CN101768135A - Preparation method of 2-amino-5-trifluoromethyl thiazole - Google Patents
Preparation method of 2-amino-5-trifluoromethyl thiazole Download PDFInfo
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- CN101768135A CN101768135A CN201010022562A CN201010022562A CN101768135A CN 101768135 A CN101768135 A CN 101768135A CN 201010022562 A CN201010022562 A CN 201010022562A CN 201010022562 A CN201010022562 A CN 201010022562A CN 101768135 A CN101768135 A CN 101768135A
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Abstract
The invention relates to a preparation method of 2-amino-5-trifluoromethyl thiazole. A target product with a structural formula disclosed in the specification is prepared from 2-amino thiazole or a salt thereof through a one-step reaction with a yield of 30-85 percent. The method has simple and easily obtained reagent, moderate reaction condition, short time, simple operation, lower requirement on equipment, simple aftertreatment and practical production significance.
Description
Technical field
The present invention relates to the preparation method of 2-amino-5-trifluoromethyl thiazole.
Background technology
The thiazolamine compounds has wide biological activity, in medicine, agricultural chemicals some commercial products has been arranged.
Belong to third generation cephalosporin as cefotaxime (Cefotaxime) in the medicine, the reason of this medicine wide spectrum is that the thiazolamine group in the molecule has increased the avidity of medicine and bacterium penicillin-binding protein, as InComprehensive Heterocyclic Chemistry II, Katritzky, A.R, etc; Pergamon:Oxford, Vol.3, (1994).Sulphathiazole (ST) be used as very early antibacterials (US 2,491,489; FR 6,773).Nitazoxanide (Nitazoxanide) be used to treat the diarrhoea that courses of infection causes (US 5,387,598; DE2,438,037).Meloxicam (Meloxicam) is a kind of NSAID (non-steroidal anti-inflammatory drug), and the activity that can selectivity suppresses cyclooxygenase-2 suppresses synthetic (US 4,233,299) of prostaglandin(PG).Ambilhar (Niridazole) is used as the medicine of treatment schistosomicide, referring to: American journal of veterinary research, Vol.34,641-645, (1973); DE 2,728, and 802).
Just there was the test of pesticide effectiveness report agricultural chemicals aspect, amicarthiazol (Amicarthiazol) before 1969, be toxicity such as low, the systemic fungicide of high-efficiency broad spectrum, and as Canadian Journal ofPlant Science, Vol.48,587-594, (1968).Guardian (Ethaboxam) is a systemic fungicide, is used to prevent and treat the downy mildew of garpe and the late blight of potato, but its mechanism of action is different from other sterilant of preventing and treating this type of disease, (EP639,574; DE 10,019, and 758; WO 2,000, and 018,766,2,001,084,930).As from the foregoing, the thiazolamine compounds has good biological activity, and its biological activity of aminothiazole that different structure is modified is very different, so their target has diversity probably, this helps delaying drug-fast development, help the medicine guide's of new mechanism of action discovery, in a word, the structure activity study of thiazolamine compounds has very wide prospect.
Recently, 2-amino-5-trifluoromethyl thiazole receives increasing concern, contains this structure in many highly active molecules, wherein representative example has: a class glucokinase activators molecule, and as WO2,008,084,872,2,006,078,621,2,004,081,001,2,004,072,031; JP 2,008, and 189,659; One class anti-HIV bioactive molecule is as Journal of Medicinal Chemistry, Vol.49,1118-1124, (2006); One class anti-inflammatory activity molecule, as: Oxidation Communications, Vol.26,168-178, (2003); One class calcium channel blocking agent molecule is as US 2,003,199,523; Herbicide intermediate is synthetic, as WO 9,637, and 466,9,533,719; One class weedicide toxinicide molecule is as EP 335,831; One series bactericidal agent molecule is as US 5,135,927; One insecticides synthetic raw material is as DE 102,005,010,215.
Although this application of compound report increases gradually, about it synthetic report seldom.The Hantzsch synthesis method is classical thiazole synthetic method, but the raw material of Synthetic 2-amino-5-trifluoromethyl thiazole: and the preparation of 2-halogen-3-trifluoro propionic aldehyde does not have the yield report, is detected in EP 2,006,078,621.And react through 5 steps from Trifluoroacetic Acid Ethyl Ester, total recovery but is lower than 16%, as: Journal of Fluorine Chemistry.Vol.73,83-86, (1995), Chem.Leg.Vol.14,889, (1985), J.Chem.Soc, Perkin Trans.1,2761-2766, (1995).The route for preparing 2-amino-5-trifluoromethyl from 2-amino-5-carboxyl thiazole and sulfur tetrafluoride, hydrogen fluoride reaction sees WO 9,637,466, does not have the report of yield equally.
Synthetic method in sum, otherwise feedstock production is loaded down with trivial details, and productive rate is not high, or severe reaction conditions, and is higher to equipment requirements.Amino-5-trifluoromethyl thiazole cost is higher for the feasible a large amount of preparation 2-of these reasons, and safety problem is outstanding.
Summary of the invention
The problem that the present invention need solve is to overcome above-mentioned defective, and the preparation method of a kind of 2-amino-5-trifluoromethyl thiazole compound is provided.
The structural formula of the 2-amino-5-trifluoromethyl thiazole that the present invention relates to is shown in (I):
The inventive method can be synthetic with following reactions steps:
CF in the formula
3X can be CF
3Cl, CF
3Br or CF
3I recommends CF
3Br or CF
3I.Reaction can be carried out under the condition of various radical initiators, as vat powder, rongalite, thiourea peroxide, Sodium Metabisulfite, sodium bisulfite or their mixture; The mineral alkali that can add suitable monovalence metal, as yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, sodium phosphate, Sodium phosphate dibasic, potassiumphosphate and or dipotassium hydrogen phosphate etc., also can be organic basess such as triethylamine, pyridine, reaction also can be carried out under the condition that does not add alkali.The salt of described thiazolamine or its respective acids, trifluoro haloalkane, radical initiator and alkali mol ratio are 1.0: 2.0～4.0: 1.0～3.0: 0～3; Be reflected in the mixed solvent of organic solvent and water and carry out, as the acetonitrile-water mixed solvent; Dimethyl formamide-water; Halogenated hydrocarbon solvent-water such as methylene dichloride, ethylene dichloride or chloroform; Dimethyl sulfoxide (DMSO)-water; Ethers-water such as dioxane or tetrahydrofuran (THF); Ketone-water such as acetone or mibk; Methyl alcohol, the mixed solvent of alcohols-water such as ethanol or Virahol; It also can be the mixture of above-mentioned solvent.The optimum solvent of this reaction is the acetonitrile-water mixed solvent.Temperature of reaction is 0～90 ℃, and the reaction times is 3-8 hour.Adopt CF as working as
3During I, temperature of reaction is that zero degree arrives room temperature, perhaps is heated to 60 ℃, and reaction can be carried out in autoclave; When being CF
3During Br, temperature of reaction is 40～90 ℃, and reaction also can be carried out in autoclave.The molar ratio of thiazolamine, trifluoro haloalkane and radical initiator is recommended as 1.0: 2.0～and 4.0: 2.0.Final product can or be made other salt such as hydrochloride through silica gel column chromatography, underpressure distillation and be further purified.
Method reaction conditions gentleness of the present invention, the time is short, and simple to operate, lower to the requirement of equipment, aftertreatment is simple, and the reagent that is adopted is simple and easy to, and has the meaning of actual production.
Embodiment
Following examples help to understand the present invention, but the present invention not merely is confined in the scope of following embodiment.
Embodiment 1
In the 2L autoclave, add 40g thiazolamine, 160g vat powder, 100g Sodium phosphate dibasic, 1.2 rise acetonitrile, 400 ml waters, sealing and equipment mechanical stirring device, autoclave is refrigerated to-78 ℃, vacuumizes, with bromotrifluoromethane displaced air three times, vacuumize, be pressed into the 180g bromotrifluoromethane, after waiting to recover room temperature, be heated to 90 ℃ of reactions 6 hours, stop to stir, be chilled to room temperature, vacuum is revolved most of acetonitrile, and it is 8-10 that the sodium hydroxide saturated aqueous solution is regulated aqueous pH values, extracted with diethyl ether, anhydrous magnesium sulfate drying concentrates the back column chromatography, (normal hexane: ethyl acetate=4: 1), get the light yellow thick liquid of pure product, yield 75%.
Embodiment 2
In the 1L autoclave, add 20g thiazolamine, 52.5g vat powder, 56.3g sodium bicarbonate, 500 milliliters of acetonitriles, 200 ml waters, sealing and equipment mechanical stirring device are refrigerated to autoclave-78 ℃, vacuumize, be pressed into the 100g bromotrifluoromethane, after waiting to recover room temperature, be heated to 40 ℃ of reactions 6 hours, stop to stir, be chilled to room temperature, vacuum is revolved most of acetonitrile, and it is 8-10 that the sodium hydroxide saturated aqueous solution is regulated aqueous pH values, extracted with diethyl ether, anhydrous magnesium sulfate drying concentrates the back column chromatography, (normal hexane: ethyl acetate=4: 1), get the light yellow thick liquid of pure product, yield 60%.
Embodiment 3
Add the 3g thiazolamine in 250ml Schlenk pipe, the 1.9g sodium bicarbonate is substituted gas three times, and the Ar protection adds 50 milliliters of acetonitriles down, 50 milliliters of dimethyl formamides, and 20 ml waters stir and make the solid dissolving.Then reaction solution is put into ice-water bath, be chilled to 3 ℃, 10 milliliters of acetonitrile solutions that add the 4g CF3I stirred two minutes.Add the 3.58g vat powder in half an hour in batches, stirred 2 hours, thin layer is analysed and is followed the tracks of reaction, the back decompression that finishes revolves acetonitrile, add appropriate amount of deionized water, sodium carbonate regulating solution is an alkalescence, and 300 milliliters of ether divide three extractions, anhydrous magnesium sulfate drying, concentrate the orange-yellow liquid of thickness, column chromatography, (normal hexane: ethyl acetate=4: 1), get the light yellow thick liquid of pure product, yield 85%.
Embodiment 4
Add the 3g thiazolamine in 250ml Schlenk pipe, substitute gas three times, the Ar protection adds 50 milliliters of acetonitriles down, 50 milliliters of dimethyl formamides, and 20 ml waters stir and make the solid dissolving.Then reaction solution is put into ice-water bath, be chilled to 3 ℃, add 10 milliliters of acetonitrile solutions of 4g CF3I, stirred two minutes.Add the 3.58g vat powder in half an hour in batches, stirred 2.5 hours, thin layer is analysed and is followed the tracks of reaction, the back decompression that finishes revolves acetonitrile, add appropriate amount of deionized water, sodium carbonate regulating solution is an alkalescence, and 300 milliliters of ether divide three extractions, anhydrous magnesium sulfate drying, concentrate the orange-yellow liquid of thickness, column chromatography, (normal hexane: ethyl acetate=4: 1), get the light yellow thick liquid of pure product, yield 55%.
Embodiment 5
Add the 0.5g thiazolamine in 100ml Schlenk pipe, substitute gas three times, the Ar protection adds 30 milliliters of acetonitriles down, and 15 ml waters stir and make the solid dissolving.Then reaction solution is put into ice-water bath, be chilled to 3 ℃, add 5 milliliters of acetonitrile solutions of 0.7g CF3I, triethylamine 1.1g stirred two minutes.Add the 0.6g vat powder, stirred 2.5 hours, thin layer is analysed and is followed the tracks of reaction, the back decompression that finishes revolves acetonitrile, adds appropriate amount of deionized water, and sodium carbonate regulating solution is an alkalescence, 300 milliliters of ether divide three extractions, washing (10 milliliters * 3), anhydrous magnesium sulfate drying, concentrate the orange-yellow liquid of thickness, column chromatography, (normal hexane: ethyl acetate=4: 1), get the light yellow thick liquid of pure product, yield 42%.
Embodiment 6
In the 1L autoclave, add the 20g thiazolamine, 53.0g vat powder, 400 milliliters of acetonitriles, 150 ml waters, sealing and equipment mechanical stirring device, autoclave is refrigerated to-78 ℃, vacuumizes, be pressed into the 120g bromotrifluoromethane, after waiting to recover room temperature, be heated to 90 ℃ of reactions 6 hours, stop to stir, be chilled to room temperature, vacuum is revolved most of acetonitrile, it is 8-10 that the sodium hydroxide saturated aqueous solution is regulated aqueous pH values, extracted with diethyl ether, anhydrous magnesium sulfate drying, concentrate the back column chromatography, (normal hexane: ethyl acetate=4: 1), get the light yellow thick liquid of pure product, yield 30%.
Embodiment 7
In the 1L autoclave, add 20g thiazolamine, 53.0g vat powder, 4.0g triethylamine, 400 milliliters of acetonitriles, 150 ml waters, sealing and equipment mechanical stirring device are refrigerated to autoclave-78 ℃, vacuumize, be pressed into the 120g bromotrifluoromethane, after waiting to recover room temperature, be heated to 90 ℃ of reactions 6 hours, stop to stir, be chilled to room temperature, vacuum is revolved most of acetonitrile, and it is 8-10 that the sodium hydroxide saturated aqueous solution is regulated aqueous pH values, extracted with diethyl ether, anhydrous magnesium sulfate drying concentrates the back column chromatography, (normal hexane: ethyl acetate=4: 1), get the light yellow thick liquid of pure product, yield 58%.
Embodiment 8
Add the 3g thiazolamine in 250ml Schlenk pipe, the 8.5g Sodium phosphate dibasic is substituted gas three times, and the Ar protection adds 50 milliliters of acetonitriles down, 50 milliliters of dimethyl formamides, and 20 ml waters stir and make the solid dissolving.Then reaction solution is put into ice-water bath, be chilled to 3 ℃, add 10 milliliters of acetonitrile solutions of 4g CF3I, stirred two minutes.Add the 3.58g vat powder in half an hour in batches, stirred 2 hours, thin layer is analysed and is followed the tracks of reaction, the back decompression that finishes revolves acetonitrile, add appropriate amount of deionized water, sodium carbonate regulating solution is an alkalescence, and 300 milliliters of ether divide three extractions, anhydrous magnesium sulfate drying, concentrate the orange-yellow liquid of thickness, column chromatography, (normal hexane: ethyl acetate=4: 1), get the light yellow thick liquid of pure product, yield 83%.
Claims (6)
1. the synthetic method of 2-amino-5-trifluoromethyl thiazole, it is characterized in that in the mixed solvent of organic solvent and water, 0～90 ℃, exist or do not exist under the condition of alkali, the salt of thiazolamine or its respective acids, trifluoro haloalkane and radical initiator reaction 3-8 hour; The salt of described thiazolamine or its respective acids, trifluoro haloalkane, radical initiator and the alkali mol ratio be 1.0: 2.0～4.0: 1.0～3.0: 0～3; Described radical initiator is vat powder, rongalite or thiourea peroxide, Sodium Metabisulfite, sodium bisulfite or their mixture; Described X is Cl, Br or I; Described alkali is the mineral alkali and the organic bases of monovalence metal.
2. the synthetic method of 2-amino as claimed in claim 1-5-trifluoromethyl thiazole, the mineral alkali that it is characterized in that described monovalence metal is yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, sodium phosphate, Sodium phosphate dibasic, potassiumphosphate or dipotassium hydrogen phosphate; Described organic bases is triethylamine or pyridine.
3. the synthetic method of 2-amino as claimed in claim 1-5-trifluoromethyl thiazole, the mixed solvent that it is characterized in that described organic solvent and water is an acetonitrile-water; Dimethyl formamide-water; Halogenated hydrocarbon-water; Dimethyl sulfoxide (DMSO)-water; Ethers-water; Ketone-water; The mixture of alcohols-water or above-mentioned solvent.
4. the synthetic method of 2-amino as claimed in claim 1-5-trifluoromethyl thiazole, when it is characterized in that described reaction is raw material with the bromotrifluoromethane, the solvent of reaction is the mixed solvent of acetonitrile-water, adding or do not adding under the condition of phosphoric acid disodium hydrogen, the salt of thiazolamine or its respective acids and the mol ratio of bromotrifluoromethane are 1: 2～1: 3, and Heating temperature was 40-80 ℃ of reaction 1～6 hour.
5. the synthetic method of 2-amino as claimed in claim 1-5-trifluoromethyl thiazole, it is characterized in that described trifluoro haloalkane is a CF3I, when solvent is the mixed solvent of acetonitrile-water and 0～15 ℃, adding or do not adding under the condition of described alkali, the salt of thiazolamine or its respective acids and the mol ratio of CF3I are 1: 1～4,0～15 ℃ stirring reactions 15 minutes～2 hours.
6. the synthetic method of 2-amino as claimed in claim 1-5-trifluoromethyl thiazole is characterized in that reaction product is through silica gel column chromatography, underpressure distillation or make corresponding hydrochloride or acetate carries out purifying.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2010100225628A CN101768135B (en) | 2010-01-08 | 2010-01-08 | Preparation method of 2-amino-5-trifluoromethyl thiazole |
| PCT/CN2011/000036 WO2011082660A1 (en) | 2010-01-08 | 2011-01-07 | 5-multifluoroalkyl- substituted 2-aminothiazole compounds, preparation methods and uses thereof |
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| CN2010100225628A CN101768135B (en) | 2010-01-08 | 2010-01-08 | Preparation method of 2-amino-5-trifluoromethyl thiazole |
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| CN102993117A (en) * | 2012-11-28 | 2013-03-27 | 张家港市大伟助剂有限公司 | Preparation method of 2-amino-5-(4-amino phenyl)-thiazole |
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| CN102993117A (en) * | 2012-11-28 | 2013-03-27 | 张家港市大伟助剂有限公司 | Preparation method of 2-amino-5-(4-amino phenyl)-thiazole |
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