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Method for recovering voriconazole resolving agent (R)-10-camphorsulfonic acid

A technology for voriconazole resolving agent and camphorsulfonic acid is applied in the field of recovery of voriconazole resolving agent-10-camphorsulfonic acid, which can solve the problems of poor optical purity, complicated process, difficult separation and the like, and achieves low production cost and optical purity. High, simple recycling process effect

Pending Publication Date: 2018-07-13
CHANGZHOU YABANG QH PHARMACHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] With the development of optically active chiral drugs, (R)-10-camphorsulfonic acid is more and more widely used. At present, (R)-10-camphorsulfonic acid is more difficult to separate than (S)-10-camphorsulfonic acid. Complex, poor optical purity, high cost and serious pollution

Method used

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  • Method for recovering voriconazole resolving agent (R)-10-camphorsulfonic acid
  • Method for recovering voriconazole resolving agent (R)-10-camphorsulfonic acid
  • Method for recovering voriconazole resolving agent (R)-10-camphorsulfonic acid

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Embodiment 1

[0029] 1. Dissolve 40 g of voriconazole camphorsulfonate in 160 ml of dichloromethane and 200 ml of water mixture, adjust the pH value to 8.5 with saturated aqueous sodium carbonate solution, separate the organic layer, extract the water layer twice with 30 ml of dichloromethane, discard the two The methyl chloride layer and the aqueous layer were acidified with concentrated sulfuric acid, adjusted to pH 0.5, concentrated and evaporated to dryness to obtain 16.2 g of solid, and 75 ml of methyl ethyl ketone was added to the solid, heated to 60 ° C to dissolve the solid, filtered, and 75 ml of cyclohexane was added to the filtrate , crystallized at room temperature for 12 hours, filtered with suction, and dried the filter cake at 85-90°C to obtain 14.6g of (R)-10-camphorsulfonic acid, melting point: 192.5-193.0°C, specific rotation: -22.3° (589nm, c= 20,H 2 (025° C.), yield: 91.4%.

[0030] figure 1 Be the infrared spectrogram of the (R)-10-camphorsulfonic acid that the presen...

Embodiment 2

[0038] Dissolve 40 g of voriconazole camphorsulfonate in 100 ml of dichloromethane and 140 ml of water mixture, adjust the pH value to 8.8 with saturated sodium bicarbonate solution, separate the organic layer, and extract the aqueous layer twice with 40 ml of dichloromethane, discard the two The methyl chloride layer and the aqueous layer were acidified with concentrated hydrochloric acid until the pH value reached 1.5, then concentrated and evaporated to dryness to obtain 15.9 g of a solid, 40 ml of acetone was added to the solid and heated to 50 ° C to dissolve the solid, filtered, and the filtrate was added with 40 ml of cyclohexane, and analyzed at room temperature After crystallization for 10 hours, filter with suction, and dry the filter cake at 85-90°C to obtain 14.4g of (R)-10-camphorsulfonic acid, melting point: 193.5-194.8°C, specific rotation: -22.5° (589nm, c=20, H 2 (025° C.), yield: 90.1%.

Embodiment 3

[0040] Dissolve 40 g of voriconazole camphorsulfonate in 150 ml of dichloromethane and 150 ml of water mixture, adjust the pH value to 9 with saturated potassium bicarbonate solution, separate the organic layer, extract the aqueous layer twice with 40 ml of dichloromethane, discard the dichloromethane The methyl chloride layer and the aqueous layer were acidified with concentrated phosphoric acid until the pH value reached 1.0, and then concentrated and evaporated to dryness to obtain 16.3 g of solid. Add 80 ml of dichloromethane to the solid and heat to 50 ° C to dissolve the solid. Filter and add 80 ml of cyclohexane to the filtrate. Crystallize at room temperature for 5 hours, filter with suction, and dry the filter cake at 85-90°C to obtain (R)-10-camphorsulfonic acid 14.5g, melting point: 193.0-194.5°C, specific rotation: -21.8° (589nm, c=20 ,H 2 (025° C.), yield: 90.8%.

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Abstract

The invention discloses a method for recovering a voriconazole resolving agent (R)-10-camphorsulfonic acid. The method comprises the following steps: (1) alkalization treatment: dissolving voriconazole camphorsulfonate in a mixed solution of dichloromethane and water, then adding an aqueous solution of a weak base for alkalization treatment, carrying out separation after layering, and leaving an aqueous layer for subsequent usage; (2) acidification treatment: adding a strong acid into the aqueous layer obtained in the step (1) for acidification treatment, then carrying out concentrating and evaporating to a dryness so as to obtain a solid, dissolving the obtained solid in an organic solvent under heating conditions, carrying out filtering, and leaving a filtrate for subsequent usage; and (3) crystallization treatment: adding cyclohexane into the filtrate obtained in the step (2), carrying out cooling and crystallization, then carrying out pumping filtration after completion of crystallization so as to obtain (R)-10-camphorsulfonic acid. The recovery method for the voriconazole resolving agent (R)-10-camphorsulfonic acid has the advantages that separation is simple; and the separated product is high in optical purity, economic and environment-friendly.

Description

technical field [0001] The invention relates to the technical fields of medicine and chemical industry, in particular to a method for recovering voriconazole resolving agent (R)-10-camphorsulfonic acid. Background technique [0002] Voriconazole (voriconazole) is the second-generation triazole antifungal drug, invented by Pfizer in 1991, and then developed tablets and injections, FDA approved listing in May 2002, for invasive aspergillosis, Boyd's For the treatment of Pseudomycetes, Actinomyces and Fusarium infections, this product has the characteristics of broad antibacterial spectrum and strong antibacterial efficacy, especially for infections caused by invasive Aspergillus infiltration. Voriconazole is a chiral drug with two chiral centers in the molecule and four isomers. They are (2R,3S / 2S,3R) and (2S,3S / 2R,3R) respectively. The structure-activity relationship study (SAR) confirmed that the antibacterial activity of the (2R, 3S / 2S, 3R) enantiomer is more than 200 tim...

Claims

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Application Information

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IPC IPC(8): C07C303/02C07C303/44C07C309/19
CPCC07C303/02C07C303/32C07C303/44C07B2200/07C07C309/19
Inventor 苏文杰王学成朱建民刘祥宜
Owner CHANGZHOU YABANG QH PHARMACHEM
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