A method for hydrogen-deuterium exchange of C(sp 3 )-H bonds under electrochemical conditions

Abstract

The present invention discloses a method for hydrogen-deuterium exchange of C(sp 3 )-H bonds under electrochemical conditions, which comprises the steps of: obtaining a deuterated compound from an aryl acetate, an aryl acetamide, an aryl acetonitrile, a ketone, a sulfone and other compounds containing C(sp 3 )-H bonds in the presence of an electric field, an electrolyte and a deuterium source; wherein the deuterium source is one or more of deuterium water and deuterated alcohol compounds. The present invention has the advantages of mild conditions, green and economical reagents, high deuteration rate, etc. Flow electrochemical experiments prove its potential for amplification and it is suitable for industrial scale-up.

Description

Technical Field:

[0001] The present invention relates to the technical field of electro-synthesis chemistry, and particularly relates to a method for C(sp 3 )-H bond hydrogen-deuterium exchange under electrochemical conditions. Background Art:

[0002] Deuterium is an inexpensive non-radioactive hydrogen isotope. Deuterated compounds are a class of important substances and have extensive and important applications in fields such as nuclear physics, organic chemistry, and pharmaceutical chemistry. Due to the difference in the atomic structures of deuterium and protium, the bond length of C-D is slightly shorter, the bond energy is slightly larger, and the metabolism is slower than that of C-H. This property can be used for isotope effect experiments, the development of new deuterated drugs, and metabolism research. Compared with hydrogen isotope exchange reactions, substitution deuteration reactions and reduction deuteration reactions have better site selectivity and higher deuteration rates, but usually require the introduction of compounds containing leaving groups or unsaturated bonds, which prolongs the reaction steps and generates more waste. The hydrogen isotope exchange reaction is an ideal method for synthesizing deuterated compounds. Under the action of a catalyst, the substrate directly undergoes hydrogen-deuterium exchange in an environment where a deuterium source is present, which is the most direct strategy for synthesizing deuterated compounds. With the discovery of new hydrogen isotope exchange catalysts and the development of photocatalytic systems, the reaction conditions for hydrogen-deuterium exchange are developing towards a more green, milder, and more selective direction.

[0003] As a green synthesis method, electro-synthesis has received attention from scientists in recent years. However, the reaction of hydrogen-deuterium exchange by electrochemical methods has not been widely studied. The present invention introduces a simple and economical method for electrochemical hydrogen-deuterium exchange using deuterium oxide or deuterated methanol as the deuterium source. Summary of the Invention:

[0004] The operation method of the present invention is as follows:

[0005] A method for C(sp 3 )-H bond hydrogen-deuterium exchange under electrochemical conditions, comprising the following steps:

[0006] (1) Insert the anode and cathode material electrodes into a dry reaction vessel respectively as the anode and cathode.

[0007] (2) Add the substrate and electrolyte to the reaction vessel. In a closed system, add the solvent and deuterium source, and stir evenly.

[0008] (3) At a certain temperature, electrolyze the reaction system under direct current, monitor the reaction progress with GC-MS, and after the reaction is completed, extract and separate to obtain the product.

[0009] Further, the anode material of the electrode is a graphite electrode, a platinum electrode, or a glassy carbon electrode, and the cathode material is a platinum electrode, a graphite electrode, a glassy carbon electrode, a nickel electrode, a lead electrode, or an iron electrode; preferably, the graphite electrode and the platinum electrode are used as the anode, and the graphite electrode and the nickel electrode are used as the cathode.

[0010] Further, the electrolyte is one or more of tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium chloride, tetrabutylammonium bromide, tetraethylammonium chloride, and tetraethylammonium bromide; preferably, tetraethylammonium chloride, tetraethylammonium bromide, and tetrabutylammonium tetrafluoroborate are used as the electrolyte.

[0011] Further, the solvent is N,N-dimethylformamide or a mixed solution of N,N-dimethylformamide and tetrahydrofuran; preferably, the solvent is N,N-dimethylformamide:tetrahydrofuran = 1:1.

[0012] Further, the deuterium source is deuterium water, deuterated methanol, deuterated ethanol, deuterated tert-butanol, etc.; preferably, the deuterium source is deuterium water and deuterated methanol.

[0013] Further, the reaction temperature is 0 to 50 °C; preferably, the reaction is carried out at room temperature.

[0014] Further, the magnitude of the direct current is 2 to 30 mA; preferably, the magnitude of the current is 5 to 20 mA.

[0015] Further, the molar ratio of the substrate to the electrolyte is 1:(0.3 to 5); preferably, the molar ratio of the substrate to the electrolyte is 1:(0.5 to 2).

[0016] Further, the molar ratio of the substrate to the deuterium source is 1:(1 to 50); preferably, the molar ratio of the substrate to the deuterium source is 1:(10 to 30).

[0017] Further, the molar concentration of the substrate is 0.05 mol / L to 0.5 mol / L; preferably, the molar concentration of the substrate is 0.1 mol / L to 0.2 mol / L.

[0018] Further, the reaction formula of the substrate and the deuterium source is shown in formula (I):

[0019]

[0020] Among them, R 1 is a C1-12 alkyl group, alkenyl group, aryl group, or heteroaryl group; the aryl group and the heteroaryl group are each independently substituted by 0, 1, 2, 3, 4, or 5 R a substituents. R a is independently an alkyl group, an alkoxy group, an alkenyl group, an aryl group, fluorine, chlorine, bromine, iodine, trifluoromethyl, cyano group, ester group, ketone carbonyl group, amide group, ether bond, etc.

[0021] Among them, R 2 is a keto carbonyl group, a sulfone group, a cyano group, an ester group, or an amide group; the ester group includes alkyl esters with C1-12 alkyl groups, cycloalkyl esters, alkenyl esters, aryl esters, 2-chloroethyl esters, 2-isopropoxyethyl esters, (S)-N-tert-butoxycarbonylpyrrolidin-2-ylmethyl esters, and stigmasteryl esters; the amide group includes alkyl amides, cycloalkyl amides, alkenamides, morpholine amides, aryl amides, etc.

[0022] Among them, R 3 is hydrogen, methyl, ethyl, aryl, heteroaryl, etc.

[0023] Furthermore, the reaction time is 1 to 8 h.

[0024] Furthermore, the product yield obtained by this method can reach 75% to 99%, and the deuteration rate can reach 90 to 94%.

[0025] The beneficial effects of the method of the present invention are as follows:

[0026] 1) The reaction conditions are mild, and the reaction has a good effect in a neutral environment at room temperature.

[0027] 2) There is no participation of transition metals, strong chemical oxidants, strong chemical reductants, strong acids or strong bases.

[0028] 3) A small amount of deuterated reagent is used as the deuterium source, with high deuterium atom utilization rate, low cost, safety, and environmental friendliness.

[0029] 4) The reaction has good compatibility with substrates and can be compatible with a variety of substrates and functional groups, and the effect is still good after scaling up. Specific embodiments:

[0030] Example 1:

[0031] In a dry three-necked flask (15 mL) equipped with a magnetic stirrer, graphite electrodes (1.5×1.5×0.03 cm 3 ) were respectively inserted into the three-necked flask as the anode and cathode. 0.5 mmol of ethyl phenylacetate (82.0 mg), 0.25 mmol of tetraethylammonium chloride (41.4 mg) as the electrolyte were added to the three-necked flask. 10 mmol of D2O (180 μL), 3.0 mL of N,N-dimethylformamide, and 3.0 mL of tetrahydrofuran were added to the closed system.

[0032] Under room temperature conditions, the reaction system was stirred under a direct current of 10 mA for electrolysis for 6 h. After the reaction was completed, extraction was carried out, and the product was separated to obtain ethyl phenylacetate-α,α-d2 with a yield of 95% and a deuteration rate of 93%.

[0033] Example 2:

[0034] In a dry three-necked flask (15 mL) equipped with a magnetic stir bar, graphite electrodes (1.5×1.5×0.03 cm 3 ) were inserted into the three-necked flask as the anode and cathode respectively. 0.3 mmol of methyl ibuprofen (66.0 mg), 0.5 mmol of tetraethylammonium chloride (82.8 mg) as the electrolyte were added to the three-necked flask. 10 mmol of CD3OD (180 μL), 4.0 mL of N,N-dimethylformamide and 2.0 mL of tetrahydrofuran were added to the closed system.

[0035] At room temperature, the reaction system was stirred under a direct current of 10 mA and electrolyzed for 5 h. After the reaction, extraction was carried out, and the product was separated to obtain methyl ibuprofen-α-d1 with a yield of 99% and a deuterium substitution rate of 90%.

[0036] Example 3:

[0037] In a dry three-necked flask (15 mL) equipped with a magnetic stir bar, graphite electrodes (1.5×1.5×0.03 cm 3 ) were inserted into the three-necked flask as the anode and cathode respectively. 0.5 mmol of methyl thiopheneacetate (78.0 mg), 0.5 mmol of tetraethylammonium chloride (82.8 mg) as the electrolyte were added to the three-necked flask. 10 mmol of D2O (180 μL), 3.0 mL of N,N-dimethylformamide and 3.0 mL of tetrahydrofuran were added to the closed system.

[0038] At room temperature, the reaction system was stirred under a direct current of 5 mA and electrolyzed for 4 h. After the reaction, extraction was carried out, and the product was separated to obtain methyl thiopheneacetate-α,α-d2 with a yield of 77% and a deuterium substitution rate of 91%.

[0039] Example 4:

[0040] In a dry three-necked flask (15 mL) equipped with a magnetic stir bar, graphite electrodes (1.5×1.5×0.03 cm 3 ) were inserted into the three-necked flask as the anode and cathode respectively. 0.5 mmol of p-iodobenzyl cyanide (121.5 mg), 0.3 mmol of tetraethylammonium bromide (63.0 mg) as the electrolyte were added to the three-necked flask. 15 mmol of D2O (270 μL), 3.0 mL of N,N-dimethylformamide and 3.0 mL of tetrahydrofuran were added to the closed system.

[0041] At room temperature, the reaction system was stirred under a direct current of 10 mA and electrolyzed for 4 h. After the reaction, extraction was carried out, and the product was separated to obtain p-iodobenzyl cyanide-α,α-d2 with a yield of 82% and a deuterium substitution rate of 93%.

[0042] Example 5:

[0043] In a dry three-necked flask (15 mL) equipped with a magnetic stir bar, a platinum electrode and a graphite electrode (1.5×1.5×0.03 cm 3 ) were inserted into the three-necked flask as the anode and cathode, respectively. 0.5 mmol of fluorene (83.1 mg), 0.25 mmol of tetrabutylammonium tetrafluoroborate (82.3 mg) as the electrolyte were added to the three-necked flask, and 15 mmol of D2O (270 μL) and 6.0 mL of N,N-dimethylformamide were added to the closed system.

[0044] At room temperature, the reaction system was stirred under a direct current of 15 mA for electrolysis for 1 h. After the reaction was completed, extraction was carried out to separate the product, obtaining fluorene-d2 with a yield of 96% and a deuteration rate of 94%.

[0045] Example 6:

[0046] In a dry three-necked flask (15 mL) equipped with a magnetic stir bar, a graphite electrode (1.5×1.5×0.03 cm 3 ) were inserted into the three-necked flask as the anode and cathode, respectively. 0.5 mmol of cyclododecanone (91.0 mg), 0.25 mmol of tetrabutylammonium hexafluorophosphate (96.8 mg) as the electrolyte were added to the three-necked flask, and 15 mmol of D2O (270 μL) and 6.0 mL of N,N-dimethylformamide were added to the closed system.

[0047] At room temperature, the reaction system was stirred under a direct current of 15 mA for electrolysis for 4 h. After the reaction was completed, extraction was carried out to separate the product, obtaining cyclododecanone-d4 with a yield of 87% and a deuteration rate of 92%.

[0048] Example 7:

[0049] In a dry three-necked flask (15 mL) equipped with a magnetic stir bar, a graphite electrode (1.5×1.5×0.03 cm 3 ) were inserted into the three-necked flask as the anode and cathode, respectively. 0.3 mmol of 4-bromophenyl sulfone (70.0 mg), 0.25 mmol of tetrabutylammonium chloride (69.5 mg) as the electrolyte were added to the three-necked flask, and 15 mmol of D2O (270 μL) and 6.0 mL of N,N-dimethylformamide were added to the closed system.

[0050] At room temperature, the reaction system was stirred under a direct current of 15 mA for electrolysis for 2 h. After the reaction was completed, extraction was carried out to separate the product, obtaining 4-bromophenyl sulfone-d3 with a yield of 81% and a deuteration rate of 91%.

[0051] Example 8:

[0052] In a dry three-necked flask (15 mL) equipped with a magnetic stir bar, a graphite electrode and a nickel electrode (1.5×1.5×0.03 cm 3) Insert a three-necked flask as the anode and cathode respectively. Add 0.5 mmol of phenacetylmorpholine (102.5 mg) and 0.25 mmol of tetrabutylammonium bromide (80.6 mg) as the electrolyte into the three-necked flask. Add 10 mmol of D2O (180 μL), 3.0 mL of N,N-dimethylformamide and 3.0 mL of tetrahydrofuran into the closed system.

[0053] Under room temperature conditions, stir the reaction system under a direct current of 15 mA and electrolyze for 5 h. After the reaction is completed, extract and separate the product to obtain phenacetylmorpholine-α,α-d2 with a yield of 84% and a deuteration rate of 90%.

[0054] Example 9:

[0055] In a dry three-necked flask (15 mL) equipped with a magnetic stirrer, insert a graphite electrode and an iron electrode (1.5×1.5×0.03 cm 3 ) as the anode and cathode respectively into the three-necked flask. Add 0.3 mmol of zolpidem (100.0 mg) and 0.5 mmol of tetraethylammonium chloride (82.5 mg) as the electrolyte into the three-necked flask. Add 10 mmol of D2O (180 μL), 3.0 mL of N,N-dimethylformamide and 3.0 mL of tetrahydrofuran into the closed system.

[0056] Under room temperature conditions, stir the reaction system under a direct current of 15 mA and electrolyze for 5 h. After the reaction is completed, extract and separate the product to obtain zolpidem-d2 with a yield of 45% and a deuteration rate of 93%.

[0057] Example 10:

[0058] In a dry reaction tube (200 mL) equipped with a magnetic stirrer, add ethyl 2-ethoxy-4-(2-ethoxy-2-oxoethyl)benzoate (2.13 g, 7.5 mmol), tetraethylammonium chloride (100 mg, 0.6 mmol), D2O (4.0 mL, 225 mmol) and DMF / THF (1:1, 70 mL). The flow cell is equipped with graphite paper (9.3 cm×9.3 cm×0.2 mm) as the anode and a platinum plate (9.3 cm×9.3 cm×0.3 mm) as the cathode (contact area 1.6 cm 2 ). The reaction mixture flows through the electrochemical reactor at a flow rate of 0.30 mL s -1 .

[0059] Under room temperature conditions, stir the reaction system under a direct current of 30 mA and electrolyze for 8 h. After the reaction is completed, extract and separate the product to obtain ethyl 2-ethoxy-4-(2-ethoxy-2-oxoethyl-1,1-d2)benzoate with a yield of 99% and a deuteration rate of 93%.

[0060] Table 1 Products, yields, and deuteration rates obtained from the reactions of different substrates and deuterium sources

[0061]

[0062]

Claims

1. A method for hydrogen-deuterium exchange of C(sp 3 )-H bonds under electrochemical conditions, characterized in that, It includes the steps of: performing a hydrogen-deuterium exchange reaction on a substrate in the presence of an electric field, an electrolyte, a solvent, and a deuterium source to obtain a deuterated chemical, wherein the deuterium source is one or more of deuterium water and deuterated alcohol compounds; The reaction formula of the substrate and the deuterium source is shown in formula (I), Among them, R 1 is C1-12 alkyl, alkenyl, aryl and heteroaryl; the aryl and heteroaryl are each independently substituted by 0, 1, 2, 3, 4, 5 R a substituents; R a is independently alkyl, alkoxy, alkenyl, aryl, fluorine, chlorine, bromine, iodine, trifluoromethyl, cyano, ester group, ketone carbonyl, amide group; Among them, R 2 is a ketone carbonyl group, a sulfone group, a cyano group, an ester group, an amide group; the ester group includes alkyl esters with C1-12, cycloalkyl esters, alkenyl esters, aryl esters, 2-chloroethyl esters, 2-isopropoxyethyl esters, (S)-N-tert-butoxycarbonylpyrrolidine-2-methyl esters, and stigmasteryl esters; the amide group includes alkyl amides, cycloalkyl amides, alkenamides, morpholine amides, and aryl amides; wherein, R 3 is hydrogen, methyl, ethyl, aryl, or heteroaryl.

2. The method for hydrogen-deuterium exchange of C(sp 3 )-H bonds under electrochemical conditions according to claim 1, characterized in that, Specifically, it includes the steps of: adding a substrate, an electrolyte, a solvent, and a deuterium source into a reaction vessel, placing an anode and a cathode in the reaction vessel, the reaction temperature is 0°C to 50°C, setting a constant current to perform hydrogen-deuterium exchange to obtain a deuterated chemical; wherein the deuterium source is one or more of deuterium water and deuterated alcohol compounds.

3. The method for hydrogen-deuterium exchange of C(sp 3 )-H bonds under electrochemical conditions according to claim 1 or 2, characterized in that, The deuterated alcohol compound is deuterated methanol, deuterated ethanol, or deuterated tert-butanol.

4. The method for hydrogen-deuterium exchange of C(sp 3 )-H bonds under electrochemical conditions according to claim 1 or 2, characterized in that, The electrolyte is one or more of tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium chloride, tetrabutylammonium bromide, tetraethylammonium chloride, and tetraethylammonium bromide.

5. The method for hydrogen-deuterium exchange of C(sp 3 )-H bonds under electrochemical conditions according to claim 1 or 2, characterized in that, The solvent is N,N-dimethylformamide or a mixed solution of N,N-dimethylformamide and tetrahydrofuran.

6. The method for hydrogen-deuterium exchange of C(sp 3 )-H bonds under electrochemical conditions according to claim 2, characterized in that, The current is 2 to 30 mA.

7. The method for hydrogen-deuterium exchange of C(sp 3 )-H bonds under electrochemical conditions according to claim 1 or 2, characterized in that, The molar ratio of the deuterium source to the substrate is greater than 1.

8. The method for hydrogen-deuterium exchange of C(sp 3 )-H bonds under electrochemical conditions according to claim 2, characterized in that, The anode material of the electrode is a platinum electrode, a graphite electrode, or a glassy carbon electrode, and the cathode material is a platinum electrode, a graphite electrode, a glassy carbon electrode, a nickel electrode, a lead electrode, or an iron electrode.

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