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A kind of synthetic method of Florfenicol intermediate

A technology for florfenicol and intermediates, which is applied in the field of synthesizing florfenicol intermediates, can solve the problems of low yield of finished products, high production cost and environmental protection cost, unrecoverable tetrafluoropropionamide and the like

Active Publication Date: 2020-12-11
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] At present, the main problem in the synthesis of Florfenicol intermediates is that the by-product tetrafluoropropionamide produced by the fluorinated reagent cannot be recovered, resulting in high production costs and environmental protection costs for this step. At the same time, the fluorinated reagent has a low yield of finished products. ; It has high requirements on the container and reaction conditions, which brings inconvenience to the operation

Method used

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  • A kind of synthetic method of Florfenicol intermediate
  • A kind of synthetic method of Florfenicol intermediate
  • A kind of synthetic method of Florfenicol intermediate

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preparation example Construction

[0087] The invention provides a kind of preparation method of Florfenicol intermediate (I), comprising the following steps:

[0088]

[0089] (1) in an organic solvent, compound (II) is reacted with an acylating reagent to form compound (III);

[0090] (2) in an organic solvent, in the presence of a catalyst, compound (III) is reacted with an oxidizing agent to form compound (IV);

[0091] (3) reacting compound (IV) with a fluorinating reagent in an organic solvent to form compound (V);

[0092] (4) In an organic solvent, compound (V) is prepared by acid hydrolysis and deprotection to obtain compound (I);

[0093] In the formula,

[0094] R 1 Benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), Wat methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methyl (or ethyl) oxycarbonyl Or other alkoxycarbonyl amino protecting groups, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o (p) nitrobenzenesulfonyl chloride (Ns), pent...

Embodiment 1

[0150] Synthesis of (4R,5R)-5-(tert-butyloxycarboxamido)-4-(4-thiamphenicolphenyl)-1,3,2-dioxathiolane-2,2-di Oxide (IV-1): In a 250mL three-necked flask, 5g (1R,2R)-2-(tert-butyloxycarboxamido)-1-(4-thiamphenylphenyl)-1,3-propanediol (II-1) was dissolved in 50 mL of dry dichloromethane, 40 mL of pyridine was added, the mixed system was cooled to -5°C, and 13.8 g of thionyl chloride was slowly added dropwise. After dropping, react at -5°C for 1h. After the reaction was completed, the filtrate was quenched by adding dilute hydrochloric acid (50mL), the aqueous phase was extracted by adding dichloromethane (60mL×3), the organic phases were combined, washed with saturated aqueous sodium bicarbonate (100mL), dried over anhydrous sodium sulfate, filtered, and reduced pressure Removal of solvent yielded crude sulfite. The obtained crude sulfite was dissolved in 10mL of water, 10mL of acetonitrile and 15mL of dichloromethane in a three-mixed system, and 4g of sodium periodate, 3mg ...

Embodiment 2

[0155] Synthesis of (4R,5R)-5-(dichloroacetamido)-4-(4-thiamphenylphenyl)-1,3,2-dioxathiolane-2,2-dioxide (IV-2): In a 250mL three-necked flask, 5g (1R,2R)-2-(dichloroacetamido)-1-(4-thiamphenylphenyl)-1,3-propanediol (II-2 ) was dissolved in 50 mL of dry dichloromethane, 40 mL of pyridine was added, the mixed system was cooled to -5°C, and 13.4 g of thionyl chloride was slowly added dropwise. After dropping, react at -5°C for 1h. After the reaction was completed, the filtrate was quenched by adding dilute hydrochloric acid (50mL), the aqueous phase was extracted by adding dichloromethane (60mL×3), the organic phases were combined, washed with saturated aqueous sodium bicarbonate (100mL), dried over anhydrous sodium sulfate, filtered, and reduced pressure Removal of solvent yielded crude sulfite. The obtained crude sulfite was dissolved in 10mL of water, 10mL of acetonitrile and 15mL of dichloromethane in a three-mixed system, and 4g of sodium periodate, 3mg of RuCl 3 .3H ...

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Abstract

The invention belongs to the field of synthesis of pharmaceutical raw materials, and specifically discloses a florfenicol intermediate synthesis method, which comprises: (1) carrying out a reaction ona compound (II) and an acylating reagent in an organic solvent to form a compound (III); (2) carrying out a reaction on the compound (III) and an oxidizing agent in an organic solvent in the presenceof a catalyst to form a compound (IV); (3) carrying out a reaction on the compound (IV) and a fluorinating reagent in an organic solvent to form a compound (V); and (4) carrying out acidolysis on thecompound (V) in an organic solvent, and carrying out deprotection to obtain a compound (I), wherein various groups in the formulas are defined in the specification. According to the present invention, the florfenicol intermediate can be used for preparing florfenicol; and the method has characteristics of novel design, mild conditions and simple operation, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical raw materials, and in particular relates to a synthesis method of a florfenicol intermediate. Background technique [0002] Florfenicol (Florfenicol) is a kind of animal-specific chloramphenicol broad-spectrum antibiotic developed on the basis of thiamphenicol by Nagab-hushan of Schering-Plough Company in the United States in 1979. In view of the fact that florfenicol is more effective than chloramphenicol and thiamphenicol in the prevention and treatment of animal diseases, it has a broader application prospect, and the synthesis of florfenicol has always received great attention. [0003] At present, the methods for industrialized production of florfenicol at home and abroad are as follows: D-p-thymphenylphenylserine ethyl ester successively undergoes reduction reaction, reacts with dichloroacetonitrile to generate oxazoline, fluorides Ishikawa reagent, and hydrolyzes to obtain fluorob...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C315/04C07C317/32C07D327/10
Inventor 张福利陈少欣邹杰倪国伟谭支敏汤佳伟孟丽丽吴浩翔
Owner SHANGHAI INST OF PHARMA IND CO LTD