CN114773174B - Synthesis method of alpha-deuterated carbonyl compound - Google Patents

Synthesis method of alpha-deuterated carbonyl compound Download PDF

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CN114773174B
CN114773174B CN202210465715.9A CN202210465715A CN114773174B CN 114773174 B CN114773174 B CN 114773174B CN 202210465715 A CN202210465715 A CN 202210465715A CN 114773174 B CN114773174 B CN 114773174B
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陈铭
樊慧柯
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Changzhou University
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
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    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/007—Steroids
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
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    • C07J1/0051—Estrane derivatives
    • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
    • C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
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Abstract

The invention belongs to the technical field of deuterated compound preparation, and particularly relates to a synthesis method of an alpha-deuterated carbonyl compound. The inorganic alkali barium oxide BaO or barium hydroxide Ba (OH) 2 is used as a catalyst, the deuterium supply reagent is used as a deuterium source, and the alpha site deuteration of the carbonyl compound is efficiently completed. The method can carry out H/D conversion reaction at the alpha position of carbonyl with high selectivity, does not influence other positions, has wide applicable substrates, and can obtain the target product with high yield and high deuteration rate in spite of the cyclic ketone and chain ketone reactions. For the reaction of nitrile compounds and sulfoxide compounds, the target product can be obtained with high yield and medium deuteration rate, and the method has the characteristics of simplicity, high efficiency and good regioselectivity.

Description

Synthesis method of alpha-deuterated carbonyl compound
Technical Field
The invention belongs to the technical field of deuterated compound preparation, and particularly relates to a synthesis method of an alpha-deuterated carbonyl compound.
Background
The alpha-deuterated carbonyl compound can be used for researching an organic chemical reaction mechanism, and can also be used for synthesizing deuterated bioactive molecules to prepare deuterated medicaments; even deuterated reagents can be prepared. As early as 1970, maciel et al (Ellis, p.; maciel, g.j.am. Chem. Soc.1970,92,5829) used inorganic base potassium carbonate as a catalyst, heavy water as a deuteration source, and deuteration reaction of alpha-position of ketone was performed under reflux condition to synthesize deuterated substrate, but the method had to go through two reaction processes and each reaction time was as high as 24 hours to obtain satisfactory target product with high deuteration rate, which required long time and inconvenient operation; thereafter, in 2004, berthelette group (Berthelette, C.; scheigetz, j.label. Comp. Radiopharm.2004,47,891) deuterated arylmethyl ketones using an organic base DBU as catalyst, again using heavy water as the deuteration source, but the process was applicable only to arylmethyl ketones, not to other ketones, and did not give good target products for arylmethyl diketones. Chen group (Zhan, M.; xie, Y.; chen, Y.; et al J.Label. Compd. Radiopharm.2014,57,533) uses pyridine as the base catalyst, which is cumbersome to work up and also requires two reaction passes, with only 40% yields of deuterated product to the alkanone. Group Wasa (Chang, y.; myers, t.; wasa, m.adv.synth.catalyst.2020, 362, 360) catalyzes the deuteration of carbonyl compounds using lewis acid B (C 6F5)3 catalyzed, lewis acid expensive and unstable in air, usually operated in glove boxes, inconvenient to use, and the process gives poor selectivity of α -deuterated carbonyl compounds, and for substrates with bare amino groups, only low deuteration yields of the desired product are obtained.
Disclosure of Invention
In order to simply and efficiently obtain the alpha-deuterated carbonyl compound, the invention provides a synthesis method of the alpha-deuterated carbonyl compound, which uses inorganic base BaO or barium hydroxide Ba (OH) 2 as a catalyst and uses a deuterium supply reagent as a deuterium source to complete the alpha-deuteration of the carbonyl compound with high efficiency. The method has simple post-treatment, and the target deuterated product with high selectivity and high deuteration rate can be obtained by deuteration once.
In order to achieve the purpose of the invention, the technical scheme adopted is as follows: the synthesis method of the alpha-deuterated carbonyl compound comprises the following steps: under the catalysis of barium oxide or barium hydroxide, the carbonyl reagent and the deuterium supply reagent undergo H/D conversion reaction to generate alpha-deuterated carbonyl compounds;
The carbonyl reagent is a compound shown in a general formula (1), a general formula (2), a general formula (3) or a general formula (4)
In the general formula (1) or the general formula (2), R 1、R2、R3 is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group; the substituent is alkyl, halogen, alkoxy and amino;
R in the general formula (3) is halogen.
Further, the alpha-deuterated carbonyl compound is shown in the general formula (5), the general formula (6), the general formula (7) or the general formula (8):
Preferably, the deuterated reaction system further comprises an organic solvent I, wherein the deuterium donor reagent acts as both a deuterium donor reagent and a solvent in the reaction, but the deuterium donor reagent is expensive, and in order to save the cost, an ether or tetrahydrofuran organic solvent I can be used for replacing part of the deuterium donor reagent, and the volume ratio of the deuterium donor reagent to the organic solvent I is as follows: 1:2-1:4; the organic solvent I is selected from one or more than two of alkane (such as pentane and/or hexane), cycloalkane (such as cyclohexane), arene (such as toluene), ether (such as diethyl ether and/or tetrahydrofuran and/or 2-methyltetrahydrofuran and/or dioxane) solvents; more preferably ethers or tetrahydrofuran. The deuteration rate of the alpha-deuterated carbonyl compound obtained by using the alkane and arene reagents is between 15 and 50 percent, and the yield is far inferior to that of ethers or tetrahydrofuran.
Preferably, the molar ratio of the carbonyl reagent to the deuterium donor reagent is: 1:50-1:200.
Preferably, the molar ratio of the carbonyl reagent to the barium oxide is: 1:0.2-1:0.5.
Preferably, the synthesis method of the alpha-deuterated carbonyl compound further comprises the following steps:
step 1: adding a required reagent into the dried reaction container, reacting for 6-12 hours at 80-100 ℃, and quenching the reaction;
step 2: adding an organic solvent II and an aqueous solution for extraction, drying and concentrating an organic phase, and purifying by column chromatography to obtain the alpha-deuterated carbonyl compound;
Preferably, in step 1, the reactor is a 4ml penicillin bottle;
preferably, in step1, quantitative barium oxide and deuterium donor reagent are added into a 4ml penicillin bottle under air condition in sequence;
Preferably, the reagent added in step 1 comprises tetrahydrofuran solvent;
Preferably, in step 2, the organic solvent II used is an ethyl acetate solution;
Preferably, in step 1, the stirring is vigorous stirring;
preferably, in step 1, adding water to quench the reaction;
Preferably, the deuterium donor reagent is any one or a combination of a plurality of heavy water (D 2 O), 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); wherein heavy water is the most preferred, and the reaction of the remaining deuterium donor reagent and carbonyl compound can produce byproducts, resulting in reduced yields of the desired product.
Furthermore, the alpha-deuterated carbonyl compound shown in the general formula (3) or the general formula (4) is used as the raw material to synthesize deuterated testosterone, deuterated estrone, deuterated progesterone and deuterated hexanone theobromine.
Further, the alpha-deuterated carbonyl compound is any one of the following.
Compared with the prior art, the invention has the following beneficial effects: (1) The invention uses barium oxide or barium hydroxide and deuterated donor reagent (heavy water) to convert carbonyl compounds into alpha-deuterated carbonyl compounds under the mild condition in air; the operation is simple and safe;
(2) The method can carry out H/D conversion reaction at the alpha position of the carbonyl group with high selectivity without affecting other positions. The main advantages are wide application range, no toxic by-product, high deuteration rate and good regioselectivity.
Detailed Description
The present invention is not limited to the following embodiments, and those skilled in the art can implement the present invention in various other embodiments according to the present invention, or simply change or modify the design structure and thought of the present invention, which fall within the protection scope of the present invention. It should be noted that, without conflict, the embodiments of the present invention and features of the embodiments may be combined with each other.
The invention is further described in detail below in connection with the examples:
In view of the characteristic that 1 H can be detected but D characteristic peak cannot be detected in 1 H NMR spectrum, the present application compares the signal peak area of hydrogen at carbonyl alpha position of the raw material carbonyl compound with the signal peak area of hydrogen at carbonyl alpha position of the product alpha-deuterated carbonyl compound, which is given by 1 H NMR test, and the following relation is obtained:
wherein A 1 is the signal peak integral area of hydrogen at the carbonyl alpha position of the carbonyl compound of the raw material carbonyl compound, and A 3 is the signal peak integral area of hydrogen at the carbonyl alpha position of the product alpha-deuterated carbonyl compound.
The yield of the application is the nuclear magnetic yield obtained by taking dibromomethane as an internal standard, and the algorithm is as follows:
The volume of added dibromomethane can be obtained from the formula (1), the molar quantity of added dibromomethane is the same as the molar quantity of the carbonyl compound of the raw material, delta 5.3 is the peak position of dibromomethane in deuterated chloroform in 1 H NMR spectrum, the position of delta 5.3 is integrated into 2, H x in the formula (2) represents the number of hydrogen atoms carried by the carbonyl compound of the raw material at the position, A x is the integral area in 1 H NMR spectrum, and the yield is:
Example 1:
To a 4mL vial was added 15.3mg (0.1 mmol) of barium oxide, 100. Mu.L (50.0 mmol) of heavy water, 400. Mu.L of tetrahydrofuran and 56.0mg (0.1 mmol) of Compound 1a, and the reaction mixture was stirred at 80℃for 12 hours. Water was then added to quench the reaction. Ethyl acetate and water are added for extraction, and the organic phase is dried and concentrated to obtain the target compound 3a with the yield of 96%, and the deuteration rate of alpha site (from left to right) is 97% and 95% respectively.
The target product 3a obtained by the synthesis method is subjected to nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection, and the test results are as follows ：1H NMR(300MHz,CDCl3)δ7.33-7.21(m,6H),7.21-7.09(m,3H),4.53(s,1H),3.14(d,J＝5.9Hz,0.08H),2.03(dd,J＝5.7,3.4Hz,0.16H),1.27(s,9H).13C NMR(75MHz,CDCl3)δ207.4,149.1,144.0,140.7,128.6,127.7,127.2,126.4,125.5,49.3,45.6,34.4,31.3,29.6.
Example 2:
To a 4mL vial was added 15.3mg (0.1 mmol) of barium oxide, 100. Mu.L (50.0 mmol) of heavy water, 400. Mu.L of tetrahydrofuran and 29.6mg (0.1 mmol) of Compound 1b, and the reaction mixture was stirred at 80℃for 12 hours. Water was then added to quench the reaction. Ethyl acetate and water are added for extraction, and the organic phase is dried and concentrated to obtain the target compound 3b with the yield of 99 percent and the deuteration rate of alpha site (from left to right) of 98 percent and 93 percent respectively. The target product 3b obtained by the synthesis method is subjected to nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection, and the test results are as follows ：1H NMR(300MHz,CDCl3)δ7.27(dd,J＝9.4,5.1Hz,2H),7.19(t,J＝6.4Hz,3H),2.87(s,2H),2.73(dd,J＝7.2,2.6Hz,0.07H),2.10(dt,J＝4.4,2.2Hz,0.18H).13C NMR(75MHz,CDCl3)δ208.3,141.0,128.5,128.3,126.3,44.7,44.4,44.2,29.6,29.3,29.1,28.9.
Example 3:
To a 4mL vial was added 15.3mg (0.1 mmol) of barium oxide, 100. Mu.L (50.0 mmol) of heavy water, 400. Mu.L of tetrahydrofuran and 39.6mg (0.1 mmol) of Compound 1c, and the reaction mixture was stirred at 80℃for 12 hours. Water was then added to quench the reaction. Ethyl acetate and water are added for extraction, and the organic phase is dried and concentrated to obtain the target compound 3c, the yield is 99%, and the deuteration rate of alpha site is 99%.
The target product 3c obtained by the synthesis method is subjected to nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection, and the test results are as follows ：1H NMR(300MHz,CDCl3)δ7.84-7.82(m,1H),7.81-7.79(m,1H),7.63-7.60(m,1H),7.60-7.57(m,1H),2.55(dt,J＝4.5,2.2Hz,0.03H).13C NMR(75MHz,CDCl3)δ197.1,135.8,131.9,129.8,128.3,25.6.
Example 4:
To a 4mL vial was added 15.3mg (0.1 mmol) of barium oxide, 100. Mu.L (50.0 mmol) of heavy water, 400. Mu.L of tetrahydrofuran and 45.6mg (0.2 mmol) of Compound 1, and the reaction mixture was stirred at 80℃for 12 hours. Water was then added to quench the reaction. Ethyl acetate and water are added for extraction, and the organic phase is dried and concentrated to obtain the target compound 3d with the yield of 99 percent and the deuteration rate of alpha site (from left to right) of 99 percent and 98 percent respectively. The target product 3d obtained by the synthesis method is subjected to nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection, and the test result is as follows ：1H NMR(300MHz,CDCl3)δ7.69-7.60(m,2H),7.52(s,1H),7.31-7.22(m,1H),7.14-7.06(m,2H),3.87(d,J＝3.4Hz,3H),2.98(s,2H),2.76(s,0.06H),2.08(d,J＝1.9Hz,0.06H).13C NMR(75MHz,CDCl3)δ208.4,157.3,136.1,133.1,129.0,128.9,127.5,127.0,126.2,118.8,105.6,65.9,55.3,44.7,44.4,44.2,29.5,29.4,29.1,15.3.
Example 5:
To a 4mL vial was added 8.0mg (0.05 mmol) of barium oxide, 100. Mu.L (50.0 mmol) of heavy water, 400. Mu.L of tetrahydrofuran and 31.4mg (0.1 mmol) of Compound 1e, and the reaction mixture was stirred at 80℃for 12h. Water was then added to quench the reaction. Ethyl acetate and water are added for extraction, and the organic phase is dried and concentrated to obtain the target compound 3e with the yield of 98 percent and the deuteration rate of alpha site of alpha 1:98％;α2:91％;α3 to 99 percent respectively. The target product 3e obtained by the synthesis method is subjected to nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection, and the test results are as follows ：1H NMR(300MHz,CDCl3)δ5.73(d,J＝1.5Hz,1H),2.55(t,J＝9.0Hz,0.09H),2.46(dd,J＝5.3,1.7Hz,0.12H),2.34(dddd,J＝14.5,7.5Hz,4.6,1.6,2H),2.21(d,J＝2.3Hz,0.03H),2.21-2.12(m,1H),2.11-2.00(m,2H),1.91-1.82(m,1H),1.73-1.42(m,7H),1.35-1.21(m,2H),1.19(s,3H),1.15-0.93(m,3H),0.66(d,J＝3.6Hz,3H).13C NMR(75MHz,CDCl3)δ210.2,197.6,170.2,124.0,57.8,55.7,53.7,37.2,36.4,35.4,34.7,33.0,32.5,31.6,26.8,24.2,20.8,19.9,19.0.
Example 6:
To a 4mL vial was added 6.0mg (0.04 mmol) of barium oxide, 100. Mu.L (50.0 mmol) of heavy water, 400. Mu.L of tetrahydrofuran and 34.8mg (0.2 mmol) of Compound 2a, and the reaction mixture was stirred at 80℃for 12 hours. Water was then added to quench the reaction. Ethyl acetate and water are added for extraction, and the organic phase is dried and concentrated to obtain the target compound 4a, the yield is 98%, and the deuteration rate of alpha site is 99%.
The target product 4a obtained by the synthesis method is subjected to nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection, and the test results are as follows ：1H NMR(300MHz,CDCl3)δ7.36-7.29(m,2H),7.27-7.19(m,3H),3.08-2.97(m,1H),2.47(d,J＝4.3Hz,0.07H),2.27-2.15(m,2H),1.93(t,J＝12.7Hz,2H).13C NMR(75MHz,CDCl3)δ211.6,144.9,128.7,126.8,126.7,42.8,41.1,40.9,40.6,34.0.
Example 7:
To a 4mL vial was added 6.0mg (0.04 mmol) of barium oxide, 100. Mu.L (50.0 mmol) of heavy water, 400. Mu.L of tetrahydrofuran and 40.8mg (0.2 mmol) of Compound 2b, and the reaction mixture was stirred at 80℃for 12h. Water was then added to quench the reaction. Ethyl acetate and water are added for extraction, and the organic phase is dried and concentrated to obtain the target compound 4b, the yield is 99%, and the deuteration rate of alpha site is 99%.
The target product 4b obtained by the synthesis method is subjected to nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection, and the test results are as follows ：1H NMR(300MHz,CDCl3)δ7.29(d,J＝4.3Hz,4H),7.26-7.20(m,1H),4.53(s,2H),3.78-3.72(m,1H),2.53(dd,J＝5.9,3.3Hz,0H),2.07(dd,J＝13.5,5.4Hz,2H),1.87(d,J＝13.4Hz,2H).13C NMR(75MHz,CDCl3)δ211.9,138.4,128.4,127.6,127.4,72.2,70.3,66.0,36.8,36.5,33.5,30.4.
Example 8:
To a 4mL vial was added 6.0mg (0.04 mmol) of barium oxide, 100. Mu.L (50.0 mmol) of heavy water, 400. Mu.L of tetrahydrofuran and 40.8mg (0.2 mmol) of Compound 2c, and the reaction mixture was stirred at 80℃for 12h. Water was then added to quench the reaction. Ethyl acetate and water are added for extraction, and the organic phase is dried and concentrated to obtain the target compound 4c, the yield is 99%, and the deuteration rate of alpha site is 99%.
The target product 4c obtained by the synthesis method is subjected to nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection, and the test results are as follows ：1H NMR(300MHz,CDCl3)δ2.34(d,J＝2.3Hz,0.13H),2.04(dd,J＝13.2,3.2Hz,2H),1.70(ddd,J＝14.4,7.2,4.0Hz,1H),1.42-1.23(m,10H),0.90(t,J＝6.8Hz,3H).13C NMR(75MHz,CDCl3)δ212.8,40.8,40.7,40.4,40.2,39.9,35.9,35.5,32.6,32.0,26.9,22.6,14.0.
Example 9:
to a 4mL vial was added 6.0mg (0.04 mmol) of barium oxide, 100. Mu.L (50.0 mmol) of heavy water, 400. Mu.L of tetrahydrofuran and 56.8mg (0.2 mmol) of Compound 2d, and the reaction mixture was stirred at 80℃for 12h. Water was then added to quench the reaction. Ethyl acetate and water are added for extraction, and the organic phase is dried and concentrated to obtain the target compound 4d, the yield is 99%, and the deuteration rate of alpha site is 89%.
The target product 4d obtained by the synthesis method is subjected to nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection, and the test results are as follows ：1H NMR(300MHz,CDCl3)δ7.30-7.17(m,2H),6.75-6.62(m,1H),3.77(d,J＝7.4Hz,2H),2.90(d,J＝4.9Hz,1H),2.47-2.16(m,1.71H),2.00(ddd,J＝16.8,11.5,4.0Hz,2H),1.69-1.39(m,7H),1.25(s,1H),0.97-0.82(m,3H).13C NMR(75MHz,CDCl3)δ214.7,157.6,137.7,132.5,126.3,113.6,111.2,55.8,50.1,48.1,43.5,37.6,32.7,29.7,27.2,26.2,14.1.
Example 10:
To a 4mL vial was added 6.0mg (0.04 mmol) of barium oxide, 100. Mu.L (50.0 mmol) of heavy water, 400. Mu.L of tetrahydrofuran and 60.5mg (0.2 mmol) of compound 2e, and the reaction mixture was stirred at 80℃for 12h. Water was then added to quench the reaction. Ethyl acetate and water are added for extraction, and the organic phase is dried and concentrated to obtain the target compound 4e with the yield of 98 percent and the deuteration rate of alpha site of 98 percent.
The target product 4e obtained by the synthesis method is subjected to nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection, and the test results are as follows ：1H NMR(300MHz,CDCl3)δ5.72(d,J＝0.8,1H),3.35(d,J＝2.3Hz,3H),3.28-3.18(m,1H),3.11(s,0.02H),2.50-2.23(m,4H),2.07-1.96(m,3H),1.71-1.45(m,6H),1.20(d,J＝6.4Hz,4H),1.04-0.90(m,3H),0.79(d,J＝6.6Hz,3H).13C NMR(75MHz,CDCl3)δ199.4,171.2,123.8,90.4,57.8,53.8,53.4,50.6,49.1,42.7,38.6,37.6,35.7,35.6,35.4,33.9,32.7,31.5,31.3,30.4,29.6,27.5,23.2,20.7,17.3,11.5.
Example 11:
To a 4mL vial was added 6.0mg (0.04 mmol) of barium oxide, 200.0. Mu.L (50.0 mmol) of heavy water, 800.0. Mu.L of tetrahydrofuran and 27.0mg (0.2 mmol) of Compound 5-S, and the reaction mixture was stirred at 80℃for 6h. Water was then added to quench the reaction. Ethyl acetate and water are added for extraction, and the organic phase is dried and concentrated to obtain the target compound 4e with the yield of 98 percent and the deuteration rate of cyano alpha position of 95 percent.
The target product 5 obtained by the synthesis method is subjected to nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection, and the test result is as follows ：1H NMR(300MHz,CDCl3)δ7.37-7.24(m,2H),7.13-7.02(m,2H),3.74(d,J＝2.3Hz,0.10H).13C NMR(75MHz,CDCl3)δ162.2,130.4,125.7,114.9,114.7.
Example 12:
to a 4mL vial was added 15.3mg (0.1 mmol) of barium oxide, 0.5mL of heavy water and 14.0mg (0.1 mmol) of compound 6-S, and the reaction mixture was stirred at 80℃for 12h. Water was then added to quench the reaction. Ethyl acetate and water are added for extraction, and the organic phase is dried and concentrated to obtain the target compound 6, the yield is 98%, and the deuteration rate of alpha-position of sulfonyl is 98%.
The hydrochloride of the target product 6 obtained by the synthesis method is subjected to nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection, and the test results are as follows ：1H NMR(300MHz,CDCl3)δ7.65(ddd,J＝6.2,4.2,2.4Hz,2H),7.61-7.47(m,3H),2.70(s,0.04H).13C NMR(75MHz,CDCl3)δ145.7,131.1,129.8,124.1,39.5.
The application also proceeds from the following examples, each of which is followed by the following procedure in example 1, except that each of which has been labeled:
The following comparative experiments were also performed, with the following equations (the other operations are the same as in example 1) except that they were shown in the equations:
Sodium hydroxide and potassium hydroxide catalysts belong to strong alkali, in the deuteration reaction of carbonyl ketone compounds, adol condensation reaction is serious, the deuteration rate can reach 90%, but the yield is only about 50%, and side reactions are serious. The BaO adopted by the method can form Ba (OD) 2 in deuterium water, has moderate alkalinity, and can be well applied to deuteration reaction of ketone compounds. In addition, the application has wide applicable substrates, and can obtain the target product with high yield and high deuteration rate in spite of the cyclic ketone and chain ketone reaction. As for the results of the reactions of the nitrile compound and the sulfoxide compound, the target product can be obtained with high yield and medium deuteration rate, and the barium oxide reaction effect in the reaction is poor when the organic base triethylamine is used for replacing the reaction.
The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should make equivalent substitutions or modifications according to the technical scheme and the concept of the present invention, and should be covered by the scope of the present invention.

Claims (7)

1. A synthesis method of an alpha-deuterated compound is characterized by comprising the following steps: the method comprises the following steps: under the catalytic action of barium oxide, the compound reagent and deuterium donor reagent heavy water undergo H/D conversion reaction to generate alpha-deuterated compounds;
The compound reagent is a compound shown in a general formula (1), a general formula (2), a general formula (3) or a general formula (4):
；
In the general formula (1) or the general formula (2), R 1 is selected from H, substituted or unsubstituted aryl; the substituent is alkyl, halogen and alkoxy;
R 2 is selected from substituted or unsubstituted aryl; the substituent is alkyl, halogen and alkoxy;
R 3 is selected from unsubstituted alkyl, or unsubstituted aryl;
R in the general formula (3) is halogen;
or the compound reagent is 、/>Or (b)The generated alpha-deuterated compound is/>、Or/>；
The molar ratio of the compound reagent to the deuterium donor reagent is as follows: 1:50 to 1:200;
the molar ratio of the compound reagent to the barium oxide is as follows: 1:0.2-1:0.5;
the H/D conversion reaction temperature is 80-100 ℃ and the reaction time is 6-12 hours;
the alpha-deuterated compound is shown in the general formula (5), the general formula (6), the general formula (7) or the general formula (8):
。
2. the method for synthesizing an α -deuterated compound according to claim 1, wherein: the deuteration reaction system also comprises organic solvent ethers; the volume ratio of deuterium donor reagent to organic solvent ether is: 1:2 to 1:4.
3. The method for synthesizing an α -deuterated compound according to claim 1, wherein: the deuteration reaction system also comprises an organic solvent tetrahydrofuran; the volume ratio of deuterium donor reagent to organic solvent tetrahydrofuran is: 1:2 to 1:4.
4. The method for synthesizing an α -deuterated compound according to claim 1, wherein: the synthesis method of the alpha-deuterated carbonyl compound further comprises the following steps:
Step 1: adding a required reagent into the dried reaction container, reacting at a set temperature, and quenching the reaction;
step 2: adding an organic solvent and an aqueous solution for extraction, drying and concentrating an organic phase, and purifying to obtain the alpha-deuterated compound.
5. The method for synthesizing an α -deuterated compound according to claim 4, wherein:
the reagent added in the step 1 is tetrahydrofuran solvent;
And/or, in the step 2, the adopted organic solvent is ethyl acetate solution;
And/or, in the step 1, adding water for quenching reaction.
6. The method for synthesizing an α -deuterated compound according to claim 1, wherein: the alpha-deuterated compound is one of the following compounds:
。
7. A synthesis method of an alpha-deuterated compound is characterized by comprising the following steps: the method comprises the following steps: under the catalytic action of barium oxide, the compound reagent and deuterium donor reagent heavy water undergo H/D conversion reaction to generate alpha-deuterated compounds;
the compound reagent is any one of the following compounds
，
Barium oxide 0.1mmol, heavy water 5 mmol, tetrahydrofuran 400 mu L and compound reagent 0.1mmol, stirring at 80deg.C 12. 12 h, adding water to quench reaction, extracting with ethyl acetate and water, drying the organic phase, concentrating to obtain alpha-deuterated compound、/>Or/>。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104016889A (en) * 2014-06-08 2014-09-03 中国科学院上海有机化学研究所 Isotope labeled sodium cyclamate and preparation method thereof
EP2970265A1 (en) * 2013-03-15 2016-01-20 Plexxikon Inc. Heterocyclic compounds and uses thereof
CN106542982A (en) * 2016-10-31 2017-03-29 上海化工研究院 A kind of preparation method of the deuterium-labeled acetone of stable isotope
CN107445798A (en) * 2016-06-01 2017-12-08 中国农业大学 A kind of synthetic method of the deuterated alcohol compound of α, α-two
CN112939732A (en) * 2021-02-03 2021-06-11 中国农业大学 Synthesis method of alpha-deuterated alcohol compound and deuterated drug
CN113292393A (en) * 2021-04-16 2021-08-24 中国农业大学 Method for synthesizing alpha, alpha-dideuterol and deuterated drugs by reducing and deuterating acyl fluoride compounds

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080194529A1 (en) * 2007-02-12 2008-08-14 Auspex Pharmaceuticals, Inc. HIGHLY SELECTIVE and LONG-ACTING PDE5 MODULATORS
WO2009051747A1 (en) * 2007-10-15 2009-04-23 Concert Pharmaceuticals, Inc. Deuterated lorcaserin

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2970265A1 (en) * 2013-03-15 2016-01-20 Plexxikon Inc. Heterocyclic compounds and uses thereof
CN104016889A (en) * 2014-06-08 2014-09-03 中国科学院上海有机化学研究所 Isotope labeled sodium cyclamate and preparation method thereof
CN107445798A (en) * 2016-06-01 2017-12-08 中国农业大学 A kind of synthetic method of the deuterated alcohol compound of α, α-two
CN106542982A (en) * 2016-10-31 2017-03-29 上海化工研究院 A kind of preparation method of the deuterium-labeled acetone of stable isotope
CN112939732A (en) * 2021-02-03 2021-06-11 中国农业大学 Synthesis method of alpha-deuterated alcohol compound and deuterated drug
CN113292393A (en) * 2021-04-16 2021-08-24 中国农业大学 Method for synthesizing alpha, alpha-dideuterol and deuterated drugs by reducing and deuterating acyl fluoride compounds

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
A Stereochemical Study of the Isomerization of Cyclopropyl Ethers to Allyl Ethers Catalyzed with Zinc Iodide;Sugimura, Takashi, et al;《Journal of Organic Chemistry 》;第61卷(第18期);第6100-6103页 *
Aerobic double dehydrogenative cross coupling between cyclic saturated ketones and simple arenes;Gigant, Nicolas, et al;《Chemistry - A European Journal》;第20卷(第20期);第5890-5894页 *
Catalytic Asymmetric (3 + 3) Cycloaddition of Oxyallyl Zwitterions with α-Diazomethylphosphonates;Liu, Yan，et al;《Organic Letters》;第23卷(第18期);第7295-7300 页 *
Catalytic Deuterium Incorporation within Metabolically Stable β-Amino C-H Bonds of Drug Molecules;Chang, Yejin, et al;《Journal of the American Chemical Society》;第141卷(第37期);第14570-14575页 *
Liu, Yan，et al.Catalytic Asymmetric (3 + 3) Cycloaddition of Oxyallyl Zwitterions with α-Diazomethylphosphonates.《Organic Letters》.2021,第23卷(第18期),第7295-7300 页. *

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