Caspofungin intermediate and synthesis method thereof

A synthesis method and compound technology, which are applied in the field of caspofungin intermediates and their synthesis, can solve the problems of increasing the cost of industrialization, low yield and stereoselectivity, polluting the environment, etc., so as to shorten reaction steps and reduce preparation and purification. The number of times, the effect of improving the yield

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

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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

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  • Caspofungin intermediate and synthesis method thereof
  • Caspofungin intermediate and synthesis method thereof
  • Caspofungin intermediate and synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] 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%.

[0032] Under the protection of nitrogen, the compound ...

Embodiment 2

[0034] 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%

[0035] Under the protection of nit...

Embodiment 3

[0037] 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%.

[0038] 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 caspofungin intermediate and a synthesis method thereof. The synthesis method of the intermediate comprises thefollowing steps of: mixing a compound as shown in a formula II and thionyl chloride dissolved in a solvent A to obtain a compound as shown in a formula III. The method replaces thiol or thiophenol compound with high toxicity, foul smell and pungent smell with the thionyl chloride so as to avoid the use of strong corrosive acid, and the formed cyclic sulfite is favorable for maintaining the configuration of a reactant; and meanwhile, the method utilizes the property that the thionyl chloride is easy to leave and does not change the chiral configuration of the reactant, directly introduces ethylenediamine groups without purification, shortens the reaction steps, reduces the times of preparation and purification, and improves the yield and purity.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a caspofungin intermediate and a synthesis method thereof. 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, vol72, 2335-2343) used 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 compound R-SH as ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/56C07K1/107
Inventor 张贵民陈迎会张清德
Owner LUNAN PHARMA GROUP CORPORATION
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