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Preparation method of 4-alkyl-5-formoxyl thiazole or 5-formoxyl thiazole

A technology of formylthiazole and alkyl, which is applied in the field of drug synthesis, can solve problems such as unfavorable industrial production and environmental protection, raw materials containing heavy metal pollutants, harsh reaction conditions, etc., and is beneficial to industrial production and environmental protection, and has a wide range of applications , easy post-processing effect

Inactive Publication Date: 2013-04-10
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The technical problem to be solved by the present invention is: in order to overcome the harsh reaction conditions, large molar volume and low yield in the existing reaction for preparing 4-alkyl-5-formylthiazole or 5-formylthiazole, after-treatment Complicated, the raw materials contain heavy metal pollutants, the price of raw materials is relatively expensive, and it is not conducive to the defects of industrial production and environmental protection, but a preparation method for 4-alkyl-5-formylthiazole or 5-formylthiazole is provided

Method used

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  • Preparation method of 4-alkyl-5-formoxyl thiazole or 5-formoxyl thiazole
  • Preparation method of 4-alkyl-5-formoxyl thiazole or 5-formoxyl thiazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment 1 prepares 4-methyl-5-formylthiazole

[0034] In a 100 mL three-necked flask, 0.5 g (3.876 mmol) of the compound of formula I was dissolved in 17 mL of dichloromethane and 2 mL of tetrahydrofuran, and stirred at a temperature of 20°C.

[0035] A solution (pH = 8-8.5) prepared by dissolving 1.5 g of sodium bicarbonate in 15 mL of water was added to the above organic solvent.

[0036] While the biphasic solution was maintained at 20°C-25°C with vigorous stirring, 0.06g (0.384mmol) of 2,2,6,6-tetramethylpiperidine-1-oxyl radical (Tempo) and 2.2g (15.38mmol) of calcium hypochlorite, while monitoring the progress of the oxidation reaction by TLC.

[0037] After the reaction is complete, filter the biphasic solution, place to separate the two phases, wash the organic phase with 10 mL of aqueous potassium bisulfate (1.0 g of solution 10 mL of water), then wash with 10 mL of water, dry over anhydrous magnesium sulfate and reduce pressure The solvent was distilled o...

Embodiment 2

[0041] Embodiment 2 prepares 4-methyl-5-formylthiazole

[0042] In a 250 mL three-necked flask, 2.0 g (15.5 mmol) of the compound of formula I was dissolved in 85 mL of dichloromethane and 10 mL of tetrahydrofuran, and stirred at a temperature of 20°C.

[0043] A solution (pH = 8-8.5) prepared by dissolving 14.2 g of sodium bicarbonate in 142 mL of water was added to the above organic solvent.

[0044] While the biphasic solution was maintained at 20°C-25°C with vigorous stirring, 0.145g (0.928mmol) of 2,2,6,6-tetramethylpiperidine-1-oxyl radical (Tempo) and 6.6g (46.15mmol) of calcium hypochlorite, while monitoring the oxidation reaction progress by TLC.

[0045] After the reaction was completed, filter the biphasic solution, place to separate the two phases, wherein the pH value of the aqueous phase was 7.2 to 7.5, and the organic phase was extracted twice with dichloromethane (20mL × 2), the organic phase was combined, and the organic phase was Wash with 30 mL of saturate...

Embodiment 3

[0046] Embodiment 3 prepares 4-methyl-5-formylthiazole

[0047] In a 250 mL three-necked flask, 1.0 g (7.75 mmol) of the compound of formula I was dissolved in 43 mL of dichloromethane and 5 mL of tetrahydrofuran, and stirred at a temperature of 20°C.

[0048] A solution (pH = 8-8.5) prepared by dissolving 7.0 g of sodium bicarbonate in 70 mL of water was added to the above organic solvent.

[0049] When the biphasic solution was maintained at 20°C-25°C with vigorous stirring, 0.070 g (0.376 mmol) of 4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl radical was added and 3.3g (23.08mmol) of calcium hypochlorite while monitoring the progress of the oxidation reaction by TLC.

[0050] After the reaction was completed, filter the biphasic solution and place to separate the two phases, wherein the pH value of the aqueous phase was 7.2 to 7.5, and the organic phase was extracted twice with dichloromethane (15mL × 2), the organic phase was combined, and the organic phase was Wash wit...

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Abstract

The invention provides a preparation method of 4-alkyl-5-formoxyl thiazole or 5-formoxyl thiazole shown by a formula II, which comprises the following step of: in mixed phase formed by organic solvent and a water solution with the pH value of 7-9, enabling a compound shown by a formula I to have oxidation reaction with oxidizing agent under the conditions that catalyst exists and the reaction temperature is 0-40 DEG C to generate a compound shown by the formula II, wherein R1 is H or linear chain or branched chain alkyl group of C1-C3, the oxidizing agent is hypochlorite or hypobromite of alkaline-earth metal or alkaline metal, and the catalyst is 2, 2, 6, 6-tetramethyl piperidine 1-oxy-free radical (Tempo) and derivatives of the 2, 2, 6, 6-tetramethyl piperidine 1-oxy-free radical (Tempo). The method is mild in reaction conditions, low in price of raw materials, easy in obtaining of raw materials and smaller in reaction molar volume, does not need KBr for catalysis, and is simple in aftertreatment, thus being suitable for industrial production and environment-friendly; and the method can be used for producing 4-methyl-5-formoxyl thiazole which is high in yield and purity and is a key intermediate of cefditoren pivoxil.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of 4-alkyl-5-formylthiazole or 5-formylthiazole. Background technique [0002] 4-Methyl-5-formylthiazole is an important side chain for the synthesis of the third-generation cephalosporin antibacterial drug cefditoren pivoxil, and their molecular structures are shown in the following formula II compound and formula III compound. Cefditoren axetil was developed by Meiji Seika Co., Ltd., and was listed in Japan under the trade name of Meiact in 1994. Cefditoren axetil has a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria. The patent expired in 2004 and has no administrative protection in China. [0003] [0004] Japanese literature Chemical and Pharmaceutical Bulletin; Vol.39; nb.9; (1991); The starting materials were used in the reactions. [0005] U.S. Patent No. 6,277,871B1 discloses a synthetic method of 4-methyl-5-formylth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/24
Inventor 姜碧波黄成军何建勋
Owner SHANGHAI INST OF PHARMA IND
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