Method for photocatalytic synthesis of dideuterated cyclopropane

Abstract

The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a synthetic method of a dideuterated cyclopropane compound. In a nitrogen environment, a cyclopropene compound is taken as a raw material, potassium carbonate is added in a 450-465nm blue photoreactor under the condition that 2, 4, 5, 6-tetra (9-carbazolyl)-isophthalonitrile is taken as a catalyst, the mixture and deuterium water are subjected to a deuteration reaction, a reaction product is subjected to quenching, extraction, filtration and column chromatography, and the dideuterated cyclopropane compound can be obtained. The catalytic system comprises a catalyst, an alkaline substance and a solvent N-methyl pyrrolidone. According to the method, deuteration of the cyclopropene compound can be realized by using a relatively low catalyst dosage, the deuteration degree is high, the operation process and the separation process are simple, and the method has relatively good safety.

Description

Technical Field

[0001] The present invention belongs to the fields of chemical synthesis and pharmacy, and particularly relates to a method for photocatalytic synthesis of bis-deuterated cyclopropane and the preparation of a pharmaceutical composition containing the derivative. Background Art

[0002] As a hydrocarbon, cyclopropane can be used to prepare various organic compounds, such as propane, propylene, etc., through reactions such as oxidation, chlorination, and hydrogenolysis. These compounds have wide applications in chemical industry production and play an important role in organic synthesis. They can be further modified and functionalized to be used as the structural basis for preparing various drug molecules. The structure of cyclopropane can be used to design and optimize the conformation and stereochemical properties of drug molecules, which is of great significance for drug efficacy and bioavailability. Moreover, the structure of cyclopropane and its derivatives can provide flexibility and diversity for drug design, promoting the discovery and development of new drugs.

[0003] By labeling deuterium at specific molecular positions to accurately determine the molecular structure and chemical environment, replacing hydrogen atoms with deuterium atoms can track the metabolic process of drugs in the body.

[0004] Currently, there are not many studies on deuterated cyclopropane. Summary of the Invention

[0005] The purpose of the present invention is to provide a preparation method for photocatalytic synthesis of bis-deuterated cyclopropane, which can achieve the deuteration of cyclopropane using a small amount of photocatalyst and base, with high yield, high deuteration degree, easy separation, and environmentally friendly and friendly reagents.

[0006] To solve the technical problems of the present invention, the technical solution adopted is: under the conditions of an inert gas, N-methylpyrrolidone, and deuterated water as solvents, and 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile as a catalyst, potassium carbonate is added, and under irradiation with 450-465 nm blue light, compound 1 and compound 2 undergo a photocatalytic radical reaction to synthesize compound 3 The preparation route is as follows:

[0007]

[0008] wherein R 1 is methyl, ethyl, tert-butyl, or benzyl;

[0009] R 2 is methyl, ethyl, or phenyl;

[0010] Ar 1is phenyl or substituted phenyl, and the substituent is: F, Cl, CF3, CH3, CH2CH3 or COOCH3;

[0011] Ar 2 is phenyl or substituted phenyl, and the substituent is: F, Cl, CH3, OCH3, COOCH3 or C2H2.

[0012] Preferably, the molar ratio of compound 1, compound 2, and potassium carbonate is 1:3:3;

[0013] The molar ratio of compound 1 to 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile is 20:1; the volume ratio of N-methylpyrrolidone to deuterated water is 90:10.

[0014] Preferably, the inert gas is nitrogen.

[0015] Preferably, the reaction temperature is room temperature, and the reaction time is 14 - 16 h.

[0016] The beneficial effects of the present invention are:

[0017] Deuterium has important applications in pharmaceutical chemistry research. As a labeling substance in nuclear magnetic resonance imaging, deuterium can accurately determine the molecular structure and chemical environment by labeling specific molecular positions, which helps in drug design and development. By replacing hydrogen atoms with deuterium atoms, the metabolic process of drugs in the body can be tracked to better understand their behavior and effects in the body. The present invention accurately determines the molecular structure and chemical environment by labeling deuterium to specific molecular positions, replaces hydrogen atoms with deuterium atoms, and can track the metabolic process of drugs in the body. The deuterated structure developed in the present invention has a certain drug-binding effect and good stability. The deuterated rate of the deuterated compounds of the present invention is relatively high, and it has good safety.

[0018] Under nitrogen conditions, there is no need to replace the solvent or add compounds midway. The reaction conditions are mild, the deuteration effect is good, and it can be used for the preparation of deuterated products of various cyclopropane compounds. It has small toxic and side effects and good safety.

[0019] The best reaction conditions are as shown in Sequence 15 in Table 1 (i.e., Example 1). The catalyst is 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, the base is potassium carbonate, the solvent is N-methylpyrrolidone and deuterated water with a volume ratio of 90:10. The reaction yield is 77%, the deuterated rates D1 = 94%, D2 = 95%, which are the best reaction conditions. Specific Embodiments

[0020] To make the objectives, technical solutions, and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with embodiments.

[0021] Reaction routes of the following examples

[0022]

[0023] Example 1

[0024] A method for preparing dimethyl (2S * , 3R * )-2-((diphenylamino)methyl)-3-phenylcyclopropane-1,1-dicarboxylic acid-2,3-d2, and the preparation route is as follows:

[0025]

[0026] Into a 10 ml dry Schlenk tube, evacuate and refill with gas three times, place it under a nitrogen atmosphere, add 3.9 mg of 2,4,5,6-tetra(9-carbazolyl)isophthalonitrile, 41.5 mg of potassium carbonate, 23.2 mg of dimethyl 2-phenylcycloprop-2-ene-1,1-dicarboxylate, 55.0 mg of N-methyldiphenylamine, 0.9 ml of N-methylpyrrolidone, and 0.1 ml of deuterated water. Stir overnight at room temperature in a 450 - 465 nm blue light reactor. After quenching with water, separating by ethyl acetate extraction, washing with sodium chloride, drying with magnesium sulfate, filtering, and concentrating by rotary evaporation, a crude product is obtained. The crude product is separated by column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain 31.5 mg of the target compound. The solid is detected to be dimethyl (2S * , 3R * )-2-((diphenylamino)methyl)-3-phenylcyclopropane-1,1-dicarboxylic acid-2,3-d2, with a yield of 75.0%. Deuteration degree: D1 is 94%, and D2 is 95%. 1 H NMR (500 MHz, CDCl3) δ 7.29–7.23 (m, 4H), 7.20 (d, J = 7.4 Hz, 3H), 7.05 (dd, J = 8.0, 1.4 Hz, 2H), 7.02 (d, J = 7.4 Hz, 4H), 6.96 (t, J = 7.4 Hz, 2H), 3.98 (d, J = 15.3 Hz, 1H), 3.88 (d, J = 15.2 Hz, 1H), 3.60 (s, 3H), 3.33 (s, 3H), 3.17 (d, J = 5.5 Hz, 0.06H), 2.90 (t, J = 6.5 Hz, 0.05H).

[0027] Example 2

[0028] A method for preparing dimethyl (2S * , 3R * )-2-(((2-chlorophenyl)(methyl)amino)methyl)-3-phenylcyclopropane-1,1-dicarboxylic acid-2,3-d2, and the preparation route is as follows:

[0029]

[0030] A 10 ml dry Schlenk tube was evacuated and refilled with nitrogen three times. Under a nitrogen atmosphere, 3.9 mg of 2,4,5,6-tetrakis(9-carbazolyl) isophthalonitrile, 41.5 mg of potassium carbonate, 23.2 mg of dimethyl 2-phenylcycloprop-2-ene-1,1-dicarboxylate, 46.7 mg of 2-chloro-N,N-dimethylaniline, 0.9 ml of N-methylpyrrolidone, and 0.1 ml of deuterated water were added. The mixture was stirred overnight at room temperature in a 450 - 465 nm blue light reactor, quenched with water, separated by extraction with ethyl acetate, washed with sodium chloride, dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to obtain a crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain 35.7 mg of the target compound. The solid was detected to be dimethyl (2S * ,3R * )-2-((2-chlorophenyl)(methyl)amino)methyl)-3-phenylcyclopropane-1,1-dicarboxylate-2,3-d2, with a yield of 90.0%. The deuteration degree: D1 was 98% and D2 was 95%. 1 H NMR (500 MHz, CDCl3) δ 7.36–7.33 (m, 1H), 7.26–7.18 (m, 4H), 7.16–7.10 (m, 3H), 6.97–

[0031] 6.93 (m, 1H), 3.72 (s, 3H), 3.42–3.34 (m, 4H), 3.29 (d, J = 13.9 Hz, 1H), 3.22 (s, 0.02H), 2.89 (s, 3H), 2.79 (t, J = 6.7 Hz, 0.05H).

[0032] Example 3

[0033] A method for preparing dimethyl (2S * ,3R * )-2-((ethyl(phenyl)amino)methyl)-3-phenylcyclopropane-1,1-dicarboxylate-2,3-d2, the preparation route is as follows:

[0034]

[0035] A 10 ml dry Schlenk tube was evacuated and filled with nitrogen three times. Under a nitrogen atmosphere, 3.9 mg of 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, 41.5 mg of potassium carbonate, 23.2 mg of dimethyl 2-phenylcycloprop-2-ene-1,1-dicarboxylate, 40.6 mg of N-methyl-N-ethylaniline, 0.9 ml of N-methylpyrrolidone, and 0.1 ml of deuterium oxide were added. The mixture was stirred overnight at room temperature in a 450 - 465 nm blue light reactor. After quenching with water, extraction with ethyl acetate, washing with sodium chloride, drying over magnesium sulfate, and filtration followed by rotary evaporation, a crude product was obtained. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 9:1) to give 17.4 mg of the target compound. The solid was detected as dimethyl (2S * ,3R * )-2-((ethyl(phenyl)amino)methyl)-3-phenylcyclopropane-1,1-dicarboxylate-2,3-d2, with a yield of 46.0%. The deuteration degree: D1 was 92% and D2 was 96%. 1 H NMR (500 MHz, CDCl3) δ 7.34–7.16 (m, 5H), 7.16–7.10 (m, 2H), 6.81 (d, J = 8.2 Hz, 2H), 6.72 (t, J = 7.2 Hz, 1H), 3.79 (s, 3H), 3.59 (d, J = 15.2 Hz, 1H), 3.48–3.38 (m, 3H), 3.36 (s, 3H), 3.31 (s, 0.08H), 2.80 (t, J = 6.3 Hz, 0.04H). 1.14 (t, J = 7.0 Hz, 3H).

[0036] Example 4

[0037] A method for preparing dimethyl (2S * ,3R * )-2-(((3-chlorophenyl)(methyl)amino)methyl)-3-phenylcyclopropane-1,1-dicarboxylate-2,3-d2, and the preparation route is as follows:

[0038]

[0039] A 10 ml dry Schlenk tube was evacuated and refilled with gas three times and placed under a nitrogen atmosphere. 3.9 mg of 2,4,5,6-tetrakis(9-carbazolyl) isophthalonitrile, 41.5 mg of potassium carbonate, 23.2 mg of dimethyl 2-phenylcycloprop-2-ene-1,1-dicarboxylate, 46.7 mg of 3-chloro-N,N-dimethylaniline, 0.9 ml of N-methylpyrrolidone, and 0.1 ml of deuterated water were added. The mixture was stirred overnight at room temperature in a 450 - 465 nm blue light reactor, quenched with water, separated by ethyl acetate extraction, washed with sodium chloride, dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to obtain a crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain 27.1 mg of the target compound. The solid was detected as dimethyl (2S * , 3R * )-2-(((3-chlorophenyl)(methyl)amino)methyl)-3-phenylcyclopropane-1,1-dicarboxylic acid-2,3-d2, with a yield of 67.0%. The deuteration degree: D1 was 96% and D2 was 92%. 1 H NMR (500 MHz, CDCl3) δ 7.34–7.19 (m, 3H), 7.18–7.10 (m, 3H), 6.76 (s, 1H), 6.73–6.64 (m, 2H), 3.77 (s, 3H), 3.63 (d, J = 15.0 Hz, 1H), 3.43 (d, J = 15.1 Hz, 1H), 3.38 (s, 3H), 3.29 (s, 0.04H), 2.96 (s, 3H), 2.76 (t, J = 6.7 Hz, 0.08H).

[0040] Example 5

[0041] A preparation method of dimethyl (2S * , 3R * )-2-(((3-methoxyphenyl)(methyl)amino)methyl)-3-phenylcyclopropane-1,1-dicarboxylic acid-2,3-d2 is as follows:

[0042]

[0043] A 10 ml dry Schlenk tube was evacuated and refilled with gas three times and placed under a nitrogen atmosphere. 3.9 mg of 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, 41.5 mg of potassium carbonate, 23.2 mg of dimethyl 2-phenylcycloprop-2-ene-1,1-dicarboxylate, 45.4 mg of 3-methoxy-N,N-dimethylaniline, 0.9 ml of N-methylpyrrolidone, and 0.1 ml of deuterated water were added. The mixture was stirred overnight at room temperature in a 450 - 465 nm blue light reactor, quenched with water, separated by ethyl acetate extraction, washed with sodium chloride, dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to obtain a crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain 17.1 mg of the target compound. The solid was detected to be dimethyl (2S * , 3R * )-2-(((3-methoxyphenyl)(methyl)amino)methyl)-3-phenylcyclopropane-1,1-dicarboxylate-2,3-d2, with a yield of 44.0%. The deuteration degree: D1 was 96% and D2 was 95%. 1 H NMR (500 MHz, CDCl3) δ 7.25 (s, 1H), 7.25–7.09 (m, 5H), 6.46 (d, J = 8.3 Hz, 1H), 6.37 (t, J = 2.5 Hz, 1H), 6.33 (d, J = 8.1 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.64 (d, J = 15.0 Hz, 1H), 3.40 (d, J = 15.0 Hz, 1H), 3.36 (s, 3H), 3.30 (s, 0.04H), 2.96 (s, 3H), 2.80–2.76 (m, 0.05H).

[0044] Example 6

[0045] A method for preparing dimethyl (2S * , 3R * )-2-(((3,5-dimethylphenyl)(methyl)amino)methyl)-3-phenylcyclopropane-1,1-dicarboxylate-2,3-d2 has the following preparation route:

[0046]

[0047] A 10 ml dry Schlenk tube was evacuated and refilled with nitrogen three times. Under a nitrogen atmosphere, 3.9 mg of 2,4,5,6-tetrakis(9-carbazolyl) isophthalonitrile, 41.5 mg of potassium carbonate, 23.2 mg of dimethyl 2-phenylcycloprop-2-ene-1,1-dicarboxylate, 44.8 mg of 3,5-dimethyl-N,N-dimethylaniline, 0.9 ml of N-methylpyrrolidone, and 0.1 ml of deuterated water were added. The mixture was stirred overnight at room temperature in a 450 - 465 nm blue light reactor. After quenching with water, extraction and separation with ethyl acetate, washing with sodium chloride, drying with magnesium sulfate, and then filtration and evaporation to dryness, a crude product was obtained. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain 29.9 mg of the target compound. The solid was detected as dimethyl (2S * ,3R * )-2-(((3,5-dimethylphenyl)(methyl)amino)methyl)-3-phenylcyclopropane-1,1-dicarboxylate-2,3-d2, with a yield of 77.0%. The deuteration degree: D1 was 96% and D2 was 93%. 1 H NMR (500 MHz, CDCl3) δ 7.27–7.18 (m, 3H), 7.14 (d, J = 6.7 Hz, 2H), 6.47 (s, 2H), 6.43 (s, 1H), 3.78 (s, 3H), 3.63 (d, J = 14.9 Hz, 1H), 3.37 (s, 3H), 3.36 (d, 1H), 3.29 (s, 0.04H), 2.94 (s, 3H), 2.79–2.75 (t, 0.07H), 2.28 (s, 6H).

[0048] Example 7

[0049] A method for preparing dimethyl (2S * ,3R * )-2-((9H-carbazol-9-yl)methyl)-3-phenylcyclopropane-1,1-dicarboxylate-2,3-d2 has the following preparation route:

[0050]

[0051] A 10 ml dry Schlenk tube was evacuated and filled with gas three times and placed under a nitrogen atmosphere. 3.9 mg of 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, 41.5 mg of potassium carbonate, 23.2 mg of dimethyl 2-phenylcycloprop-2-ene-1,1-dicarboxylate, 54.4 mg of N-methylcarbazole, 0.9 ml of N-methylpyrrolidone, and 0.1 ml of deuterium oxide were added. The mixture was stirred overnight at room temperature in a 450 - 465 nm blue light reactor, quenched with water, separated by ethyl acetate extraction, washed with sodium chloride, dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to obtain a crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain 28.0 mg of the target compound. The solid was detected to be dimethyl (2S * ,3R * )-2-((9H-carbazol-9-yl)methyl)-3-phenylcyclopropane-1,1-dicarboxylate-2,3-d2, with a yield of 66.0%. The deuterium incorporation: D1 was 98% and D2 was 92%. 1 H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 7.6 Hz, 2H), 7.55–7.44 (m, 4H), 7.24 (t, J = 7.3 Hz, 2H), 7.14–7.09 (m, 3H), 6.92 (m, J = 6.5, 2.9 Hz, 2H), 4.65 (d, J = 15.5 Hz, 1H), 4.45 (d, J = 15.4 Hz, 1H), 3.83 (s, 3H), 3.34 (s, 3H), 3.21 (s, 0.02H), 3.12 (t, 0.08H).

[0052] Example 8

[0053] A method for preparing dimethyl (2S * ,3R * )-2-(4-(tert-butyl)phenyl)-3-(diphenylamino)methyl)cyclopropane-1,1-dicarboxylate-2,3-d2 has the following preparation route:

[0054]

[0055] A 10 ml dry Schlenk tube was evacuated and refilled with gas three times and placed under a nitrogen atmosphere. 3.9 mg of 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, 41.5 mg of potassium carbonate, 28.8 mg of dimethyl 2-(4-(tert-butyl)phenyl)cycloprop-2-ene-1,1-dicarboxylate, 55.0 mg of N-methyl diphenylamine, 0.9 ml of N-methylpyrrolidone, and 0.1 ml of deuterated water were added. The mixture was stirred overnight at room temperature in a 450 - 465 nm blue light reactor, quenched with water, separated by ethyl acetate extraction, washed with sodium chloride, dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to obtain a crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain 32.9 mg of the target compound. The solid was detected to be dimethyl (2S * ,3R * )-2-(4-(tert-butyl)phenyl)-3-((diphenylamino)methyl)cyclopropane-1,1-dicarboxylate-2,3-d2, with a yield of 70.0%. The deuteration degree: D1 was 95%, and D2 was 96%. 1 H NMR (500 MHz, CDCl3) δ 7.30–7.25 (m, 2H), 7.27–7.20 (m, 4H), 7.05–6.98 (m, 5H), 7.00–6.93 (m, 3H), 3.96 (d, J = 15.3 Hz, 1H), 3.88 (d, J = 15.3 Hz, 1H), 3.59 (s, 3H), 3.32 (s, 3H), 3.15 (s, 0.05H), 2.89 (t, J = 6.4 Hz, 0.06H), 1.26 (s, 9H).

[0056] Example 9

[0057] A method for preparing dimethyl (2R * ,3S * )-2-(4-bromophenyl)-3-((diphenylamino)methyl)cyclopropane-1,1-dicarboxylate-2,3-d2, the preparation route is as follows:

[0058]

[0059] A 10 ml dry Schlenk tube was evacuated and filled with gas three times and placed under a nitrogen atmosphere. 3.9 mg of 2,4,5,6-tetrakis(9-carbazolyl) isophthalonitrile, 41.5 mg of potassium carbonate, 31.1 mg of dimethyl 2-(4-bromophenyl)cycloprop-2-ene-1,1-dicarboxylate, 55.0 mg of N-methyldiphenylamine, 0.9 ml of N-methylpyrrolidone, and 0.1 ml of deuterium oxide were added. The mixture was stirred overnight at room temperature in a 450 - 465 nm blue light reactor, quenched with water, separated by extraction with ethyl acetate, washed with sodium chloride, dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to obtain a crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain 31.1 mg of the target compound. The solid was detected as dimethyl (2R * ,3S * )-2-(4-bromophenyl)-3-((diphenylamino)methyl)cyclopropane-1,1-dicarboxylate-2,3-d2, with a yield of 63.0%. The deuterium incorporation: D1 was 94% and D2 was 96%. 1 H NMR (500 MHz, CDCl3) δ 7.32 (d, J = 8.4 Hz, 2H), 7.29–7.22 (m, 4H), 7.03–6.93 (m, 6H), 6.90 (d, J = 8.4 Hz, 2H), 3.99 (d, J = 15.1 Hz, 1H), 3.82 (d, J = 15.2 Hz, 1H), 3.63 (s, 3H), 3.38 (s, 3H), 3.33 (s, 0.06H), 2.83 (t, J = 6.5 Hz, 0.04H).

[0060] Example 10

[0061] A method for preparing dimethyl (2S * ,3R * )-2-((diphenylamino)methyl)-3-(4-fluorophenyl)cyclopropane-1,1-dicarboxylate-2,3-d2 has the following preparation route:

[0062]

[0063] A 10 ml dry Schlenk tube was evacuated and filled with gas three times and placed under a nitrogen atmosphere. 3.9 mg of 2,4,5,6-tetra(9-carbazolyl) isophthalonitrile, 41.5 mg of potassium carbonate, 25.0 mg of dimethyl 2-(4-fluorophenyl)cycloprop-2-ene-1,1-dicarboxylate, 55.0 mg of N-methyl diphenylamine, 0.9 ml of N-methylpyrrolidone, and 0.1 ml of deuterated water were added. The mixture was stirred overnight at room temperature in a 450 - 465 nm blue light reactor. After quenching with water, extraction and separation with ethyl acetate, washing with sodium chloride, drying with magnesium sulfate, and then filtering and concentrating by evaporation, a crude product was obtained. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain 28.8 mg of the target compound. The solid was detected as dimethyl (2S * , 3R * )-2-((diphenylamino)methyl)-3-(4-fluorophenyl)cyclopropane-1,1-dicarboxylate-2,3-d2, with a yield of 65.0%. The deuteration degree: D1 was 94% and D2 was 96%. 1 H NMR (500 MHz, CDCl3) δ 7.26 (m, J = 8.6, 7.2 Hz, 4H), 7.04–6.97 (m, 6H), 6.98–6.85 (m, 4H), 3.99 (d, J = 15.2 Hz, 1H), 3.83 (d, J = 15.2 Hz, 1H), 3.63 (s, 3H), 3.36 (s, 3H), 3.12 (s, 0.06H), 2.84 (t, J = 6.5 Hz, 0.04H).

[0064] Example 11

[0065] A preparation method of diethyl (2S * , 3R * )-2-((diphenylamino)methyl)-3-phenylcyclopropane-1,1-dicarboxylate-2,3-d2 is as follows:

[0066]

[0067] A 10 ml dry Schlenk tube was evacuated and filled with gas three times and placed under a nitrogen atmosphere. 3.9 mg of 2,4,5,6-tetra(9-carbazolyl) isophthalonitrile, 41.5 mg of potassium carbonate, 26.0 mg of diethyl 2-phenylcycloprop-2-ene-1,1-dicarboxylate, 55.0 mg of N-methyl diphenylamine, 0.9 ml of N-methylpyrrolidone, and 0.1 ml of deuterated water were added. The mixture was stirred overnight at room temperature in a 450 - 465 nm blue light reactor. After quenching with water, extraction and separation with ethyl acetate, washing with sodium chloride, drying with magnesium sulfate, and then filtering and concentrating by evaporation, a crude product was obtained. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain 27.6 mg of the target compound. The solid was detected as diethyl (2S* ,3R * )-2-((Diphenylamino)methyl)-3-phenylcyclopropane-1,1-dicarboxylic acid-2,3-d2, with a yield of 62.0%, deuterium degree: D1 is 94%, D2 is 95%. 1 H NMR (500 MHz, CDCl3) δ 7.29–7.22 (m, 4H), 7.22–7.14 (m, 3H), 7.08–7.00 (m, 6H), 6.99–6.91 (m, 2H), 4.23–4.16 (m, 1H), 4.06–3.96 (m, 2H), 3.86–3.78 (m, 3H), 3.15 (s, 0.06H), 2.86 (t, J = 6.5 Hz, 0.05H), 1.22 (t, J = 7.2 Hz, 3H), 0.84 (t, J = 7.1 Hz, 3H).

[0068] Example 12

[0069] A preparation method of dimethyl (2R * ,3S * )-2-(4-chlorophenyl)-3-((diphenylamino)methyl)cyclopropane-1,1-dicarboxylic acid-2,3-d2 is as follows:

[0070]

[0071] Into a 10 ml dry Schlenk tube, evacuated and replaced with gas three times, under a nitrogen atmosphere, add 3.9 mg of 2,4,5,6-tetrakis(9-carbazolyl)isophthalonitrile, 41.5 mg of potassium carbonate, 26.7 mg of dimethyl 2-(4-chlorophenyl)cycloprop-2-ene-1,1-dicarboxylate, 55.0 mg of N-methyldiphenylamine, 0.9 ml of N-methylpyrrolidone, and 0.1 ml of deuterated water. Stir overnight at room temperature in a 450 - 465 nm blue light reactor. After quenching with water, separating by ethyl acetate extraction, washing with sodium chloride, drying with magnesium sulfate, filtering and concentrating to obtain the crude product. The crude product is separated by column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain 33.9 mg of the target compound. The solid is detected as dimethyl (2R * ,3S * )-2-(4-chlorophenyl)-3-((diphenylamino)methyl)cyclopropane-1,1-dicarboxylic acid-2,3-d2, with a yield of 75.0%, deuterium degree: D1 is 94%, D2 is 95%. 11H NMR (500 MHz, CDCl3) δ 7.30–7.23 (m, 4H), 7.20–7.15 (m, 2H), 7.04–6.98 (m, 4H), 7.00–6.94 (m, 4H), 4.00 (d, J = 15.1 Hz, 1H), 3.83 (d, J = 15.2 Hz, 1H), 3.63 (s, 3H), 3.38 (s, 3H), 3.10 (s, 0.06H), 2.84 (t, J = 6.5 Hz, 0.05H).

[0072] Example 13

[0073] A method for preparing dimethyl (2S * , 3R * )-2-(((2-(2-(4-isobutylphenyl)propanoyl)oxy)ethyl)(phenyl)amino)methyl)-3-phenylcyclopropane-1,1-dicarboxylate-2,3-d2, the preparation route is as follows:

[0074]

[0075] Into a 10 ml dry Schlenk tube, evacuated and replaced with gas three times, under a nitrogen atmosphere, add 3.9 mg of 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, 41.5 mg of potassium carbonate, 23.2 mg of dimethyl 2-phenylcycloprop-2-ene-1,1-dicarboxylate, 101.8 mg of ethyl 2-(methyl(phenyl)amino)-2-(4-isobutylphenyl)propionate, 0.9 ml of N-methylpyrrolidone, 0.1 ml of deuterium water, stir overnight at room temperature in a 450 - 465 nm blue light reactor, quench with water, extract and separate with ethyl acetate, wash with sodium chloride, dry with magnesium sulfate, then filter and evaporate to dryness to obtain the crude product. The crude product is separated by column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain 40.1 mg of the target compound. The solid is detected as dimethyl (2S * , 3R * )-2-(((2-(2-(4-isobutylphenyl)propanoyl)oxy)ethyl)(phenyl)amino)methyl)-3-phenylcyclopropane-1,1-dicarboxylate-2,3-d2, the yield is 70.0%, and the deuteration degree: D1 is 94%, D2 is 80%. 1 1H NMR (500 MHz, CDCl3) δ

[0076] 7.27–7.18(m, 5H), 7.18–7.08(m, 4H), 7.09–7.03(m, 2H), 6.81(dd, J=8.5, 2.7Hz, 2H), 6.75(t, J=7.3Hz, 1H), 4.28–4.13(m, 2H), 3.74(d, J=7.0Hz, 3H), 3.67–3.60(m, 1H), 3.57(q, J=6.0Hz, 2H), 3.50(dd, J=15.2, 4.7Hz, 1H), 3.45–3.38(m, 1H), 3.35(d, J=1.8Hz, 3H), 3.27(s, 0.06H), 2.78(q, J=6.0Hz, 0.20H), 2.42(d, J=7.2Hz, 2H), 1.83(dt, J=13.4, 6.9Hz, 1H), 1.46–1.39(m, 3H), 0.89(dd, J=6.5, 1.5Hz, 6H).

[0077] Example 14

[0078] A method for preparing dimethyl (2S * , 3R * )-2-(((2-(2-(adamantan-1-yl)acetoxy)ethyl)(phenyl)amino)methyl)-3-phenylcyclopropane-1,1-dicarboxylate-2,3-d2, the preparation route is as follows:

[0079]

[0080] In a 10 ml dry Schlenk tube, evacuate and refill with gas three times, place it under a nitrogen atmosphere, add 3.9 mg of 2,4,5,6-tetrakis(9-carbazolyl) isophthalonitrile, 41.5 mg of potassium carbonate, 23.2 mg of dimethyl 2-phenylcycloprop-2-ene-1,1-dicarboxylate, 98.2 mg of ethyl 2-(methyl(phenyl)amino)-2-(adamantan-1-yl)acetate, 0.9 ml of N-methylpyrrolidone, and 0.1 ml of deuterated water. Stir overnight at room temperature in a 450 - 465 nm blue light reactor. After quenching with water, separating by ethyl acetate extraction, washing with sodium chloride, drying with magnesium sulfate, filtering and concentrating to obtain the crude product. The crude product is separated by column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain 41.5 mg of the target compound. The solid is detected as dimethyl (2S * , 3R * )-2-(((2-(2-(adamantan-1-yl)acetoxy)ethyl)(phenyl)amino)methyl)-3-phenylcyclopropane-1,1-dicarboxylate-2,3-d2, with a yield of 74.0%, and the deuteration degree: D1 is 95%, D2 is 90%. 11H NMR (500 MHz, CDCl3) δ 7.28–7.19 (m, 5H), 7.15–7.09 (m, 2H), 6.86 (d, J = 8.1 Hz, 2H), 6.75 (t, J = 7.3 Hz, 1H), 4.21 (t, J = 6.4 Hz, 2H), 3.78 (s, 3H), 3.66–3.59 (m, 3H), 3.49 (d, J = 15.2 Hz, 1H), 3.36 (s, 3H), 3.31 (s, 0.05H), 2.81 (t, J = 6.3 Hz, 0.10H), 2.03 (s, 2H), 1.94 (s, 3H), 1.71–1.66 (m, 3H), 1.62–1.56 (m, 9H).

[0081] Example 15

[0082] Use of the target product prepared in the above examples: In the deuteration reaction, deuterium is introduced to replace hydrogen. Since deuterium has a larger mass, the accuracy of analysis is improved. It has been found through investigation that deuterated compounds usually have higher reactivity than hydrogenated compounds, which can be used to study and optimize reaction conditions, thereby improving the reaction efficiency. It has been found through investigation that deuterium-labeled compounds can help track hydrogen atoms in reactants and products. In drug research, deuterated drugs are often used to study the metabolic pathways and stability of drugs in the body. Deuterated drugs can reduce the degradation of drugs in the body, thereby improving the effectiveness and safety of drugs. For example, the deuterium in Example 13 replaces a derivative of ibuprofen. The different physicochemical properties after deuteration can be used to further explore the role of deuteration of the derivative in subsequent research.

[0083] Deuterated drugs are prepared by replacing hydrogen atoms at specific positions in the original drug molecular structure with deuterium atoms. This replacement is based on the physical and chemical properties of deuterium, including the smaller molar volume of deuterium and the fact that its mass is twice that of hydrogen, resulting in the carbon-deuterium bond (C-D) in the compound being more stable than the carbon-hydrogen bond (C-H), about 6 - 9 times more stable. This stability makes deuterated drugs more difficult to be metabolized in the body, thereby slowing down the systemic clearance rate and prolonging the half-life of the drug in the body. This property enables deuterated drugs to maintain the same therapeutic level while reducing the dosage, reducing side effects, and enhancing the efficacy.

[0084] In addition, the introduction of deuterated drugs can also increase the resistance of the molecule to chemical bond cleavage without significantly changing its steric hindrance or electronic properties, which may make it a safer bioisostere than other metabolic blockers. Deuterated drugs can also change the binding affinity and / or selectivity of the drug for its target, which can improve its therapeutic index and reduce off-target effects. Therefore, generally speaking, introducing deuterium into drug molecules is expected to improve the pharmacokinetics (PK) and safety of drugs, and enhance their efficacy and selectivity.

[0085] In summary, deuterated drugs, through their unique physical and chemical properties, effectively reduce the degradation of drugs in the body, thereby improving the effectiveness and safety of drugs, and providing patients with better treatment effects and lower side effect risks.

[0086] Comparative Example 1

[0087]

[0088] A method for preparing dimethyl (2S * ,3R * )-2-((diphenylamino)methyl)-3-phenylcyclopropane-1,1-dicarboxylate-2,3-d2 is basically the same as that in Example 1, except that:

[0089] (1) As shown in Sequences 1-5 in Table 1, when the base in Example 1 was replaced with dipotassium hydrogen phosphate, the solvent was N-methylpyrrolidone, and the catalysts were bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium bis(hexafluorophosphate), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile, eosin, carbon nitride, and riboflavin sodium phosphate, the yields of the products formed were 75%,

[0090] 79%, 0%, 0%, 0%, and no deuteration occurred without adding deuterated water. It can be seen that 5 mol% of the catalyst

[0091] 4CzIPN had a better reaction yield.

[0092] (2) As shown in Sequences 6-7 in Table 1, when the solvent in Example 1 was replaced with acetonitrile and the base was potassium carbonate

[0093] , and the catalysts were bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium bis(hexafluorophosphate) and 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile, the yields of the products formed were 49% and 40% respectively, and no deuteration occurred without adding deuterated water. It can be seen that compared with the reaction solvent CH3CN, the reaction solvent NMP had a better reaction yield.

[0094] (3) As shown in Sequences 8-9 in Table 1, when the base in Example 1 was replaced with dipotassium hydrogen phosphate, the catalyst was 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile, and the solvent was replaced with a mixture of acetonitrile, N-methylpyrrolidone, and water with a volume ratio of 95:5, the yields of the products formed were 66% and 83% respectively, and no deuteration occurred without adding deuterated water.

[0095] (4) As shown in Sequences 10 - 11 in Table 1, when the base in Example 1 was replaced with dipotassium hydrogen phosphate, the solvent was replaced with a 95:5 volume ratio of N - methylpyrrolidone to deuterated water, and the catalysts were 2,4,5,6 - tetra(9 - carbazolyl) - isophthalonitrile and iridium bis[2 - (2,4 - difluorophenyl) - 5 - trifluoromethylpyridine][2 - 2'-bipyridine(4 - tert - butylpyridine)] bis(hexafluorophosphate) respectively, the yields of the resulting products were 86% and 86% respectively, and the deuteration rates of the resulting products were D1 = 87% / D2 = 44% and D1 = 80% / D2 = 50% respectively.

[0096] (5) As shown in Sequences 12 - 14 in Table 1, when the solvent in Example 1 was replaced with a 95:5 volume ratio of N - methylpyrrolidone to deuterated water, the catalyst was 2,4,5,6 - tetra(9 - carbazolyl) - isophthalonitrile, and the bases were replaced with potassium carbonate, cesium carbonate, and potassium phosphate respectively, the yields of the resulting products were 83%, 79%,

[0097] 76% respectively, and the deuteration rates of the resulting products were D1 = 88% / D2 = 86%, D1 = 85% / D2 = 86%,

[0098] D1 = 84% / D2 = 85%. It can be seen that potassium carbonate as the base gives a better reaction yield.

[0099] (6) As shown in Sequences 15 - 16 in Table 1, when the solvent in Example 1 was divided into a 90:10 volume ratio of N - methylpyrrolidone to deuterated water and an 85:15 volume ratio of N - methylpyrrolidone to deuterated water, the catalyst was 2,4,5,6 - tetra(9 - carbazolyl) - isophthalonitrile, and the base was potassium carbonate, the yields of the resulting products were

[0100] 77% and 61% respectively, and the deuteration rates of the resulting products were D1 = 94% / D2 = 95%,

[0101] D1 = 95% / D2 = 95%. It can be seen that NMP:D2O = 90:10 gives better reaction yield and deuteration rate.

[0102] Conclusion: In summary, the optimal reaction conditions are as shown in Sequence 15 in Table 1 (i.e., Example 1), the catalyst is 2,4,5,6 - tetra(9 - carbazolyl) - isophthalonitrile, the base is potassium carbonate, the solvent is a 90:10 volume ratio of N - methylpyrrolidone to deuterated water, the reaction yield is 77%, the deuteration rates are D1 = 94% and D2 = 95%, which are the optimal reaction conditions.

[0103] Table 1

[0104]

[0105]

[0106] This solution was extended to other unsaturated hydrocarbons, verifying that this method has good tolerance for various olefins. The research on deuterated unsaturated hydrocarbons was carried out to develop a green, environmentally friendly and efficient organic synthesis method and achieve the universality of this solution.

[0107] The above-described embodiments are only a preferred solution of the present invention and cannot be used to limit the scope of the rights of the present invention. If equivalent changes are made in the claims of the present invention, they are still covered by this invention.

Claims

1. A method for photocatalytic synthesis of bis-deuterated cyclopropane, characterized in that: In the presence of an inert gas, N-methylpyrrolidone, and deuterium oxide as solvents, and 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile as a catalyst, potassium carbonate is added, and under irradiation with blue light at 450 - 465 nm, Compound 1 and Compound 2 undergo a photocatalytic radical reaction to synthesize Compound 3 The preparation route is as follows: wherein R 1 is methyl, ethyl, tert-butyl or benzyl; R 2 is methyl, ethyl or phenyl; Ar 1 is phenyl or substituted phenyl, and the substituent is: F, Cl, CF3, CH3, CH2CH3 or COOCH3; Ar 2 is phenyl or substituted phenyl, and the substituent is: F, Cl, CH3, OCH3, COOCH3 or C2H2.

2. The method for photocatalytic synthesis of bis-deuterated cyclopropane according to claim 1, wherein: The molar ratio of Compound 1, Compound 2, and potassium carbonate is 1:3:3; the molar ratio of Compound 1 to 2,4,5,6-tetra(9-carbazolyl) isophthalonitrile is 20:1; the volume ratio of N-methylpyrrolidone to deuterium oxide is 90:

10.

3. The method for photocatalytic synthesis of bis-deuterated cyclopropane according to claim 1, wherein: The inert gas described is nitrogen.

4. The method for photocatalytic synthesis of bis-deuterated cyclopropane according to claim 1, wherein: The reaction temperature is room temperature and the reaction time is 14 - 16 h.

5. The method for photocatalytic synthesis of bis-deuterated cyclopropane according to claim 1, wherein: The reaction route is any one of the following:

6. The method for photocatalytic synthesis of bis-deuterated cyclopropane according to claim 5, wherein: Dimethyl (2S * , 3R * )-2-(((2-(2-(4-Isobutylphenyl)propanoyloxy)ethyl)(phenyl)amino)methyl)-3-phenylcyclopropane-1,1-dicarboxylic acid-2,3-d2 Preparation method, the preparation route is as follows: A 10 ml dry Schlenk tube was evacuated and refilled with nitrogen three times. Under a nitrogen atmosphere, 3.9 mg of 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, 41.5 mg of potassium carbonate, 23.2 mg of dimethyl 2-phenylcycloprop-2-ene-1,1-dicarboxylate, 101.8 mg of ethyl 2-(methyl(phenyl)amino)-2-(4-isobutylphenyl)propionate, 0.9 ml of N-methylpyrrolidone, and 0.1 ml of deuterium oxide were added. The mixture was stirred overnight at room temperature in a 450 - 465 nm blue light reactor. After quenching with water, extraction and separation with ethyl acetate, washing with sodium chloride, drying over magnesium sulfate, and filtration followed by rotary evaporation, a crude product was obtained. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 9:1) to give 40.1 mg of the target compound. The solid was detected as dimethyl (2S * ,3R * )-2-(((2-(2-(4-isobutylphenyl)propanoyl)oxy)ethyl)(phenyl)amino)methyl)-3-phenylcyclopropane-1,1-dicarboxylate-2,3-d2, with a yield of 70.0%. The deuteration degree: D1 was 94% and D2 was 80%.

7. The method for photocatalytic synthesis of bis-deuterated cyclopropane according to claim 5, wherein: Dimethyl (2S * , 3R * )-2-((2-chlorophenyl)(methyl)amino)methyl)-3-phenylcyclopropane-1,1-dicarboxylic acid-2,3-d2 Preparation method, the preparation route map is as follows: A 10 ml dry Schlenk tube was evacuated and filled with nitrogen three times. Under a nitrogen atmosphere, 3.9 mg of 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, 41.5 mg of potassium carbonate, 23.2 mg of dimethyl 2-phenylcycloprop-2-ene-1,1-dicarboxylate, 46.7 mg of 2-chloro-N,N-dimethylaniline, 0.9 ml of N-methylpyrrolidone, and 0.1 ml of deuterated water were added. The mixture was stirred overnight at room temperature in a 450 - 465 nm blue light reactor. After quenching with water, extraction and separation with ethyl acetate, washing with sodium chloride, drying with magnesium sulfate, and filtration and evaporation to dryness, a crude product was obtained. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain 35.7 mg of the target compound. The solid was detected as dimethyl (2S * ,3R * )-2-((2-chlorophenyl)(methyl)amino)methyl)-3-phenylcyclopropane-1,1-dicarboxylate-2,3-d2, with a yield of 90.0%. The deuteration degree: D1 was 98% and D2 was 95%.

8. The method for photocatalytic synthesis of bis-deuterated cyclopropane according to claim 5, wherein: Dimethyl (2S * , 3R * )-2-((diphenylamino)methyl)-3-phenylcyclopropane-1,1-dicarboxylic acid-2,3-d2 preparation method, the preparation route is as follows: A 10 ml dry Schlenk tube was evacuated and refilled with nitrogen three times. Under a nitrogen atmosphere, 3.9 mg of 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile, 41.5 mg of potassium carbonate, 23.2 mg of dimethyl 2-phenylcycloprop-2-ene-1,1-dicarboxylate, 55.0 mg of N-methyl diphenylamine, 0.9 ml of N-methylpyrrolidone, and 0.1 ml of deuterated water were added. The mixture was stirred overnight at room temperature in a 450 - 465 nm blue light reactor. After quenching with water, extraction with ethyl acetate, washing with sodium chloride solution, drying over magnesium sulfate, and filtration followed by rotary evaporation, a crude product was obtained. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 9:1) to give 31.5 mg of the target compound. The solid was detected to be dimethyl (2S * ,3R * )-2-((diphenylamino)methyl)-3-phenylcyclopropane-1,1-dicarboxylate-2,3-d2, with a yield of 75.0%. The deuteration degree: D1 was 94% and D2 was 95%.

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