Chiral catalytic synthesis method of thiamphenicol

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

Active Publication Date: 2014-03-12
MASTEAM BIO TECH
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  • 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

[0030] Synthesis of 3-chloro-1-(4-(methylthio)phenyl)-1-acetone: Add aluminum trichloride (35.7 g, 268 mmol) and 200 ml of dichloromethane to a 500 ml three-necked flask at room temperature. Anhydrous calcium chloride pre-drying), connect the system to the drying tube, stir, pour 3-chloropropionyl chloride (37.2 g, 293 mmol) into the reaction flask, cool to 0 ℃ in an ice bath, add anisole (27.7 g, 223 mmol), drip in 2 hours (control the liquid temperature between -5-10 ℃), after dripping, move the reaction flask into an oil bath and heat up to 25 ℃ for 1-3 hours. Pour the reaction solution into a 1000 ml beaker, add 100 ml of water while stirring under ice bath, separate the layers, extract with dichloromethane, combine the organic phases, wash with saturated sodium bicarbonate once, wash twice with water, dry with anhydrous sodium sulfate, and filter The sodium sulfate was removed, the filter cake was washed with dichloromethane, the filtrate was recrystallized with dichlorome...

Embodiment 2

[0032] Synthesis of compound 2-bromo-3-chloro-1-(4-(methylthio)phenyl)-1-acetone: Add 3-chloro-1-(4-(methylthio) to a 500 ml three-necked flask at room temperature ) Phenyl)-1-acetone (16.0 g, 74.5 mmol), 100 ml of dichloromethane (pre-dried with anhydrous calcium chloride), stir. 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 well, pour it into a constant pressure dropping funnel, and place it on the reaction flask . The reaction flask was cooled in an ice-water bath, and when the liquid temperature dropped to 0 ℃, the dichloromethane solution of bromine was added dropwise. Keep the liquid temperature at about 0 ℃. After dripping within 1-2 h, the reaction was kept at 0 ℃, followed by TLC. After the addition, react for 1 hour. Add saturated sodium bicarbonate solution under ice bath until the water phase is alkaline, separate liquids, add saturated sodium thiosulfonate solut...

Embodiment 3

[0034] Synthetic compound 1-benzyl-2-(4-(methylthio)phenyl) formyl aziridine: add 2-bromo-3-chloro-1-(4-methylthiophenyl) to a 250 ml three-necked flask )-1-acetone (5.0 g, 17 mmol), 100 ml of dichloromethane, stir to dissolve, add benzylamine (1.8 g, 17 mmol), triethylamine (3.6 g, 36 mmol) and dichloromethane dropwise at room temperature The 50 ml 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 light yellow solid with 95.5% detected by HPLC.

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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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Patent Type & Authority Patents(China)
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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