of action and a reduction in drug uptake. In addition to optimizing pharmacokinetics, selective deuteration of the drug-active site also has the advantages of increasing biological activity, stabilizing stereoisomers, altering metabolic pathways, and even reducing drug interactions to reduce toxicity (Reference: Nature 2009, 45(8), 269. Journal of the American Chemical Society 2008, 140(1), 235-243. Journal of Medicinal Chemistry 2014, 57(9), 3595-3611. Nature Medicine 2013, 19(6), 656.). In addition, deuterated labeling experiments are widely used in research on chemical reaction kinetics and the revelation of organic reaction mechanisms (Reference: Journal of Agricultural and Food Chemistry 2016, 54(45), 8667-8677). The research in this patent mainly involves the synthesis of deuterated alcohols.

[0003] Studies have shown that alcohols and their derivatives are the basic building blocks of many small molecule drugs and natural products. The C-H bond at the oxygen-ortho position is a metabolic soft spot for many alcohols; therefore, highly regioselective α-deuterated alcohols have wide applications in drug development and kinetic studies. The synthesis of these compounds mainly utilizes catalysts to achieve hydrogen-deuterium exchange reactions of alcohols via a hydrogen-borrowing mechanism. However, the reaction requires the addition of excess reducing agent and the generation of ketone intermediates during hydrogen borrowing, making it impossible to obtain highly regioselective deuterated alcohols. Thus, the synthetic methods for highly deuterated, highly regioselective deuterated alcohols are very limited, severely restricting further research on deuterated alcohols. Therefore, it is necessary to develop novel reaction systems to achieve the synthesis of α-deuterated alcohols.

[0004] Alcohols are abundant and inexpensive because they can be prepared by hydroxylation of alkenes or by reaction of haloalkanes with hydroxides. Furthermore, many alcohols are naturally occurring, and their skeletons are highly diverse. Therefore, converting inexpensive and readily available alcohols into high-value deuterated products has wide applications in both drug development and pharmacokinetic studies.

[0005] In our study, we used supported transition metals as catalysts to achieve point-selective hydrogen-deuterium exchange reactions of alkyl-aryl secondary alcohols, alkyl-alkyl secondary alcohols, and secondary alcohol drugs to prepare corresponding α-point-selective deuterated alkyl-aryl secondary alcohols, alkyl-alkyl secondary alcohols, and secondary alcohol drugs. In our developed method, the reaction can yield the target deuterated compounds with high deuteration rates and yields. Summary of the Invention

[0006] The purpose of this invention is to develop a synthetic method for preparing α-point-selective deuterated alcohols by high-point-selectivity hydrogen-deuterium exchange reaction of alcohols catalyzed by a supported catalyst.

[0007]

[0008] Wherein R1 and R2 are each individually one or more of the following substituents:

[0009] Wherein R1 and R2 are each individually one or more of the following substituents:

[0010]

[0011] * indicates the position of the substituent on the carbon atom connected to the hydroxyl group;

[0012]

[0013] C1-C 20 A chain-like hydrocarbon group; containing one or more C1-C groups of amino, acyl, and ketone groups. 10 A chain-like hydrocarbon group; or one or more of a C3-C8 cyclic hydrocarbon group containing one or more of an amino group, an acyl group, and a ketone group.

[0014] The specific operating steps are as follows (reaction equation 1):

[0015] Alcohol compound 1, deuterium source, catalyst, and atmosphere were added sequentially to a reaction vessel and reacted under heating and pressure conditions; after the reaction was completed, deuterated compound 2 was obtained by separation.

[0016] The catalyst used can be a supported catalyst, which consists of a metallic active component and a support. The metallic active component includes one or more of the following: scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, cadmium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, azimuth, ruthenium, niobium, and mercury. The carrier includes one or more of the following: carbon materials, metal oxides, and silica gel; the carbon materials include one or more of the following: activated carbon, graphene, carbon nanotubes, carbon black, porous carbon materials, activated carbon fibers, carbon foam, carbon ceramics, organic framework materials, and modified carbon materials; the metal oxides include one or more of the following: iron oxide, nickel oxide, zinc oxide, titanium oxide, manganese oxide, cobalt oxide, copper oxide, and cerium oxide, and are different from the supported metal active component; the silica gel materials include one or more of the following: ordinary silica gel (SiO2), modified silica gel (amino-modified silica gel), porous silica gel (spherical porous silica gel, mesoporous silica gel, macroporous silica gel), colloidal siloxane (modified polysiloxane), nano silica gel (silica nanoparticles), silicates (zeolite, montmorillonite), organic-inorganic hybrid silica gel (organosilane-modified mesoporous silica gel), and polymer-coated silica gel (polymer-coated silica nanoparticles), with palladium catalyst supported on metal oxides preferred as the catalyst for the reaction.

[0017] The loading of the active metal component (mass of active metal / mass of support) is 0.01wt%-10wt%, preferably 0.1wt%; the amount of catalyst metal is 0.10-100% molar equivalent (based on active metal, molar equivalent is relative to the molar equivalent of the raw material alcohol compound 1), preferably 0.01%-3.0% molar equivalent, more preferably 0.05% molar equivalent.

[0018] The deuterium source used can be one or more of the following: deuterated water, deuterated methanol, deuterated ethanol, deuterated propanol, deuterated dimethyl sulfoxide, deuterated chloroform, deuterated acetone, deuterated acetic acid, deuterated formic acid, deuterated benzene, and deuterated toluene; deuterated water is preferred as the deuterium source for the reaction.

[0019] The amount of deuterium source used is 1.0-100 mL / mol equivalent (mol equivalent relative to the molar equivalent of the raw material alcohol compound 1), preferably 1-5 mL / mol equivalent, more preferably 2 mL / mol equivalent.

[0020] The reaction gas is hydrogen and / or deuterium, and the gas pressure is 0.1 MPa-4.0 MPa, preferably 0.5-2.0 MPa, and more preferably 1.0 MPa.

[0021] The temperature used is 25-200 degrees Celsius, preferably 60-110 degrees Celsius, and more preferably 90 degrees Celsius;

[0022] The reaction time is 1-120 hours, preferably 2-48 hours, and more preferably 24 hours.

[0023] The alcohol may be one or more of the following alkyl-aryl secondary alcohols, alkyl-alkyl secondary alcohols, and related secondary alcohol drugs:

[0024]

[0025] This invention starts with inexpensive and readily available alcohol compounds and proceeds through a one-step catalytic reaction to obtain a series of highly selective α-point-selective deuterated alcohols.

[0026] This law has the following advantages:

[0027] First, the reactant alcohols are inexpensive, readily available, easy to store, and commercially available products. Second, the high activity of the heterogeneous catalyst in the hydrogen-deuterium exchange reaction allows for highly efficient deuteration. Furthermore, the catalyst's single active site and stable structure prevent over-deuteration that occurs in homogeneous catalysis, achieving high point selectivity for deuteration. The prepared deuterated compounds exhibit high deuteration rates and high point selectivity. Finally, the resulting deuterated compounds have high added value and can be derivatized to obtain various deuterated drugs. For example, Myrbetriq, a drug used to treat urinary urgency, frequency, or urge incontinence in adult patients with overactive bladder (OAB), can be deuterated to synthesize α-deuterated Myrbetriq; Phenylephrine, a commonly used ingredient in influenza medications, can also be deuterated to synthesize deuterated Phenylephrine; and the process proposed in this invention can yield point-selectively deuterated α-deuterated Myrbetriq, deuterated Phenylephrine, and other secondary alcohol drugs, which have broad application prospects.

[0028] In this invention, the α-position refers to the position on the carbon atom directly bonded to the hydroxyl group, the β-position refers to the carbon atom adjacent to the α-position, and the γ-position refers to the third carbon atom adjacent to the β-position. The reaction yield = (amount of raw material corresponding to the product recovered after the reaction / amount of raw material fed) * 100% (molar amount), and no by-products are generated unless otherwise specified. The deuteration rate of the reaction is determined by NMR, and the deuteration rate = (number of deuterated hydrogen atoms at the corresponding carbon sites / number of hydrogen atoms at the corresponding carbon sites) * 100%.

[0029]

[0030] 1a (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Fe2O3 (Pd / 1a: 0.05 mol%), and H2 (1.0 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 48 hours. After the reaction was completed, the deuterated compound 2a (α-deuterated Myrbetriq) was obtained by column chromatography with a yield of 80% and a deuteration rate of 85%. The structure of the compound was identified by NMR (H1N and C1N spectra).

[0031] The test data is as follows:

[0032]

[0033] 1 H NMR(400MHz, DMSO-d6)δ9.97(s,1H),7.45(d,J=8.5Hz,2H),7.30-7.22(m,4H),7.17(ddd,J=8.6,5.3,2.3Hz,1H),7.07(d, J=8.5Hz,2H),6.87(s,2H),6.26(s,1H),5.19(d,J=4.2Hz,1H),3.40(s,2H),2.70(q,J=7.1,6.5Hz,2H),2.63-2.54(m,4H).

[0034] 13 C NMR(100MHz,DMSO-d6)δ168.76,168.34,146.42,145.19,137.71,135.65,12 9.32,128.44,127.28,126.40,119.49,103.10,72.01,58.11,51.34,35.93.

[0035] HRMS calculated for C 21 H 24 DN4O2S[M+H] + 3981755, found: 3981752.

[0036]

[0037] 1b (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / TiO2 (Pd / 1b: 0.05 mol%), and H2 (1.0 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 24 hours. After the reaction, the deuterated compound 2b (α-deuterated Phenylephrine) was obtained with a yield of 78% and a deuteration rate of 76%. The structure of the compound was identified by NMR (H1N and C1N NMR).

[0038] The test data is as follows:

[0039]

[0040] 1 H NMR (400MHz, CD3OD) δ7.12(t,J=8.0Hz,1H),6.82-6.77(m,2H),6.65(ddd,J=8.0,2.5,1.1Hz,1H),2.78-2.59(m,2H),2.38(s,3H).

[0041] 13 C NMR (100MHz, CD3OD) δ157.51,144.59,129.04,116.69,114.24,112.55,71.54,58.41,34.43.

[0042] HRMS calculated for C9H 11 D3NO2[M+H] + 171.1208, found: 171.1205.

[0043]

[0044] In a reaction vessel, 1c (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Fe2O3 (Pd / 1c: 0.05 mol%), and H2 (1.0 MPa) were added sequentially and reacted at 90 °C for 24 hours. After the reaction was completed, the deuterated compound 2c (α-deuterated Formoterol) was obtained with a yield of 87% and a deuteration rate of 78%.

[0045]

[0046] 1d (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Fe2O3 (Pd / 1d: 0.05 mol%), and H2 (1.0 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 24 hours. After the reaction was completed, the deuterated compound 2d (α-deuterated Advair) was obtained with a yield of 89% and a deuteration rate of 69%.

[0047]

[0048] 1e (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Fe2O3 (Pd / 1e: 0.05 mol%), and H2 (1.0 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 24 hours. After the reaction was completed, the deuterated compound 2e (α-deuterated Umeclidinium) was obtained with a yield of 76% and a deuteration rate of 53%.

[0049]

[0050] 1f (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Fe2O3 (Pd / 1f: 0.05 mol%), and H2 (1.0 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 24 hours. After the reaction was completed, the deuterated compound 2f (α-deuterated Ventolin) was obtained with a yield of 77% and a deuteration rate of 89%.

[0051]

[0052] 1 g (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Fe2O3 (Pd / 1 g: 0.05 mol%), and H2 (1.0 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 24 hours. After the reaction was completed, 2 g of deuterated compound (α-deuterated Samsca) was obtained with a yield of 85% and a deuteration rate of 69%.

[0053]

[0054] In a reaction vessel, 1h (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / TiO2 (Pd / 1h: 0.05 mol%), and H2 (1.0 MPa) were added sequentially, and the reaction was carried out at 90 °C for 24 hours. After the reaction was completed, the deuterated compound 2h (α-deuterated Toprol-XL) was obtained with a yield of 90% and a deuteration rate of 77%.

[0055] The key to the success of this reaction lies in the development of a supported heterogeneous transition metal catalyst, which enables the synthesis of α-point-selective deuterated alcohols from alcohols and deuterium water via a highly selective hydrogen-deuterium exchange reaction under hydrogen or deuterium atmospheres. Through investigation of different catalysts, simple and readily available alcohols are efficiently and selectively converted into high-value-added α-point-selective deuterated alcohols. Finally, using the synthesized α-point-selective deuterated alcohol compounds, the synthesis of related deuterated drugs is achieved. Detailed Implementation

[0056] For example:

[0057] The catalysts used in this invention are Pd / Fe2O3, Pd / TiO2, and Pd / Al2O3, synthesized respectively by impregnation method. The synthesis methods are as follows:

[0058] Pd / Fe2O3: 5g of Fe2O3 (Aladdin, >20nm) was dispersed in 200g of water, and 0.11g of a 10wt% palladium precursor aqueous solution was added dropwise. The mixture was then stirred for 12 hours and aged for 12 hours. After filtration, the mixture was washed with water 5 times, dried, ground, and calcined in air at 600℃ for 4 hours to obtain Pd / Fe2O3 with a Pd loading of 0.1wt%.

[0059] Pd / TiO2: 4g of TiO2 (P25) was dispersed in 200g of water, and 0.11g of a 10wt% palladium precursor aqueous solution was added dropwise. The mixture was then stirred for 12 hours and aged for 12 hours. After filtration, the mixture was washed with water 5 times, dried, ground, and calcined in air at 600℃ for 4 hours to obtain Pd / TiO2 with a Pd loading of 0.1wt%.

[0060] Pd / Al2O3: 4g of Al2O3 (Aladdin, >20nm) was dispersed in 200g of water, and 0.11g of a 10wt% palladium precursor aqueous solution was added dropwise. The mixture was then stirred for 12 hours and aged for 12 hours. After filtration, the mixture was washed with water 5 times, dried, ground, and calcined in air at 600℃ for 4 hours to obtain Pd / Al2O3 with a Pd loading of 0.1wt%.

[0061] To better understand the present invention, the following examples are provided. The reaction materials and results of Examples 1-11 are shown in Table 1.

[0062] Table 1. Reaction results with different substituted substrates

[0063]

[0064]

[0065]

[0066]

[0067] Example 1

[0068] The starting material alcohol 1i (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Fe2O3 (0.001 mmol as Pd), and H2 (1.0 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 24 hours. The product was a deuterated compound 2i with a yield of 86% and a deuteration rate of 92%. The structure of the compound was identified by nuclear magnetic resonance (NMR) (H1N and N2N spectroscopy).

[0069] The test data is as follows:

[0070]

[0071] 1 H NMR (400MHz, CDCl3) δ7.41-7.30(m,4H),7.29-7.24(m,1H),1.49(s,3H).

[0072] 13 C NMR (100MHz, CDCl3) δ145.82,128.61,127.59,125.48,70.06(t,J C-D =21.58Hz), 25.09.

[0073] HRMS calculated for C8H8D2O[M] + 124.0852, found: 124.0849.

[0074] Example 2

[0075] The starting material alcohol 1j (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Al2O3 (0.001 mmol as Pd), and H2 (1.0 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 24 hours. The product was a deuterated compound 2j with a yield of 69% and a deuteration rate of 89%. The structure of the compound was identified by nuclear magnetic resonance (NMR) (H1N and N2N spectroscopy).

[0076] The test data is as follows:

[0077]

[0078] 1H NMR (400MHz, CDCl3) δ7.38-7.32(m,4H),7.29-7.26(m,1H),1.87-1.68(m,2H),0.90(t,J=7.4Hz,3H).

[0079] 13 C NMR (100MHz, CDCl3) δ144.58,128.49,127.60,126.05,75.58(t,J C-D =22.40Hz), 31.81, 10.19.

[0080] HRMS calculated for C9H 10 D2O[M] + 138.1008, found: 138.1004.

[0081] Example 3

[0082] The starting material ethanol 1k (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Fe2O3 (0.001 mmol as Pd), and H2 (1.0 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 24 hours. The product was a deuterated compound 2k with a yield of 71% and a deuteration rate of 86%. The structure of the compound was identified by nuclear magnetic resonance (NMR) (H1N and NMR).

[0083] The test data is as follows:

[0084]

[0085] 1 H NMR (400MHz, CDCl3) δ7.28 (d, J = 4.3Hz, 4H) δ7.23-7.17 (m, 1H), 1.78-1.56 (m, 2H), 1.42-1.20 (m, 3H), 0.86 (t, J = 7.4Hz, 3H).

[0086] 13 C NMR (100MHz, CDCl3) δ144.95,128.51,127.57,125.98,74.06(t,J C-D =21.63Hz),41.20,19.10,14.05.

[0087] HRMS calculated for C 10 H 12 D2O[M] + 152.1165, found: 152.1161.

[0088] Example 4

[0089] 1L of starting alcohol (0.20mmol, 1.0eq.), 2.0mL of heavy water, 0.001mmol of Pd / Fe2O3 (based on Pd), and 0.3MPa of H2 were added sequentially to a reaction vessel and reacted at 120℃ for 48 hours. The product was a deuterated compound 2L with a yield of >95% and a deuteration rate of 88%. The structure of the compound was identified by nuclear magnetic resonance (NMR) (H1N and NMR).

[0090] The test data is as follows:

[0091]

[0092] 1 H NMR (400MHz, CDCl3) δ7.36-7.31(m,4H),7.30-7.22(m,1H),1.83-1.64(m,2H),1.44-1.36(m,1H),1.30-1.26(m,5H),0.86(t,J=6.7Hz,3H).

[0093] 13 C NMR (100MHz, CDCl3) δ144.96,128.53,127.58,125.98,74.82,39.03,31.81,25.37,22.66,14.11.

[0094] HRMS calculated for C 12 H 16 D2O[M] + 1180.1478, found: 180.1474. Example 5

[0095] The starting alcohol 1m (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Al2O3 (0.001 mmol as Pd), and H2 (0.1 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 24 hours. The product was a deuterated compound 2m with a yield of >95% and a deuteration rate of >95%. The structure of the compound was identified by NMR (H1N and C1N NMR).

[0096] The test data is as follows:

[0097]

[0098] 1H NMR (400MHz, CDCl3) δ7.39-7.23(m,5H),2.01-1.92(m,1H),0.99(d,J=6.7Hz,3H),0.79(d,J=6.9Hz,3H).

[0099] 13 C NMR (100MHz, CDCl3) δ143.68,128.29,127.52,126.67,79.65(t,J C-D =45.06Hz),35.24,19.08,18.34.

[0100] HRMS calculated for C 10 H 13 DO[M] + 151.1102, found: 151.1094.

[0101] Example 6

[0102] The starting material alcohol 1n (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Fe2O3 (0.001 mmol as Pd), and H2 (1.0 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 6 hours. The product was a deuterated compound 2n with a yield of >95% and a deuteration rate of 67%. The structure of the compound was identified by nuclear magnetic resonance (NMR) (H1N and N2N) spectra.

[0103] The test data is as follows:

[0104]

[0105] 1 H NMR (400MHz, CDCl3) δ7.19 (d, J = 8.3Hz, 2H), 7.09 (d, J = 7.9Hz, 2H), 2.27 (s, 3H), 1.41 (d, J = 6.4Hz, 3H).

[0106] 13 C NMR (100MHz, CDCl3) δ142.88,137.26,129.26,125.45,69.84(t,J C-D =21.70Hz), 24.99, 21.17.

[0107] HRMS calculated for C9H 10 D2O[M] + 138.1008 found: 138.1005.

[0108] Example 7

[0109] The starting material alcohol 1o (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Al2O3 (0.001 mmol as Pd), and H2 (1.0 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 24 hours. The product was a deuterated compound 2o with a yield of 75% and a deuteration rate of α-H (92%) and β-H (21%). The structure of the compound was identified by nuclear magnetic resonance (H1N and C1N spectra).

[0110] The test data is as follows:

[0111]

[0112] 1 H NMR (400MHz, CDCl3) δ7.15 (d, J = 8.4Hz, 2H), 6.65 (d, J = 8.4Hz, 2H), 1.44 (d, J = 6.8Hz, 2H).

[0113] 13 C NMR (100MHz, CDCl3) δ145.90,135.97,126.75,115.17,24.45(t,J C-D =19.3Hz).

[0114] HRMS calculated for C8H8D3NO[M] + 140.1023, found: 140.1021.

[0115] Example 8

[0116] The starting material ethanol 1p (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Fe2O3 (0.001 mmol as Pd), and H2 (1.0 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 6 hours. The product was a deuterated compound 2p with a yield of 80% and a deuteration rate of α-H (75%) and β-H (9%). The structure of the compound was identified by nuclear magnetic resonance (H1N and C1N spectra).

[0117] The test data is as follows:

[0118]

[0119] 1 H NMR (400MHz, CDCl3) δ7.29 (d, J = 8.7Hz, 2H), 6.88 (d, J = 8.7Hz, 2H), 3.80 (s, 3H), 1.47 (d, J = 6.3Hz, 3H).

[0120] 13 C NMR (100MHz, CDCl3) δ159.08,138.04,126.76,113.94,69.65(t,J C-D =44.0Hz), 55.38, 24.96.

[0121] HRMS calculated for C9H 11 DO2[M] + 158.0895, found: 158.0895.

[0122] Example 9

[0123] The starting material alcohol 1q (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Fe2O3 (0.001 mmol as Pd), and H2 (0.3 MPa) were added sequentially to a reaction vessel and reacted at 120 °C for 48 hours. The product was a deuterated compound 2q with a yield of 80% and a deuteration rate of 28%. The structure of the compound was identified by NMR (1H and 1C spectra).

[0124] The test data is as follows:

[0125]

[0126] 1 H NMR (400MHz, CDCl3) δ7.32 (dd, J=7.5, 1.7Hz, 1H), 7.24 (ddd, J=8.2, 7.4, 1.7Hz, 1H), 6.95 (td, J= 7.5,1.1Hz,1H),6.87(d,J=9.3Hz,1H),5.07(q,J=6.6Hz,1H),3.85(s,3H),1.50(d,J=6.5Hz,3H).

[0127] 13 C NMR (100MHz, CDCl3) δ156.68,133.46,128.41,126.21,120.90,110.53,66.69,55.35,22.90.

[0128] Example 10

[0129] The starting material alcohol 1r (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Fe2O3 (0.001 mmol as Pd), and H2 (1.0 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 24 hours. The product was a deuterated compound 2r with a yield of >95% and a deuteration rate of 90%. The structure of the compound was identified by NMR (H1N and C1N NMR).

[0130] The test data is as follows:

[0131]

[0132] 1 H NMR (400MHz, CDCl3) δ8.54 (d, J = 6.1 Hz, 2H), 7.30 (d, J = 4.3 Hz, 2H), 1.48 (s, 3H).

[0133] 13 C NMR (100MHz, CDCl3) δ154.75,149.87,120.47,25.00.

[0134] HRMS calculated for C7H7D2NO[M] + 125.0804, found: 125.0796.

[0135] Example 11

[0136] The starting material ethanol 1s (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Fe2O3 (0.001 mmol as Pd), and H2 (0.3 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 48 hours. The product was a deuterated compound 2s with a yield of 70% and a deuteration rate of 86%. The structure of the compound was identified by NMR (1H and 1C spectra).

[0137] The test data is as follows:

[0138]

[0139] 1 H NMR (400MHz, CD3OD) δ7.42 (d, J = 7.1Hz, 2H), 7.37-7.17 (m, 9H), 6.89 (d, J = 7.2Hz, 3H), 4.02 (s, 2H).

[0140] 13 C NMR (100MHz, CD3OD) δ158.94,141.28,129.14,128.08,127.51,126.19,120.59,114.37,72.83,71.77(t,J C-D =22.6Hz).

[0141] HRMS calculated for C 14 H 13 DO2[M] +215.1051, found: 215.1046.

[0142] Example 12

[0143] 1 t of starting alcohol (0.20 mmol, 1.0 eq.), 2.0 mL of heavy water, 0.001 mmol of Pd / Fe2O3 (based on Pd), and 1.0 MPa of H2 were added sequentially to a reaction vessel and reacted at 90 °C for 24 hours. 2 t of deuterated compound were produced, with a yield of >95% and a deuteration rate of 67%. The structure of the compound was identified by NMR (H1N and C1N NMR).

[0144] The test data is as follows:

[0145]

[0146] 1 H NMR (400MHz, CD3OD) δ7.35-7.29(m,4H),7.26-7.21(m,1H),2.81-2.72(m,2H).

[0147] 13 C NMR (100MHz, CD3OD) δ142.91,128.09,127.24,125.75,74.57,48.72.

[0148] HRMS calculated for C8H 11 DNO[M+H] + 139.0976, found: 139.0982. Example 13

[0149] The starting material ethanol 1u (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Fe2O3 (0.001 mmol as Pd), and H2 (1.0 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 24 hours. The product was a deuterated compound 2u, with a yield of 89% and a deuteration rate of 76%. The structure of the compound was identified by NMR (1H and 1C spectra).

[0150] The test data is as follows:

[0151]

[0152] 1 H NMR (400MHz, DMSO-d6) δ7.23-7.09 (m, 10H), 3.93 (d, J = 5.9Hz, 1H).

[0153] 13C NMR(100MHz,DMSO-d6)δ144.08,143.57,128.34,127.98,127.88,127.55,127.32,126.87,77.57(t,J C-D =21.2Hz), 61.88.

[0154] HRMS calculated for C 14 H 15 DNO[M+H] + 215.1289, found: 215.1291. Example 14

[0155] The starting material alcohol 1v (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / TiO2 (0.001 mmol as Pd), and H2 (1.0 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 6 hours. The product was a deuterated compound 2v with a yield of 88% and a deuteration rate of 87%. The structure of the compound was identified by nuclear magnetic resonance (NMR) (H1N and NMR).

[0156] The test data is as follows:

[0157]

[0158] 1 H NMR (400MHz, CDCl3) δ7.45-7.39(m,1H),7.23-7.16(m,2H),7.14-7.03(m,1H),2.89-2.65(m,2H),2.05-1.84(m,3H),1.82-1.72(m,1H).

[0159] 13 C NMR (100MHz, CDCl3) δ138.78,137.26,129.12,128.76,127.70,126.28,32.18,29.33,18.85.

[0160] HRMS calculated for C 10 H 11 DO[M] + 149.0945, found: 149.0932.

[0161] Example 15

[0162] The starting alcohol 1w (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Fe2O3 (0.001 mmol as Pd), and H2 (1.0 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 24 hours. The product was a deuterated compound 2w, with a yield of 93% and a deuteration rate of 89%. The structure of the compound was identified by NMR (1H and 1C spectra).

[0163] The test data is as follows:

[0164]

[0165] 1 H NMR (400MHz, CDCl3) δ7.31 (dd, J=7.6, 1.7Hz, 1H), 7.23-7.19 (m, 1H), 6.94-6. 90(m,1H),6.84(dd,J=8.3,1.0Hz,1H),4.29-4.23(m,2H),2.17-1.98(m,2H).

[0166] 13 C NMR (100MHz, CDCl3) δ154.68,129.83,129.77,124.33,120.69,117.1,62.89(t,J C-D =46.7Hz), 62.00, 30.77.

[0167] HRMS calculated for C9H9DO2[M] + 151.0738, found: 151.0730.

[0168] Example 16

[0169] The starting alcohol 1x (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Al2O3 (0.001 mmol as Pd), and H2 (1.0 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 6 hours. The product was a deuterated compound 2x with a yield of >95% and a deuteration rate of α-H (93%) and γ-H (52%). The structure of the compound was identified by nuclear magnetic resonance (H1N and C1N NMR).

[0170] The test data is as follows:

[0171]

[0172] 1H NMR (400MHz, CDCl3) δ7.41 (d, J = 7.1Hz, 1H), 7.25-7.22 (m, 3H), 3.09-3.01 (m, 1H), 2.85-2.78 (m, 1H).

[0173] 13 C NMR (100MHz, CDCl3) δ144.99,143.48,128.45,126.81,125.02,124.31,35.53,29.78(t,J C-D =19.34Hz).

[0174] HRMS calculated for C9H7D3O[M] + 137.0914, found: 137.0902.

[0175] Example 17

[0176] The starting material alcohol 1y (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Fe2O3 (0.001 mmol as Pd), and H2 (1.0 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 6 hours. The product was a deuterated compound 2y with a yield >95% and a deuteration rate of α-H (95%) and γ-H (54%). The structure of the compound was identified by nuclear magnetic resonance (H1N and C1N spectra).

[0177] The test data is as follows:

[0178]

[0179] 1 H NMR (400MHz, CDCl3) δ7.29(d,J=7.6Hz,1H),7.05(d,J=11.7Hz,2H),3.01(dd,J=16.3,6.7Hz,1H),2.76(dd,J=16.2,6.7Hz,1H),2.34(s,3H).

[0180] 13 C NMR (100MHz, CDCl3) δ143.79,142.22,138.35,127.67,125.63,124.08,36.06,29.68(t,J C-D =19.3Hz), 21.49.

[0181] HRMS calculated for C 10 H9D3O[M] +151.1071, found: 151.1058.

[0182] Example 18

[0183] The starting material ethanol 1z (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Fe2O3 (0.001 mmol as Pd), and H2 (0.3 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 120 hours. The product was a deuterated compound 2z with a yield of 93% and a deuteration rate of 65%. The structure of the compound was identified by NMR (1H and 1C spectra).

[0184] The test data is as follows:

[0185]

[0186] 1 H NMR (400MHz, CDCl3) δ3.38-3.31(m,1H),1.95(m,2H),1.80-1.59(m,2H),1.25(m,4H).

[0187] 13 C NMR (100MHz, CD3OD) δ74.82, 32.76, 23.98.

[0188] HRMS calculated for C6H 10 D2O2[M] + 118.0957, found: 118.0955.

[0189] Example 19

[0190] The starting material ethanol 1aa (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Fe2O3 (0.001 mmol as Pd), and H2 (0.1 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 24 hours. The product was a deuterated compound 2aa with a yield of >95% and a deuteration rate of α-H (3%) and γ-H (93%). The structure of the compound was identified by nuclear magnetic resonance (H1N and C1N NMR).

[0191] The test data is as follows:

[0192]

[0193] 1H NMR (400MHz, CDCl3) δ7.32-7.28(m,2H),7.23-7.18(m,3H),3.87-3.80(m,1H),1.82-1.72(m,2H),1.24(d,J=6.2Hz,3H).

[0194] 13 C NMR (100MHz, CDCl3) δ142.14,128.51,125.93,67.56,40.79,37.1(t,J C-D =37.9Hz), 23.69.

[0195] HRMS calculated for C 10 H 12 D2O[M] + 152.1165, found: 152.1163.

[0196] Example 20

[0197] The starting material ethanol 1ab (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Al2O3 (0.001 mmol as Pd), and H2 (0.1 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 24 hours. The product was a deuterated compound 2ab with a yield of >95% and a deuteration rate of α-H (5%) and β-H (58%). The structure of the compound was identified by nuclear magnetic resonance (H1N and C1N spectra).

[0198] The test data is as follows:

[0199]

[0200] 1 H NMR (400MHz, CDCl3) δ7.32-7.28(m,2H),7.23-7.18(m,3H),4.05-3.97(m,1H),1.24(d,J=6.2Hz,3H).

[0201] 13 C NMR (100MHz, CDCl3) δ138.55,129.49,128.67,126.60,68.94,45.50(t,J C-D =40.9Hz), 22.86.

[0202] HRMS calculated for C9H 10 D2O[M] + 138.1008, found: 138.1000.

[0203] Example 21

[0204] The starting material alcohol 1ac (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Fe2O3 (0.001 mmol as Pd), and H2 (0.1 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 48 hours. The product was a deuterated compound 2ac with a yield of 88% and a deuteration rate of α-H (6%) and γ-H (>95%). The structure of the compound was identified by nuclear magnetic resonance (H1N and C1N spectra).

[0205] The test data is as follows:

[0206] 1 H NMR (400MHz, CDCl3) δ7.32-7.20 (m, 5H), 3.96-3.89

[0207] (m,1H),3.39(dd,J=9.4,3.1Hz,1H),3.21(dd,J=9.4,8.1Hz,1H),1.07(d,J=6.4Hz,3H).

[0208] 13 C NMR(100MHz, CDCl3)δ137.95,128.57,127.89,75.82,66.61,18.71.HRMScalculated for C 10 H 12 D2O2[M] + 168.1114, found: 168.1106.

[0209] Example 22

[0210] The starting material ethanol 1ad (0.20 mmol, 1.0 eq.), heavy water (2.0 mL), Pd / Fe2O3 (0.001 mmol as Pd), and H2 (0.5 MPa) were added sequentially to a reaction vessel and reacted at 90 °C for 24 hours. The product was a deuterated compound 2ad with a yield of >95% and a deuteration rate of α-H (>95%) and β-H (20%). The structure of the compound was identified by nuclear magnetic resonance (H1N and C1N spectra).

[0211] The test data is as follows:

[0212]

[0213] 1H NMR(400MHz,CDCl3)δ7.39-7.30(m,4H),7.29-7.23(m,1H),2.85-2.65(m,2H),2.45(s,3H).

[0214] 13 C NMR(100MHz,CDCl3)δ142.60,128.50,127.61,125.91,59.12,36.05.

[0215] HRMS calculated for C9H 13 D2NO[M+H] + 153.1133,found:153.1132.

Claims

1. A synthetic method for preparing α-point-selective deuterated alcohols by catalytic high-point-selectivity hydrogen-deuterium exchange reaction, characterized in that: The reaction conditions are as follows: alcohol compound 1 (molar amount of 0.2 mmol), heterogeneous transition metal catalyst (transition metal content of 0.1-100 mol% of alcohol molar amount), deuterium source (1-100 mL), reaction atmosphere gas hydrogen and / or deuterium (0.1-4.0 MPa), temperature 25-200℃, 1-120 h; where D represents deuterium; Wherein R1 and R2 are each individually one or more of the following substituents: * indicates the position of the substituent on the carbon atom connected to the hydroxyl group; C1-C 20 A chain-like hydrocarbon group; containing one or more C1-C groups of amino, acyl, and ketone groups. 10 A chain-like hydrocarbon group; or one or more of a C3-C8 cyclic hydrocarbon group containing one or more of an amino group, an acyl group, and a ketone group.

2. The method according to claim 1, characterized in that: Wherein alcohol compound 1 may be one or more of the following alkyl-aryl secondary alcohols, alkyl-alkyl secondary alcohols, and secondary alcohol drugs; They are one or more of the following compounds: Specifically, alcohol compound 1 may be one or more of the following alkyl-aryl secondary alcohols, alkyl-alkyl secondary alcohols, and related secondary alcohol drugs: Among them, the alkyl-aryl secondary alcohols are as follows: 1-(4-fluorophenyl)-1-ethanol, 1-(4-chlorophenyl)-1-ethanol, 1-(4-bromophenyl)-1-ethanol, 1-(4-trifluoromethylbenzene)-1-ethanol, 1-(4-methoxybenzene)-1-ethanol, 1-(4-trifluoromethoxybenzene)-1-ethanol, 1-(4-aminobenzene)-1-ethanol, 1-(4-cyanophenyl)-1-ethanol, 1-(4-methylbenzene)-1-ethanol, 1-(4-isopropylphenyl)-1-ethanol, 1-(4-Isobutylphenyl)1-ethanol 1-(4-phenylbenzene)-1-ethanol, 1-phenylethanol, 1-(4-hydroxybenzene)-1-ethanol, 1-(4-methyl benzoate)-1-ethanol 1-(3,5-Dichlorophenyl)ethanol 1-(3-bromo-5-methylphenyl)ethanol, 1-(3-iodo-5-methylphenyl)ethanol, 1-(3,4-dimethoxyphenyl)ethanol, 2-methyl-1-phenyl-1-propanol, C-3 to C-20 benzyl alcohol, 2-phenoxy-1-phenylethanol, 2-amino-1-phenylethanol, α-(methaminomethyl)benzyl alcohol, (1R,2S)-(-)-2-amino-1,2-diphenylethanol, (1R,2R)-2-(methylamino)-1,2-diphenylethanol, alpha-(2,4-dichlorophenyl)-1H-imidazol-1-ethanol, 1-(4-pyridyl)ethanol, 1-(4-pyridyl)ethanol One or more of the following: pyridyl)ethanol, 1-(3-pyridyl)ethanol, 1-indanone alcohol, 2,3-dihydro-1-benzothiophene-3-ol, 5-chloro-2,3-dihydro-1H-indan-1-ol, 5-methyl-1-indanol, 1a,6a-dihydro-6H-indan[1,2-b]epoxyenyl-6-ol, α-tetrahydronaphthol, 4-diacetol, 1,5-dihydroxy-1,2,3,4-tetrahydronaphthol, 7-amino-1,2,3,4-tetrahydronaphthol, 1-naphthylethanol, 2-naphthylethanol, 1-(isoquinoline-1-yl)-1-ethanol, and 1,3,4,5-tetrahydrobenzo[cd]indole-6-ol; Among them, alkyl-alkyl secondary alcohols include: α-methyl alcohols from C-3 to C-20, 1,2-cyclohexanediol, 4-hydroxycyclohexanone, bicyclo(2,2,1)hept-2-ol, 2-phenyl-1,3-dioxane-5-ol, (1R,2R)-2-aminocyclohexanol, 2-chlorocyclohexanol, α-methylbenzyl alcohol from C-1 to C-20, and 1-(phenylmethoxy)ethanol, or two or more of these compounds; Among them, the relevant secondary alcohol drugs are as follows: one or more of Formoterol, Advair, Myrbetriq, Umeclidinium, Ventolin, Samsca, Phenylephrine, and Toprol-XL.

3. The synthesis method according to claim 1, characterized in that: The specific steps are as follows: Alcohol compound 1, deuterium source, catalyst, and reaction atmosphere gas hydrogen and / or deuterium are added sequentially to a reaction vessel and reacted under heating and pressure; after the reaction is completed, deuterated compound 2 is obtained by separation.

4. The method according to claim 1 or 3, characterized in that: The multiphase transition metal catalyst used can be a supported catalyst, which consists of a metal active component and a support; The active metal components include one or more of the following transition metals: scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, cadmium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, azimuth, ruthenium, bismuth, and mercury. The carrier includes one or more of the following: carbon materials, metal oxides, and silica gel; Carbon materials include one or more of the following: activated carbon, graphene, carbon nanotubes, carbon black, porous carbon materials, activated carbon fibers, carbon foam, carbon ceramics, organic framework materials, and modified carbon materials. Metal oxides include one or more of iron oxide, nickel oxide, zinc oxide, titanium oxide, manganese oxide, cobalt oxide, copper oxide, and cerium oxide, and the metal in the metal oxide is different from the metal element of the metal active component it supports; Silica materials include one or more of the following: ordinary silica gel (SiO2), modified silica gel (amino-modified silica gel), porous silica gel (spherical porous silica gel, mesoporous silica gel, macroporous silica gel), colloidal siloxane (modified polysiloxane), nano silica gel (silica nanoparticles), silicates (zeolite, montmorillonite), organic-inorganic hybrid silica gel (organosilane-modified mesoporous silica gel), and polymer-coated silica gel (polymer-coated silica nanoparticles). The loading of active metal components in the catalyst (mass of active metal / mass of support) is 0.01wt%-10wt%, preferably 0.08-0.15wt%. The catalyst dosage is 0.10-100% molar equivalent (based on the active metal component, where the molar amount of the active metal is relative to the molar amount of the raw material alcohol compound 1), preferably 0.01%-3.0% molar equivalent, and more preferably 0.05%-2% molar equivalent.

5. The method according to claim 1 or 3, characterized in that: The deuterium source used can be one or more of the following: deuterated water, deuterated methanol, deuterated ethanol, deuterated propanol, deuterated dimethyl sulfoxide, deuterated chloroform, deuterated acetone, deuterated acetic acid, deuterated formic acid, deuterated benzene, and deuterated toluene; deuterated water is preferred as the deuterium source for the reaction. The amount of deuterium source used is 1.0-100 mL / 1 mole of alcohol compound (the volume of deuterium source used is relative to the molar amount of alcohol compound 1 per 0.20 mmol), preferably 1-5 mL / 1 mole of alcohol compound 1, more preferably 1.5-2.5 mL / 1 mole of alcohol compound.

6. The method according to claim 1 or 3, characterized in that: The reaction atmosphere gas is hydrogen and / or deuterium, and the gas pressure is 0.1 MPa-4.0 MPa, preferably 0.5-2.0 MPa, and more preferably 1.0-1.5 MPa.

7. The method according to claim 1 or 3, characterized in that: The temperature used is 25-200 degrees Celsius, preferably 60-110 degrees Celsius, and more preferably 80-95 degrees Celsius.

8. The method according to claim 1 or 4, characterized in that: The reaction time is 1-120 hours, preferably 2-48 hours, and more preferably 18-30 hours.

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