Method for preparing deuterated phenylacetonitrile compound by using heterogeneous catalyst

Abstract

The invention belongs to the technical field of preparation of deuterated phenylacetonitrile compounds, discloses a method for preparing deuterated phenylacetonitrile compounds by using a heterogeneous catalyst, and particularly relates to regioselective deuteration of alpha-position hydrogen of p-phenylacetonitrile compounds. The deuterated phenylacetonitrile is prepared by taking phenylacetonitrile as a raw material, heavy water as a deuterium source and ETS-10 zeolite as a catalyst under a mild reaction condition (30-80 DEG C). The method has the advantages of simplicity and convenience in operation, simple reaction conditions, high efficiency, greenness and the like, and has potential application value for realizing regioselective deuteration of nitrile compounds.

Description

Technical Field

[0001] The invention belongs to the technical field of deuterated benzyl cyanide chemistry and discloses a method for preparing deuterated benzyl cyanide compounds by utilizing a heterogeneous catalyst. Background Art

[0002] The replacement of hydrogen at a specific position in a drug molecule by deuterium can change its absorption, distribution, metabolism and excretion characteristics while maintaining its biological activity. Deuterium-labeled drug molecules can be used as effective probes to identify human metabolic pathways, and are helpful for qualitative analysis of human metabolites and research on metabolic mechanisms.

[0003] Nitrile compounds are an important class of bioactive molecules. As an important pharmaceutical raw material, more than 30 nitrile-containing compounds have been used as drugs. In addition, there are many candidate drugs of nitrile compounds under clinical development. Therefore, converting hydrogen at specific positions in nitrile compounds to deuterium has high research value.

[0004] In recent years, many researchers have made great efforts to achieve the deuteration of aromatic nitriles. For example, Milstein et al. used manganese chelates to achieve the hydration of nitriles and the preparation of α-deuterated nitriles (ACS Catal. 2021, 11, 10239-10245). However, the reaction temperature of this homogeneous catalytic system is relatively high, and the use of metal complexes is required. Large-scale production will cause serious pollution to the ecological environment.

[0005] Therefore, from the perspective of sustainable development, it is of great research value to develop a green, efficient and mild heterogeneous catalytic system to achieve the selective deuteration of aromatic nitrile compounds. Summary of the invention

[0006] In order to solve the above problems, the present invention aims to provide a simple method for achieving selective deuteration of benzyl cyanide at the α-position, using ETS-10 zeolite as a catalyst and inexpensive D2O as a deuterium source, under mild reaction conditions, and without the need for additional additives, selective deuteration of benzyl cyanide at the α-position can be achieved to obtain deuterated benzyl cyanide compounds.

[0007] The technical solution of the present invention is as follows:

[0008] A set amount of ETS-10, D2O, and benzyl cyanide compounds are added to the reaction equipment, and the reaction is carried out at a set reaction temperature for a period of time. After the reaction is completed, the reaction liquid is centrifuged, filtered, extracted, rotary evaporated, and dried to obtain the target product.

[0009]

[0010] R=H, electron withdrawing group or electron donating group.

[0011] Furthermore, R is independently selected from hydrogen, fluorine, chlorine, bromine, alkyl, and alkoxy, and the position of the substituent can be ortho, meta, or para.

[0012] Furthermore, the reaction temperature in the present invention is 30-80°C, preferably 30-60°C.

[0013] Furthermore, the reaction time in the present invention is 12-36 hours, preferably 12-24 hours.

[0014] Furthermore, in the present invention, the molar ratio of the benzyl cyanide compound to D2O is 1:(40-100), preferably 1:(45-95), and more preferably 1:(50-80).

[0015] Furthermore, the molar ratio of the mass of the ETS-10 catalyst to the benzyl cyanide compound in the present invention is (10-60):1 (mg / mmol), preferably (15-55):1 (mg / mmol), and more preferably (20-50):1 (mg / mmol).

[0016] Furthermore, the ETS-10 catalyst is prepared by a conventional hydrothermal synthesis method, that is, water glass, sodium hydroxide, potassium fluoride, and titanium trichloride solution are mixed and stirred evenly, and then loaded into a reaction kettle for crystallization. After the crystallization is completed, ETS-10 is obtained by filtering, washing, drying, and calcining.

[0017] Compared with the prior art, the present invention has the following advantages:

[0018] (1) The reaction conditions of the present invention are simple, and no metal complex needs to be added. Compared with common alkaline catalysts such as sodium hydroxide, triethylamine, pyrrolidine, etc. in deuteration reactions, the zeolite of the present invention has good thermal stability and chemical stability, will not destroy its crystal structure during the reaction, and is easy to separate after the reaction. Conventional alkalis exist in the reaction solution in the form of ions or molecules, which easily produce a large amount of waste and by-products and are not easy to separate. In addition, when traditional homogeneous alkaline catalysts are used to deuterate multiple hydrogens in the target compound, the same reaction steps need to be repeated many times to fully achieve all deuterations. However, after using zeolite molecular sieves as catalysts for one reaction, all deuterations of the target positions in the compound can be achieved.

[0019] (2) The catalyst is easy to separate and recover, has good catalytic performance, can be recycled, and has industrial prospects.

[0020] (3) The catalyst has excellent catalytic activity and can obtain excellent yield and deuteration rate. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Deuterated benzyl cyanide of Example 11 H NMR spectrum.

[0022] Figure 2 Deuterated 4-fluorobenzeneacetonitrile of Example 2 1 H NMR spectrum.

[0023] Figure 3 Deuterated 4-chlorobenzeneacetonitrile of Example 3 1 H NMR spectrum.

[0024] Figure 4 Deuterated 3-bromobenzeneacetonitrile of Example 4 1 H NMR spectrum.

[0025] Figure 5 Example 5 deuterated 4-methylbenzene acetonitrile 1 H NMR spectrum.

[0026] Figure 6 Example 6 deuterated 4-methoxyphenylacetonitrile 1 H NMR spectrum. DETAILED DESCRIPTION

[0027] In order to further understand the purpose, content and advantages of the present invention, the specific embodiments of the present invention are described in detail below, but they are not limited to the examples described below, and the reaction conditions should be changed according to the actual situation. Unless otherwise specified, the reagents and instruments used in the following examples are commercially available products. In the examples: The preparation method of ETS-10 catalyst is as follows:

[0028] Weigh 20.6g of water glass and add it to a 150mL beaker, weigh 2.8g of NaOH solid and add 10mL of distilled water to dissolve it, and add the NaOH solution to the water glass; weigh 2.3g of KF solid and add 20.0mL of distilled water to make a KF solution, add the KF solution to the above water glass mixed solution, and after it is fully stirred, add 11.6g of TiCl3 solution dropwise to it, stir for 30min, and then put it into a polytetrafluoroethylene-lined reactor and crystallize it at 230℃ for 60h. After crystallization, wash it with water until it is neutral, filter, dry it, and calcine it at 500℃ for 5h to obtain the ETS-10 catalyst. The molar ratio of the reaction gel system is: Na2O:K2O:SiO2:TiO2:H2O=4.7:1.56:6.9:1:199.3.

[0029] Embodiment 1:

[0030]

[0031] Weigh 10 mg of ETS-10 zeolite into a reaction tube, add 58.5 mg of benzyl cyanide and 500 mg of D2O, and react on a 50°C heating plate in an air atmosphere for 24 hours. After the reaction system cools to room temperature, the reaction solution is centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 56.2 mg of the target product, deuterated benzyl cyanide, with a yield of 94.5%. The deuteration rate of the product is determined by 1 H NMR analysis showed that the deuterium substitution rate of benzyl cyanide was 98.5%. Figure 1 The data of nuclear magnetic resonance hydrogen spectrum are as follows: 1 HNMR(400MHz,Chloroform-d)δ7.41-7.28(m,5H),3.72-3.69(m,0.03H).

[0032] The deuterium substitution rate is calculated after measuring the hydrogen nuclear magnetic resonance spectrum.

[0033] Specifically, it is calculated by integrating the peaks of the chemical shift corresponding to the hydrogen at the target deuterated position in the compound on the NMR spectrum. The calculation formula is:

[0034]

[0035] Where D% represents the deuterium substitution rate;

[0036] Sp represents the integrated peak area of ​​the chemical shift corresponding to the hydrogen at the target deuterated position in the deuterated product in the H NMR spectrum;

[0037] S R It represents the integrated peak area of ​​the chemical shift corresponding to the undeuterated hydrogen in the substrate in the H NMR spectrum.

[0038] Embodiment 2:

[0039]

[0040] Weigh 10 mg of ETS-10 zeolite into a reaction tube, add 67.5 mg of 4-fluorobenzeneacetonitrile and 500 mg of D2O, and react on a 50°C heating plate in an air atmosphere for 24 hours. After the reaction system cools to room temperature, the reaction solution is centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 62.8 mg of the target product, deuterated 4-fluorobenzeneacetonitrile, with a yield of 91.6%. The deuterated rate of the product is determined by 1 HNMR analysis showed that the deuterium substitution rate of 4-fluorobenzeneacetonitrile was 96.0%. Figure 2 The data of nuclear magnetic resonance hydrogen spectrum are as follows: 1H NMR (400MHz, Chloroform-d) δ7.30 (dd, J=8.7, 5.1Hz, 2H), 7.07 (t, J=8.6Hz, 2H), 3.75-3.67 (m, 0.08H).

[0041] Embodiment 3:

[0042]

[0043] Weigh 10 mg of ETS-10 zeolite into a reaction tube, add 75.8 mg of 4-chlorobenzeneacetonitrile and 500 mg of D2O, and react on a 50°C heating plate in an air atmosphere for 24 hours. After the reaction system cools to room temperature, the reaction solution is centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 70.1 mg of the target product, deuterated 4-chlorobenzeneacetonitrile, with a yield of 91.3%. The deuterated rate of the product is determined by 1 HNMR analysis showed that the deuterium substitution rate of 4-chlorobenzeneacetonitrile was 97.0%. Figure 3 The data of nuclear magnetic resonance hydrogen spectrum are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.35 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 3.73-3.69 (m, 0.06H).

[0044] Embodiment 4:

[0045]

[0046] Weigh 10 mg of ETS-10 zeolite into a reaction tube, add 98.02 mg of 3-bromobenzeneacetonitrile and 500 mg of D2O, and react on a 50°C heating plate in an air atmosphere for 24 hours. After the reaction system cools to room temperature, the reaction solution is centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 89.7 mg of the target product, deuterated 3-bromobenzeneacetonitrile, with a yield of 90.6%. The deuterated rate of the product is determined by 1 HNMR analysis showed that the deuterium substitution rate of 3-bromobenzeneacetonitrile was 97.0%. Figure 4 The data of nuclear magnetic resonance hydrogen spectrum are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.46 (dd, J=8.7, 2.1Hz, 2H), 7.25 (d, J=6.0Hz, 2H), 3.73-3.69 (m, 0.06H).

[0047] Embodiment 5:

[0048]

[0049] Weigh 10 mg of ETS-10 zeolite into a reaction tube, add 65.6 mg of 4-methylbenzeneacetonitrile and 500 mg of D2O, and react on a 50°C heating plate in an air atmosphere for 24 hours. After the reaction system cools to room temperature, the reaction solution is centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 61.4 mg of the target product, deuterated 4-methylbenzeneacetonitrile, with a yield of 92.2%. The deuterated rate of the product is determined by 1 H NMR analysis showed that the deuterium substitution rate of 4-methylbenzeneacetonitrile was 96.5%. Figure 5 The data of nuclear magnetic resonance hydrogen spectrum are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.20 (d, J = 8.3Hz, 2H), 7.16 (d, J = 8.3Hz, 2H), 3.66 (s, 0.07H), 2.34 (s, 3H).

[0050] Embodiment 6:

[0051]

[0052] Weigh 10 mg of ETS-10 zeolite into a reaction tube, add 73.6 mg of 4-methoxybenzeneacetonitrile and 500 mg of D2O, and react on a 50°C heating plate in an air atmosphere for 24 hours. After the reaction system cools to room temperature, the reaction solution is centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 68.5 mg of the target product, deuterated 4-methoxybenzeneacetonitrile, with a yield of 91.8%. The deuterated rate of the product is determined by 1 H NMR analysis showed that the deuterium substitution rate of 4-methoxyphenylacetonitrile was 96.0%. Figure 6 The data of nuclear magnetic resonance hydrogen spectrum are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.23 (d, J = 8.8Hz, 2H), 6.89 (d, J = 8.7Hz, 2H), 3.80 (s, 3H), 3.67 (s, 0.08H).

[0053] Embodiment 7:

[0054] Weigh 10 mg of ETS-10 zeolite into a reaction tube, add 58.5 mg of benzyl cyanide and 500 mg of D2O, and react on a 30°C heating plate in an air atmosphere for 24 hours. After the reaction system cools to room temperature, the reaction solution is centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 53.6 mg of the target product, deuterated benzyl cyanide, with a yield of 90.1%. The deuteration rate of the product is determined by 1 H NMR analysis revealed that the deuteration rate of benzyl cyanide was 53.0%.

[0055] Embodiment 8:

[0056] Weigh 10 mg of ETS-10 zeolite into a reaction tube, add 58.5 mg of benzyl cyanide and 500 mg of D2O, and react on a 40°C heating plate in an air atmosphere for 24 hours. After the reaction system cools to room temperature, the reaction solution is centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 54.1 mg of the target product, deuterated benzyl cyanide, with a yield of 90.9%. The deuteration rate of the product is determined by 1 H NMR analysis revealed that the deuteration rate of benzyl cyanide was 65.0%.

[0057] Embodiment 9:

[0058] Weigh 10 mg of ETS-10 zeolite into a reaction tube, add 58.5 mg of benzyl cyanide and 500 mg of D2O, and react on a 60°C heating plate in an air atmosphere for 24 hours. After the reaction system cools to room temperature, the reaction solution is centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 57.3 mg of the target product, deuterated benzyl cyanide, with a yield of 96.3%. The deuteration rate of the product is determined by 1 H NMR analysis revealed that the deuteration rate of benzyl cyanide was 98.5%.

[0059] Embodiment 10:

[0060] Weigh 10 mg of ETS-10 zeolite into a reaction tube, add 58.5 mg of benzyl cyanide and 500 mg of D2O, and react on a 50°C heating plate in an air atmosphere for 12 hours. After the reaction system cools to room temperature, the reaction solution is centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 50.6 mg of the target product, deuterated benzyl cyanide, with a yield of 85.0%. The deuteration rate of the product is determined by 1 H NMR analysis revealed that the deuteration rate of benzyl cyanide was 77.0%.

[0061] Embodiment 11:

[0062] Weigh 10 mg of ETS-10 zeolite into a reaction tube, add 58.5 mg of benzyl cyanide and 500 mg of D2O, and react on a 50°C heating plate in an air atmosphere for 16 hours. After the reaction system cools to room temperature, the reaction solution is centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 53.3 mg of the target product, deuterated benzyl cyanide, with a yield of 89.6%. The deuteration rate of the product is determined by 1 H NMR analysis revealed that the deuterium substitution rate of benzyl cyanide was 85.0%.

[0063] Embodiment 12:

[0064] Weigh 10 mg of ETS-10 zeolite into a reaction tube, add 58.5 mg of benzyl cyanide and 500 mg of D2O, and react on a 50°C heating plate in an air atmosphere for 20 hours. After the reaction system cools to room temperature, the reaction solution is centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 55.3 mg of the target product, deuterated benzyl cyanide, with a yield of 92.9%. The deuteration rate of the product is determined by 1 H NMR analysis revealed that the deuteration rate of benzyl cyanide was 91.0%.

[0065] Comparative Example 1:

[0066] Weigh 10 mg of KOH into a reaction tube, add 58.5 mg of benzyl cyanide and 500 mg of D2O, and react on a 50°C heating plate in an air atmosphere for 24 hours. After the reaction system cools to room temperature, the reaction solution is extracted, rotary evaporated, and dried to obtain 48.3 mg of the target product, deuterated benzyl cyanide, with a yield of 81.2%. The deuteration rate of the product is determined by 1 H NMR analysis revealed that the deuteration rate of benzyl cyanide was 44.0%.

[0067] Comparative Example 2:

[0068] Weigh 10 mg of K2CO3 into a reaction tube, add 58.5 mg of benzyl cyanide and 500 mg of D2O, and react on a 50°C heating plate in an air atmosphere for 24 hours. After the reaction system cools to room temperature, the reaction solution is extracted, rotary evaporated, and dried to obtain 45.8 mg of the target product, deuterated benzyl cyanide, with a yield of 76.9%. The deuteration rate of the product is determined by 1 H NMR analysis revealed that the deuterium substitution rate of benzyl cyanide was 39.0%.

[0069] Comparative Example 3:

[0070] Weigh 10 mg of TS-1 zeolite into a reaction tube, add 58.5 mg of benzyl cyanide and 500 mg of D2O, and react on a 50°C heating plate in an air atmosphere for 24 hours. After the reaction system cools to room temperature, the reaction solution is centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 49.5 mg of the target product, deuterated benzyl cyanide, with a yield of 83.2%. The deuterated rate of the product is determined by 1 H NMR analysis showed that the deuterium substitution rate of benzyl cyanide was 15.0%.

[0071] Weigh 10 mg of Beta zeolite into a reaction tube, add 58.5 mg of benzyl cyanide and 500 mg of D2O, and react on a 50°C heating plate in an air atmosphere for 24 hours. After the reaction system cools to room temperature, the reaction solution is centrifuged, filtered, extracted, rotary evaporated, and dried to obtain 50.3 mg of the target product, deuterated benzyl cyanide, with a yield of 84.5%. The deuteration rate of the product is determined by 1 H NMR analysis revealed that the deuteration rate of benzyl cyanide was 26.0%.

Claims

1. A method for preparing deuterated benzyl cyanide compounds using a heterogeneous catalyst, Features: Compound 1a and a deuterated reagent are reacted in the presence of ETS-10 catalyst to obtain the target product 2a; The reaction formula is: Wherein, R is independently selected from hydrogen, halogen, alkyl, and alkoxy.

2. The method for preparing deuterated benzyl cyanide using a heterogeneous catalyst according to claim 1, Features: The deuterated reagent is D 2 O.

3. The method for preparing deuterated benzyl cyanide using a heterogeneous catalyst according to claim 1, Features: The molar ratio of compound 1a to the deuterated reagent is 1:(40-100).

4. The method for preparing deuterated benzyl cyanide using a heterogeneous catalyst according to claim 1, Features: The molar ratio of the mass of the ETS-10 catalyst to the benzyl cyanide compound is (10-60) mg:1 mmol.

5. The method for preparing deuterated benzyl cyanide using a heterogeneous catalyst according to claim 1, Features: The reaction temperature is: 30-80°C.

6. The method for preparing deuterated benzyl cyanide using a heterogeneous catalyst according to claim 1, Features: The reaction time is: 12-36h.

7. The method for preparing deuterated benzyl cyanide using a heterogeneous catalyst according to claim 1, Features: After the reaction, the temperature was cooled to room temperature, and the reaction solution was centrifuged, filtered, extracted, rotary evaporated, and dried to obtain the target product 2a.

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