Background technology
O-[N-(5-nitro-2-thiazolyl) formamyl] and phenylacetate (o-[N-(5-Nitrothiazol-2-yl) carbamoyl] phenyl acetate) be the bulk drug of synthetic drugs nitazoxanide (Nitazoxanide); trade(brand)name Alinia; it is a kind of new antiprotozoal drug, by the diarrhoea of 1~11 years old children due to its liquid preparation treatment cryptosporidiosis (Cry-tosporidium parvum) of drugs approved by FDA and the giardia intestinalis (Giardialamblia).This drug oral absorbs fast, is easy to drain.[Chen Fuxin, Han Honggang, nitazoxanide---plant new antiprotozoal drug, Chinese pharmacist, 2004,7 (5), 394~395].
About o-[N-(5-nitro-2-thiazolyl) formamyl] phenylacetate synthetic, the synthetic method of bibliographical information mainly contains two kinds.
A kind of method is to be raw material with amino 5-nitrothiazole of 2-and acetylsalicylic acid, and acetylsalicylic acid is through chloride, and is synthetic with the amino 5-nitrothiazole reaction of 2-again.[Rossignol; Jean-Francois (FR); Cavier; Raymond (FR) .New derivatives of 2-benzamido-5-nitrothiazoles (P); U.S.3950351; April 13,1976], this method main drawback is that acetylsalicylic acid is easily taken off ethanoyl on it in last reaction process.React wayward.
The synthetic method of another kind of report is to be raw material with amino 5-nitrothiazole of 2-and Whitfield's ointment; Whitfield's ointment reacts with the amino 5-nitrothiazole of 2-by chloride again; reaction back products therefrom again through the diacetyl oxide acetylize obtain product [Li Shaohua. Xiong Yuanzhen. the strand of rectifying; the improvement of nitazoxanide synthetic method; contemporary Chinese is used pharmaceutical journal; 2006.10,23 (5), 368~369].This method step is more, and strict demand is anhydrous in the reaction process, and this has just brought inconvenience to industrial production.
Summary of the invention
The synthetic method that the purpose of this invention is to provide a kind of synthesizing nitryl thiazole benzamide compound (o-[N-(5-Nitrothiazol-2-yl) carbamoyl] phenyl acetate).
The technical solution used in the present invention is may further comprise the steps:
1) adding mol ratio in acetone is 2: 1 acetylsalicylic acid and 2-amino-5-nitrothiazole, and acetone and acetysalicylic ratio are 10ml: 10mmol ,-2 ℃~3 ℃ stirrings 0.5~1 hour down;
2) add again with 2-amino-5-nitrothiazole ratio be 3~1: 1 condensing agent DCC, after dropwising, add then with 2-amino-5-nitrothiazole mol ratio be 4: 1 triethylamine; Stirred 3-6 hour down at-2 ℃~3 ℃;
3) reaction back mixture filters with B step 2), and filtrate is concentrating under reduced pressure under 100~300Pa, gets light yellow oil, oily matter ethyl acetate and water extraction, and its volume ratio is 10: 1; The ethyl acetate layer anhydrous sodium sulfate drying, activated carbon decolorizing; Underpressure distillation concentrates under 100~300Pa, and concentrated solution uses Virahol at-2 ℃~3 ℃ stirrings, precipitation and crystallization; Obtain thick product, use the methylene dichloride recrystallization, can obtain purity and be 98~99% product.Its structural formula is as follows:
The beneficial effect that the present invention has is: the reaction conditions gentleness, and simple to operate, be easy to control.And speed of response is fast, reaction conversion ratio reaches 75.3~90.5%, and product yield reaches 60.5~78.2%, and the purity of product reaches 98~99% behind the process recrystallization, and synthetic whole process solvent for use all is a low toxicity or nontoxic, and it is a kind of synthetic method that industrial prospect is arranged very much.
Embodiment
The invention will be further described below in conjunction with embodiment.
Embodiment 1
With acetylsalicylic acid (20mmol, 3.62g) and 2-amino-5-nitrothiazole (10mmol, 1.45g) join in the 10ml acetone, under-2 ℃~3 ℃, stirred 0.5~1 hour, slowly drip DCC/ acetone soln (20mmol/20ml), begin to drip triethylamine/acetone soln (40mol/10ml) after dropwising, restir 3~5 hours (above process all stirs down at-2 ℃~3 ℃ and carries out), reaction mixture filters with B, filter cake 5ml washing with acetone. filtrate is evaporated to 5ml under 100~300Pa, concentrated solution water and ethyl acetate extraction, the amount of water and ethyl acetate is respectively 40ml and 400ml, ethyl acetate is used anhydrous sodium sulfate drying mutually, filter, filtrate is used 1.5g decolorizing with activated carbon, filtered while hot, filtrate underpressure distillation under 100~300Pa concentrates, concentrated solution stirs down at-2 ℃~3 ℃ with the 20ml Virahol, and precipitation and crystallization gets light yellow thick product.Thick product gets straight product 2.35g, productive rate 78.0% with 40ml methylene dichloride recrystallization.Purity 99%.
Embodiment 2
With acetylsalicylic acid (20mmol, 3.62g) and 2-amino-5-nitrothiazole (10mmol, 1.45g) join in the 10ml acetone, under-2 ℃~3 ℃, stirred 0.5~1 hour, slowly drip DCC/ acetone soln (15mmol/20ml), begin to drip triethylamine/acetone soln (40mol/10ml) after dropwising, restir 3~5 hours (above process is all carried out under-2 ℃~3 ℃), reaction mixture filters with B, filter cake 5ml washing with acetone. and filtrate is evaporated to 5ml under 100~300Pa, concentrated solution water and ethyl acetate extraction, the amount of water and ethyl acetate is respectively 40ml and 400ml, and ethyl acetate dewaters with anhydrous sodium sulphate, filters, filtrate is used the 1.5g decolorizing with activated carbon, the underpressure distillation under 100~300Pa of filtered while hot, filtrate concentrates, and concentrated solution stirs down at-2 ℃~3 ℃ with the 20ml Virahol, precipitation and crystallization, getting light yellow thick product. thick product gets straight product 2.20g, productive rate 73.2% with 40ml methylene dichloride recrystallization.Purity 98%.
Embodiment 3
With acetylsalicylic acid (20mmol, 3.62g) and 2-amino-5-nitrothiazole (10mmol, 1.45g) join in the 10ml acetone, under-2 ℃~3 ℃, stirred 0.5~1 hour, slowly drip DCC/ acetone soln (10mmol/20ml), begin to drip triethylamine/acetone soln (40mol/10ml) after dropwising, restir 3~5 hours (above process is all carried out under-2 ℃~3 ℃), reaction mixture filters with B, filter cake 5ml washing with acetone. filtrate is evaporated to 5ml under 100~300Pa, concentrated solution water and ethyl acetate extraction, the amount of water and ethyl acetate is respectively 40ml and 400ml, and ethyl acetate dewaters with anhydrous sodium sulphate, filter, filtrate is used the 1.5g decolorizing with activated carbon, filtered while hot, and filtrate underpressure distillation under 100~300Pa concentrates, concentrated solution stirs down at-2 ℃~3 ℃ with the 20ml Virahol, precipitation and crystallization gets light yellow thick product, thick product 40ml methylene dichloride recrystallization, get straight product 2.0g, productive rate 65.0%.Purity 98%.
Embodiment 4
With acetylsalicylic acid (20mmol, 3.62g) and 2-amino-5-nitrothiazole (10mmol, 1.45g) join in the 10ml acetone, under-2 ℃~3 ℃, stirred 0.5~1 hour, slowly drip DCC/ acetone soln (30mmol/20ml), begin to drip triethylamine/acetone soln (40mol/10ml) after dropwising, restir 3~5 hours (above process is all carried out under-2 ℃~3 ℃), reaction mixture filters with B, filter cake 5ml washing with acetone. and filtrate is evaporated to 5ml under 100~300Pa, concentrated solution water and ethyl acetate extraction, the amount of water and ethyl acetate is respectively 40ml and 400ml, and ethyl acetate dewaters with anhydrous sodium sulphate, filters, filtrate is used the 1.5g decolorizing with activated carbon, the underpressure distillation under 100~300Pa of filtered while hot, filtrate concentrates, and concentrated solution stirs down at-2 ℃~3 ℃ with the 20ml Virahol, precipitation and crystallization, getting light yellow thick product. thick product gets straight product 2.4g, productive rate 78.2% with 40ml methylene dichloride recrystallization.Purity 99%.