CN114436765B - Benzyl deuterated alpha, alpha-dideuterobenzyl iodide, dideuterobenzylamine and dideuterol drug molecules and synthesis method thereof - Google Patents

Benzyl deuterated alpha, alpha-dideuterobenzyl iodide, dideuterobenzylamine and dideuterol drug molecules and synthesis method thereof Download PDF

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CN114436765B
CN114436765B CN202111600467.6A CN202111600467A CN114436765B CN 114436765 B CN114436765 B CN 114436765B CN 202111600467 A CN202111600467 A CN 202111600467A CN 114436765 B CN114436765 B CN 114436765B
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阳华
郑雨
向皞月
陈凯
何显臣
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Abstract

The invention provides a benzyl deuterated alpha, alpha-dideuterobenzyl iodide and a synthesis method thereof, wherein the synthesis method comprises the following steps: mixing raw materials of benzyl chloride or benzyl bromide and triphenylphosphine according to a certain proportion, adding dry tetrahydrofuran under the condition of argon atmosphere, then reacting for 10-15h at the temperature of 60-70 ℃, and transferring the reaction liquid to an ice bath for cooling; adding a certain amount of methyllithium to react for 10-20min; adding a certain amount of iodine, transferring the reaction solution to normal temperature for reaction for 6-10h, immediately adding a deuterium aqueous solution of sodium hydroxide into the reaction solution, and purifying the reaction solution through a chromatographic column after the reaction is completed to prepare the benzyl deuterated alpha, alpha-dideuterio benzyl iodine. The synthesis method of the invention adopts benzyl chloride or benzyl bromide as raw material and deuterium water as deuterium source, and adopts one-pot synthesis, thus having low synthesis cost and high yield. The invention also provides a method for synthesizing the benzyl deuterated alpha, alpha-dideuterobenzyl amine and the benzyl deuterated alpha, alpha-dideuterobenzyl drug molecule by a one-pot method.

Description

Benzyl deuterated alpha, alpha-dideuterobenzyl iodide, dideuterobenzylamine and dideuterol drug molecules and synthesis method thereof
Technical Field
The invention relates to the technical field of organic compounds and organic synthesis, in particular to a benzyl deuterated alpha, alpha-dideuterobenzyl iodide, dideuterobenzylamine, dideutero drug molecule and a synthesis method thereof.
Background
The metabolism of human body to the medicine mainly depends on the oxidation free radical reaction, so the change of the medicine metabolism mainly aims at the site which is easy to be oxidized and the targeted deuteration, because the C-H bond on the benzyl position which is relatively easy to be oxidized is replaced by the more stable C-D bond, the oxidation resistance and the stability on the benzyl position of the medicine molecule are increased, the metabolic pathway of the medicine molecule can be improved, and the modification of the medicine molecule is realized. In 2017, the first deuterated drug, deutetrabenazine, approved by the FDA caused a hot tide in research with deuterated drugs. Benzyl iodide is used as a high-activity intermediate and widely applied to organic synthesis. In view of the fact that many medicines contain a plurality of benzyl positions which are easy to oxidize, a simple method for synthesizing deuterated benzyl iodide is developed and has great significance for the synthesis of deuterated active medicine molecules.
In the prior art, the methods for synthesizing deuterated benzyl iodide are very few, and reports about the deuterated methods mostly relate to the use of noble metals Pd, ir or Rh and expensive deuterium sources such as sodium boron deuteride or lithium aluminum deuteride, and have the defects of high cost, complex process, low yield and the like; meanwhile, the synthesized alpha, alpha-dideuter benzyl iodine has few varieties.
In view of this, it is very important to develop a new synthesis process to solve the above technical problems.
Disclosure of Invention
The invention aims to solve the technical problem of providing benzyl deuterated alpha, alpha-dideuterobenzyl iodide and a synthesis method thereof.
In order to solve the problems, the technical scheme of the invention is as follows:
a benzyl deuterated alpha, alpha-dideuterobenzyl iodide has the following structural formula:
Figure GDA0003979738310000021
wherein R is F, cl or CH 3 、t-Bu、OCH 3 、CN、COOt-Bu、SO 2 NEt 2 、Ph、2-CNC 6 H 5 Or R group and a benzene ring form quinoline or naphthalene.
The synthesis method of the benzyl deuterated alpha, alpha-dideuterobenzyl iodide comprises the following steps:
mixing raw materials of benzyl chloride with an R substituent or benzyl bromide with the R substituent and triphenylphosphine according to a certain proportion, carrying out argon protection, adding dry tetrahydrofuran under the argon atmosphere condition, then reacting for 10-15h at the temperature of 60-70 ℃, and transferring reaction liquid to an ice bath for cooling after the reaction; adding a certain amount of methyllithium or bis (trimethylsilyl) amino potassium under the ice-bath condition and reacting for 10-20min; adding a certain amount of iodine, transferring the reaction solution to normal temperature for reaction for 6-10h, immediately adding a deuterium aqueous solution of sodium hydroxide into the reaction solution, and counting a plate to monitor that the reaction is finished to obtain the reaction solution; wherein the reaction temperature of the raw material benzyl chloride or benzyl bromide and triphenylphosphine in the organic solvent can be 60 ℃, 65 ℃,68 ℃ or 70 ℃, and also can be other temperature values in the range;
purifying the reaction liquid by a chromatographic column to obtain a white solid, and drying to obtain the benzyl deuterated alpha, alpha-dideuterobenzyl iodide.
Further, the molar ratio of benzyl chloride with R substituent or benzyl bromide with R substituent, triphenylphosphine, methyllithium/potassium bis (trimethylsilyl) amide, iodine and sodium hydroxide is 1.05-1.2; such as: 1.05.
Further, the molar volume ratio of the benzyl chloride with the R substituent or the benzyl bromide with the R substituent to the mixed solvent is 0.1-0.2mmol/ml, wherein the mixed solvent comprises an organic solvent and a deuterium aqueous solution; the molar volume ratio of the benzyl chloride having an R substituent or the benzyl bromide having an R substituent to the mixed solvent may be 0.1mmol/ml, 0.2mmol/ml, 0.12mmol/ml, 0.15mmol/ml, 0.17mmol/ml, or other ratios within this range.
Further, the column uses (0-1)% by volume of ethyl acetate and petroleum ether as eluent.
Based on the benzyl deuterated alpha, alpha-dideuterobenzyl iodide and the synthesis method thereof, the invention also provides a method for synthesizing benzyl deuterated alpha, alpha-dideuterobenzylamine by using the benzyl deuterated alpha, alpha-dideuterobenzyl iodide as a synthesis monomer. In particular, the method comprises the following steps of,
a benzyl deuterated alpha, alpha-dideuterylbenzylamine having the formula:
Figure GDA0003979738310000031
wherein R' is one of fluorine, phenyl and hydrogen.
The synthesis method of the benzyl deuterated alpha, alpha-dideutery benzylamine comprises the following steps:
mixing raw materials of benzyl chloride with an R 'substituent or benzyl bromide with an R' substituent and triphenylphosphine according to a certain proportion, carrying out argon protection, adding dry tetrahydrofuran under the argon atmosphere condition, then reacting for 10-15h at the temperature of 60-70 ℃, and transferring the reaction liquid to an ice bath for cooling after the reaction; adding a certain amount of methyllithium or bis (trimethylsilyl) amino potassium under the ice-bath condition and reacting for 10-20min; then adding a certain amount of iodine and transferring the reaction liquid to normal temperature for reaction for 6-10 hours; adding a deuterium aqueous solution of potassium phthalimide into the reaction solution, and obtaining the reaction solution after the point plate monitoring reaction is finished; wherein the reaction temperature of the raw material benzyl chloride or benzyl bromide and triphenylphosphine in the organic solvent can be 60 ℃, 65 ℃,68 ℃ or 70 ℃, and also can be other temperature values in the range;
and purifying the reaction liquid by a chromatographic column to obtain a white solid, and drying to obtain the benzyl deuterated alpha, alpha-dideutery benzylamine.
Further, the molar ratio of benzyl chloride with R 'substituent or benzyl bromide with R' substituent, triphenylphosphine, methyllithium/potassium bis (trimethylsilanyl) amide, iodine and potassium phthalimide is 1.05-1.2; such as: 1.05.
Further, the molar volume ratio of the benzyl chloride with the R 'substituent or the benzyl bromide with the R' substituent to the mixed solvent is 0.1-0.2mmol/ml; wherein the mixed solvent comprises an organic solvent and a deuterium aqueous solution; the molar volume ratio of the benzyl chloride having an R 'substituent or the benzyl bromide having an R' substituent to the mixed solvent may be 0.1mmol/ml, 0.2mmol/ml, 0.12mmol/ml, 0.15mmol/ml, 0.17mmol/ml, or may be other ratios within this range.
Further, the chromatographic column adopts ethyl acetate and petroleum ether with the volume ratio of 10-20% as eluent.
Based on the benzyl deuterated alpha, alpha-dideuterobenzyl iodide and the synthesis method thereof, the invention also provides a method for synthesizing the benzyl deuterated alpha, alpha-dideuterobenzyl iodide by using the benzyl deuterated alpha, alpha-dideuterobenzyl iodide as a synthesis monomer. In particular, the method comprises the following steps of,
a benzyl deuterated alpha, alpha-dideuterium drug molecule has the following structural formula:
Figure GDA0003979738310000041
wherein R is F, cl or CH 3 、t-Bu、OCH 3 、CN、COOt-Bu、SO 2 NEt 2 、Ph、2-CNC 6 H 5 Or R group and benzene ring form quinoline or naphthalene; r 1 ，R 2 To form one of 1- (4-chloro-benzhydryl) piperazine and 5- (piperazine-1-yl) pyrimidine.
The method for synthesizing the benzyl deuterated alpha, alpha-dideuterio drug molecule comprises the following steps:
mixing raw materials of benzyl chloride with an R substituent or benzyl bromide with the R substituent and triphenylphosphine according to a certain proportion, carrying out argon protection, adding dry tetrahydrofuran under the argon atmosphere condition, then reacting for 10-15h at the temperature of 60-70 ℃, and transferring reaction liquid to an ice bath for cooling after the reaction; adding a certain amount of methyllithium or bis (trimethylsilyl) amino potassium under the ice-bath condition and reacting for 10-20min; adding a certain amount of iodine, transferring the reaction solution to normal temperature for reaction for 6-10 hours, immediately adding deuterium aqueous solution of sodium hydroxide into the reaction solution, reacting for 15-20 hours, and adding a certain amount of HNR 1 R 2 Reacting for 3-5h, and obtaining a reaction solution after the reaction is finished by monitoring the point plate; wherein the reaction temperature of the raw materials of the benzyl chloride or the benzyl bromide and the triphenylphosphine in the organic solvent can be 60 ℃, 65 ℃,68 ℃ or 70 ℃, and can also be other temperature values in the range;
and purifying the reaction liquid by a chromatographic column to obtain a white solid, and drying to obtain the benzyl deuterated alpha, alpha-dideuterium drug molecule.
Further, benzyl chloride having R substituent or benzyl bromide having R substituent, triphenylphosphine, methyllithium/bis (trimethylsilyl) amino potassium, iodine, sodium hydroxide and HNR 1 R 2 1.05-1.2: 1.05-1.2; such as: 1.05:1.05, 1.2.
Further, the molar volume ratio of the benzyl chloride with the R substituent or the benzyl bromide with the R substituent to the mixed solvent is 0.1-0.2mmol/ml; wherein the mixed solvent comprises an organic solvent and a deuterium aqueous solution; the molar volume ratio of the benzyl chloride having an R substituent or the benzyl bromide having an R substituent to the mixed solvent may be 0.1mmol/ml, 0.2mmol/ml, 0.12mmol/ml, 0.15mmol/ml, 0.17mmol/ml, or other ratios within this range.
Further, the chromatographic column adopts ethyl acetate and petroleum ether with the volume ratio of 10-20% as eluent.
Compared with the prior art, the benzyl deuterated alpha, alpha-dideuterobenzyl iodide, dideuterobenzylamine, dideutero drug molecules and the synthesis method thereof have the beneficial effects that:
1. the benzyl deuterated alpha, alpha-dideuterobenzyl iodide is synthesized by using benzyl chloride or benzyl bromide as a raw material and deuterium water as a deuterium source by adopting a one-pot method, and has the advantages of simple synthesis process, low cost, high yield and deuteration rate, and 86% yield and 97% deuteration rate.
2. The benzyl deuterated alpha, alpha-dideuterobenzyl iodide is used as an important synthetic monomer, and by adding phthalimide potassium or secondary amine into a reaction system, the benzyl deuterated alpha, alpha-dideuterobenzylamine and the benzyl deuterated alpha, alpha-dideuterobenzyl drug molecule can be further synthesized under the condition of a one-pot method, so that the practical value of the synthetic method is fully demonstrated.
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FIG. 19 is a mass spectrum of the product of example 19.
FIG. 20 is a mass spectrum of the product of example 20.
FIG. 21 is a mass spectrum of the product of example 21.
FIG. 22 is a mass spectrum of the product of example 22.
FIG. 23 is a mass spectrum of the product of example 23.
FIG. 24 is a mass spectrum of the product of example 24.
Detailed Description
The following description of the present invention is provided to enable those skilled in the art to better understand the technical solutions in the embodiments of the present invention and to make the above objects, features and advantages of the present invention more comprehensible.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual values, and between the individual values may be combined with each other to yield one or more new ranges of values, which ranges of values should be considered as specifically disclosed herein.
The synthesis method of the benzyl deuterated alpha, alpha-dideuterobenzyl iodide comprises the following steps:
mixing raw materials of benzyl chloride with an R substituent or benzyl bromide with the R substituent and triphenylphosphine according to a certain proportion, carrying out argon protection, adding dry tetrahydrofuran under the argon atmosphere condition, then reacting for 10-15h at the temperature of 60-70 ℃, and transferring reaction liquid to ice bath for cooling after reaction; adding a certain amount of methyllithium or bis (trimethylsilyl) amino potassium under the ice-bath condition and reacting for 10-20min; adding a certain amount of iodine, transferring the reaction solution to normal temperature for reaction for 6-10h, immediately adding a deuterium aqueous solution of sodium hydroxide into the reaction solution, and counting a plate to monitor that the reaction is finished to obtain the reaction solution;
purifying the reaction liquid by a chromatographic column to obtain a white solid, and drying to obtain the benzyl deuterated alpha, alpha-dideuterobenzyl iodide.
The synthesis route is as follows:
Figure GDA0003979738310000061
the structural formula of the prepared benzyl deuterated alpha, alpha-dideuterio benzyl iodide is as follows:
Figure GDA0003979738310000071
wherein R is F, cl or CH 3 、t-Bu、OCH 3 、CN、COOt-Bu、SO 2 NEt 2 、Ph、2-CNC 6 H 5 Or R group and a benzene ring form quinoline or naphthalene.
The benzyl deuterated alpha, alpha-dideuterobenzyl iodide is used as a synthetic monomer, and phthalimide potassium or secondary amine is added into a reaction system, so that the benzyl deuterated alpha, alpha-dideuterobenzylamine and the benzyl deuterated alpha, alpha-dideuterobenzyl drug molecule can be further synthesized under the condition of a one-pot method, and the specific synthesis process comprises the following steps:
a synthetic method of alpha, alpha-dideutery benzylamine with deuterated benzyl position comprises the following steps:
mixing raw materials of benzyl chloride with an R 'substituent or benzyl bromide with an R' substituent and triphenylphosphine according to a certain proportion, carrying out argon protection, adding dry tetrahydrofuran under the argon atmosphere condition, then reacting for 10-15h at the temperature of 60-70 ℃, and transferring the reaction liquid to an ice bath for cooling after the reaction; adding a certain amount of methyllithium or bis (trimethylsilyl) amino potassium under the ice-bath condition and reacting for 10-20min; then adding a certain amount of iodine and transferring the reaction liquid to normal temperature for reaction for 6-10 hours; adding a deuterium aqueous solution of potassium phthalimide into the reaction solution, and obtaining the reaction solution after the point plate monitoring reaction is finished;
and purifying the reaction liquid by a chromatographic column to obtain a white solid, and drying to obtain the benzyl deuterated alpha, alpha-dideutery benzylamine.
The synthesis route is as follows:
Figure GDA0003979738310000072
the structural formula of the prepared benzyl deuterated alpha, alpha-dideuterylbenzylamine is as follows:
Figure GDA0003979738310000073
wherein R' is one of fluorine, phenyl and hydrogen.
A method for synthesizing benzyl deuterated alpha, alpha-dideuterium drug molecules comprises the following steps:
mixing raw materials of benzyl chloride with an R substituent or benzyl bromide with the R substituent and triphenylphosphine according to a certain proportion, carrying out argon protection, adding dry tetrahydrofuran under the argon atmosphere condition, then reacting for 10-15h at the temperature of 60-70 ℃, and transferring reaction liquid to an ice bath for cooling after the reaction; adding a certain amount of methyllithium or bis (trimethylsilyl) amino potassium under the ice-bath condition and reacting for 10-20min; adding a certain amount of iodine, transferring the reaction solution to normal temperature for reaction for 6-10 hours, immediately adding a deuterium aqueous solution of sodium hydroxide into the reaction solution, reacting for 15-20 hours, and adding a certain amount of HNR 1 R 2 Reacting for 3-5h, and obtaining a reaction solution after the reaction is finished by monitoring a point plate;
and purifying the reaction liquid by a chromatographic column to obtain a white solid, and drying to obtain the benzyl deuterated alpha, alpha-dideuterium drug molecule.
The synthesis route is as follows:
Figure GDA0003979738310000081
the structural formula of the prepared benzyl deuterated alpha, alpha-dideuterium drug molecule is as follows:
Figure GDA0003979738310000082
wherein R is F, cl or CH 3 、t-Bu、OCH 3 、CN、COOt-Bu、SO 2 NEt 2 、Ph、2-CNC 6 H 5 Or R group and benzene ring form quinoline or naphthalene; r 1 ，R 2 To form one of 1- (4-chloro-benzhydryl) piperazine and 5- (piperazine-1-yl) pyrimidine.
The present invention provides a benzyl deuterated α, α -dideuterobenzyl iodide, a benzyl deuterated α, α -dideuterobenzylamine, a benzyl deuterated α, α -dideutero drug molecule, and a synthesis process thereof.
Example 1
0.8mmol of the starting material 1 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon shield. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to reduce the temperature. At this temperature 0.84mmol of methyllithium was added and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature to react for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. When the solution is clear, performing spotting, after the reaction is confirmed to be finished, passing the reaction solution through a chromatographic column, eluting by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain 183mg of white solid, wherein the yield is 77%, and performing nuclear magnetic, infrared and mass spectrometry on the solid.
Figure GDA0003979738310000091
The nuclear magnetic test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.58–7.54(m,2H),7.52–7.48(m,2H),7.46–7.39(m,4H),7.36–7.31(m,1H),4.48(d,J＝4.8Hz,0.07H)；
13 C NMR(101MHz,Chloroform-d)δ140.77,140.43,138.15,129.14,128.79,127.50(d,J＝5.5 Hz),127.00,6.12–4.44(m)；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M-I) - ] + calcd for C 13 H 9 D 2 + 169.0981 and found 169.0981 (the structure is shown in figure 1);
the infrared test results are: IR (neat) v 3027,2269,1793,1483,1117,895,754,687cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectrometry, product 1 of this example has the following structure:
Figure GDA0003979738310000092
example 2
0.8mmol of the starting material 2 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon shield. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to reduce the temperature. At this temperature 0.84mmol of methyllithium was added and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature to react for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. When the solution is clear, performing spotting, after the reaction is confirmed to be finished, passing the reaction solution through a chromatographic column, eluting by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain a white solid 147mg, wherein the yield is 57%, the deuteration rate is 93%, and performing nuclear magnetic, infrared and mass spectrometry on the solid.
Figure GDA0003979738310000093
The nuclear magnetic test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.76(ddd,J＝7.8,1.4,0.6Hz,1H),7.64(td,J＝7.7,1.4Hz,1H),7.52–7.51(m,1H),7.50(s,4H),7.45(td,J＝7.6,1.2Hz,1H),4.50(d,J＝4.8Hz,0.15H)；
13 C NMR(101MHz,Chloroform-d)δ144.73,139.82,137.63,133.84,132.93,130.00,129.20(d,J＝8.8Hz),127.79,118.64,111.15,5.34–3.87(m)；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M-I) - ] + Calcd for C 14 H 8 D 2 N + 194.0933, found 194.0932, (structure shown in fig. 2);
the infrared test results are: IR (neat) v 2923,2219,1913,1593,1401,1111,902,756cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectrometry tests, the structure of product 2 of this example can be obtained as follows:
Figure GDA0003979738310000101
example 3
0.8mmol of the starting material 3 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon shield. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to cool. 0.84mmol of methyllithium was added at this temperature and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature to react for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. And (3) when the solution is clear, performing spotting, after the reaction is confirmed to be finished, enabling the reaction solution to pass through a chromatographic column, eluting by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain a white solid 118mg, wherein the yield is 62%, the deuteration rate is 96%, and performing nuclear magnetic, infrared and mass spectrometry on the solid.
Figure GDA0003979738310000102
The nuclear magnetic test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.33(td,J＝7.6,1.8Hz,1H),7.23(tdd,J＝7.4,5.2,1.8Hz,1H),7.06(td,J＝7.6,1.2Hz,1H),6.99(ddd,J＝9.7,8.2,1.2Hz,1H),4.41(d,J＝5.3Hz,0.09H)；
13 C NMR(101MHz,Chloroform-d)δ161.63,159.15,130.78,129.93(d,J＝8.2Hz),124.53(d,J＝3.7 Hz),116.03,115.82,-3.31–-4.27(m)；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M-I) - ] + Calcd for C 7 H 4 D 2 F + 111.0574, found 111.0567 (the structure is shown in fig. 3);
the infrared test results are: IR (neat) v 2917,2849,1583,1492,1454,1236,899,753cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectrometry, product 3 of this example has the following structure:
Figure GDA0003979738310000111
example 4
0.8mmol of the starting material 4 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon shield. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to cool. At this temperature 0.84mmol of methyllithium was added and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. And when the solution is clear, performing spotting, after the reaction is confirmed to be finished, passing the reaction solution through a chromatographic column, eluting by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain a white solid 163mg, wherein the yield is 80%, the deuteration rate is 91%, and performing nuclear magnetic, infrared and mass spectrometry on the solid.
Figure GDA0003979738310000112
The nuclear magnetic test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.37(dt,J＝7.4,3.7Hz,1H),7.33–7.28(m,1H),7.20–7.14(m,2H),4.48(d,J＝5.5Hz,0.18H)；
13 C NMR(101MHz,Chloroform-d)δ134.27(d,J＝5.2Hz),131.41,128.20,127.76,127.04,124.95,1.00–-1.24(m)；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M-I) - +OH - +Na] + Calcd for C 7 H 5 D 2 ClNaO + 167.0203, found 167.0215 (structure shown in FIG. 4);
the infrared test results are: IR (neat) v 2916,1593,1419,1411,1217,1047,846,751cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectrometry, the structure of product 3 of this example is as follows:
Figure GDA0003979738310000121
example 5
0.8mmol of the starting material 5 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon shield. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to reduce the temperature. 0.84mmol of methyllithium was added at this temperature and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature to react for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. And (3) when the solution is clear, performing spotting, after the reaction is confirmed to be finished, enabling the reaction solution to pass through a chromatographic column, eluting by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain a white solid of 128mg, wherein the yield is 68%, the deuteration rate is 95%, and performing nuclear magnetic, infrared and mass spectrometry on the solid.
Figure GDA0003979738310000122
The nuclear magnetic test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.20–7.12(m,3H),7.02(s,1H),4.38(s,0.10H),2.30(s,3H)；
13 C NMR(101MHz,Chloroform-d)δ139.14(d,J＝5.9Hz),138.53,129.50,128.81,125.88,21.41,6.61–5.34(m)；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M-I) - +OH - +Na] + Calcd for C 8 H 8 D 2 KO + 163.0489, found 163.0467 (structure shown in figure 5);
the infrared test results are: IR (neat) v 1998,1746,1530,1343,1206,937,773cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectrometry, product 5 of this example has the following structure:
Figure GDA0003979738310000131
example 6
0.8mmol of raw material 6 (structural formula shown below) and 0.84mmol of triphenylphosphine were mixed, and then the reaction system was protected with argon. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to reduce the temperature. 0.84mmol of methyllithium was added at this temperature and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. And (3) when the solution is clear, performing spotting, after the reaction is confirmed to be finished, enabling the reaction solution to pass through a chromatographic column, eluting by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain a white solid of 125mg, wherein the yield is 66%, the deuteration rate is 95%, and performing nuclear magnetic, infrared and mass spectrometry on the solid.
Figure GDA0003979738310000132
The nuclear magnetic test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.24(td,J＝8.0,5.8Hz,1H),7.13(dt,J＝7.6,1.3Hz,1H),7.06(dt,J＝9.5,2.1Hz,1H),6.92(tdd,J＝8.4,2.6,1.0Hz,1H),4.38(dd,J＝3.8,2.4Hz,0.10H)；
13 C NMR(101MHz,Chloroform-d)δ163.88,161.43,141.49,130.32,124.40,115.74(d,J＝22.0Hz),114.95(d,J＝21.1Hz),4.50–3.09(m)；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M-I) - ] + Calcd for C 7 H 4 D 2 F + 111.0574, found 111.0568 (the structure is shown in fig. 6);
the infrared test results are: IR (neat) v 2251,1684,1439,1265,1151,858,779,684cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectrometry, product 6 of this example has the following structure:
Figure GDA0003979738310000141
example 7
0.8mmol of the starting material 7 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon protection. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to reduce the temperature. At this temperature 0.84mmol of methyllithium was added and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature to react for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. And (3) when the solution is clear, performing spotting, after the reaction is confirmed to be finished, enabling the reaction solution to pass through a chromatographic column, eluting by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain a white solid of 164mg, the yield of 82% and the deuteration rate of 95%, and performing nuclear magnetic, infrared and mass spectrometry on the solid.
Figure GDA0003979738310000142
The nuclear magnetic test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.13–7.06(m,1H),6.88–6.83(m,1H),6.82–6.77(m,1H),6.70–6.65(m,1H),4.30(d,J＝4.8Hz,0.10H),3.68(s,3H).
13 C NMR(101MHz,Chloroform-d)δ159.71,140.58,129.89,121.10,114.23,113.72,55.34,6.61–4.50(m)；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M-I) - ] + Calcd for C 8 H 17 D 2 O + 123.0773; mount 123.0773 (structure shown in fig. 7);
the infrared test results are as follows: IR (neat) v 2932,2357,1597,1485,1263,1036,773,687cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectrometry, product 7 of this example has the following structure:
Figure GDA0003979738310000151
example 8
0.8mmol of the starting material 8 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon shield. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to reduce the temperature. 0.84mmol of methyllithium was added at this temperature and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature to react for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. And (3) when the solution is clear, performing spotting, after the reaction is confirmed to be finished, enabling the reaction solution to pass through a chromatographic column, eluting by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain a white solid of 125mg, wherein the yield is 66%, the deuteration rate is 96%, and performing nuclear magnetic, infrared and mass spectrometry on the solid.
Figure GDA0003979738310000152
The nuclear magnetic test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.37–7.30(m,2H),6.96(t,J＝8.6Hz,2H),4.41(d,J＝5.1Hz,0.09H)；
13 C NMR(101MHz,Chloroform-d)δ163.36,160.90,135.12,130.42,115.91,115.70,4.92–3.65(m)；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M-I) - ] + Calcd for C 7 H 4 D 2 F + 111.0574, found 111.0555 (structure shown in fig. 8);
the infrared test results are as follows: IR (neat) v 2921,2851,1603,1508,1230,816,543cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectroscopy, product 8 of this example has the following structure:
Figure GDA0003979738310000153
example 9
0.8mmol of raw material 9 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon protection. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to reduce the temperature. 0.84mmol of methyllithium was added at this temperature and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature to react for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. When the solution is clear, performing a spotting plate, after the reaction is confirmed to be finished, enabling the reaction solution to pass through a chromatographic column, and eluting by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain 175mg of white solid, wherein the yield is 86%, the deuteration rate is 97%, and performing nuclear magnetic, infrared and mass spectrometry on the solid.
Figure GDA0003979738310000161
The nuclear magnetic test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.25(q,J＝8.5Hz,4H),4.37(d,J＝4.6Hz,0.06H).
13 C NMR(101MHz,Chloroform-d)δ137.78,133.62,130.10,129.06,4.92–3.44(m)；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M-I) - ] + Calcd for C 7 H 4 D 2 Cl + 127.0278, found 127.0278 (structure shown in fig. 9);
the infrared test results are as follows: IR (neat) v 2916,2274,1905,1592,1490,1224,1087,818cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectroscopy, product 9 of this example has the following structure:
Figure GDA0003979738310000162
example 10
0.8mmol of the starting material 10 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon shield. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to reduce the temperature. 0.84mmol of methyllithium was added at this temperature and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature to react for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. And (3) when the solution is clear, performing spotting, after the reaction is confirmed to be finished, enabling the reaction solution to pass through a chromatographic column, eluting by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain 175mg of white solid, wherein the yield is 86% and the deuteration rate is 97%, and performing nuclear magnetic, infrared and mass spectrometry on the solid.
Figure GDA0003979738310000171
The nuclear magnetic test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.61–7.56(m,2H),7.49–7.44(m,2H),4.43(d,J＝4.6Hz,0.13H)；
13 C NMR(101MHz,Chloroform-d)δ144.61,132.62,129.44,118.50,111.55,3.41–2.48(m)；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M-I) - +OH - +H] + Calcd for C 8 H 6 D 2 NO + 136.0726, found 136.0725 (structure shown in fig. 10);
the infrared test results are: IR (neat) v 2917,2222,1932,1605,1503,833,812,736cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectroscopy, the structure of product 10 of this example is shown below:
Figure GDA0003979738310000172
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example 11
0.8mmol of the starting material 11 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon shield. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to reduce the temperature. 0.84mmol of methyllithium was added at this temperature and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. And when the solution is clear, performing spotting, after the reaction is confirmed to be finished, enabling the reaction solution to pass through a chromatographic column, eluting by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain 188mg of a white solid, wherein the yield is 85%, the deuteration rate is 95%, and performing nuclear magnetic, infrared and mass spectrometry on the solid.
Figure GDA0003979738310000181
The nuclear magnetic test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.30(s,4H),4.44(d,J＝5.0Hz,0.11H),1.30(s,9H).
13 C NMR(101MHz,Chloroform-d)δ151.03,136.06,128.47,125.82,34.67,31.28,6.18–5.60(m)；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M-I) - ] + Calcd for C 11 H 13 D 2 + 149.1294, found 149.1291 (structure shown in FIG. 11);
the infrared test results are: IR (neat) v 3049,2958,2066,1599,1505,1191,799,473cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectroscopy, product 11 of this example has the following structure:
Figure GDA0003979738310000182
example 12
0.8mmol of the starting material 12 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon shield. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to cool. 0.84mmol of methyllithium was added at this temperature and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. And when the solution is clear, performing spotting, after the reaction is confirmed to be finished, passing the reaction solution through a chromatographic column, eluting by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain 156mg of white solid, wherein the yield is 61%, the deuteration rate is 91%, and performing nuclear magnetic, infrared and mass spectrometry on the solid.
Figure GDA0003979738310000191
The nuclear magnetic test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.83–7.79(m,2H),7.31–7.28(m,2H),4.33(d,J＝4.8Hz,0.18H),1.49(s,9H)；
13 C NMR(101MHz,Chloroform-d)δ165.15,143.74,131.45,129.95,128.56,81.11,28.23,4.50–3.65(m)；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M-I) - ] + Calcd for C 12 H 13 D 2 O 2 + 193.1192, found 193.1169 (structure shown in fig. 12);
the infrared test results are: IR (neat) v 2813,2533,1670,1420,1280,1016,849,695cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectrometry, the structure of the product of this example can be obtained as follows:
Figure GDA0003979738310000192
example 13
0.8mmol of the starting material 13 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon protection. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to reduce the temperature. 0.84mmol of methyllithium was added at this temperature and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature to react for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. And (3) when the solution is clear, performing spotting, after the reaction is confirmed to be finished, enabling the reaction solution to pass through a chromatographic column, eluting by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain 241mg of white solid, wherein the yield is 85%, the deuteration rate is 96%, and performing nuclear magnetic, infrared and mass spectrometry on the solid.
Figure GDA0003979738310000201
The nuclear magnetic test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.71(d,J＝8.3Hz,2H),7.49(d,J＝8.4Hz,2H),4.45(d,J＝4.7Hz,0.09H),3.23(q,J＝7.1Hz,4H),1.12(t,J＝7.2Hz,6H).
13 C NMR(101MHz,Chloroform-d)δ143.84,139.52,129.38,127.44,42.17,14.29,4.08–2.67(m)；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M-I) - ] + Calcd for C 11 H 14 D 2 NO 2 S + 228.1022, found 228.1025 (structure shown in fig. 13);
the infrared test results are: IR (neat) v 2972,2928,1932,1464,1326,1145,1087,941cm –1 ；
The infrared test results are: IR (KBr) v 3062,2920,1642,1466,1260,1209,1172,832,763,696,525cm -1 ；
Combining the results of nuclear magnetic, infrared and mass spectroscopy, product 13 of this example has the following structure:
Figure GDA0003979738310000202
example 14
0.8mmol of the starting material 14 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon shield. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to reduce the temperature. 0.84mmol of methyllithium was added at this temperature and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature to react for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. And when the solution is clear, performing spotting, after the reaction is confirmed to be finished, enabling the reaction solution to pass through a chromatographic column, eluting by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain a white solid 106mg, wherein the yield is 50%, the deuteration rate is 95%, and performing nuclear magnetic, infrared and mass spectrometry on the solid.
Figure GDA0003979738310000211
The nuclear magnetic test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ6.84(dt,J＝4.5,2.0Hz,2H),6.69(d,J＝8.4Hz,2H),5.92(s,2H),4.41(d,J＝5.0Hz,0.10H)；
13 C NMR(101MHz,Chloroform-d)δ147.85,147.39,132.88,122.19,109.26,108.41,101.35,7.45–5.76(m)；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M-I) - ] + Calcd for C 8 H 5 D 2 O 2 + 137.0566, found 137.0557, (structure shown in fig. 14);
the infrared test results are: IR (neat) v 2192,1980,1529,1343,1206,1148,937cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectroscopy, the structure of product 14 of this example is given below:
Figure GDA0003979738310000212
example 15
0.8mmol of the starting material 15 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon shield. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to cool. 0.84mmol of methyllithium was added at this temperature and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. When the solution is clear, performing spotting, after the reaction is confirmed to be finished, passing the reaction solution through a chromatographic column, eluting by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain 197mg of white solid, wherein the yield is 91%, the deuteration rate is 96%, and performing nuclear magnetic, infrared and mass spectrometry on the solid.
Figure GDA0003979738310000213
The nuclear magnetic test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.82–7.73(m,4H),7.49–7.40(m,3H),4.59(d,J＝5.0Hz,0.08H)；
13 C NMR(101MHz,Chloroform-d)δ136.50,133.32,132.84,128.78,127.80(d,J＝6.6Hz),127.06,126.93,126.50,126.41,6.74–5.96(m)；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M-I) - +OH - +Na] + Calcd for C 11 H 8 D 2 NaO + 183.0749, found 183.0772 (structure shown in FIG. 15);
the infrared test results are: IR (neat) v 2174,1980,1734,1528,1344,1145,918cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectroscopy, the structure of product 15 of this example is shown below:
Figure GDA0003979738310000221
example 16
0.8mmol of the starting material 16 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon shield. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to reduce the temperature. 0.84mmol of methyllithium was added at this temperature and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. And (3) when the solution is clear, performing spotting, after the reaction is confirmed to be finished, enabling the reaction solution to pass through a chromatographic column, eluting by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain 241mg of white solid, wherein the yield is 85%, the deuteration rate is 96%, and performing nuclear magnetic, infrared and mass spectrometry on the solid.
Figure GDA0003979738310000222
The nuclear magnetic test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ8.52(s,1H),8.19(s,1H),8.13(d,J＝7.7Hz,2H),7.97(d,J＝8.6Hz,1H),7.71(d,J＝7.7Hz,2H),7.61(d,J＝8.6Hz,1H),3.95(s,3H)；
13 C NMR(101MHz,Chloroform-d)δ170.3(d,J＝16Hz),166.7,155.6,149.5(d,J＝248Hz),143.0(d,J＝40Hz),143.1,137.3,133.0,130.3,129.8,127.1,125.1(d,J＝7Hz),124.2,119.2,52.2；
19 F NMR(376MHz,Chloroform-d)δ-165.37；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M + Na ]] + calcd for C 17 H 11 FNaO 4 + 321.0534, found 321.0565 (results are shown in FIG. 16);
the infrared test results are: IR (KBr) v 3078,2157,1712,1657,1289,1178,1113,828,767,708cm -1 ；
Combining the results of nuclear magnetic, infrared and mass spectroscopy, product 16 of this example has the following structure:
Figure GDA0003979738310000231
example 17
0.8mmol of the starting material 2 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon shield. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to reduce the temperature. 0.84mmol of methyllithium was added at this temperature and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. After the solution is clarified, 0.84mmol of raw material amine 1 (structural formula shown in the specification) is added to react for 4 hours, a point plate is arranged, after the reaction is confirmed to be finished, the reaction solution passes through a chromatographic column, and is eluted by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain 241mg of white solid, the yield is 85%, the deuteration rate is 96%, and the solid is subjected to nuclear magnetic, infrared and mass spectrometry.
Figure GDA0003979738310000232
The nuclear magnetic test results are as follows: 1 H NMR(CDCl 3 ,400MHz)δ7.83–7.77(m,1H),7.71(d,J＝7.6Hz,1H),7.59(t,J＝7.7Hz,1H),7.52–7.37(m,6H),7.34–7.23(m,3H),7.16(d,J＝7.9Hz,2H),5.42(s,0.11H),3.72(s,3H),2.92(t,J＝7.9Hz,2H),2.77(s,3H),1.87(h,J＝7.5Hz,2H),1.05(t,J＝7.4Hz,3H)；
13 C{ 1 H}NMR(CDCl 3 ,101MHz)δ156.41,154.62,144.54,143.20,142.90,137.88,136.70,136.41(d,J＝6.1Hz),134.90,133.74,132.9,129.96,129.49(d,J＝13.4Hz),127.80,126.53,123.98,122.48,122.27,119.49,118.53,111.14,109.58,108.81,47.13–45.66(m),31.81,29.81,21.85,16.89,14.09；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M + Na ]] + Calcd for C 33 H 27 D 2 N 5 Na + 520.2441；Found 520.2449 (results shown in fig. 17);
the infrared test results are as follows: IR (neat) v 2921,2223,1595,1282,863,763,562cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectroscopy, product 17 of this example was obtained with the following structure:
Figure GDA0003979738310000241
example 18
0.8mmol of the starting material 4 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon shield. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to reduce the temperature. At this temperature 0.84mmol of methyllithium was added and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature to react for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. After the solution is clarified, 0.84mmol of raw material amine 2 (structural formula shown in the specification) is added to react for 4 hours, a point plate is arranged, after the reaction is confirmed to be finished, the reaction solution passes through a chromatographic column, and is eluted by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain 241mg of white solid, the yield is 85%, the deuteration rate is 96%, and the solid is subjected to nuclear magnetic, infrared and mass spectrometry.
Figure GDA0003979738310000242
The nuclear magnetic test results are as follows: 1 H NMR(CDCl 3 ,400MHz)δ7.52(dd,J＝7.6,1.9Hz,1H),7.33(dd,J＝7.7,1.5Hz,1H),7.18(dtd,J＝22.4,7.4,1.7Hz,2H),7.02(d,J＝5.2Hz,1H),6.67(d,J＝5.1Hz,1H),3.78(d,J＝9.3Hz,0.18H),3.60(s,2H),2.86(d,J＝4.6Hz,2H),2.82(dd,J＝6.2,3.6Hz,2H)；
13 C{ 1 H}NMR(CDCl 3 ,101MHz)δ136.18(d,J＝5.5Hz),134.36,134.01,133.50,130.74,129.53,128.31,126.81,125.35,122.70,58.58–57.11(m),53.18,50.78,25.66；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M + Na ]] + Calcd for C 14 H 12 D 2 ClNNaS + 288.0553; found 288.0557 (results shown in fig. 18);
the infrared test results are: IR (neat) v 2917,1650,1436,1242,1025,748,697cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectroscopy, product 18 of this example has the following structure:
Figure GDA0003979738310000251
example 19
0.8mmol of the starting material 5 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon shield. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to reduce the temperature. At this temperature 0.84mmol of methyllithium was added and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature to react for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. After the solution is clarified, 0.84mmol of raw material amine 3 (structural formula shown in the specification) is added to react for 4 hours, a point plate is arranged, after the reaction is confirmed to be finished, the reaction solution passes through a chromatographic column, and is eluted by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain 241mg of white solid, the yield is 85%, the deuteration rate is 96%, and the solid is subjected to nuclear magnetic, infrared and mass spectrometry.
Figure GDA0003979738310000252
The nuclear magnetic test results are as follows: 1 H NMR(CDCl 3 ,400MHz)δ7.32(t,J＝7.7Hz,4H),7.20(q,J＝8.5,7.9Hz,4H),7.14(q,J＝7.7Hz,2H),7.10–7.04(m,2H),7.01(d,J＝7.4Hz,1H),3.42(d,J＝5.1Hz,0.10H),2.42(d,J＝22.9Hz,8H),2.29(s,3H)；
13 C{ 1 H}NMR(CDCl 3 ,101MHz)δ142.31,141.53,137.83(d,J＝5.8Hz),132.58,130.11,129.34,128.68(d,J＝6.3Hz),128.16,127.95(d,J＝10.3Hz),127.20,126.50,75.55,63.15–61.82(m),53.41,51.91,21.53；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M + H ]] + Calcd for C 25 H 26 D 2 ClN 2 + 393.2061; found 393.2077 (results are shown in fig. 19);
the infrared test results are as follows: IR (neat) v 3024,2803,2042,1679,1486,1139,756cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectroscopy, product 19 of this example was obtained with the following structure:
Figure GDA0003979738310000261
example 20
0.8mmol of the starting material 11 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon shield. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to cool. At this temperature 0.84mmol of methyllithium was added and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature to react for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. After the solution is clarified, 0.84mmol of raw material amine 3 (structural formula shown in the specification) is added to react for 4 hours, a point plate is arranged, after the reaction is confirmed to be finished, the reaction solution passes through a chromatographic column, and is eluted by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain 241mg of white solid, the yield is 85%, the deuteration rate is 96%, and the solid is subjected to nuclear magnetic, infrared and mass spectrometry.
Figure GDA0003979738310000262
The nuclear magnetic test results are as follows: 1 H NMR(CDCl 3 ,400MHz)δ7.34–7.27(m,6H),7.23–7.15(m,6H),7.11(t,J＝7.3Hz,1H),4.18(s,1H),3.44(d,J＝12.1Hz,0.11H),2.41(d,J＝24.8Hz,8H),1.27(s,9H)；
13 C{ 1 H}NMR(CDCl 3 ,101MHz)δ149.97,142.34,141.57,135.03(d,J＝7.1Hz),132.63,129.40,129.17,128.73(d,J＝6.7Hz),128.06,127.25,125.20,75.62,62.88–61.51(m),53.40,52.01,34.60,31.63；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M + Na ]] + Calcd for C 28 H 31 D 2 ClN 2 Na + 457.2350; found 457.2319 (results are shown in fig. 20);
the infrared test results are: IR (neat) v 2960,2803,1738,1487,1139,906,731,543cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectroscopy, the structure of product 20 of this example is shown below:
Figure GDA0003979738310000271
example 21
0.8mmol of the starting material 14 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon shield. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to reduce the temperature. At this temperature 0.84mmol of methyllithium was added and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature for 8 hours. When the reaction solution became solid, 1mL of aqueous deuterium solution containing 2.4mmol of sodium hydroxide was added to the reaction solution at this temperature and reacted for 18 hours. After the solution is clarified, 0.84mmol of raw material amine 4 (structural formula shown in the specification) is added to react for 4 hours, a point plate is carried out, after the reaction is confirmed to be finished, the reaction solution passes through a chromatographic column, and is eluted by using ethyl acetate and petroleum ether with the volume ratio of (0-1)% to obtain 241mg of white solid, the yield is 85%, the deuteration rate is 96%, and the solid is subjected to nuclear magnetic, infrared and mass spectrometry.
Figure GDA0003979738310000272
The nuclear magnetic test results are as follows: 1 H NMR(CDCl 3 ,400MHz)δ8.28(d,J＝4.7Hz,2H),6.88(s,1H),6.75(s,2H),6.44(t,J＝4.7Hz,1H),5.93(s,2H),3.86–3.77(m,4H),3.42(d,J＝12.3Hz,0.09H),2.52–2.42(m,4H).
13 C{ 1 H}NMR(CDCl 3 ,101MHz)δ161.66,157.65,147.67,146.67,131.73,122.21,109.68,109.48,107.88,100.88,62.18(dq,J＝40.9,20.4Hz),52.76,43.69；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M + K ]] + Calcd for C 16 H 16 D 2 KN 4 O 2 + 339.1187; found 339.1189 (results are shown in fig. 21);
the infrared test results are as follows: IR (neat) v 2923,2056,1578,1480,1248,1037,886,638cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectrometry, product 21 of this example has the following structure:
Figure GDA0003979738310000281
example 22
0.8mmol of the starting material 1 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon shield. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to reduce the temperature. 0.84mmol of methyllithium was added at this temperature and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature to react for 8 hours. When the reaction liquid became solid, 1mL of a deuterium aqueous solution containing 2.4mmol of potassium phthalimide was added to the reaction liquid at this temperature to react for 18 hours. And (3) performing spotting after the solution is clarified, after the reaction is confirmed to be finished, enabling the reaction solution to pass through a chromatographic column, eluting by using ethyl acetate and petroleum ether with the volume ratio of (10-15)% to obtain a white solid 202mg, wherein the yield is 80%, the deuteration rate is 98%, and performing nuclear magnetic, infrared and mass spectrometry on the solid.
Figure GDA0003979738310000282
The nuclear magnetic test results are as follows: 1 H NMR(CDCl 3 ,400MHz)δ7.77(tt,J＝5.1,2.5Hz,1H),7.63(td,J＝5.3,2.1Hz,2H),7.48–7.41(m,5H),7.33(t,J＝7.5Hz,2H),7.27–7.22(m,1H),4.80(d,J＝5.9Hz,0.04H)；
13 C{ 1 H}NMR(CDCl 3 ,100MHz)δ168.09,140.85,135.26,134.01,132.17,129.12,128.76,127.40(d,J＝9.7Hz),127.11,123.38,40.85(dd,J＝24.6,18.9Hz)；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M + Na ]] + Calcd for C 21 H 13 D 2 NNaO 2 + 338.1121; found 338.1120 (results are shown in fig. 22);
the infrared test results are: IR (neat) v 2165,1769,1700,1485,1185,918,729,525cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectroscopy, product 22 of this example was obtained with the following structure:
Figure GDA0003979738310000291
example 23
0.8mmol of the starting material 8 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon shield. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to cool. 0.84mmol of methyllithium was added at this temperature and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature to react for 8 hours. When the reaction liquid became solid, 1mL of aqueous deuterium solution containing 2.4mmol of potassium phthalimide was added to the reaction liquid at this temperature and reacted for 18 hours. And (3) performing spotting after the solution is clarified, after the reaction is confirmed to be finished, enabling the reaction solution to pass through a chromatographic column, eluting by using ethyl acetate and petroleum ether with the volume ratio of (10-15)% to obtain a white solid 101mg, wherein the yield is 50%, the deuteration rate is 98%, and performing nuclear magnetic, infrared and mass spectrometry on the solid.
Figure GDA0003979738310000292
The nuclear magnetic test results are as follows: 1 H NMR(CDCl 3 ,400MHz)δ7.82(dd,J＝5.4,3.1Hz,2H),7.68(dd,J＝5.5,3.1Hz,2H),7.45–7.39(m,2H),7.02–6.94(m,2H),4.78(s,0.04H)；
13 C{ 1 H}NMR(CDCl 3 ,101MHz)δ167.90,163.57,161.12,134.00,132.06,130.56(d,J＝8.2 Hz),123.32,115.60,115.39,41.02–39.81(m)；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M + Na ]] + Calcd for C 15 H 8 D 2 FNNaO 2 + 280.0713; found 280.0689 (results are shown in fig. 23);
the infrared test results are: IR (neat) v 3071,1762,1709,1506,1388,1186,917,716cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectroscopy, product 23 of this example was obtained with the following structure:
Figure GDA0003979738310000301
example 24
0.8mmol of the starting material 17 (structural formula shown below) was mixed with 0.84mmol of triphenylphosphine, and then the reaction system was subjected to argon shield. 4mL of dry tetrahydrofuran was added under an argon atmosphere and then reacted at 65 ℃. After 12h, the reaction was transferred to a 0 ℃ ice bath to reduce the temperature. 0.84mmol of methyllithium was added at this temperature and reacted for 15 minutes. 0.84mmol of iodine was added and the reaction solution was transferred to room temperature to react for 8 hours. When the reaction liquid became solid, 1mL of aqueous deuterium solution containing 2.4mmol of potassium phthalimide was added to the reaction liquid at this temperature and reacted for 18 hours. And (3) performing spotting after the solution is clarified, after the reaction is confirmed to be finished, enabling the reaction solution to pass through a chromatographic column, eluting by using ethyl acetate and petroleum ether with the volume ratio of (10-15)% to obtain a white solid 72mg, wherein the yield is 38% and the deuteration rate is 98%, and performing nuclear magnetic, infrared and mass spectrometry on the solid.
Figure GDA0003979738310000302
The nuclear magnetic test results are as follows: 1 H NMR(CDCl 3 ,400MHz)δ7.80(dt,J＝7.4,3.7Hz,2H),7.71–7.61(m,2H),7.46–7.39(m,2H),7.35–7.21(m,3H),4.82(d,J＝5.5Hz,0.04H)；
13 C{ 1 H}NMR(CDCl 3 ,100MHz)δ168.00,136.30,133.95,132.14,128.66(d,J＝3.5Hz),127.84,123.31,41.14(dt,J＝42.2,21.4Hz)；
the mass spectrum test result is as follows: HRMS (ESI) M/z [ M + Na ]] + Calcd for C 15 H 8 D 2 FNNaO 2 + 280.0713; found 280.0689 (results are shown in fig. 24);
the infrared test results are: IR (neat) v 3071,1762,1709,1506,1388,1186,917,716cm –1 ；
Combining the results of nuclear magnetic, infrared and mass spectroscopy, the structure of product 24 of this example is given below:
Figure GDA0003979738310000311
compared with the prior art, the benzyl deuterated alpha, alpha-dideuterobenzyl iodide, dideuterobenzylamine, dideutero drug molecules and the synthesis method thereof have the beneficial effects that:
1. the alpha, alpha-dideuterobenzyl iodide with deuterated benzyl is synthesized by taking benzyl chloride or benzyl bromide as a raw material and deuterium water as a deuterium source by adopting a one-pot method, and has the advantages of simple synthesis process, low cost, high yield and deuteration rate, and 86% yield and 97% deuteration rate.
2. The benzyl deuterated alpha, alpha-dideuterobenzyl iodide is used as an important synthetic monomer, and phthalimide potassium or secondary amine is added into a reaction system, so that benzyl deuterated alpha, alpha-dideuterobenzylamine and benzyl deuterated alpha, alpha-dideuterobenzyl drug molecules can be further synthesized under the condition of a one-pot method, and the practical value of the synthetic method is fully demonstrated.
The embodiments of the present invention have been described in detail, but the present invention is not limited to the described embodiments. Various changes, modifications, substitutions and alterations to these embodiments will occur to those skilled in the art without departing from the spirit and scope of the present invention.

Claims (12)

1. A synthetic method of alpha, alpha-dideuterobenzyl iodide with deuterated benzyl is characterized by comprising the following steps:
mixing raw materials of benzyl chloride with an R substituent or benzyl bromide with the R substituent and triphenylphosphine according to a certain proportion, carrying out argon protection, adding dry tetrahydrofuran under the argon atmosphere condition, then reacting for 10-15h at the temperature of 60-70 ℃, and transferring reaction liquid to an ice bath for cooling after the reaction; adding a certain amount of methyllithium or bis (trimethylsilyl) amino potassium under the ice-bath condition and reacting for 10-20min; then adding a certain amount of iodine, transferring the reaction solution to normal temperature for reaction for 6-10h, immediately adding a deuterium aqueous solution of sodium hydroxide into the reaction solution, and obtaining the reaction solution after the reaction is finished by monitoring a point plate;
purifying the reaction liquid by a chromatographic column to obtain a white solid, and drying to obtain the benzyl deuterated alpha, alpha-dideuterio benzyl iodide, wherein the structural formula is as follows:
Figure FDA0003979738300000011
wherein R is F, cl or CH 3 、t-Bu、OCH 3 、CN、COOt-Bu、SO 2 NEt 2 、Ph、2-CNC 6 H 5 Or R group and a benzene ring form quinoline or naphthalene.
2. The method of synthesizing benzyl deuterated α, α -dideuterylbenzyliodide as claimed in claim 1, wherein the molar ratio of benzyl chloride with R substituent or benzyl bromide with R substituent, triphenylphosphine, methyllithium/bis (trimethylsilanyl) amino potassium, iodine and sodium hydroxide is 1.05-1.2.
3. The method of synthesizing benzyl deuterated α, α -dideuterobenzyl iodide as claimed in claim 1, wherein the molar volume ratio of the benzyl chloride having R substituent or the benzyl bromide having R substituent to the solvent mixture is 0.1-0.2mmol/ml.
4. The method of synthesizing benzyl deuterated α, α -dideuterobenzyl iodide as claimed in claim 1, wherein the column is eluted with (0-1)% by volume of ethyl acetate and petroleum ether.
5. A synthesis method of alpha, alpha-dideutery benzylamine with deuterated benzyl is characterized by comprising the following steps:
mixing raw materials of benzyl chloride with an R 'substituent or benzyl bromide with the R' substituent and triphenylphosphine according to a certain proportion, carrying out argon protection, adding dry tetrahydrofuran under the argon atmosphere condition, then reacting for 10-15h at the temperature of 60-70 ℃, and transferring reaction liquid to ice bath for cooling after reaction; adding a certain amount of methyllithium or bis (trimethylsilyl) amino potassium under the ice-bath condition and reacting for 10-20min; then adding a certain amount of iodine and transferring the reaction liquid to normal temperature for reaction for 6-10 hours; adding a deuterium aqueous solution of potassium phthalimide into the reaction solution, and obtaining the reaction solution after the reaction is finished by monitoring the point plate;
purifying the reaction liquid by a chromatographic column to obtain a white solid, and drying to obtain the benzyl deuterated alpha, alpha-dideutery benzylamine, wherein the structural formula is as follows:
Figure FDA0003979738300000021
wherein R' is one of fluorine, phenyl and hydrogen.
6. The method of synthesizing benzyl deuterated α, α -dideuterylbenzylamine according to claim 5, wherein the molar ratio of benzyl chloride with R 'substituent or benzyl bromide with R' substituent, triphenylphosphine, methyllithium/potassium bis (trimethylsilanyl) amide, iodine and potassium phthalimide is 1.05-1.2.
7. The method for synthesizing benzyl deuterated α, α -dideuterylbenzylamine according to claim 5, wherein the molar volume ratio of benzyl chloride having R 'substituent or benzyl bromide having R' substituent to the mixed solvent is 0.1 to 0.2mmol/ml.
8. The method of synthesizing benzyl deuterated α, α -dideuterylbenzylamine according to claim 5, wherein the column is eluted with 10-20% by volume of ethyl acetate and petroleum ether.
9. A synthetic method of benzyl deuterated alpha, alpha-dideuterium drug molecules is characterized by comprising the following steps:
mixing raw materials of benzyl chloride with an R substituent or benzyl bromide with the R substituent and triphenylphosphine according to a certain proportion, carrying out argon protection, adding dry tetrahydrofuran under the argon atmosphere condition, then reacting for 10-15h at the temperature of 60-70 ℃, and transferring reaction liquid to ice bath for cooling after reaction; adding a certain amount of methyllithium or bis (trimethylsilyl) amino potassium under the ice-bath condition and reacting for 10-20min; adding a certain amount of iodine, transferring the reaction solution to normal temperature for reaction for 6-10 hours, immediately adding deuterium aqueous solution of sodium hydroxide into the reaction solution, reacting for 15-20 hours, and adding a certain amount of HNR 1 R 2 Reacting for 3-5h, and obtaining a reaction solution after the reaction is finished by monitoring the point plate;
purifying the reaction liquid by a chromatographic column to obtain a white solid, and drying to obtain the benzyl deuterated alpha, alpha-dideuterium drug molecule, wherein the structural formula is as follows:
Figure FDA0003979738300000031
wherein R is F, cl or CH 3 、t-Bu、OCH 3 、CN、COOt-Bu、SO 2 NEt 2 、Ph、2-CNC 6 H 5 Or R group and benzene ring form quinoline or naphthalene; r 1 ，R 2 Form one of 1- (4-chloro-benzhydryl) piperazine and 5- (piperazine-1-yl) pyrimidine.
10. The method of claim 9, wherein the benzyl chloride with R substituent or benzyl bromide with R substituent, triphenylphosphine, methyllithium/bis (trimethylsilyl) amino potassium, iodine, sodium hydroxide and HNR 1 R 2 1.05-1.2: 1.05-1.2.
11. The method of synthesizing a benzylic deuterated α, α -dideuterio drug molecule as claimed in claim 9, wherein the molar volume ratio of the benzyl chloride with R substituent or the benzyl bromide with R substituent to the solvent mixture is 0.1-0.2mmol/ml.
12. The method of synthesizing benzyl deuterated α, α -dideuterio drug molecules as claimed in claim 9, wherein the column is eluted with 10-20% by volume of ethyl acetate and petroleum ether.
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