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Method for preparing retapamulin

A technology of retapamulin and compounds, which is applied in the field of chemical drug synthesis, can solve problems such as flammability, low yield, and potential safety hazards, and achieve the effects of easy purification, reduced environmental impact, and simple operation

Active Publication Date: 2015-12-30
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, the β-tropine thiol in the first step is obtained by reacting α-tropine alcohol and AcSH through Mitsunobu. The diisopropyl azodicarboxylate (DIAD) used in this reaction is expensive, and triphenylphosphine not easy to remove
Column chromatography is used in the second step of condensation, which is not conducive to industrial production
Phosphorus pentasulfide is highly toxic, flammable, and has potential safety hazards
Low yields in the preparation of β‐tropinethiol
Not conducive to scale-up production

Method used

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  • Method for preparing retapamulin
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  • Method for preparing retapamulin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Preparation of (1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yldiethylaminodithiocarbamate

[0053] Add endo-8-methyl-8-azabicyclo[3.2.1]octane-3-methanesulfonate (20g, 91.2mmol) and EtOH (200ml) to a 500ml four-necked flask with a thermometer and a condenser tube, After stirring and dissolving, N,N-diethyl dithiosodium trihydrate (30.82 g, 136.8 mmol) and water (20 ml) were added, and the temperature was raised to 50° C. to react for 2 h. The ethanol was evaporated under reduced pressure (external temperature 40°C), water (80ml) and ethyl acetate (80ml) were added, mixed, separated and separated, and the aqueous phase was extracted with ethyl acetate (60ml). The organic phases were combined, washed with 1mol / L NaOH (20ml), washed with water (20ml), and washed with 6mol / L HCl (30ml+30ml+15ml). The hydrochloric acid layers were combined, adjusted to pH 6-7 (75ml) with 6mol / L NaOH under an ice-water bath, a large amount of solid was precipitated, filtered with suction, t...

Embodiment 2

[0055] Preparation of (1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yldiethylaminodithiocarbamate

[0056] 25ml single-neck bottle was added with internal-8-methyl-8-azabicyclo[3.2.1]octane-3-methanesulfonate (1g, 4.6mmol), H 2 O (10ml), stir to dissolve, add N,N-diethyldithiocarbamate sodium trihydrate (1.54g, 6.84mmol), and react at 25°C for 10h. Add ethyl acetate (15ml+15ml) for extraction. The organic phases were combined and washed with 6mol / L HCl (5ml+3ml+3ml). The acid water layers were combined and adjusted to pH ≈ 6 with 6 mol / L NaOH under an ice-water bath. The solid was precipitated, filtered with suction, and the filter cake was washed with water, and dried at 60°C for 8 hours to obtain 0.44 g of an off-white solid with a yield of 35%.

Embodiment 3

[0058] Preparation of (1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yldiethylaminodithiocarbamate

[0059] To a 500ml four-necked flask with a thermometer and a condenser tube, add endo-8-methyl-8-azabicyclo[3.2.1]octane-3-methanesulfonate (20g, 91.2mmol), DMF (100ml), After stirring and dissolving, sodium N,N-diethyldithiocarbamate trihydrate (30.82 g, 136.8 mmol) was added, and the temperature was raised to 120° C. to react for 1 h. DMF was evaporated under reduced pressure (external temperature 70°C), water (80ml) and ethyl acetate (80ml) were added, mixed, separated and separated, and the aqueous phase was extracted with ethyl acetate (60ml). The organic phases were combined, washed with 1mol / L NaOH (20ml), washed with water (20ml), and washed with 6mol / L HCl (30ml+30ml+15ml). The hydrochloric acid layers were combined, and the pH was adjusted to 6-7 with 6 mol / L NaOH under an ice-water bath to precipitate a large amount of solid, which was filtered with suction, washed w...

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PUM

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Abstract

The invention discloses a method for preparing retapamulin. The method comprises the following steps that a compound of a formula 3 and a compound of a formula 4 are subjected to a nucleophilic substitution reaction to obtain a compound of a formula 5; the compound of the formula 5 is subjected to a hydrolysis reaction to obtain beta-tropine mercaptan shown in a formula 6; the beta-tropine mercaptan shown in the formula 6 is not separated and purified to be subjected to condensation with a compound of a formula 2 to obtain retapamulin 1; the reaction formula is shown in the specification, wherein M in the compound of the formula 4 is a metal ion of a potassium ion or a sodion or a calcium ion or an iron ion or an ammonium ion, n corresponds to the valence of the metal ion M and is 1 or 2 or 3, and R is alkyl groups C1-C3 or a phenyl group or a substituted phenyl group or a benzyl group or a substituted benzyl group. The method is easy and convenient to implement, a cheap reagent is adopted, the influences on the environment are greatly reduced, intermediate products are easy to purify, no column chromatography is needed, the defects of reported methods for preparing beta-tropine mercaptan and retapamulin are overcome, and the method has obvious positive and progressive effects and practical application value.

Description

technical field [0001] The invention relates to the field of chemical drug synthesis, in particular to a new method for preparing retamorelin, which is used in the treatment of impetigo or secondary infectious trauma. Background technique [0002] Retapamulin with the chemical name: (3aS,4R,5S,6S,8R,9aR,10R)-2-(exo-8-methyl-8-azabicyclo [3.2.1] Oct-3-ylmercapto)acetic acid 5-hydroxy-4,6,9,10-tetramethyl-1-oxo-6-vinyl perhydrogenation-3a,9-n-propylcyclopentanocyclooctane ‐8‐yl ester with the following chemical structure: [0003] [0004] Retamorelin is the first topical pleuromutilin antibiotic developed by GlaxoSmithKline (GSK). In April 2007, the US FDA approved Retamorelin for impetigo caused by Staphylococcus aureus or Streptococcus pyogenes in children over 9 months old, children and adults (trade name: Altabax); in June of the same year, the European Union It is approved for the treatment of impetigo and infected small lacerations, abrasions and sutured wounds (t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D451/02
Inventor 黄火明郝群周伟澄张清泉黄浩李鸿雁
Owner SHANGHAI INST OF PHARMA IND CO LTD
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