Amine compound for fungi medicine and preparation method of amine compound

Abstract

The invention relates to the field of drug synthesis, in particular to an amine compound for fungi drugs and a preparation method of the amine compound. Comprising the following steps: 1) adding N-bromosuccinimide (NBS) into 4-iodobenzene serving as an initial raw material in an acetonitrile solvent in the presence of benzoyl peroxide serving as a catalyst, and reacting to obtain a 1-bromomethyl-4-iodobenzene compound II; 2) adding N-methylacetamide into the compound II in a tetrahydrofuran solvent by using potassium carbonate as alkali, and reacting to obtain an N-(4-iodobenzyl)-N-methylacetamide compound III; and 3) heating the compound III in a sodium hydroxide solution for deacetylation to obtain the compound IN-methyl-1-(4-iodophenyl) methylamine. The invention aims to provide a preparation process of the N-methyl-1-(4-iodophenyl) methylamine compound I, which is simple, convenient, green, environment-friendly and suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug synthesis, more specifically, it relates to an amine compound for fungal drugs and a preparation method thereof. BACKGROUND

[0002] The N-methyl-1-(4-iodophenyl)methylamine compound contains iodine elements, and iodine can be used to prepare a developer or a targeted therapeutic drug if it is a radioisotope (such as iodine-125, iodine-131). The iodine atom in the para position of the benzene ring makes it an ideal coupling reaction precursor (such as SUZUKI, HECK, Ullmann reaction, etc.), which is used to construct carbon-carbon or carbon-nitrogen heteroatom bonds to synthesize more complex organic drug molecules.

[0003] In the prior art, patent application number WO2021113263A1 reports that the antagonist of the corticotropin-releasing factor (CRF) receptor is N-methyl-1-(4-iodophenyl)methylamine (compound I) as an important structural fragment; in addition, patent application number CN116924959A reports a HDAC11 subtype selective inhibitor and a preparation method thereof, wherein compound 9a is a palladium-catalyzed cross-coupling reaction using compound I as an important structural fragment; it has potential application value in the fields of pesticides, medicines, optoelectronic materials, coordination chemistry, and analytical chemistry, and has broad market prospects.

[0004] Patent application number CN103242273B reports a method as shown in the following formula, which uses a batch addition of 1-bromomethyl-4-iodo (II) and a methylamine solution to prepare compound I. Since the activity of the secondary amine product is higher than that of the primary amine, a large amount of by-product I is generated after the nitrogen alkylation, and it is difficult to obtain a compound I with high purity, and it is difficult to realize large-scale production. '

[0005] According to the method reported in European Journal of Organic Chemistry, 2018, vol. 2018, #27, p. 3701-3704, compound IV is reacted with chloromethane in the presence of sodium hydride as a base to obtain compound III. Since a large amount of hydrogen gas is released during the reaction process, the operation is dangerous, and it is difficult to realize large-scale production with sodium hydride as a base. In addition, chloromethane is volatile and belongs to a genotoxic reagent, and the limit of the drug research and development API needs to be controlled according to the ICH related guidelines.

[0006] SUMMARY ​

[0007] The present application provides an amine compound for fungal drugs and a preparation method thereof, and aims to provide a preparation process of N-methyl-1-(4-iodophenyl)methylamine compound I which is simple, convenient, green, environmentally friendly and suitable for industrial production.

[0008] In a first aspect, the present application provides an amine compound for fungal drugs, and a synthetic route of the amine compound is as follows: In a second aspect, the present application provides a preparation method of an amine compound for fungal drugs, which comprises the following steps: 4-iodotoluene as a starting material is reacted in acetonitrile solvent, benzoyl peroxide is used as an initiator, and N-bromosuccinimide is added to obtain 1-bromomethyl-4-iodobenzene compound II; Compound II is reacted with N-methylacetamide in tetrahydrofuran solvent using potassium carbonate as a base to obtain N-(4-iodobenzyl)-N-methylacetamide compound III; Compound III is heated in sodium hydroxide solution to remove acetyl to obtain compound I N-methyl-1-(4-iodophenyl)methylamine.

[0009] Preferably, in step 1), the solvent is selected from one of acetonitrile, dioxane, N-methylpyrrolidone, dichloromethane, chloroform, carbon tetrachloride, N,N-dimethylformamide and N,N-dimethylacetamide, and acetonitrile is preferred.

[0010] Preferably, in step 1), the free radical initiator is selected from benzoyl peroxide (BPO) or azobis isobutyl cyanide (AIBN), and benzoyl peroxide is preferred according to the different cleavage temperatures of the two.

[0011] Preferably, in step 1), the amount of N-bromosuccinimide (NBS) is 0.8-1.5 times the molar equivalent of the starting material 4-iodotoluene, and more preferably 1.0-1.2 times the molar equivalent.

[0012] Preferably, in step 1), the reaction temperature is 40-80 ℃, more preferably 50-80 ℃, and most preferably 70-80 ℃.

[0013] Preferably, in step 2), the solvent is selected from one of acetonitrile, dioxane, N-methylpyrrolidone, dichloromethane, chloroform, carbon tetrachloride, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran and 2-methyltetrahydrofuran, and tetrahydrofuran is preferred.

[0014] Preferably, in step 2), the amount of potassium carbonate is 1.0-8.0 times the molar equivalent of compound II; more preferably 2.0-5.0 times the molar equivalent; most preferably 2.0-3.0 times the molar equivalent.

[0015] Preferably, in step 2), the reaction temperature is 20-45 ℃; more preferably 30-40 ℃.

[0016] Preferably, in step 3), the base is one of lithium hydroxide, sodium hydroxide, and potassium hydroxide; preferably sodium hydroxide; the amount of base is 1.0-5.0 times the molar equivalent of compound III; more preferably 2.0-3.0 times the molar equivalent.

[0017] Preferably, in step 3), the reaction temperature is 40-100 ℃; more preferably 50-80 ℃, most preferably 60-80 ℃.

[0018] In summary, the present application has the following advantages: The present application has the following advantages: (1) the raw material 4-iodotoluene and the reaction reagents used in the preparation process are conventional synthetic reagents, which are inexpensive and easy to obtain; (2) the reaction conditions of each step are mild, the purity of each target compound in the reaction system is high, and the post-treatment operation is simple; (3) the reaction yield is high, and the product purity is high; (4) the batch addition of NBS avoids the generation of a large amount of dibromide; (5) N-methylacetamide is used as a raw material, which effectively avoids the generation of by-product I'; it can be seen that the preparation process of the present application is convenient to operate, the product cost is low, and meets the requirements of industrial production.

[0019] It should be understood that the above general description and the following detailed description are only exemplary and explanatory, and cannot limit the protection scope of the present application. DETAILED DESCRIPTION

[0020] The present application will be further described in detail below in combination with examples, and it is particularly pointed out that: in the following examples, the specific conditions not specified are carried out according to the conventional conditions or the conditions recommended by the manufacturer, and the raw materials used in the following examples can be obtained from ordinary commercial sources unless otherwise specified.

[0021] Example Example 1 The preparation method of compound II comprises the following steps: Compound II was prepared according to the following procedure: Compound IV (20.0 g, 91.7 mmol) was dissolved in acetonitrile (200 mL), and benzoyl peroxide (0.6 g, 2.48 mmol) was added. The reaction mixture was heated to reflux, and NBS (17.75 g, 100.9 mmol) was added portionwise. After the addition was complete, the reaction mixture was refluxed for 1 h. The reaction progress was monitored by thin layer chromatography (TLC) (PE:EA = 20:1). After the starting material was consumed, the solvent was removed under reduced pressure. The residue was dissolved in 100 mL of water and extracted with 100 mL of ethyl acetate three times. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound II was obtained as a white solid in 83% yield (22.60 g) by crystallization from ethyl acetate: petroleum ether (1:8).

[0022] 1H NMR (400 MHz, CDC13) δ (ppm): 7.67 (d, J = 7.90 Hz, 2H), 7.13 (d, J = 8.03 Hz, 2H), 4.42 (s, 2H).

[0023] Example 2 The preparation method of compound III comprises the following steps: Compound II (1000.0 g, 3367.8 mmol) was dissolved in tetrahydrofuran (1000 mL), and N-methylacetamide (27.0 g, 370.46 mmol) was added. Potassium carbonate (934 g, 6735.6 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction progress was monitored by TLC (CH2Cl2:MeOH = 20:1). After the starting material was consumed, the solvent was removed under reduced pressure. The residue was dissolved in 200 mL of water and extracted with 500 mL of dichloromethane three times. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound III was obtained as a yellow solid in 90% yield (876.3 g).

[0024] 1H NMR (400 MHz, CDC13) δ (ppm): 7.74-7.67 (d, 2H), 7.04-6.95 (d, 2H), 4.55-4.50 (q, 2H), 2.95 (s, 3H), 2.19 (t, 3H). LC-MS: [M+1] = 290.00.

[0025] Example 3 The preparation method of compound I comprises the following steps: In a 250 mL three-necked round bottom flask, compound III (45.0 g, 196.30 mmol) was added, followed by 450 mL of 3 mol / L sodium hydroxide solution. Then the temperature was raised to 60-70 °C and stirred for about 4 h, and the reaction progress was monitored by thin layer chromatography (developing agent ratio: ethyl acetate: petroleum ether = 1:1). The reaction solution was extracted with 150 mL of dichloromethane for 3 times, the combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound I 39.28 g; yield 95%; as a yellow liquid.

[0026] 1 HNMR (400 MHz, CDCI3) δ (ppm): 7.66-7.63 (d, 1H), 7.08-7.06 (d, 1H), 3.69 (s, 2H), 2.44 (s, 3H). LC-MS: [M+1]=247.99.

[0027] The above merely illustrates the specific embodiments of the present application, but the protection scope of the present application is not limited thereto, any person skilled in the art can easily think of the changes or replacements within the technical range disclosed by the present application, which should be covered in the protection scope of the present application. Therefore, the protection scope of the present application should be subject to the protection scope of the claims.

Claims

1. An amine compound for fungal drugs, characterized in that: The synthetic route of the amine compound is: 。 2. The method for preparing an amine compound for fungal drugs according to claim 1, characterized in that: The following steps are involved: 1) Using 4-iodotoluene as the starting material in acetonitrile solvent, benzoyl peroxide as the initiator, and N-bromosuccinimide as the initiator, the reaction yields ‌1-bromomethyl-4-iodobenzene compound II; 2) Compound II is reacted in tetrahydrofuran solvent with potassium carbonate as a base and N-methylacetamide to obtain N-(4-iodobenzyl)-N-methylacetamide compound III; 3) Compound III is heated in sodium hydroxide solution for deacetylation to obtain compound I‌N-methyl-1-(4-iodophenyl)methanamine.

3. The method for preparing an amine compound for fungal drugs according to claim 2, characterized in that: In step 1), the solvent is selected from one or more of acetonitrile, dioxane, N-methylpyrrolidone, dichloromethane, chloroform, carbon tetrachloride, N,N-dimethylformamide and N,N-dimethylacetamide.

4. The method for preparing an amine compound for fungal drugs according to claim 2, characterized in that: In step 1), the initiator is selected from one of benzoyl peroxide and azobisisobutyl cyanide.

5. The method for preparing an amine compound for fungal drugs according to claim 2, characterized in that: In step 1), the molar ratio of N-bromosuccinimide to 4-iodotoluene is 0.8-1.5:

1.

6. The method for preparing an amine compound for fungal drugs according to claim 2, characterized in that: In step 1), the reaction temperature is 40-80°C.

7. The method for preparing an amine compound for fungal drugs according to claim 2, characterized in that: In step 2), the solvent is selected from one or more of acetonitrile, dioxane, N-methylpyrrolidone, dichloromethane, chloroform, carbon tetrachloride, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran and 2-methyltetrahydrofuran.

8. The method for preparing an amine compound for fungal drugs according to claim 2, characterized in that: In step 2), the base is one or more of sodium hydride, calcium hydride, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.

9. The method for preparing an amine compound for fungal drugs according to claim 2, characterized in that: In step 2), the molar ratio of potassium carbonate to compound II is 1.0-8.0:1; and the reaction temperature is 20-45°C.

10. The method for preparing an amine compound for fungal drugs according to claim 2, characterized in that: In step 3), the base is one of lithium hydroxide, sodium hydroxide, and potassium hydroxide; the molar ratio of the base to compound III is 1.0-5.0:1; and the reaction temperature is 40-100°C.

Images