CN101007792A - Synthesis process of nitro thiazoly benzamide compound - Google Patents

Abstract

The invention discloses a method for synthesizing nitrothiazole benzamide compounds. Add acetylsalicylic acid and 2-amino-5-nitrothiazole in a molar ratio of 2:1 into acetone, and stir at -2°C to 3°C. Then add the condensing agent DCC (N, N-dicyclohexylcarbodiimide), and then add triethylamine. Stir at -2°C to 3°C for 3-6 hours. The system was filtered, the filtrate was extracted with ethyl acetate and water, the ethyl acetate layer was dried over anhydrous sodium sulfate, and decolorized with activated carbon. Concentrate by distillation under reduced pressure at 100-300Pa, stir the concentrate with isopropanol at -2°C-3°C, and crystallize. A crude product was obtained, which was recrystallized with dichloromethane to obtain a relatively pure product. The invention has mild reaction conditions, simple operation and easy control. Moreover, the reaction speed is fast, the reaction conversion rate reaches 75.3-90.5%, the product yield reaches 60.5-78.2%, the purity of the product after recrystallization reaches 98-99%, and the solvents used in the whole synthesis process are all low-toxic or non-toxic. It is a synthetic method with great industrial prospects.

Description

A kind of method for synthesizing nitrothiazole benzamide compound

technical field

The invention relates to a method for synthesizing o-[N-(5-nitrothiazol-2-yl)carbamoyl]phenyl acetate (o-[N-(5-Nitrothiazol-2-yl)carbamoyl]phenyl acetate) method.

Background technique

o-[N-(5-Nitrothiazol-2-yl)carbamoyl]phenyl acetate is the synthetic drug nitazoxanide (Nitazoxanide) raw material drug, trade name Alinia, it is a new antiprotozoal drug, approved by the U.S. FDA for its liquid preparation to treat cryptosporidiosis (Cry-tosporidium parvum) and intestinal giardia (Giardialamblia) caused by 1 Diarrhea in children up to 11 years old. The drug is rapidly absorbed orally and easily excreted. [Chen Fuxin, Han Honggang, Nitazoxanide—a new antiprotozoal drug, Chinese Pharmacist, 2004, 7(5), 394～395].

Regarding the synthesis of o-[N-(5-nitro-2-thiazolyl)carbamoyl]phenyl acetate, there are mainly two synthetic methods reported in the literature.

One method is to use 2-amino 5-nitrothiazole and acetylsalicylic acid as raw materials, acetylsalicylic acid is chlorinated, and then reacted with 2-amino 5-nitrothiazole to synthesize. [Rossignol, Jean-Francois (FR), Cavier, Raymond (FR). New derivatives of 2-benzamido-5-nitrothiazoles (P), U.S.3950351, April 13, 1976], the main shortcoming of this method is that in the final reaction process In acetylsalicylic acid, it is easy to remove the acetyl group on it. The reaction is not easy to control.

Another reported synthetic method is to use 2-amino 5-nitrothiazole and salicylic acid as raw materials, and salicylic acid is reacted with 2-amino 5-nitrothiazole by acyl chloride, and the product obtained after the reaction is subjected to acetic anhydride Acetylation to obtain products [Li Shaohua. Xiong Yuanzhen. Kuang Binhai, Improvement of the synthesis method of nitazoxanide, Chinese Journal of Modern Applied Pharmacy, 2006.10, 23(5), 368-369]. There are many steps in this method, and anhydrous is strictly required in the reaction process, which brings inconvenience to industrial production.

Contents of the invention

The object of the present invention is to provide a kind of synthetic method of nitrothiazol benzamide compound (o-[N-(5-Nitrothiazol-2-yl)carbamoyl]phenyl acetate).

The technical solution adopted in the present invention comprises the following steps:

1) Add acetylsalicylic acid and 2-amino-5-nitrothiazole in acetone with a molar ratio of 2:1, the ratio of acetone to acetylsalicylic acid is 10ml:10mmol, and stir at -2°C to 3°C 0.5 to 1 hour;

2) Then add the condensing agent DCC with a ratio of 3 to 1:1 to 2-amino-5-nitrothiazole. Triethylamine; Stir at -2°C to 3°C for 3-6 hours;

3) The reaction mixture in step 2) is filtered with a Buchner funnel, and the filtrate is concentrated under reduced pressure at 100 to 300 Pa to obtain a light yellow oil, which is extracted with ethyl acetate and water in a volume ratio of 10:1; acetic acid The ethyl ester layer was dried with anhydrous sodium sulfate and decolorized with activated carbon; concentrated by distillation under reduced pressure at 100-300Pa, the concentrated solution was stirred with isopropanol at -2°C to 3°C, and crystallized; the crude product was obtained and reconstituted with dichloromethane Crystallization, a product with a purity of 98-99% can be obtained. Its structural formula is as follows:

The invention has the beneficial effects of mild reaction conditions, simple operation and easy control. Moreover, the reaction speed is fast, the reaction conversion rate reaches 75.3-90.5%, the product yield reaches 60.5-78.2%, the purity of the product after recrystallization reaches 98-99%, and the solvents used in the whole synthesis process are all low-toxic or non-toxic. It is a synthetic method with great industrial prospects.

Detailed ways

The present invention will be further described below in conjunction with embodiment.

Example 1

Add acetylsalicylic acid (20mmol, 3.62g) and 2-amino-5-nitrothiazole (10mmol, 1.45g) into 10ml of acetone, stir at -2°C to 3°C for 0.5 to 1 hour, drop slowly Add DCC/acetone solution (20mmol/20ml), after the dropwise addition, start to add triethylamine/acetone solution (40mol/10ml) dropwise, and then stir for 3 to 5 hours (the above process is carried out at -2°C to 3°C) ), the reaction mixture was filtered with a Buchner funnel, and the filter cake was washed with 5ml of acetone. The filtrate was concentrated to 5ml under reduced pressure at 100～300Pa, and the concentrated solution was extracted with water and ethyl acetate. The amount of water and ethyl acetate was 40ml and 400ml respectively , the ethyl acetate phase was dried with anhydrous sodium sulfate, filtered, the filtrate was decolorized with 1.5g of activated carbon, filtered while hot, the filtrate was concentrated by distillation under reduced pressure at 100-300Pa, and the concentrated solution was heated with 20ml of isopropanol at -2°C to 3 Stir at ℃ to crystallize to obtain a pale yellow crude product. The crude product was recrystallized with 40ml of dichloromethane to obtain 2.35g of pure product with a yield of 78.0%. 99% pure.

Example 2

Add acetylsalicylic acid (20mmol, 3.62g) and 2-amino-5-nitrothiazole (10mmol, 1.45g) into 10ml of acetone, stir at -2°C to 3°C for 0.5 to 1 hour, drop slowly Add DCC/acetone solution (15mmol/20ml), after the dropwise addition, start to drop triethylamine/acetone solution (40mol/10ml), and stir for 3 to 5 hours (all the above processes are carried out at -2°C to 3°C) , the reaction mixture was filtered with a Buchner funnel, and the filter cake was washed with 5ml of acetone. The filtrate was concentrated to 5ml under reduced pressure at 100～300Pa, and the concentrated solution was extracted with water and ethyl acetate. The amounts of water and ethyl acetate were 40ml and 400ml respectively, The ethyl acetate phase was dehydrated with anhydrous sodium sulfate, filtered, the filtrate was decolorized with 1.5g of activated carbon, filtered while hot, the filtrate was concentrated by distillation under reduced pressure at 100-300Pa, and the concentrated solution was heated with 20ml of isopropanol at -2°C to 3 Stir at ℃ and crystallize to obtain a pale yellow crude product. The crude product is recrystallized with 40 ml of dichloromethane to obtain 2.20 g of a pure product with a yield of 73.2%. 98% purity.

Example 3

Add acetylsalicylic acid (20mmol, 3.62g) and 2-amino-5-nitrothiazole (10mmol, 1.45g) into 10ml of acetone, stir at -2°C to 3°C for 0.5 to 1 hour, drop slowly Add DCC/acetone solution (10mmol/20ml), after the dropwise addition, start to drop triethylamine/acetone solution (40mol/10ml), and then stir for 3 to 5 hours (all the above processes are carried out at -2°C to 3°C) , the reaction mixture was filtered with a Buchner funnel, and the filter cake was washed with 5ml of acetone. The filtrate was concentrated to 5ml under reduced pressure at 100～300Pa, and the concentrated solution was extracted with water and ethyl acetate. The amount of water and ethyl acetate was 40ml and 400ml respectively, The ethyl acetate phase was dehydrated with anhydrous sodium sulfate, filtered, the filtrate was decolorized with 1.5g activated carbon, filtered while hot, the filtrate was concentrated by distillation under reduced pressure at 100-300Pa, and the concentrated solution was heated with 20ml of isopropanol at -2°C to 3 Stir at ℃, and crystallize to obtain a light yellow crude product, which is recrystallized with 40 ml of dichloromethane to obtain 2.0 g of a pure product, with a yield of 65.0%. 98% purity.

Example 4

Add acetylsalicylic acid (20mmol, 3.62g) and 2-amino-5-nitrothiazole (10mmol, 1.45g) into 10ml of acetone, stir at -2°C to 3°C for 0.5 to 1 hour, drop slowly Add DCC/acetone solution (30mmol/20ml), after the dropwise addition, start to drop triethylamine/acetone solution (40mol/10ml), and stir for 3 to 5 hours (all the above processes are carried out at -2°C to 3°C) , the reaction mixture was filtered with a Buchner funnel, and the filter cake was washed with 5ml of acetone. The filtrate was concentrated to 5ml under reduced pressure at 100～300Pa, and the concentrated solution was extracted with water and ethyl acetate. The amount of water and ethyl acetate was 40ml and 400ml respectively, The ethyl acetate phase was dehydrated with anhydrous sodium sulfate, filtered, the filtrate was decolorized with 1.5g activated carbon, filtered while hot, the filtrate was concentrated by distillation under reduced pressure at 100-300Pa, and the concentrated solution was heated with 20ml of isopropanol at -2°C to 3 Stir at ℃ and crystallize to obtain a light yellow crude product. The crude product is recrystallized with 40 ml of dichloromethane to obtain 2.4 g of a pure product with a yield of 78.2%. 99% pure.

Claims (1)

1, a kind of method for synthesizing nitrothiazole benzamide compound, it is characterized in that comprising the following steps: 1) Add acetylsalicylic acid and 2-amino-5-nitrothiazole in a molar ratio of 2:1 to acetone, and stir at -2°C to 3°C for 0.5 to 1 hour; 2) Then add the condensing agent DCC with a ratio of 3 to 1:1 to 2-amino-5-nitrothiazole. Triethylamine; Stir at -2°C to 3°C for 3-6 hours; 3) The reaction mixture in step 2) is filtered with a Buchner funnel, and the filtrate is concentrated under reduced pressure at 100 to 300 Pa to obtain a light yellow oil, which is extracted with ethyl acetate and water in a volume ratio of 10:1; acetic acid The ethyl ester layer was dried with anhydrous sodium sulfate and decolorized with activated carbon; concentrated by distillation under reduced pressure at 100-300Pa, the concentrated solution was stirred with isopropanol at -2°C to 3°C, and crystallized; the crude product was obtained and reconstituted with dichloromethane Crystallization, a product with a purity of 98-99% can be obtained;