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Chiral catalytic synthesis method of thiamphenicol

A technology of thiamphenicol and a synthesis method, which is applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve the problems of high waste water treatment cost, time-consuming, long route, etc., and achieves cost reduction and environmental impact. pollution, avoid splitting process, avoid the effect of waste water pollution

Active Publication Date: 2013-01-09
MASTEAM BIO TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This production process will produce a large amount of copper sulfate wastewater during the production process, which makes the treatment cost of wastewater very high, and chiral resolution wastes 50% of the raw materials in terms of atomic economy, and the production operation is time-consuming.
Although the latter method uses asymmetric synthesis to avoid waste of raw materials, it uses highly toxic reagents (HCN, NaCN, POCl 3 etc.), but also used a relatively expensive reducing reagent (Dibal reagent), the synthetic route is relatively long, which is not conducive to the expansion of industrial production, and the waste liquid is very toxic, and the follow-up cost is too high

Method used

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  • Chiral catalytic synthesis method of thiamphenicol

Examples

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Effect test

Embodiment 1

[0031] Synthesis of 3-chloro-1-(4-(methylthio)phenyl)-1-propanone: Add aluminum trichloride (35.7 g, 268 mmol) and 200 ml of dichloromethane ( Anhydrous calcium chloride pre-dried), the system was connected to a drying tube, stirred, poured 3-chloropropionyl chloride (37.2 g, 293 mmol) into the reaction bottle, cooled to 0 ℃ in an ice bath, and added dropwise sulfide anisole (27.7 g, 223 mmol), after 2 hours dropwise (control the liquid temperature between -5-10°C), after the dropwise addition, move the reaction bottle into an oil bath and raise the temperature to 25°C to react for 1-3 hours. Pour the reaction solution into a 1000 ml beaker, add 100 ml of water while stirring in an ice bath, separate the liquids, extract with dichloromethane, combine the organic phases, wash once with saturated sodium bicarbonate, wash twice with water, dry over anhydrous sodium sulfate, and filter Sodium sulfate was removed, and the filter cake was washed with dichloromethane. After removing ...

Embodiment 2

[0034] Synthesis of compound 2-bromo-3-chloro-1-(4-(methylthio)phenyl)-1-propanone: add 3-chloro-1-(4-(methylthio) to a 500 ml three-necked flask at room temperature ) phenyl)-1-propanone (16.0 g, 74.5 mmol), dichloromethane 100 ml (anhydrous calcium chloride pre-dried), stirred. Add 4.0 ml of bromine (12.5 g, 78 mmol) and 100 ml of dichloromethane (pre-dried with anhydrous calcium chloride) into a 250 ml beaker, stir and mix evenly, pour into a constant pressure dropping funnel, and place on the reaction bottle . Cool the reaction flask in an ice-water bath. When the liquid temperature drops to 0°C, start adding bromine dichloromethane solution dropwise. After the addition was complete, the reaction was carried out for 1 hour. Add saturated sodium bicarbonate solution under ice bath until the aqueous phase is alkaline, separate the liquids, add saturated thiosulfate sodium solution to the organic phase under stirring until the organic phase is a colorless and transparent so...

Embodiment 3

[0036] Synthetic compound 1-benzyl-2-(4-(methylthio)phenyl)formyl aziridine: add 2-bromo-3-chloro-1-(4-methylthiophenyl )-1-propanone (5.0 g, 17 mmol), dichloromethane 100 ml, stirred and dissolved, and benzylamine (1.8 g, 17 mmol), triethylamine (3.6 g, 36 mmol) and dichloromethane were added dropwise at room temperature 50 ml of the mixed solution was reacted at room temperature for 3 hours, quenched by adding water, the organic phase was washed three times with water, dried over anhydrous sodium sulfate, and the organic solvent was removed to obtain 4.7 g of a light yellow solid with an HPLC detection content of 95.5%.

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Abstract

The invention relates to a chiral catalytic synthesis method of thiamphenicol which is a chloramphenicol broad-spectrum antibiotic. Thioanisole serves as an initating raw material, acylation and bromo are achieved, nitrogen iridine containing substituent groups is synthetized, and a qualified product which meets the requirement of drug administration is synthetized through chiral catalytic reduction, oxidizing reaction, acidification loop opening, deprotection and acylation reaction. The chiral catalytic reduction includes that under the action of a catalyst trans-RuC12[(R)-xylbinap][(S)-DPEN], [1-substituent group nitrogen iridine-2-group] [4-(methylthio group) phenyl group] ketone is subjected to hydrogenation reduction to obtain [1-substituent group nitrogen iridine-2-group] [4-(methylthio group) phenyl group] ketone with a high ee value and a high de value. D-methylsulfonylphenyl serine ethyl ester used in industrial production serves as a raw material to synthetize the thiamphenicol, the D-methylsulfonylphenyl serine ethyl ester is obtained through chemical chiral resolution by using a racemic compound, and the other half of the raw material is wasted. According to the unsymmetrical chiral catalytic dynamic reduction method, waste of the other half of the raw material is avoided, the utilization rate of a material is improved, and the production cost is reduced.

Description

technical field [0001] The invention relates to a chiral synthesis method of the antibiotic thiamphenicol, which belongs to the technical field of organic chemical industry, and also belongs to the technical field of synthesis of veterinary drugs and pharmaceutical raw materials. Background technique [0002] Thiamphenicol (Thiamphenicol) is a broad-spectrum chloramphenicol antibiotic, its antibacterial spectrum is basically similar to that of chloramphenicol, and it is mainly used for various infectious diseases caused by sensitive bacteria. It is produced by chemical synthesis. There are two One chiral center, four isomers, only one of which is biologically active. [0003] At present, there are three main methods for preparing thiamphenicol at home and abroad: [0004] 1. Thiamphenicol (DE2349496, US3927054) is prepared from p-thiamphenicol through condensation, esterification, chiral resolution, hydroboration reduction, dichloroacetylation, acidification purification, ...

Claims

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Application Information

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IPC IPC(8): C07C317/32C07C315/04
Inventor 彭要武田文敬桂耀海叶青
Owner MASTEAM BIO TECH
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