CN101007792A - Synthesis process of nitro thiazoly benzamide compound - Google Patents
Synthesis process of nitro thiazoly benzamide compound Download PDFInfo
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- CN101007792A CN101007792A CN 200710067119 CN200710067119A CN101007792A CN 101007792 A CN101007792 A CN 101007792A CN 200710067119 CN200710067119 CN 200710067119 CN 200710067119 A CN200710067119 A CN 200710067119A CN 101007792 A CN101007792 A CN 101007792A
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- Prior art keywords
- amino
- nitrothiazole
- product
- nitro
- ethyl acetate
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- 238000000034 method Methods 0.000 title claims abstract description 14
- -1 benzamide compound Chemical class 0.000 title claims abstract description 12
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 title 1
- 230000015572 biosynthetic process Effects 0.000 title 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 title 1
- 238000003786 synthesis reaction Methods 0.000 title 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 42
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 40
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 21
- MIHADVKEHAFNPG-UHFFFAOYSA-N 2-Amino-5-nitrothiazole Chemical compound NC1=NC=C([N+]([O-])=O)S1 MIHADVKEHAFNPG-UHFFFAOYSA-N 0.000 claims abstract description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000003756 stirring Methods 0.000 claims abstract description 12
- 229940018167 2-amino-5-nitrothiazole Drugs 0.000 claims abstract description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 10
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229960001138 acetylsalicylic acid Drugs 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- 238000001953 recrystallisation Methods 0.000 claims abstract description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000001035 drying Methods 0.000 claims abstract description 4
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 3
- 239000000047 product Substances 0.000 claims description 20
- 239000000706 filtrate Substances 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 239000012141 concentrate Substances 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 238000004821 distillation Methods 0.000 claims description 6
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 6
- 238000001556 precipitation Methods 0.000 claims description 6
- 238000003809 water extraction Methods 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 9
- 208000012839 conversion disease Diseases 0.000 abstract description 2
- 239000007788 liquid Substances 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 abstract 2
- 235000019439 ethyl acetate Nutrition 0.000 abstract 2
- 238000001914 filtration Methods 0.000 abstract 2
- 229910052799 carbon Inorganic materials 0.000 abstract 1
- 231100000956 nontoxicity Toxicity 0.000 abstract 1
- 230000036632 reaction speed Effects 0.000 abstract 1
- YQNQNVDNTFHQSW-UHFFFAOYSA-N acetic acid [2-[[(5-nitro-2-thiazolyl)amino]-oxomethyl]phenyl] ester Chemical compound CC(=O)OC1=CC=CC=C1C(=O)NC1=NC=C([N+]([O-])=O)S1 YQNQNVDNTFHQSW-UHFFFAOYSA-N 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 229960002480 nitazoxanide Drugs 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 241000224467 Giardia intestinalis Species 0.000 description 2
- 239000003904 antiprotozoal agent Substances 0.000 description 2
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- 208000008953 Cryptosporidiosis Diseases 0.000 description 1
- 206010011502 Cryptosporidiosis infection Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- 229940022682 acetone Drugs 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229940054685 alinia Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940085435 giardia lamblia Drugs 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- TYUHMMUUMWZPDB-UHFFFAOYSA-N n-(5-nitro-1,3-thiazol-2-yl)benzamide Chemical class S1C([N+](=O)[O-])=CN=C1NC(=O)C1=CC=CC=C1 TYUHMMUUMWZPDB-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing nitro-thiazol benzamide compound. It comprises following steps: adding acetylsalicylic acid and 2- amino- 5- nitro-thiazole into acetone with their molar ratio being 2:1, stirring at -2-3 Deg. C, adding condensating agent DCC (N, N- ) dicyclo hexylcar bodiimide, adding triethylamine, stirring at -2-3 Deg. C for 3 to 6 hours, filtering, extracting filtering solution with acetic ester and water, drying acetic ester layer with anhydrous sodium sulfate, decolouring with active carbon., vacuum distilling and condensing at 100- 300 Pa, stirring condensing liquid with petrohol at -2-3 Deg. C, crystallizing and getting coarse product, re-crystallizing with carrene and getting pure product. The invention is characterized by temperate reaction condition, easy operation, convenient control, fast reaction speed, high reaction conversion rate of 75.3- 90.5%, high productivity of 60.5- 78.2%, high ;product purity of 98-99% after re-crystallization, low or non- toxicity of used solution and sound industry prospect.
Description
Technical field
The present invention relates to a kind of synthetic o-[N-(5-nitro-2-thiazolyl) formamyl] method of phenylacetate (o-[N-(5-Nitrothiazol-2-yl) carbamoyl] phenyl acetate).
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%.
Claims (1)
1, a kind of method of synthesizing nitryl thiazole benzamide compound is characterized in that may further comprise the steps:
1) adding mol ratio in acetone is 2: 1 acetylsalicylic acid and 2-amino-5-nitrothiazole, stirs 0.5～1 hour down at-2 ℃～3 ℃;
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;
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710067119A CN101007792B (en) | 2007-01-31 | 2007-01-31 | Synthesis process of nitro thiazoly benzamide compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710067119A CN101007792B (en) | 2007-01-31 | 2007-01-31 | Synthesis process of nitro thiazoly benzamide compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101007792A true CN101007792A (en) | 2007-08-01 |
| CN101007792B CN101007792B (en) | 2010-05-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200710067119A Expired - Fee Related CN101007792B (en) | 2007-01-31 | 2007-01-31 | Synthesis process of nitro thiazoly benzamide compound |
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| Country | Link |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101602744B (en) * | 2009-06-30 | 2011-06-01 | 青岛康地恩药业有限公司 | Preparation method of nitazoxanide |
| CN105175352A (en) * | 2015-10-27 | 2015-12-23 | 杭州澳医保灵药业有限公司 | Preparation method of nitazoxanide |
| CN106831640A (en) * | 2015-12-03 | 2017-06-13 | 江苏正大丰海制药有限公司 | A kind of preparation method of Nitazoxanide crystal |
| FR3110164A1 (en) * | 2020-05-15 | 2021-11-19 | Phv Pharma | Process for preparing nitazoxanide and its derivatives and use for the prevention or treatment of pathological conditions due to infection by viruses of the coronavirus type, and more particularly of the SARS-CoV-2 type |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1437800A (en) * | 1973-08-08 | 1976-06-03 | Phavic Sprl | Derivatives of 2-benzamido-5-nitro-thiazoles |
-
2007
- 2007-01-31 CN CN200710067119A patent/CN101007792B/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101602744B (en) * | 2009-06-30 | 2011-06-01 | 青岛康地恩药业有限公司 | Preparation method of nitazoxanide |
| CN105175352A (en) * | 2015-10-27 | 2015-12-23 | 杭州澳医保灵药业有限公司 | Preparation method of nitazoxanide |
| CN106831640A (en) * | 2015-12-03 | 2017-06-13 | 江苏正大丰海制药有限公司 | A kind of preparation method of Nitazoxanide crystal |
| FR3110164A1 (en) * | 2020-05-15 | 2021-11-19 | Phv Pharma | Process for preparing nitazoxanide and its derivatives and use for the prevention or treatment of pathological conditions due to infection by viruses of the coronavirus type, and more particularly of the SARS-CoV-2 type |
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| Publication number | Publication date |
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| CN101007792B (en) | 2010-05-26 |
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Assignee: Fuzhou Sanhe Pharmachem Co., Ltd. Assignor: Zhejiang University Contract record no.: 2011360000080 Denomination of invention: Synthesis process of nitro thiazoly benzamide compound Granted publication date: 20100526 License type: Exclusive License Open date: 20070801 Record date: 20110707 |
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