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A kind of synthetic method of the amine compound containing sulfur nitrogen heterocycle of medicine intermediate

A technology of mixtures and systems, applied in the direction of organic chemistry, can solve problems such as inability to promote, and achieve the effects of saving synthesis steps, high yield, and saving raw materials

Active Publication Date: 2020-09-04
烟台宁远药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A preparation method and application of 2-(4-thiazolinone-2-imino)thiazole-5-carboxylate is given in CN201510741004.X, and a 2-(4- Preparation method and application of oxythiazoline-2-imino)thiazole-4-acetic acid derivatives, CN201280046499.9 provides a phthalimide-containing benzothiazole derivative and a pharmaceutical composition containing it , these are examples of the application and synthesis of isoquinoline derivatives, but the 4-isopropyl-5-aminothiazole mentioned in this application is rarely used as a pharmaceutical intermediate, or there are documents or materials published
Due to the properties of this molecule, the method cannot be extended to the synthesis of other similar structures

Method used

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  • A kind of synthetic method of the amine compound containing sulfur nitrogen heterocycle of medicine intermediate
  • A kind of synthetic method of the amine compound containing sulfur nitrogen heterocycle of medicine intermediate
  • A kind of synthetic method of the amine compound containing sulfur nitrogen heterocycle of medicine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] S1. Raw material preparation: 4 grams of ethyl 4-methyl-3-oxopentanoate, 40 ml of dichloromethane, and 4 grams of sulfonyl chloride. Select a 2L four-necked bottle with a water separator, and first put 4 grams of Dissolve ethyl 4-methyl-3-oxopentanoate in 40ml of dichloromethane, then put the mixture into a four-neck flask, stir and lower the temperature to below 0°C, add 4 grams of sulfuric acid dropwise at a very slow speed Acyl chlorides, used for no more than 30 minutes, then adjusted to pH = 7.5 with saturated aqueous sodium bicarbonate solution, then separated and extracted with 400ml of dichloromethane, washed with saturated brine, dried, and removed from the solvent to obtain the product of step S1 2-chloro-4- Ethyl Methyl-3-oxopentanoate.

[0022] S2. Take another 2L four-neck bottle, put 100ml of ethanol in it, and slowly add 12 grams of thiourea under stirring, keep the system at room temperature, and dropwise add the product of the aforementioned S1 step 2-c...

Embodiment 2

[0028] S1. Prepare 5 grams of ethyl 4-methyl-3-oxopentanoate, 50 ml of dichloromethane, and 5 grams of sulfonyl chloride as raw materials. Select a 2L four-necked bottle with a water separator, and first put 5 grams of Dissolve ethyl 4-methyl-3-oxopentanoate in 50ml of dichloromethane, then put the mixture into a four-necked flask, stir and lower the temperature to below 0°C, and drop 5 grams of sulfur at a very slow speed Acyl chloride, used for no more than 30 minutes, then adjusted to pH=8 with saturated aqueous sodium bicarbonate solution, then separated and extracted with 500ml of dichloromethane, washed with saturated brine, dried, and removed from the solvent to obtain the product of step S1 2-chloro-4- Ethyl Methyl-3-oxopentanoate.

[0029] S2. Take another 2L four-neck bottle, put 150ml of ethanol in it, and slowly add 13.7g of thiourea under stirring, keep the system at room temperature, and dropwise add the product 2-chloro-4-methyl-3-oxo of the aforementioned S1 st...

Embodiment 3

[0035] S1. Raw materials prepare 6 grams of ethyl 4-methyl-3-oxopentanoate, 60 ml of dichloromethane, and 6 grams of sulfonyl chloride. Select a 2L four-necked bottle with a water separator, and first put 6 grams of Dissolve ethyl 4-methyl-3-oxopentanoate in 60ml of dichloromethane, then put the mixture into a four-neck flask, stir and lower the temperature to below 0°C, add 6 grams of sulfur Acyl chlorides, used for no more than 30 minutes, then adjusted to pH=8.5 with saturated aqueous sodium bicarbonate solution, then separated and extracted with 600ml of dichloromethane, washed with saturated brine, dried, and removed from the solvent to obtain the product of step S1 2-chloro-4- Ethyl Methyl-3-oxopentanoate.

[0036] S2. Take another 2L four-neck bottle, put 200ml of ethanol in it, and slowly add 15 grams of thiourea under stirring, keep the system at room temperature, and dropwise add the product of the aforementioned S1 step 2-chloro-4-methyl-3-oxo 25 grams of ethyl val...

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Abstract

The invention relates to a method for synthesizing a pharmaceutical intermediate sulfur-containing nitrogen heterocyclic amine compound. The method comprises that ethyl 4-methyl-3-oxo-pentanoate, dichloromethane and sulfonyl chloride as raw materials undergo a reaction, the reaction product is subjected to pH adjustment until pH of 7, the treated reaction product is extracted so that ethyl 2-chloro-4-methyl-3-oxopentanoate is obtained, the ethyl 2-chloro-4-methyl-3-oxopentanoate and thiourea undergo a reaction in the presence of ethanol as a solvent to produce ethyl 2-amino-4-isopropylthiazole-5-formate, isoamyl nitrite is added into ethyl 2-amino-4-isopropylthiazole-5-formate in the presence of tetrahydrofuran as a solvent to obtain 4-isopropylthiazole-5-formate, a NaOH solution is addedinto the 4-isopropylthiazole-5-formate in the presence of anhydrous methanol as a solvent so that 4-isopropylthiazole-5-formic acid is obtained, the 4-isopropylthiazole-5-formic acid and azophosphoryldiphenyl ester undergo a reaction in the presence of tert-butyl alcohol as a solvent and triethylamine, the reaction product is extracted, the extract is washed so that 5-N-BOC-4-isopropylthiazole isobtained, the 5-N-BOC-4-isopropylthiazole and HCl undergo a reaction in the presence of anhydrous methanol as a solvent to produce 4-isopropyl-5-aminothiazole. The method has the advantages of clearprocesses, less waste, high yield, raw material saving and operation easiness.

Description

technical field [0001] The invention relates to the field of pharmaceutical intermediates, in particular to a method for synthesizing amine compounds containing sulfur nitrogen heterocycles as pharmaceutical intermediates. Background technique [0002] Thiazoles and their derivatives are an important class of compounds with strong biological activity and are widely used in medicine, pesticides and other fields. Therefore, the synthesis of pyrazole derivatives has received extensive attention, especially among pharmaceutical intermediates. application. A preparation method and application of 2-(4-thiazolinone-2-imino)thiazole-5-carboxylate is given in CN201510741004.X, and a 2-(4- Preparation method and application of oxythiazoline-2-imino)thiazole-4-acetic acid derivatives, CN201280046499.9 provides a phthalimide-containing benzothiazole derivative and a pharmaceutical composition containing it , these are examples of the application and synthesis of isoquinoline derivativ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/40
CPCC07D277/40
Inventor 邢立新
Owner 烟台宁远药业有限公司
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