Preparation method of deuterated methyl-containing benzamide compound

Abstract

The invention belongs to the field of organic chemical synthesis, and relates to a preparation method of a deuterated methyl-containing benzamide compound. A benzamide compound 1 and a deuterated methylation reagent 2 react under the action of a catalyst and alkali to prepare a benzamide compound 3 containing deuterated methyl. An environment-friendly reagent system is adopted, the operation safety is excellent, and the process is simple and convenient. The method effectively overcomes the problems of complex steps, long reaction time, need of expensive catalyst, low atomic efficiency and the like in the traditional synthesis route.

Description

Technical Field

[0001] The present invention belongs to the field of organic chemical synthesis and relates to a method for preparing a benzamide compound containing a deuterated methyl group. Background Art

[0002] Nitrogen-containing compounds are important structural units in natural products and bioactive pharmaceutical molecules, and have a wide range of biological activities and pharmacological effects. As an important class of nitrogen-containing compounds, benzamide compounds are widely used in drug synthesis and the construction of natural products. In recent years, the research on deuterated compounds has gradually attracted attention. Due to their unique chemical and pharmacological properties, deuterated benzamide compounds exhibit broad application prospects.

[0003] Methyl, as a simple organic substituent, is widely present in various structural units and commercial drugs. By introducing a methyl group into a candidate drug, the solubility, hydrophilicity, and conformation of the drug can be adjusted, thereby significantly enhancing its biological activity, pharmacokinetic properties, and physical properties. In fact, this simple structural modification has been proven to increase the potency of some lead compounds by more than 2000 times. Therefore, it is of great significance to develop a method that can achieve selective methyl substitution at a specific position.

[0004] Deuterium is the most readily available stable non-radioactive isotope of hydrogen. Since the C-D bond is more stable than the C-H bond, deuterium substitution of hydrogen can change the properties of candidate drugs such as absorption, distribution, metabolism, and excretion. Currently, a variety of deuterium-labeled candidate drugs have entered the clinical trial stage. However, a key challenge in achieving deuteromethylation is to find a suitable "CD" source. For example, Komarapuri et al. reported a method in 2008 for successfully synthesizing 19,19,19-trideuterated steroids by introducing C-19 using deuterated iodomethane (99.5% D3) before the closure of the steroid A ring, without increasing the total number of synthesis steps (J. Labelled Compd. Radiopharm. 2008, 51, 430–434). In addition, Jiang, X. et al. developed a general method for N-deuteromethylation of amines and nitro compounds using deuterated dimethyl sulfoxide in 2014 (Chem. A Eur. J. 2014, 20, 58–63). However, existing deuteromethylation reagents (such as deuterated iodomethane, deuterated reducing agents, and d6-DMSO solutions) have significant drawbacks such as volatility, corrosiveness, toxicity, and carcinogenicity. To overcome these limitations, it is particularly crucial to develop a new deuteromethylation reagent that can achieve direct, scalable, and selective deuteromethylation under mild conditions. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a method for preparing a benzamide compound containing a deuterated methyl group in view of the deficiencies of the prior art.

[0006] To solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0007] The present invention discloses a preparation method of a benzoamide compound containing a deuterated methyl group. The benzoamide compound 1 and the deuterated methylation reagent 2 react under the action of a catalyst and a base to obtain the benzoamide compound 3 containing a deuterated methyl group;

[0008] Among them, the structural formula of the benzoamide compound 1 is shown in Formula 1, the structural formula of the deuterated methylation reagent 2 is shown in Formula 2, and the structural formula of the benzoamide compound 3 containing a deuterated methyl group is shown in Formula 3:

[0009]

[0010] Among them,

[0011] n is an integer between 0 and 4;

[0012] n R1s are independently selected from C1-C6 alkyl, phenyl or C1-C6 alkoxy;

[0013] R2 is selected from C1-C8 alkyl, dimethylamino, phenyl or morpholinyl.

[0014] In some embodiments, preferably,

[0015] n is an integer between 0 and 2;

[0016] n R1s are independently selected from methyl, ethyl, isopropyl, tert-butyl, phenyl or methoxy;

[0017] R2 is selected from methyl, n-heptyl, phenyl, dimethylamino, tert-butyl or morpholinyl.

[0018] In some embodiments, further preferably,

[0019] n is an integer between 0 and 2;

[0020] n R1s are independently selected from methyl, ethyl, isopropyl, tert-butyl, phenyl or methoxy;

[0021] R2 is selected from methyl or tert-butyl.

[0022] In some embodiments, even more preferably, the benzoamide compound 1 is selected from any of the following structures:

[0023]

[0024] In some embodiments, the catalyst is any one or a combination of several of [1,3-bis(diphenylphosphino)propane] palladium(II) trifluoromethanesulfonate, palladium chloride, bis(acetonitrile)palladium(II) chloride, and palladium acetate.

[0025] In some embodiments, preferably, the catalyst is any one or a combination of two of [1,3-bis(diphenylphosphino)propane] palladium(II) trifluoromethanesulfonate and palladium acetate.

[0026] In some embodiments, more preferably, the catalyst is palladium acetate.

[0027] In some embodiments, the base is any one or a combination of several of triethylamine, cesium carbonate, potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate.

[0028] In some embodiments, preferably, the base is any one or a combination of two of sodium carbonate and sodium bicarbonate.

[0029] In some embodiments, preferably, the base is sodium bicarbonate.

[0030] In some embodiments, the solvent used in the reaction is any one or a combination of several of toluene, ethyl acetate, dichloromethane, 1,2-dichloroethane, and tert-amyl alcohol.

[0031] In some embodiments, preferably, the solvent used in the reaction is any one or a combination of two of dichloromethane and 1,2-dichloroethane.

[0032] In some embodiments, more preferably, the solvent used in the reaction is dichloromethane.

[0033] Among them, there is no special requirement for the amount of the solvent, and it is only necessary to dissolve or disperse the raw materials evenly.

[0034] In some embodiments, the molar ratio of the benzamide compound 1 to the deuterated methylation reagent 2 is 1.0:(1.0 - 2.0).

[0035] In some embodiments, preferably, the molar ratio of the benzamide compound 1 to the deuterated methylation reagent 2 is 1.0:1.5.

[0036] In some embodiments, the molar ratio of the benzamide compound 1 to the catalyst is (8.0 - 10.0):1.0.

[0037] In some embodiments, preferably, the molar ratio of the benzamide compound 1 to the catalyst is 10.0:1.0.

[0038] In some embodiments, the molar ratio of the benzamide compound 1 to the base is (1.0 to 2.0):(2.0 to 5.0).

[0039] In some embodiments, preferably, the molar ratio of the benzamide compound 1 to the base is 1.0:2.0.

[0040] In some embodiments, for the reaction, the reaction temperature is 25°C to 120°C.

[0041] In some embodiments, preferably, for the reaction, the reaction temperature is 50°C to 60°C.

[0042] Beneficial effects:

[0043] (1) The preparation method of the present invention uses reagents with low pollution and high safety, is easy to operate, and improves the reaction rate and product selectivity.

[0044] (2) The preparation method of the present invention does not need to use noble metal catalysts, thus greatly reducing the reaction cost and solving the environmental pollution problem caused by post-treatment in traditional methods.

[0045] (3) The preparation method of the present invention only needs to be heated to 50°C, which conforms to the development concept of green chemistry.

[0046] (4) The deuterated methylation reagent used in the present invention can be synthesized from cheap and easily available raw materials through simple steps, avoiding the problem of using strongly polluting deuterated methylation reagents in traditional methods.

[0047] (5) The yield of the benzamide compound containing deuterated methyl obtained by the preparation method of the present invention can reach 74% to 94%.

[0048] (6) The present invention adopts an environmentally friendly reagent system, has excellent operation safety and a simple process. The present invention effectively overcomes the problems existing in traditional synthesis routes, such as complex steps, long reaction time, the need for expensive catalysts and low atomic efficiency. Description of the drawings

[0049] The following further specifically describes the present invention in conjunction with the drawings and specific embodiments, and the above and / or other advantages of the present invention will become clearer.

[0050] Figure 1 It is the 1H NMR spectrum of TT-CD3+OTf-.

[0051] Figure 2 It is the 13C NMR spectrum of TT-CD3+OTf-.

[0052] Figure 3 It is the 1H NMR spectrum of product 3a.

[0053] Figure 4 It is the carbon-13 NMR spectrum of product 3a. Detailed implementation manners

[0054] The present invention can be better understood according to the following embodiments. However, those skilled in the art can easily understand that the content described in the embodiments is only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0055] In the following embodiments, the experimental methods are all conventional methods unless otherwise specified; the reagents and materials can be obtained from commercial channels unless otherwise specified.

[0056] 1. The 5-(trideuteriomethyl)-5H-thianthrene-5-trifluoromethanesulfonate used in the embodiments of the present application can be commercially purchased or prepared according to the following method:

[0057]

[0058] (1) Add formic acid (4.0 mL, 106 mmol) and deuterated methanol (10.0 mL, 247 mmol, 99% D) to a 50 mL round-bottom flask; then, while stirring the above solution, gradually add sulfuric acid (5.0 mL, 94 mmol, 98%) to the solution to obtain a mixture; heat the mixture at 60 °C and continuously react for 4 hours. After the reaction is completed, directly distill the formic acid-d3 formate containing a small amount of deuterated methanol under normal pressure (33 °C to 38 °C) to obtain formic acid-d3 formate, which is directly used in the next reaction without further purification.

[0059] (2) Add thianthrene (TT, 30 mmol, 1.0 equiv.) and the above-distilled formic acid-d3 formate to a 100 mL round-bottom flask to obtain a mixture; stir the mixture at 0 °C and dropwise add TfOH (16.0 mL, 180 mmol, 6.0 equiv.) while stirring, and then heat the reaction to 30 °C and stir overnight. After the reaction is completed, pour the reaction product into water (50 mL), extract with dichloromethane (50 mL × 3), dry with anhydrous sodium sulfate, and concentrate under vacuum. Wash the obtained crude product with ether (25 mL × 3) and dry under vacuum to obtain the trideuteriomethyl reagent, 5-(trideuteriomethyl)-5H-thianthrene-5-trifluoromethanesulfonate, denoted as TT-CD3 + OTf - (10.6 g, 92%, 99% D).

[0060] The characterization data of TT-CD3 + OTf- are as follows: 11H NMR (400 MHz, CDCl3) δ 8.37 (dd, J = 7.8, 1.3 Hz, 2H), 7.84 (dd, J = 7.9, 1.2 Hz, 2H), 7.75 (td, J = 7.7, 1.4 Hz, 2H), 7.68 (td, J = 7.7, 1.4 Hz, 2H). 13 13C NMR (100 MHz, CDCl3) δ 135.6, 134.4, 134.2, 130.2, 130.0, 118.8. 19 19F NMR (376 MHz, CDCl3) δ 78.25. HRMS (ESI) m / z: calcd for C 13 H8D3S2 + [M–OTf] + : 234.0484, found: 234.0487. The 1H NMR spectrum of TT-CD3+OTf- is as shown in Figure 1 Figure, and the 13C NMR spectrum is as shown in Figure 2 Figure.

[0061] Example 1:

[0062]

[0063] 3-Acetamidotoluene (0.2 mmol, 1.0 equiv.), 5-(trideuteriomethyl)-5H-thianthren-5-trifluoromethanesulfonate (0.3 mmol, 1.5 equiv.), palladium(II) acetate (0.02 mmol, 0.1 equiv.), and sodium bicarbonate (0.4 mmol, 2.0 equiv.) were successively weighed and added to a dry Schlenk reaction tube. 2 mL of dichloromethane (DCM) was injected into the Schlenk reaction tube using a syringe, and the mixture was stirred at 50 °C for 12 h in air. After the reaction was completed, it was cooled to room temperature, and TLC was used for detection. The reaction solution was extracted with ethyl acetate and saturated brine (3 × 25 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The final product N-[5-methyl-2-(trideuteriomethyl)phenyl]acetamide, denoted as 3a, was obtained by silica gel column chromatography with a yield of 91%.

[0064] The characterization data of product 3a are as follows: 1 1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 7.22 (s, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 2.24 (s, 3H), 2.05 (s, 3H). 1313C NMR (100 MHz, DMSO-d6) δ 168.6, 136.8, 135.3, 130.5, 128.7, 126.1, 126.0, 23.7, 21.1. HRMS (ESI) m / z: calcd for C 10 H 10 D3NONa [M + Na]+: 189.1078, found: 189.1076. The 1H NMR spectrum of Product 3a is as shown in Figure 3 Figure Figure 4 as shown.

[0065] Example 2:

[0066]

[0067] The experimental method was the same as that in Example 1, except that the solvent dichloromethane was replaced with 1,2-dichloroethane (DCE), and finally Product 3a was prepared with a yield of 78%.

[0068] Example 3:

[0069]

[0070] The experimental method was the same as that in Example 1, except that the reaction temperature was 60 °C, and finally Product 3a was prepared with a yield of 91%.

[0071] Example 4:

[0072]

[0073] The experimental method was the same as that in Example 1, except that the palladium acetate catalyst was replaced with [1,3-bis(diphenylphosphino)propane]palladium(II) trifluoromethanesulfonate, and finally Product 3a was prepared with a yield of 79%.

[0074] Example 5:

[0075]

[0076] The experimental method was the same as that in Example 1, except that the base was replaced with sodium carbonate, and finally Product 3a was prepared with a yield of 74%.

[0077] Example 6:

[0078]

[0079] The experimental method was the same as that in Example 1, with the same material dosage, except that 3-acetamidotoluene was replaced with N-(3-ethylphenyl)acetamide, and finally Product 3b was prepared with a yield of 88%.

[0080] The characterization data of Product 3b are as follows:1 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.25 (s, 1H), 7.10 (d, J = 7.7 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 2.55 (q, J = 7.6 Hz, 2H), 2.06 (s, 3H), 1.16 (t, J = 7.6 Hz, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ 168.6, 141.8, 136.9, 130.5, 129.1, 124.9, 124.8, 28.2, 23.7, 16.1. HRMS (ESI) m / z: calcd for C 11 H 12 D3NONa [M+Na] + : 203.1234, found: 203.1239.

[0081] Example 7:

[0082]

[0083] The experimental method was the same as that in Example 1, with the same amount of materials used. The difference was that 3-acetamidotoluene was replaced by N-(3-isopropylphenyl)acetamide, and finally the product 3c was prepared with a yield of 93%.

[0084] The characterization data of the product 3c are as follows: 1 1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 7.29–7.25 (m, 1H), 7.11 (d, J = 7.8 Hz, 1H), 6.96 (dd, J = 7.8, 1.6 Hz, 1H), 2.87–2.80 (m, 1H), 2.07 (s, 3H), 1.19 (d, J = 6.9 Hz, 6H). 13 13C NMR (100 MHz, DMSO-d6) δ 168.6, 146.5, 136.9, 130.5, 129.4, 123.4, 33.5, 24.4, 23.7. HRMS (ESI) m / z: calcd for C 12 H 14 D3NONa [M+Na] + : 217.1391, found: 217.1394.

[0085] Example 8:

[0086]

[0087] The experimental method was the same as that of Example 1, and the amounts of materials used remained unchanged. The difference was that 3-acetamidotoluene was replaced by N-(3-tert-butylphenyl)acetamide, and finally the product 3d was prepared with a yield of 94%.

[0088] The yield characterization data of the product 3d are as follows: 1 H NMR(400MHz,DMSO-d6)δ9.27(s,1H),7.37(s,1H),7.09(s,2H),2.04(s,3H),1.24(s,9H). 13 C NMR(100MHz,DMSO-d6)δ168.5,148.8,136.7,130.3,129.3,122.4,34.5,31.6,23.7.HRMS(ESI)m / z:calcd for C 13 H 16 D3NONa[M+Na] + :231.1547,found:231.1548.

[0089] Example 9:

[0090]

[0091] The experimental method was the same as that of Example 1, and the amounts of materials used remained unchanged. The difference was that 3-acetamidotoluene was replaced by N-([1,1'-biphenyl]-3-yl)acetamide, and finally the product 3e was prepared with a yield of 76%.

[0092] The characterization data of the product 3e are as follows: 1 H NMR(400MHz,DMSO-d6)δ9.38(s,1H),7.76(s,1H),7.60(d,J=7.5Hz,2H),7.44(t,J=7.6Hz,2H),7.38–7.31(m,2H),7.28(d,J=7.9Hz,1H),2.11(s,3H). 13 C NMR(100MHz,DMSO-d6)δ168.8,140.4,138.5,137.6,131.3,131.0,129.4,127.7,126.9,123.6,123.5,23.9.HRMS(ESI)m / z:calcd for C 15 H 12 D3NONa[M+Na] + :251.1234,found:251.1236.

[0093] Example 10:

[0094]

[0095] The experimental method was the same as that in Example 1, and the amounts of materials used remained unchanged. The difference was that 3-acetamidotoluene was replaced by N-(3,4-dimethylphenyl)acetamide, and finally the product 3f was prepared with a yield of 94%.

[0096] The characterization data of the product 3f are as follows: 1 H NMR(400MHz,DMSO-d6)δ9.16(s,1H),7.11(s,1H),6.92(s,1H),2.13(s,6H),2.02(s,3H). 13 C NMR(100MHz,DMSO-d6)δ168.5,134.5,133.7,133.2,131.7,129.2,126.8,23.6,19.4,19.2.HRMS(ESI)m / z:calcd for C 11 H 12 D3NONa[M+Na] + :203.1234,found:203.1234.

[0097] Example 11:

[0098]

[0099] The experimental method was the same as that in Example 1, and the amounts of materials used remained unchanged. The difference was that 3-acetamidotoluene was replaced by N-(4-methoxy-3-methylphenyl)acetamide, and finally the product 3g was prepared with a yield of 88%.

[0100] The characterization data of the product 3g are as follows: 1 H NMR(400MHz,DMSO-d6)δ9.12(s,1H),7.03(s,1H),6.74(s,1H),3.74(s,3H),2.07(s,3H),2.00(s,3H). 13 C NMR(100MHz,DMSO-d6)δ168.6,155.2,131.2,129.2,128.4,123.0,112.3,55.7,23.5,16.0.HRMS(ESI)m / z:calcd forC 11 H 12 D3NO2Na[M+Na] + :219.1183,found:219.1187.

[0101] Example 12:

[0102]

[0103] The experimental method was the same as that of Example 1, and the amounts of materials used remained unchanged. The difference was that 3-acetamidotoluene was replaced by N-(3,4-dimethoxyphenyl)acetamide, and finally product 3h was prepared with a yield of 83%.

[0104] The characterization data of product 3h are as follows: 1 H NMR(400MHz,DMSO-d6)δ9.18(s,1H),6.94(s,1H),6.77(s,1H),3.72(s,3H),3.68(s,3H),2.02(s,3H). 13 C NMR(100MHz,DMSO-d6)δ168.6,146.9,146.7,129.5,124.4,114.1,110.6,56.1,56.0,23.6.HRMS(ESI)m / z:calcd forC 11 H 12 D3NO3Na[M+Na] + :235.1132,found:235.1134.

[0105] Example 13:

[0106]

[0107] The experimental method was the same as that of Example 1, and the amounts of materials used remained unchanged. The difference was that 3-acetamidotoluene was replaced by N-m-tolyl pivalamide, and finally product 3i was prepared with a yield of 90%.

[0108] The characterization data of product 3i are as follows: 1 H NMR(400MHz,DMSO-d6)δ9.10(s,1H),7.44(d,J=8.2Hz,1H),7.15(t,J=7.8Hz,1H),6.85(d,J=7.5Hz,1H),2.27(s,3H),1.22(s,9H). 13 CNMR(100MHz,DMSO-d6)δ176.8,139.7,137.9,128.7,124.3,121.3,117.9,27.7,21.6.HRMS(ESI)m / z:calcd for C 13 H 16 D3NONa[M+Na] + :231.1547,found:231.1548.

[0109] The present invention provides an idea and method for preparing a benzamide compound containing deuterated methyl. There are many methods and ways to specifically implement this technical solution. The above description is only the preferred embodiment of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention. Each component not clearly defined in this embodiment can be implemented by existing technologies.

Claims

1. A method for preparing a benzamide compound containing deuterated methyl, characterized in that, The benzamide compound 1 reacts with the deuterated methylation reagent 2 under the action of a catalyst and a base to obtain a benzamide compound 3 containing a deuterated methyl group; Among them, the structural formula of the benzamide compound 1 is as shown in Formula 1, the structural formula of the deuterated methylation reagent 2 is as shown in Formula 2, and the structural formula of the benzamide compound 3 containing a deuterated methyl group is as shown in Formula 3: Among them, n is an integer between 0 and 4; n R1s are independently selected from C1-C6 alkyl, phenyl or C1-C6 alkoxy; R2 is selected from C1-C8 alkyl, dimethylamino, phenyl or morpholinyl.

2. The preparation method according to claim 1, wherein n is an integer between 0 and 2; n R1s are independently selected from methyl, ethyl, isopropyl, tert-butyl, phenyl or methoxy; R2 is selected from methyl, n-heptyl, phenyl, dimethylamino, tert-butyl or morpholinyl; Preferably, n is an integer between 0 and 2; n R1s are independently selected from methyl, ethyl, isopropyl, tert-butyl, phenyl or methoxy; R2 is selected from methyl or tert-butyl.

3. The preparation method according to claim 1, characterized in that, The benzamide compound 1 is selected from any of the following structures:

4. The preparation method according to claim 1, characterized in that, The catalyst is any one or a combination of several of [1,3-bis(diphenylphosphino)propane] palladium(II) trifluoromethanesulfonate, palladium chloride, bis(acetonitrile)palladium(II) chloride and palladium acetate.

5. The preparation method according to claim 1, characterized in that, The base is any one or a combination of several of triethylamine, cesium carbonate, potassium carbonate, potassium bicarbonate, sodium carbonate and sodium bicarbonate.

6. The preparation method according to claim 1, characterized in that The solvent used in the reaction is any one or a combination of several of toluene, ethyl acetate, dichloromethane, 1,2-dichloroethane and tert-amyl alcohol.

7. The preparation method according to claim 1, wherein The molar ratio of the benzamide compound 1 to the deuterated methylation reagent 2 is 1.0:(1.0-2.0).

8. The preparation method according to claim 1, wherein, The molar ratio of the benzamide compound 1 to the catalyst is (8.0-10.0):1.

0.

9. The preparation method according to claim 1, wherein The molar ratio of the benzamide compound 1 to the base is (1.0-2.0):(2.0-5.0).

10. The preparation method according to claim 1, characterized in that, For the reaction, the reaction temperature is 25°C to 120°C.

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