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Preparation method of 5-aminothiazole-4-formamide

A technology of aminothiazole and formamide, which is applied in the field of preparation of 5-aminothiazole-4-carboxamide and the synthesis of intermediates, can solve the problems of harsh reaction conditions, low yield, easy deliquescence of formic acetic anhydride, etc., and achieve mild reaction conditions , simple reaction process, simple post-processing effect

Inactive Publication Date: 2014-04-09
SHANGHAI INSTITUTE OF TECHNOLOGY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Route 1 uses compound (1-4) to synthesize target compound (1) through compound (1-5). The synthesis method of this route has the following disadvantages: the second step of the reaction uses zinc powder and aluminum amalgam to react, and the cost is relatively high And the reaction by-products are difficult to handle; the formic acetic anhydride in the fourth step is easy to deliquescence, strong corrosion, and high toxicity; the yield of the last step is too low
The second route is to use compound (1-4) to directly synthesize the target compound, and the yield in the last step reaches 92%, but the polyphosphoric acid used in this synthesis method is easy to deliquescence, strong corrosion, high toxicity, and harsh reaction conditions. And more importantly, the synthetic method is difficult to repeat

Method used

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  • Preparation method of 5-aminothiazole-4-formamide
  • Preparation method of 5-aminothiazole-4-formamide
  • Preparation method of 5-aminothiazole-4-formamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Compound ( 2-2 )Synthesis

[0034]

[0035] In a 250ml four-neck bottle, add the compound ( 2-1 ) 2-Amino-2 cyanoacetamide (6.5g, 65.6mmol) and 70ml methanol were added 12ml (0.199mol) carbon disulfide, the reaction mixture was heated and refluxed for 1 hour, a large amount of solid precipitated out, cooled to 5℃, filtered with suction, The solid was washed with EA and dried to obtain the compound ( 2-2 ) Light yellow solid 10.9g, yield 94.8%.

[0036] Compound ( 2-3 )Synthesis

[0037]

[0038] In a 100ml three-necked flask, add the product compound of the previous step ( 2-2 ) (3.5g, 20mmol), 25ml of water and sodium hydroxide (0.88g, 22mmol). After stirring uniformly, it was cooled in an ice bath, and 2.1 ml of dimethyl sulfate (22 mmol) was added dropwise. Then react at room temperature for 1 hour, TLC shows that the reaction is complete. Cool to 0-5°C, filter with suction, wash the solid with a small amount of water, and dry to obtain 3.6 g of a yellow solid product wi...

Embodiment 2

[0043] Compound ( 2-2 )Synthesis

[0044]

[0045] In a 250ml four-necked flask, add 4.8ml (0.0798mol) carbon disulfide and 100ml ethyl acetate, cool to 0 °C, batch compound ( 2-1 ) 2-Amino-2 cyanoacetamide (5.5g, 54mmol), remove the ice bath, react for 1 hour, basically no reaction. Add 5.2ml (0.0865mol) carbon disulfide and 20ml methanol. The reaction mixture was heated and refluxed for 1 hour. A large amount of solid precipitated. Cooled to 5°C, filtered with suction, washed with EA, and dried to obtain 7.8g of light yellow solid. The rate is 80%.

[0046] Compound ( 2-3 )Synthesis

[0047]

[0048] In a 150ml three-necked flask, add the product compound of the previous step ( 2-2 ) (7.0g, 40mmol), 50ml water and sodium hydroxide (1.76g, 44mmol). Stir well and cool with an ice bath. When the temperature is 0℃-5℃, add 4.2ml of dimethyl sulfate (44mmol) dropwise. Then it was reacted at room temperature for 1 hour, TLC showed that the reaction was not complete. Then sodium hydrox...

Embodiment 3

[0053] Compound ( 2-2 )Synthesis

[0054]

[0055] In a 250ml four-neck bottle, add the compound ( 2-1 ) (19.5g, 196.8mmol) and 200ml of methanol, add 36ml (0.598mol) of carbon disulfide, the reaction mixture is heated to reflux for 30 minutes, a large amount of solid precipitates, cooled to 5 °C, suction filtered, the solid was washed with methanol, and dried to obtain Light yellow solid 26.7g, TLC has fluorescence. The mother liquor was left overnight, and another solid was precipitated, and 3.0 g of yellow solid was obtained by suction filtration. The total yield is 86.1%

[0056] Compound ( 2-3 )Synthesis

[0057]

[0058] In a 150ml four-neck bottle, add the product compound of the previous step ( 2-2 ) (3.5g, 20mmol), 25ml of water and sodium carbonate (2.4g, 22mmol). Stir well and cool with an ice bath. When the temperature drops to 0-5°C, add 2.1ml of dimethyl sulfate (22mmol) dropwise. After the addition is complete, the ice bath is removed, and the reaction is performed...

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Abstract

The invention relates to a preparation method of 5-aminothiazole-4-formamide. The method includes: taking 2-amino-2-cyanoacetamide as a raw material, in an organic solvent, subjecting the raw material and a disulfide to heating reflux to undergo ring closing reaction, thus obtaining 5-amino-2-mercaptothiazole-4-formamide; under an alkaline condition, letting 5-amino-2-mercaptothiazole-4-formamide and dimethyl sulfate undergo methylation reaction, thus obtaining 5-amino-2-methyl sulfonyl thiazole-4-formamide; and subjecting 5-amino-2-methyl sulfonyl thiazole-4-formamide, Raney nickel and ammonia water to heating reflux reaction, and removing mercaptomethyl, thus obtaining 5-aminothiazole-4-formamide. The method provided by the invention has the advantages of simple operation, simple and easily available reaction raw materials, mild reaction conditions, a total reaction yield up to 78.8%, simple post-treatment, and environmental friendliness, thus being suitable for mass production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a method for synthesizing an intermediate, specifically a method for preparing 5-aminothiazole-4-carboxamide. [0002] Background technique [0003] 5-Aminothiazole-4-carboxamide is a key drug intermediate for the synthesis of thiazo[5,4-d]pyrimidine, and thiazo[5,4-d]pyrimidine and its derivatives, as bioisoelectronic analogues of purine, are potential The biologically active molecules show unique pharmacological activities, such as: anticancer, antipsychotic, antibacterial, anti-inflammatory and other properties. In addition, thiazo[5,4-d]pyrimidine can also be used to synthesize pyrazoline derivatives to obtain antibacterial drugs with better activity. [0004] However, there are few reports on the synthetic method of 5-aminothiazole-4-carboxamide. At present, only Yasumitsu Tamura has reported two synthetic routes ("Preparation of 5-aminothiazole-4-carboxylic acid derivat...

Claims

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Application Information

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IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 鲁彦王进郭建宇罗静怡胡俊杰周健升刘倩王咪咪
Owner SHANGHAI INSTITUTE OF TECHNOLOGY
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