A kind of preparation method of 4-amino-2-fluoro-n-methylbenzamide

Abstract

The invention belongs to the field of pharmaceutical engineering and in particular relates to a preparation method of novel antiandrogen drug MDV (Marek's Disease Virus) 3100 key intermediate 4-amino-2-fluoro-methyl benzamide. In order to overcome the problem that the environment is polluted in the preparation process of the 4-amino-2-fluoro-methyl benzamide in the prior art, the invention provides a method for preparing 4-amino-2-fluoro-methyl benzamide by using 2-fluoro-4-nitrotoluen as the material through potassium permanganate oxidation, methylamination and Pd / C hydrogenation reduction reaction. The preparation method is a cleaning process production technology, simple in process operation and suitable for large-scale production. The preparation method of the 4-amino-2-fluoro-methyl benzamide disclosed by the invention has the advantages as follows: the yield of the process for obtaining 4-amino-2-fluoro-methyl benzamide by Pd / C catalytic hydrogenation is as high as 98%, the product purity is 98% or higher, the wastewater amount is less, and the catalyst and the organic solvent can be recycled for use; and in terms of the 2-fluoro-4-nitrotoluen, the tree-step total yield is as high as 68.2%.

Description

technical field

[0001] The invention belongs to the field of pharmaceutical engineering, in particular to a method for preparing a key intermediate 4-amino-2-fluoro-N-methylbenzamide of a novel antiandrogen drug Enzalutamide (MDV3100). Background technique

[0002] Prostate cancer (PCa) is one of the common malignant tumors in middle-aged and elderly men. In recent years, it has rapidly risen to a global tumor disease. rate occupies the second place. The incidence of prostate cancer in my country is relatively low, but with the rapid economic development and the gradual Europeanization of people's diet, prostate cancer is on the rise in my country. Androgen deprivation therapy (Androgen Deprivation Therapy, ADT) is the first choice for the treatment of prostate cancer, but almost all patients develop drug resistance after 12 to 18 months, and the tumor metastasizes, which is difficult to treat and can easily lead to Death of androgen-resistant prostate cancer (Castration-R...

Examples

Embodiment 1

[0026] Preparation of 2-fluoro-4-nitrobenzoic acid

[0027] Add 2-fluoro-4-nitrotoluene (31.1g, 0.2mol), water (500ml), sodium hydroxide (10.0g, 0.25mol) and tetrabutylammonium bromide (3.2g, 0.01 mol), stir evenly and heat to 95°C, add potassium permanganate (79.0g, 0.5mol) in batches under stirring, react at 85°C for 8 hours, follow the reaction by TLC, filter while hot to remove di Manganese oxide, the filtrate was adjusted to pH 2 by adding concentrated hydrochloric acid, a white precipitate was precipitated, left to stand, filtered, washed with water, and dried to obtain off-white solid 2-fluoro-4-nitrobenzoic acid (27.3g), the yield was 73.7% (with 2 -Fluoro-4-nitrotoluene), with a content of more than 98%, 1 H NMR: (400Hz, DMSO-d), δ (ppm), 8.23 ​​(d, J=10.5Hz, 1H), 8.06-8.18 (m, 2H);

[0028] Other conditions remain unchanged, without adding sodium hydroxide and tetrabutylammonium bromide, when potassium permanganate is used to directly oxidize 2-fluoro-4-nitrobenzoi...

Embodiment 2

[0035] Preparation of 2-fluoro-4-nitrobenzoic acid

[0036] Add 2-fluoro-4-nitrotoluene (31.1g, 0.2mol), water (1000ml), sodium hydroxide (8.0g, 0.2mol) and triethylbenzyl ammonium chloride (4.56 g, 0.02mol), stir evenly and heat to 75°C, add potassium permanganate (94.8g, 0.6mol) in batches under stirring, react at 80°C for 18 hours, follow the reaction by TLC, and complete the reaction while hot Remove manganese dioxide by filtration, add concentrated hydrochloric acid to the filtrate to adjust the pH to 4, a white precipitate precipitates out, let stand, filter, wash with water, and dry to obtain off-white solid 2-fluoro-4-nitrobenzoic acid (27.9g), yield 75.3% (calculated as 2-fluoro-4-nitrotoluene), the content is more than 98%, 1 H NMR: (400Hz, DMSO-d), δ (ppm), 8.23 ​​(d, J=10.5Hz, 1H), 8.06-8.18 (m, 2H);

[0037] Preparation of 2-fluoro-4-nitro-N-methylbenzamide

[0038] Add 2-fluoro-4-nitrobenzoic acid (27.9g, 0.15mol), chloroform (450ml), triethylamine (1.0ml) int...

Embodiment 3

[0042] Preparation of 2-fluoro-4-nitrobenzoic acid

[0043] Add 2-fluoro-4-nitrotoluene (31.1g, 0.2mol), water (500ml), sodium hydroxide (20.0g, 0.50mol) and tetrabutylammonium chloride (6.22g, 0.022 mol), stir evenly and heat to 80°C, add potassium permanganate (64.8g, 0.41mol) in batches under stirring, react at 95°C for 16 hours, follow the reaction by TLC, filter while hot to remove di Manganese oxide, the filtrate was adjusted to pH 2 by adding concentrated hydrochloric acid, white precipitates were precipitated, left to stand, filtered, washed with water, and dried to obtain off-white solid 2-fluoro-4-nitrobenzoic acid (27.5g), yield 74.2 (with 2- Fluoro-4-nitrotoluene), the content is more than 98%.

[0044] Preparation of 2-fluoro-4-nitro-N-methylbenzamide

[0045] Add 2-fluoro-4-nitrobenzoic acid (27.5g, 0.148mol), 1,2-dichloroethane (275ml), N,N-dimethylformamide (1.38ml) into a 1L reaction flask, Add thionyl chloride (26.3g, 0.22mol) dropwise, stir at room temper...

technical field

[0001] The invention belongs to the field of pharmaceutical engineering, in particular to a method for preparing a key intermediate 4-amino-2-fluoro-N-methylbenzamide of a novel antiandrogen drug Enzalutamide (MDV3100). Background technique

[0002] Prostate cancer (PCa) is one of the common malignant tumors in middle-aged and elderly men. In recent years, it has rapidly risen to a global tumor disease. rate occupies the second place. The incidence of prostate cancer in my country is relatively low, but with the rapid economic development and the gradual Europeanization of people's diet, prostate cancer is on the rise in my country. Androgen deprivation therapy (Androgen Deprivation Therapy, ADT) is the first choice for the treatment of prostate cancer, but almost all patients develop drug resistance after 12 to 18 months, and the tumor metastasizes, which is difficult to treat and can easily lead to Death of androgen-resistant prostate cancer (Castration-R...

Examples

Embodiment 1

[0026] Preparation of 2-fluoro-4-nitrobenzoic acid

[0027] Add 2-fluoro-4-nitrotoluene (31.1g, 0.2mol), water (500ml), sodium hydroxide (10.0g, 0.25mol) and tetrabutylammonium bromide (3.2g, 0.01 mol), stir evenly and heat to 95°C, add potassium permanganate (79.0g, 0.5mol) in batches under stirring, react at 85°C for 8 hours, follow the reaction by TLC, filter while hot to remove di Manganese oxide, the filtrate was adjusted to pH 2 by adding concentrated hydrochloric acid, a white precipitate was precipitated, left to stand, filtered, washed with water, and dried to obtain off-white solid 2-fluoro-4-nitrobenzoic acid (27.3g), the yield was 73.7% (with 2 -Fluoro-4-nitrotoluene), with a content of more than 98%, 1 H NMR: (400Hz, DMSO-d), δ (ppm), 8.23 ​​(d, J=10.5Hz, 1H), 8.06-8.18 (m, 2H);

[0028] Other conditions remain unchanged, without adding sodium hydroxide and tetrabutylammonium bromide, when potassium permanganate is used to directly oxidize 2-fluoro-4-nitrobenzoi...

Embodiment 2

[0035] Preparation of 2-fluoro-4-nitrobenzoic acid

[0036] Add 2-fluoro-4-nitrotoluene (31.1g, 0.2mol), water (1000ml), sodium hydroxide (8.0g, 0.2mol) and triethylbenzyl ammonium chloride (4.56 g, 0.02mol), stir evenly and heat to 75°C, add potassium permanganate (94.8g, 0.6mol) in batches under stirring, react at 80°C for 18 hours, follow the reaction by TLC, and complete the reaction while hot Remove manganese dioxide by filtration, add concentrated hydrochloric acid to the filtrate to adjust the pH to 4, a white precipitate precipitates out, let stand, filter, wash with water, and dry to obtain off-white solid 2-fluoro-4-nitrobenzoic acid (27.9g), yield 75.3% (calculated as 2-fluoro-4-nitrotoluene), the content is more than 98%, 1 H NMR: (400Hz, DMSO-d), δ (ppm), 8.23 ​​(d, J=10.5Hz, 1H), 8.06-8.18 (m, 2H);

[0037] Preparation of 2-fluoro-4-nitro-N-methylbenzamide

[0038] Add 2-fluoro-4-nitrobenzoic acid (27.9g, 0.15mol), chloroform (450ml), triethylamine (1.0ml) int...

Embodiment 3

[0042] Preparation of 2-fluoro-4-nitrobenzoic acid

[0043] Add 2-fluoro-4-nitrotoluene (31.1g, 0.2mol), water (500ml), sodium hydroxide (20.0g, 0.50mol) and tetrabutylammonium chloride (6.22g, 0.022 mol), stir evenly and heat to 80°C, add potassium permanganate (64.8g, 0.41mol) in batches under stirring, react at 95°C for 16 hours, follow the reaction by TLC, filter while hot to remove di Manganese oxide, the filtrate was adjusted to pH 2 by adding concentrated hydrochloric acid, white precipitates were precipitated, left to stand, filtered, washed with water, and dried to obtain off-white solid 2-fluoro-4-nitrobenzoic acid (27.5g), yield 74.2 (with 2- Fluoro-4-nitrotoluene), the content is more than 98%.

[0044] Preparation of 2-fluoro-4-nitro-N-methylbenzamide

[0045] Add 2-fluoro-4-nitrobenzoic acid (27.5g, 0.148mol), 1,2-dichloroethane (275ml), N,N-dimethylformamide (1.38ml) into a 1L reaction flask, Add thionyl chloride (26.3g, 0.22mol) dropwise, stir at room temper...

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