阅读说明：本技术 一种α-一氘代胺类化合物、氘代药物及其制备方法 (Alpha-deuterated amine compound, deuterated drug and preparation method thereof ) 是由 安杰 宁磊 马媛 李恒朝 于 2021-01-12 设计创作，主要内容包括：本发明涉及α-一氘代胺类化合物及用于制备α-一氘代胺类化合物的一种肟类化合物的还原氘化方法,其特征在于通式(1)所示的肟类化合物与二价镧系过渡金属化合物、氘供体试剂在有机溶剂I中反应生成通式(2)所示的α-一氘代胺类化合物；任选地,将通式(2)化合物加入有机酸和/或无机酸-有机溶剂溶液得到通式(2)的铵盐。本发明解决现有技术中α-一氘代胺类化合物制备方法需要采用昂贵且毒性较大的过渡金属催化剂或者昂贵易燃的金属氘化物,且产生毒副产物的缺陷。(The invention relates to an alpha-deuterated amine compound and a reduction deuteration method of an oxime compound for preparing the alpha-deuterated amine compound, which is characterized in that the oxime compound shown in a general formula (1) reacts with a bivalent lanthanide transition metal compound and a deuterium donor reagent in an organic solvent I to generate the alpha-deuterated amine compound shown in a general formula (2); optionally, the compound of formula (2) is added to an organic acid and/or inorganic acid-organic solvent solution to give the ammonium salt of formula (2). The invention solves the defects that the preparation method of the alpha-deuterated amine compound in the prior art needs to adopt an expensive transition metal catalyst with larger toxicity or an expensive and flammable metal deuteride and generates toxic byproducts.)

1. a synthesis method of alpha-deuterated amine compound shown in a general formula (2) is characterized in that an oxime compound shown in the general formula (1) reacts with a bivalent lanthanide series transition metal compound and a deuterium donor reagent in an organic solvent I to generate the alpha-deuterated amine compound shown in the general formula (2);

optionally, adding the compound of formula (2) to an organic acid and/or inorganic acid-organic solvent solution to obtain an ammonium salt of formula (2);

in the general formula (1), R¹Selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl; r²Selected from hydrogen or methyl; r¹Wherein the substituent is alkyl, halogen, alkoxy, trifluoroalkyl and cyano;

the deuterium donor agent is selected from deuterium oxide, deuterated alcohol or mixtures thereof.

2. The method of synthesis according to claim 1, comprising the steps of:

step 1: after argon protection is carried out on the reactor, constant temperature treatment is carried out, and organic solvent I is added to prepare divalent lanthanide series transition metal compound solution;

step 2: preparing oxime compounds and an organic solvent I into a solution, and adding the solution into a reactor;

and step 3: adding a deuterium donor reagent to the reactor;

and 4, step 4: stirring the mixed solution for a certain time, and then quenching the reaction;

and 5: adding an organic solvent II and an alkali solution for extraction, drying and concentrating an organic phase, and purifying to obtain the compound of the general formula (2).

3. The method of synthesis according to claim 1,

in the step 1, the reactor is a round-bottom flask;

in the step 1 and the step 2, the same organic solvent is adopted;

in step 3, adding a quantitative deuterium donor reagent into the reactor under the condition of constant temperature;

in the step 4, the stirring is violent stirring;

in the step 4, the quenching reaction is to introduce air;

and step 5, adding ethyl acetate and saturated sodium hydroxide solution for extraction, drying and concentrating an organic phase, and performing column chromatography to obtain a compound of the general formula (2), or adding cyclopentyl methyl ether hydrochloride solution to obtain ammonium hydrochloride of the general formula (2).

4. The synthetic method of claim 1 wherein the deuterium donor reagent is selected from the group consisting of deuterium oxide, deuterated alcohols, and mixtures thereof;

preferably, the deuterated alcohol is one in which the hydroxyl group is deuterated;

preferably, the deuterium donor reagent is heavy water (D)₂O), deuterated methanol (Me)OD), deuterated ethanol (EtOD), deuterated n-propanol (n-PrOD), deuterated isopropanol (i-PrOD), deuterated n-butanol (n-BuOD) and deuterated tert-butanol (t-BuOD) are selected from one or more combinations;

more preferably, the deuterium donor reagent is heavy water (D)₂O)。

5. The method of claim 1, wherein the α -deuterated amine compound represented by formula (2) is synthesized by the method of claim: the divalent lanthanide transition metal compound is selected from one or the combination of more than two of a divalent samarium compound, a divalent dysprosium compound, a divalent neodymium compound, a divalent ytterbium compound, a divalent cerium compound and a divalent europium compound;

preferably, the divalent lanthanide transition metal compound is selected from samarium diiodide (SmI)₂) Dysprosium diiodide (DyI)₂) Neodymium diiodide (NdI)₂) Ytterbium diiodide (YbI)₂) Cerium diiodide (CeI)₂) And europium (II) perchlorate (Eu (ClO)₄)₂) One or a combination of two or more of them;

preferably, the divalent lanthanide transition metal compound is samarium diiodide (SmI)₂)。

6. The method of claim 1, wherein the α -deuterated amine compound represented by formula (2) is synthesized by the method of claim: the organic solvent I is selected from one or the combination of more than two of micromolecular alkane, naphthenic hydrocarbon, aromatic hydrocarbon, ether and cyclic ether solvents;

preferably, the organic solvent I is one or a combination of more than two of n-hexane, n-pentane, hexane, cyclohexane, toluene, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and dioxane;

preferably, the organic solvent I is tetrahydrofuran.

7. The method of claim 1, wherein the α -deuterated amine compound represented by formula (2) is synthesized by the method of claim: the ratio of the organic solvent I to the oxime compound is 1 mL: 1-300 mg.

8. The method of claim 1, wherein the α -deuterated amine compound represented by formula (2) is synthesized by the method of claim: the reaction temperature is-40 to 60 ℃; the reaction time is 0.1-60 min.

9. A deuterated tebufenpyrad synthesized by using alpha-deuterated amine compounds shown as a general formula (2) as raw materials.

10. The compound of the general formula (2) and the ammonium salt thereof prepared by the method for synthesizing α -deuterated amine compound according to any one of claims 1 to 8 are preferably the following compounds of the specific general formula (2) and the ammonium salt thereof:

Technical Field

The invention relates to alpha-deuterated amine, deuterated drugs and a method for deuterating oxime compounds by reduction for synthesizing alpha-deuterated amine compounds.

Background

In scientific research, deuterated organic compounds are currently widely used as biological probes, mass spectrometry internal standards, and for studying chemical reaction mechanisms (angelw.chem., int.ed.2018,57, 1758-. In addition, deuterium-labeled drugs and active molecules are more stable due to the Deuterium Kinetic Isotope Effect (DKIE), and have great potential in improving pharmacokinetic characteristics, reducing metabolic toxicity, and improving drug activity. This has made the development of deuterated drugs into a recent hot field (j.med. chem.2019,62, 5276-5297). During drug metabolism, the chiral center of a drug molecule with the chiral center containing an acidic proton is easy to undergo configuration transformation and racemization, thereby leading to reduced efficacy and even increased toxicity. Since the C-D bond is more stable than the C-H bond, the deuterated drug at the chiral center has a more stable configuration, and the in vivo and in vitro configuration conversion and racemization are reduced, thereby ensuring the drug effect (DOI: 10.1021/acsmedlett.0c00052). Chiral amine is an important drug intermediate, so the preparation of deuterated chiral amine has important significance for synthesizing drugs with deuterated chiral centers.

There are currently two main approaches to the synthesis of α -deuterated amines: (1) method for hydrogen deuterium exchange: the traditional acid/base catalytic system has narrow application range, harsh conditions and lower deuteration rate. By-product formation in hydrogen and deuterium exchange using Ru as catalystAnd the regioselectivity was poor (European J.org.chem.2016,2016, 4230-4235). (2) Using reducing agents containing deuterium, e.g. NaBD₄And LiAlD₄The method has good regioselectivity and high deuteration rate, but has poor chemical selectivity, expensive reagent and considerable safety problem (org. Lett.2003,5, 3555-3558).

Disclosure of Invention

In order to overcome the defects of low deuteration rate, poor regioselectivity, poor chemical selectivity, expensive reagents and the like in the preparation of alpha-deuteration amine compounds in the prior art, the invention establishes a reduction deuteration method of oxime compounds based on a single electron transfer reduction deuteration reaction for preparing the alpha-deuteration amine compounds shown as a general formula (2), and synthesizes a deuteration pesticide molecule tebufenpyrad by taking the alpha-deuteration amine compounds as synthesis building blocks. The method has the advantages of simple operation, mild conditions, wide substrate application range and good chemical selectivity.

The method for synthesizing the alpha-deuterated amine compound shown in the general formula (2) is characterized in that: the oxime compound shown in the general formula (1) reacts with a bivalent lanthanide transition metal compound and a deuterium donor reagent in an organic solvent I to generate an alpha-deuterated amine compound shown in the general formula (2);

optionally, the compound of formula (2) is added to an organic acid and/or inorganic acid-organic solvent solution to give the ammonium salt of formula (2).

In the general formula (1), R¹Selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl; r²Selected from hydrogen or methyl; r¹Wherein the substituent is alkyl, halogen, alkoxy, trifluoroalkyl and cyano.

The deuterium donor agent is selected from deuterium oxide, deuterated alcohol or mixtures thereof.

A method for synthesizing alpha-deuterated amine compounds shown as a general formula (2) is characterized by comprising the following steps:

step 1: after argon protection is carried out on the reactor, constant temperature treatment is carried out, and organic solvent I is added to prepare divalent lanthanide series transition metal compound solution;

step 2: preparing oxime compounds and an organic solvent I into a solution, and adding the solution into a reactor;

and step 3: adding a deuterium donor reagent to the reactor;

and 4, step 4: stirring the mixed solution for a certain time, and then quenching the reaction;

and 5: adding an organic solvent II and an alkali solution for extraction, drying and concentrating an organic phase, and purifying to obtain a compound of a general formula (2), or adding an organic acid and/or an inorganic acid-organic solvent solution to obtain an ammonium salt of the general formula (2);

preferably, in step 1, the reactor is a round-bottom flask;

preferably, in step 1 and step 2, the same organic solvent is used;

preferably, in step 3, a quantitative amount of deuterium donor reagent is added to the reactor under constant temperature conditions;

preferably, in step 4, the stirring is vigorous stirring;

preferably, in step 4, the quenching reaction is carried out by introducing air;

preferably, in the step 5, ethyl acetate and saturated sodium hydroxide solution are added for extraction, and after drying and concentration of an organic phase, a compound of the general formula (2) is obtained through column chromatography, or cyclopentyl methyl ether hydrochloride solution is added to obtain ammonium hydrochloride of the general formula (2).

The deuterium donor agent is selected from deuterium oxide, deuterated alcohol or mixtures thereof;

preferably, the deuterated alcohol is one in which the hydroxyl group is deuterated;

preferably, the deuterium donor reagent is heavy water (D)₂O), deuterated methanol (MeOD), deuterated ethanol (EtOD), deuterated n-propanol (n-PrOD), deuterated isopropanol (i-PrOD), deuterated n-butanol (n-BuOD) and deuterated tert-butanol (t-BuOD);

more preferably, the deuterium donor reagent is heavy water (D)₂O)。

The divalent lanthanide transition metal compound is selected from one or the combination of more than two of a divalent samarium compound, a divalent dysprosium compound, a divalent neodymium compound, a divalent ytterbium compound, a divalent cerium compound and a divalent europium compound;

preferably, the divalent lanthanide transition metal compound is selected from samarium diiodide (SmI)₂) Dysprosium diiodide (DyI)₂) Neodymium diiodide (NdI)₂) Ytterbium diiodide (YbI)₂) Cerium diiodide (CeI)₂) And europium (II) perchlorate (Eu (ClO)₄)₂) One or a combination of two or more of them;

more preferably, the divalent lanthanide transition metal compound is samarium diiodide (SmI)₂)。

The organic solvent I is selected from one or the combination of more than two of micromolecular alkane, naphthenic hydrocarbon, aromatic hydrocarbon, ether and cyclic ether solvents;

preferably, the organic solvent I is one or a combination of more than two of n-hexane, n-pentane, hexane, cyclohexane, toluene, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and dioxane;

preferably, the organic solvent I is tetrahydrofuran.

The ratio of the organic solvent I to the oxime compound is 1 mL: 1-300 mg.

The reaction temperature is-40 to 60 ℃; the reaction time is 0.1-60 min.

A deuterated tebufenpyrad synthesized by using alpha-deuterated amine compounds shown as a general formula (2) as raw materials.

Preferably, the α -monodeuterated amine compound represented by the general formula (2) and the ammonium salt thereof are characterized in that: ammonium salts of the compounds of the following specific general formula (2), preferably ammonium salts of hydrochloride of the compounds of the following specific general formula (2):

the invention has the beneficial effects that:

(1) the method of the present invention uses inexpensive, safe reagents, such as Smi₂-D₂O, can be oximesThe compound is converted into an alpha-deuterated amine compound. Can synthesize a large amount of alpha-deuterated amine compounds with high deuteration rate which can not be synthesized by the known method, and creates conditions for the synthesis of important single-configuration drugs, pesticides and deuterated photoelectric materials.

(2) The method has the advantages of high deuteration rate of the product, good regioselectivity and chemical selectivity, low reagent price, simple operation, mild condition and wide substrate application range.

(3) Compared with the known H/D exchange method, the method has the advantages that the dosage of the deuterium donor reagent is small, the cost can be obviously reduced, and the utilization rate of deuterium atoms is improved.

(4) The method can be used for drug molecules, pesticide molecules, hormone molecules and derivatives of natural products.

Detailed Description

The following examples are given to further illustrate the embodiments of the present invention.

Example 1:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, Compound 1a (32.6mg, 0.200mmol) were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 36.6mg of hydrochloride of the target compound 2a, wherein the yield is 98 percent, and the deuteration rate is 96 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2a obtained by adopting the synthesis method, and the test results are as follows:¹H NMR(300MHz,CDCl₃)δ8.41(br,3H),7.28–7.14(m,5H),2.75(t,J＝7.9Hz,2H), 2.15(m,1H),1.92(m,1H),1.41(s,3H)；¹³C{¹H}NMR(75MHz,CDCl₃)δ140.2,128.6,128.5, 126.3,47.7(t,J_C-D＝21.1Hz),36.4,31.7,18.8.

example 2:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂) To 14mL of a solution in tetrahydrofuran (0.1mol/L) were added 224mg (11.2mmol) of heavy water, compound 1b (33.4mg, 0.200mmol), and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 32.4mg of hydrochloride of the target compound 2b, wherein the yield is 85 percent, and the deuteration rate is 96 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2b obtained by adopting the synthesis method, and the test results are as follows:¹H NMR(300MHz,DMSO-d₆)δ8.25(br,3H),7.29(m,2H),7.15(m,2H),3.03(d,J＝13.3Hz, 1H),2.67(d,J＝13.3Hz,1H),1.10(s,3H)；¹³C{¹H}NMR(75MHz,DMSO-d₆)δ161.1(d,J_C-F＝242.3Hz),132.9(d,J_C-F＝3.0Hz),131.1(d,J_C-F＝8.1Hz),115.2(d,J_C-F＝21.1Hz),47.6(t, J_C-D＝21.8Hz),38.9,17.3.

example 3:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, Compound 1c (36.7mg, 0.200mmol) were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding a cyclopentyl methyl ether hydrochloride solution(3.0mol/L) to obtain 35.2mg of the hydrochloride of the objective compound 2c in a yield of 85% and a deuteration rate of 96%.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2c obtained by adopting the synthesis method, and the test results are as follows:¹H NMR(300MHz,DMSO-d₆)δ8.29(br,3H),7.38(m,2H),7.28(m,2H),3.05(d,J＝13.3 Hz,1H),2.69(d,J＝13.3Hz,1H),1.10(s,3H)；¹³C{¹H}NMR(75MHz,DMSO-d₆)δ135.8, 131.4,131.1,128.4,47.4(t,J_C-D＝22.7Hz),39.0,17.3.

example 4:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, compound 1d (45.6mg, 0.200mmol) were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 45.3mg of hydrochloride of the target compound 2d, wherein the yield is 90 percent, and the deuteration rate is 96 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2d obtained by adopting the synthesis method, and the test results are as follows:¹H NMR(300MHz,DMSO-d₆)δ8.40(br,3H),7.62(m,1H),7.42–7.32(m,2H),7.22(m, 1H),3.18(d,J＝13.5Hz,1H),2.90(d,J＝13.5Hz,1H),1.13(s,3H)；¹³C{¹H}NMR(75MHz, DMSO-d₆)δ136.1,132.7,131.8,129.0,128.0,124.0,46.3(t,J_C-D＝22.1Hz),39.6,17.3.

example 5:

to a 25mL single neck round bottom flask under argon protection was added diiodoSamarium chloride (Smi)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, compound 1e (35.8mg, 0.200mmol) were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 38.5mg of hydrochloride of the target compound 2e, wherein the yield is 95 percent, and the deuteration rate is 96 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2e obtained by adopting the synthesis method, and the test results are as follows:¹H NMR(300MHz,DMSO-d₆)δ8.25(br,3H),7.14(m,2H),6.88(m,2H),3.72(s,3H), 2.99(d,J＝13.3Hz,1H),2.59(d,J＝13.3Hz,1H),1.08(s,3H)；¹³C{¹H}NMR(75MHz, DMSO-d₆)δ158.0,130.2,128.6,113.9,55.0,47.8(t,J_C-D＝20.5Hz),38.9,17.2.

example 6:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)16mL of a solution in tetrahydrofuran (0.1mol/L), 256mg (12.8mmol) of heavy water, compound 1f (29.4mg, 0.200mmol) were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 28.0mg of hydrochloride of the target compound 2f, wherein the yield is 82 percent, and the deuteration rate is 96 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2f obtained by the synthesis method, and the test results are as follows:¹H NMR(300MHz,DMSO-d₆)δ8.51(br,3H),7.26(m,2H),7.18(m,2H),3.25(d,J＝16.4 Hz,2H),3.01(d,J＝16.4Hz,2H)；¹³C{¹H}NMR(75MHz,DMSO-d₆)δ139.8,126.8,124.6, 50.0(t,J_C-D＝23.0Hz),37.1.

example 7:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, 1g (33.0mg, 0.200mmol) of the compound were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Ethyl acetate and 1mol/L sodium hydroxide solution are added for extraction, the organic phase is dried and concentrated, and cyclopentyl methyl ether hydrochloride solution (3.0mol/L) is added to obtain 37.0mg of target compound 2g of hydrochloride, the yield is 98%, and the deuteration rate is 96%.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on 2g of the target product obtained by the synthesis method, and the test results are as follows:¹H NMR(300MHz,DMSO-d₆)δ8.32(br,3H),2.10-1.96(m,4H),1.86–1.65(m,8H), 1.57-1.47(m,2H)；¹³C{¹H}NMR(75MHz,DMSO-d₆)δ54.2(t,J_C-D＝21.5Hz),36.8,36.1, 29.8,29.4,26.4,26.3.

example 8:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, compound 1h (38.7mg, 0.200mmol) were added and stirred vigorously. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 37.7mg of target compound hydrochloride for 2h, wherein the yield is 86 percent, and the deuteration rate is 97 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2h obtained by adopting the synthesis method, and the test results are as follows:¹H NMR(300MHz,DMSO-d₆)δ7.95(br,3H),1.96(m,3H),1.72–1.44(m,12H),1.10(s, 3H)；¹³C{¹H}NMR(75MHz,DMSO-d₆)δ55.1(t,J_C-D＝21.2Hz),37.0,36.1,33.9,27.4,12.5.

example 9:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, compound 1i (34.3mg, 0.200mmol) were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Ethyl acetate and 1mol/L sodium hydroxide solution were added for extraction, the organic phase was dried and concentrated, and cyclopentyl methyl ether hydrochloride solution (3.0mol/L) was added to obtain 33.9mg of the hydrochloride of the objective compound 2i, with a yield of 87% and a deuteration rate of 96%.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2i obtained by adopting the synthesis method, and the test results are as follows:¹H NMR(300MHz,DMSO-d₆)δ8.08(br,3H),1.58(m,1H),1.39(m,1H),1,33–1.19(m, 12H),1.16(s,3H),0.84(t,J＝6.9Hz,3H)；¹³C{¹H}NMR(75MHz,DMSO-d₆)δ46.3(t,J_C-D＝ 21.3Hz),33.9,31.2,28.7(×2),28.5,24.7,22.0,17.9,13.9.

example 10:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, compound 1j (27.0mg, 0.200mmol) were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding hydrochloric acidCyclopentyl methyl ether solution (3.0mol/L) provided 27.0mg of hydrochloride of the objective compound 2j, yield 85%, deuteration rate 96%.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2j obtained by the synthesis method, and the test results are as follows:¹H NMR(300MHz,CDCl₃)δ8.67(br,3H),7.52–7.43(m,2H),7.39–7.30(m,3H),1.63 (s,3H)；¹³C{¹H}NMR(75MHz,CDCl₃)δ137.7,129.1,129.0,127.0,51.5(t,J_C-D＝24.8Hz), 20.4.

example 11:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, compound 1k (27.0mg, 0.200mmol) were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 31.1mg of hydrochloride of the target compound 2k, wherein the yield is 98 percent, and the deuteration rate is 95 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2k obtained by adopting the synthesis method, and the test results are as follows:¹H NMR(500MHz,CDCl₃)δ8.54(br,3H),7.36(m,2H),7.14(m,2H),2.31(s,3H),1.60(s, 3H)；¹³C NMR(126MHz,CDCl₃)δ138.7,134.8,129.8,127.0,51.3(t,J_C-D＝20.2Hz),21.2, 20.4.

example 12:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water was added,compound 1l (33.0mg, 0.200mmol) was stirred vigorously. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 35.8mg of target compound 2L hydrochloride, wherein the yield is 95 percent, and the deuteration rate is 96 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2l obtained by the synthesis method, and the test results are as follows:¹H NMR(300MHz,CDCl₃)δ8.48(br,3H),7.40(m,2H),6.86(m,2H),3.76(s,3H),1.59(s, 3H)；¹³C{¹H}NMR(75MHz,CDCl₃)δ159.9,129.8,128.5,114.4,55.3,50.9(t,J_C-D＝16.4Hz), 20.3.

example 13:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, 1m (52.2mg, 0.200mmol) of the compound were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 54.1mg of hydrochloride of the target compound 2m, wherein the yield is 95 percent, and the deuteration rate is 95 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2m obtained by adopting the synthesis method, and the test results are as follows:¹H NMR(400MHz,DMSO-d₆)δ8.71(br,3H),7.77(m,2H),7.36(m,2H),1.48(s,3H)；¹³C{¹H}NMR(101MHz,DMSO-d₆)δ139.1,137.3,129.2,94.6,49.2(t,J_C-D＝21.0Hz),20.4.

example 14:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, compound 1n (3.0mg, 0.200mmol) were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 33.1mg of hydrochloride of the target compound 2n, wherein the yield is 90 percent, and the deuteration rate is 96 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2n obtained by adopting the synthesis method, and the test results are as follows:¹H NMR(300MHz,DMSO-d₆)δ8.84(br,3H),7.91(m,2H),7.77(m,2H),1.51(s,3H)；¹³C{¹H}NMR(75MHz,DMSO-d₆)δ144.7,132.5,128.0,118.5,111.0,49.3(t,J_C-D＝20.6Hz), 20.4.

example 15:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, compound 1o (32.2mg, 0.200mmol) were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 36.2mg of hydrochloride of the target compound 2o, wherein the yield is 98 percent, and the deuteration rate is 95 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2o obtained by adopting the synthesis method, and the test results are as follows:¹H NMR(300MHz,DMSO-d₆)δ8.65(br,3H),7.62(m,1H),7.30–7.13(m,3H),2.84– 2.63(m,2H),2.12–1.85(m,3H),1.72(m,1H)；¹³C{¹H}NMR(75MHz,DMSO-d₆)δ137.6, 132.5,129.2,128.8,128.1,125.9,47.3(t,J_C-D＝19.8Hz),28.4,27.2,18.1.

example 16:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, compound 1p (39.4mg, 0.200mmol) were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 42.8mg of hydrochloride of the target compound 2p, wherein the yield is 97 percent, and the deuteration rate is 96 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2p obtained by the synthesis method, and the test results are as follows:¹H NMR(300MHz,DMSO-d₆)δ9.29(br,3H),7.62–7.55(m,4H),7.44–7.30(m,6H)；¹³C{¹H}NMR(75MHz,DMSO-d₆)δ138.3,128.6,128.2,127.3,56.8(t,J_C-D＝20.2Hz).

example 17:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, compound 1q (51.3mg, 0.200mmol) were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 54.8mg of hydrochloride of the target compound 2q, wherein the yield is 98 percent, and the deuteration rate is 95 percent.

For the target product obtained by the synthesis method2q performing nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection, and obtaining the following test results:¹H NMR(300MHz,DMSO-d₆)δ8.92(br,1H),8.57(br,3H),7.01–6.86(m,4H),6.82– 6.69(m,3H),1.46(s,3H)；¹³C{¹H}NMR(75MHz,DMSO-d₆)δ142.2,141.8,138.5,127.5, 126.3,126.1,121.8,119.9,116.5,116.0,114.6,113.0,49.2(t,J_C-D＝20.1Hz),20.0.

example 18:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, compound 1r (37.0mg, 0.200mmol) were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 20.9mg of target compound 2r hydrochloride, wherein the yield is 50 percent, and the deuteration rate is 96 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2r obtained by adopting the synthesis method, and the test results are as follows:¹H NMR(300MHz,DMSO-d₆)δ8.83(br,3H),8.17(m,1H),8.03–7.92(m,2H),7.83(m, 1H),7.66–7.54(m,3H),1.63(m,3H)；¹³C{¹H}NMR(75MHz,DMSO-d₆)δ135.5,133.2, 129.6,128.8,128.5,126.7,126.0,125.3,123.1,122.6,45.31(t,J_C-D＝21.7Hz),21.0.

example 19:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, compound 1s (41.1mg, 0.200mmol) were added, and the mixture was vigorously stirred. Inverse directionThe mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 38.9mg of hydrochloride of the target compound 2s, wherein the yield is 85 percent, and the deuteration rate is 96 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2s obtained by adopting the synthesis method, and the test results are as follows:¹H NMR(300MHz,DMSO-d₆)δ8.05(br,3H),7.16(m,2H),7.10(m,2H),2.84(hept,J＝ 7.2Hz,1H),2.68(m,2H),2.34(dd,J＝13.5,8.2Hz,1H),2.00(m,1H),1.17(d,J＝6.9Hz,6H), 0.87(d,J＝6.6Hz,3H)；¹³C{¹H}NMR(75MHz,DMSO-d₆)δ146.0,136.8,128.8,126.1,43.6 (t,J_C-D＝21.5Hz),33.0,32.9,23.9(×2),16.8.

example 20:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, 1t (27.8mg, 0.200mmol) of the compound were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 25.0mg of target compound 2t hydrochloride, wherein the yield is 77 percent, and the deuteration rate is 96 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2t obtained by adopting the synthesis method, and the test results are as follows:¹H NMR(300MHz,DMSO-d₆)δ8.59(br,3H),7.58(m,2H),7.24(m,2H),3.97(m,1H)；¹³C{¹H}NMR(75MHz,DMSO-d₆)δ162.0(d,J_C-F＝244.4Hz),131.3(d,J_C-F＝8.4Hz),130.3 (d,J_C-F＝3.3Hz),115.3(d,J_C-F＝21.5Hz),41.0(t,J_C-D＝20.8Hz).

example 21:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, compound 1u (31.4mg, 0.200mmol) were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 28.9mg of hydrochloride of the target compound 2u, wherein the yield is 80 percent, and the deuteration rate is 96 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2u obtained by the synthesis method, and the test results are as follows:¹H NMR(300MHz,DMSO-d₆)δ8.62(br,3H),7.70(m,1H),7.34(m,1H),7.18(m,1H), 4.00(m,1H)；¹³C{¹H}NMR(75MHz,DMSO-d₆)δ162.4(dd,J_C-F＝247.8,12.4Hz),160.5(dd, J_C-F＝249.2,12.5Hz),132.8(dd,J_C-F＝10.2,4.9Hz),117.5(dd,J_C-F＝14.9,3.8Hz),111.7(dd, J_C-F＝21.4,3.6Hz),104.0(t,J_C-F＝25.9Hz),34.7(t,J_C-D＝21.2Hz).

example 22:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, 1v (37.9mg, 0.200mmol) of the compound were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying the organic phase, concentrating, adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 29.8mg of target compound 2v hydrochloride with the yield of 70%And the deuteration rate is 96 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2v obtained by adopting the synthesis method, and the test results are as follows:¹H NMR(300MHz,DMSO-d₆)δ8.73(br,3H),7.81–7.72(m,4H),4.10(m,1H)；¹³C{¹H} NMR(75MHz,DMSO-d₆)δ138.7,129.8,128.8(q,J_C-F＝31.9Hz),125.3(q,J_C-F＝3.8Hz), 124.1(q,J_C-F＝272.2Hz),41.3(t,J_C-D＝21.7Hz).

example 23:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, 1w (38.0mg, 0.200mmol) of the compound, and vigorous stirring were added. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 42.3mg of target compound 2w hydrochloride, wherein the yield is 99 percent, and the deuteration rate is 96 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2w obtained by adopting the synthesis method, and the test results are as follows:¹H NMR(300MHz,DMSO-d₆)δ8.68(br,3H),7.86(d,J＝1.9Hz,1H),7.68(d,J＝8.3Hz, 1H),7.53(dd,J＝8.3,1.9Hz,1H),4.01(m,1H)；¹³C{¹H}NMR(75MHz,DMSO-d₆)δ135.1, 131.2,131.0,130.9,130.6,129.5,40.6(t,J_C-D＝20.9Hz).

example 24:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂) Solution in tetrahydrofuran (0.1 mol)/L)10mL, 160mg (8.00mmol) of heavy water, compound 1X (37.1mg, 0.200mmol) were added and stirred vigorously. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 39.7mg of hydrochloride of the target compound 2x, wherein the yield is 95 percent, and the deuteration rate is 96 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2x obtained by adopting the synthesis method, and the test results are as follows:¹H NMR(300MHz,DMSO-d₆)δ8.56(br,3H),7.64(d,J＝2.2Hz,1H),7.46(dd,J＝8.5, 2.2Hz,1H),7.17(d,J＝8.5Hz,1H),3.92(m,1H),3.85(s,3H)；¹³C{¹H}NMR(75MHz, DMSO-d₆)δ154.5,130.7,129.4,127.1,120.7,112.7,56.2,40.8(t,J_C-D＝20.6Hz).

example 25:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, compound 1y (39.3mg, 0.200mmol) were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 37.4mg of hydrochloride of the target compound 2y, wherein the yield is 85 percent, and the deuteration rate is 96 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2y obtained by adopting the synthesis method, and the test results are as follows:¹H NMR(300MHz,CDCl₃)δ8.25(br,3H),2.05(m,3H),1.64(m,12H)；¹³C{¹H}NMR(75 MHz,CDCl₃)δ57.0(t,J_C-D＝22.7Hz),38.0,36.7,34.8,28.1,12.2(m).

example 26:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, compound 1z (35.5mg, 0.200mmol) were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 39.3mg of hydrochloride of the target compound 2z, wherein the yield is 98 percent, and the deuteration rate is 96 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2z obtained by adopting the synthesis method, and the test results are as follows:¹H NMR(500MHz,DMSO-d₆)δ8.57(br,3H),7.46–7.38(m,4H),3.93(m,1H),1.27(s, 9H)；¹³C{¹H}NMR(126MHz,DMSO-d₆)δ150.9,131.1,128.8,125.3,41.5(t,J_C-D＝21.1Hz), 34.3,31.1.

example 27:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, compound 1aa (48.7mg, 0.200mmol) were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 52.3mg of hydrochloride of the target compound 2aa, wherein the yield is 98 percent, and the deuteration rate is 96 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2aa obtained by adopting the synthesis method, and the test results are as follows:¹H NMR(300MHz,DMSO-d₆)δ8.30(br,3H),7.78–7.70(m,2H),7.63(s,1H),7.34(m, 1H),7.27(d,J＝2.2Hz,1H),7.13(dd,J＝8.9,2.2Hz,1H),3.84(s,3H),2.79(m,2H),2.03(m, 1H),1.81(m,1H),1.26(s,3H)；¹³C{¹H}NMR(75MHz,DMSO-d₆)δ156.8,136.1,132.8, 128.7,128.5,127.5,126.8,125.9,118.5,105.8,55.1,46.0(t,J_C-D＝18.7Hz),35.6,30.7,17.9.

example 28:

to a 25mL single neck round bottom flask under argon protection was added samarium diiodide (SmI)₂)10mL of a solution in tetrahydrofuran (0.1mol/L), 160mg (8.00mmol) of heavy water, compound 1ab (66.3mg, 0.200mmol) were added, and the mixture was vigorously stirred. The reaction mixture was stirred at room temperature for 15min, after which air was passed in to quench the reaction. Adding ethyl acetate and 1mol/L sodium hydroxide solution for extraction, drying and concentrating an organic phase, and adding cyclopentyl methyl ether hydrochloride solution (3.0mol/L) to obtain 34.8mg of target compound 2ab hydrochloride, wherein the yield is 49 percent, and the deuteration rate is 96 percent.

The nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is carried out on the target product 2ab obtained by the synthesis method, and the test results are as follows: NMR data of the mixture of two solvents:¹H NMR(400MHz,DMSO-d₆)δ7.75(m, 3H),5.25(m,1H),3.23(m,1H),2.18–2.02(m,2H),2.00–1.84(m,2H),1.82–1.63(m,3H), 1.62–1.27(m,8H),1.26–0.84(m,12H),0.71(m,3H)；¹³C{¹H}NMR(101MHz,DMSO-d₆)δ 141.3,120.3,70.0,55.8,53.8,53.7,49.4,49.4,42.2,41.7,41.4,38.3,37.1,36.9,36.1,36.0,31.4, 31.3,31.2,31.2,26.1,25.5,23.7,23.5,20.4,20.3,19.1,19.1,18.8,18.7,11.6,11.5.

application of alpha-deuterated amine compound

Partial hydrogen atoms in the commercial drug are deuterated to form a deuterated drug, and the deuterated drug is important for drug consistency evaluation, drug metabolism research and drug residue detection. To illustrate the practical application of the α -mono-deuterated amine compound recited in claim 8, the following deuterated pesticides were synthesized by using mono-deuterated amine as a synthesis block.

Examples of the applications

With reference to the reported synthetic method of non-deuterated drugs (Yan, Z.; Liu, A.; Huang, M.; Liu, M.; Pei, H.; Huang, L.; Yi, H.; Liu, W.; Hu, A.Eur.J.Med.chem.2018,149, 170-181), deuterated Tebufenpyrad (Tebufenpyrad-d) can be synthesized by using 2z as a synthetic block₁)。

For the synthesized deuterated pesticide Tebufenpyrad-d₁Performing nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection, and obtaining the following test results:¹H NMR(500MHz,CDCl₃)δ7.38(m,2H),7.28(m,2H),7.07(d,J＝4.9Hz,1H),4.58(m,1H), 4.12(s,3H),2.61(q,J＝7.6Hz,2H),1.31(s,9H),1.23(t,J＝7.6Hz,3H)；¹³C NMR(126MHz, CDCl₃)δ158.4,150.5,149.4,134.4,131.1,127.3,125.6,107.5,42.8(t,J_C-D＝18.7Hz),40.5, 34.4,31.3,19.1,12.8。