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Synthesis method of caspofungin

A synthesis method and compound technology, applied in the preparation method of peptides, chemical instruments and methods, organic chemistry, etc., can solve the problems of low yield and stereoselectivity, increase of industrialization cost, and wastes, etc., and reduce the cost of preparation and purification The effect of increasing the number of times, increasing the purity and yield, and reducing the generation of impurities

Active Publication Date: 2019-05-07
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

CN 102367267A describes the synthesis of caspofungin using hydroxyl, benzyloxy, phenoxy, substituted phenoxy, substituted aromatic ring mercapto compound R'-SH as a strong leaving group, preferably for Hydroxythiophenol, but it is difficult to avoid the shortcomings of its toxicity and stench
CN102219833A reports the use of stereostructure selector 2-mercaptobenzothiazole or 1-phenyl-5-mercapto-tetrazolium to synthesize caspofungin, and the actual yield is not high
The synthetic steps in some methods must be carried out in a strictly anhydrous environment (dehydration with molecular sieves or dehydrating agents); most methods require the use of highly toxic, foul-smelling, pungent-smelling mercaptan or thiophenol compounds, which seriously damage the health of operators , seriously pollute the environment; in some existing synthetic methods, the introduction of cyano groups inevitably leads to the formation of isomers, the yield and stereoselectivity are not high, and the use of expensive metals as catalysts increases the cost of industrialization; many times The use of preparative chromatography increases the cost of industrialization and produces a large amount of three wastes

Method used

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  • Synthesis method of caspofungin
  • Synthesis method of caspofungin
  • Synthesis method of caspofungin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Formula II compound (10.00g, 9.4mmol) and chloroform (200mL) were placed in a 500mL three-neck flask, under nitrogen protection, placed in a low-temperature bath, and dropped to -30°C, and slowly added dropwise at this temperature Thionyl chloride ( SOCl 2 , 0.37g, 3.1mmol) in chloroform (20mL) solution, after the dropwise addition, the reaction was started, and the reaction process was followed and monitored by HPLC, and the reaction time was 1h. Add cold saturated potassium carbonate aqueous solution to the reaction solution until no more bubbles are generated, separate the organic layer, extract the aqueous layer with chloroform (50mL×2), combine the organic layers, wash with cold pure water until nearly neutral, and rinse with anhydrous sulfuric acid Sodium drying overnight, filtration, distillation under reduced pressure and vacuum drying gave the compound of formula III as a pale yellow solid. Yield 90.6%.

[0041] Under the protection of nitrogen, the compound ...

Embodiment 2

[0043] The compound of formula II (10.00g, 9.4mmol) and dichloromethane (200mL) were placed in a 500mL three-necked flask, under the protection of nitrogen, placed in a low-temperature bath, down to -5°C, and dichloromethane was slowly added dropwise at this temperature Sulfone (SOCl 2, 0.37g, 3.1mmol) in dichloromethane (20mL) solution, after the dropwise addition, the reaction was started, and the reaction process was tracked and monitored by HPLC, and the reaction time was 3h. Add cold saturated potassium carbonate aqueous solution to the reaction solution until no more bubbles are generated, separate the organic layer, extract the aqueous layer with dichloromethane (50mL×2), combine the organic layers, wash with cold pure water until nearly neutral, and wash with dry Dry over sodium sulfate with water, filter, distill under reduced pressure and dry under vacuum to obtain the compound of formula III as a pale yellow solid. Yield 90.2%.

[0044] Under the protection of nit...

Embodiment 3

[0046] The compound of formula II (10.00g, 9.4mmol) and chloroform (200mL) were placed in a 500mL three-neck flask, under the protection of nitrogen, placed in a low-temperature bath, down to -25°C, and slowly added dropwise at this temperature Thionyl chloride ( SOCl 2 , 0.37g, 3.1mmol) in chloroform (20mL) solution, start to react after dropwise addition, HPLC tracking and monitoring reaction process, reaction time 1.5h. Add cold saturated potassium carbonate aqueous solution to the reaction solution until no more bubbles are generated, separate the organic layer, extract the aqueous layer with chloroform (50mL×2), combine the organic layers, wash with cold pure water until nearly neutral, and rinse with anhydrous sulfuric acid Sodium drying overnight, filtration, distillation under reduced pressure and vacuum drying gave the compound of formula III as a pale yellow solid. Yield 90.1%.

[0047] Under the protection of nitrogen, the compound of formula III was dissolved in ...

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a synthesis method of caspofungin. The synthesis method comprise the following steps: mixing a compound shown asformula II and thionyl chloride dissolved in a solvent A to form a compound shown as formula III, mixing the compound shown as the formula III without purification and ethidene diamine dissolved in asolvent B to form a compound shown as formula IV, mixing the compound shown as the formula IV and a borane complex to form a compound shown as formula I. The synthesis method replaces virulent and malodorous thiol or thiophenol compound with an irritating odor with thionyl chloride, and avoids using highly corrosive acid; formed cyclic sulphite facilitates configuration retention of a reactant; atthe same time, an ethidene diamine group is directly introduced into cyclic sulphite without the purification since cyclic sulphite has properties that cyclic sulphite is easy to remove and does notchange a chiral configuration of the reactant; a reaction procedure is shortened; the number of times of the purification for preparation is reduced; and the purity and yield are improved.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for synthesizing caspofungin, an echinococcus antifungal drug. Background technique [0002] Caspofungin acetate is an echinocandin compound with unique action site, broad spectrum and low toxicity, which has been widely used as an antifungal agent for treatment or prevention. [0003] The chemical structural formula of caspofungin acetate is as shown in formula I: [0004] [0005] William R. Leonard (William R. Leonard, Jr., the Journal of Organic Chemistry, 2007, 7, v ol72, 2335-2343) uses pneumocantine B 0 Synthesize caspofungin with thiophenol. As a stereoselective agent, thiophenol can be used for selective mono-substitution. However, thiophenol is highly toxic, foul-smelling, and irritating. It is not suitable for industrial production, especially batch drug production. [0006] CN101648994A reports the synthesis of caspofungin using a mercapto aromatic com...

Claims

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Application Information

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IPC IPC(8): C07K7/56C07K1/04C07K1/30
Inventor 张贵民陈迎会朱兵峰
Owner LUNAN PHARMA GROUP CORPORATION
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