Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Synthetic method of all-trans vitamin A acid medicament

A synthesis method and all-trans technology, applied in the direction of organic chemistry, etc., can solve the problems of high catalyst price, low selectivity, heavy metal residues, etc., and achieve the effects of high product purity, high yield and low cost.

Inactive Publication Date: 2012-07-11
HUNAN NORMAL UNIVERSITY
View PDF9 Cites 5 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Roche Company reported a method of isomerizing 11 cis, 13 trans-acitretin ethyl ester into medicinal 11 trans, 13 trans-acitretin ethyl ester (Helv. Chim. Acta. 1989, 370) , the selectivity is not high, the content of acitretin in the product is only 65%, and the Pd(NO3)2 catalyst used will cause heavy metal residues, and the price of the catalyst is high , difficult to recycle

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Synthetic method of all-trans vitamin A acid medicament

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] (1) Preparation of 11 cis, 13 trans-retinoic acid and 11 trans, 13 trans-retinoic acid mixture (5a):

[0020] Mix 1.37Kg (12.00mol) of 5-hydroxy-4-methyl-2-furanone, 2.70Kg (49.98mol) of sodium methoxide with 20L of anhydrous methanol, o Stir at C for 2h, cool to -5~0 o C, 5.01Kg (10.00 mol) [3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadiene]-triphenyl Dissolve the phosphine chloride salt in 15L of anhydrous methanol, and slowly add it dropwise to the above solution, keeping the temperature at -5~0 o C, after the addition, keep warm for 4 hours, then react at room temperature for 6-10 hours, add 40L of ice water, extract with a mixed solvent of 2×30L ethyl acetate / petroleum ether=1:4, and adjust the pH of the water layer with concentrated hydrochloric acid= 3~4, stirred for 30min, extracted with 3×30L ethyl acetate / petroleum ether=1:3 mixed solvent, combined the organic layer, then washed with 2×20L water, dried over anhydrous sodium sulfate, evaporated th...

Embodiment 2

[0024] (1) Preparation of 11 cis, 13 trans-retinoic acid and 11 trans, 13 trans-retinoic acid mixture (5a):

[0025] Mix 1.37g (12.0mmol) of 5-hydroxy-4-methyl-2-furanone, 1.26g (52.6mmol) of lithium hydroxide and 15ml of N,N-dimethylformamide, o Stir at C for 2h, cool to -5~0 oC, 5.01g (10mmol) [3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadiene]-triphenyl Dissolve phosphine chloride salt in 15ml N,N-dimethylformamide, slowly add dropwise to the above solution, keep the temperature at -5~0 o C. After the addition, keep the reaction for 4 hours, then react at room temperature for 6-10 hours, add 40ml of ice water, extract with a mixed solvent of 2×30ml ethyl acetate / petroleum ether=1:4, and adjust the pH of the water layer to 3 with concentrated hydrochloric acid ~4, stirred for 30min, extracted with a mixed solvent of 3×30ml ethyl acetate / petroleum ether=1:3, combined the organic layers, then washed with 2×20ml water, dried over anhydrous sodium sulfate, and evap...

Embodiment 3

[0029] (1) Preparation of 11-cis, 13 trans-acitretin and 11 trans, 13 trans-acitretin mixture (5b)

[0030] Mix 0.627Kg (5.49mol) of 5-hydroxy-4-methyl-2-furanone, 1.35Kg (24.99mol) of sodium methoxide with 10L of anhydrous methanol, and o Stir at C for 2h, cool to -5~0 o C, 2.64Kg (5.00mol) [5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadiene]-triphenylphosphine Dissolve the chloride salt (3c) in 7.5L of anhydrous methanol, and slowly add it dropwise to the above solution, keeping the temperature at -5~0 o After adding C, keep it warm for 4 hours, then react at room temperature for 6-10 hours, add 20L of ice water, extract with a mixed solvent of 2×15L ethyl acetate / petroleum ether=1:4, and adjust the pH of the water layer to 3 with concentrated hydrochloric acid ~4, a yellow solid precipitated, stirred for 30min, filtered, washed with water, dried to obtain 1.225Kg yellow solid, HPLC showed 11-cis, 13 trans-acitretin: 11trans, 13trans-acitretin=50: 50.

[0031] ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a synthetic method of an all-trans vitamin A acid medicament. The method comprises the following steps of: (1) preparing an intermediate: adding a solvent and 2-5 equivalent weight of alkali into 5-hydroxy-4-methyl-2-furanone, reacting at the temperature of 35-40 DEG C for 1-3 hours, undergoing a ring opening reaction, cooling to between 5 DEG C below zero and 0 DEG C below zero, dropwise adding 0.75-1.0 equivalent weight of a C15-triphenyl phosphine salt solution slowly for reacting for 3-4 hours, heating to the room temperature for reacting for 6-10 hours, adding 40L of ice water, extracting with a mixed solvent consisting of ethyl acetate and petroleum ether in the ratio of 1:4, combining organic phases, washing with water for 2-3 times, and drying with anhydrous sodium sulfate to obtain a mixture of a 11cis,13contra-vitamin A acid and a 11contra,13contra-vitamin A acid compound; and (2) isomerizing: dissolving a 11cis,13contra and 11contra,13contra-vitamin A acid mixture solid obtained in the step (1) with a solvent, adding 0.1-20 percent by mole of iodine, and stirring and reacting at the temperature of 25-35 DEG C for 25-48 hours to obtain the all-trans vitamin A acid medicament. The synthetic method has the advantages of easiness for operating, high yield, low cost, high product content and capability of avoiding pollution of heavy metals.

Description

technical field [0001] The invention relates to a method for synthesizing all-trans retinoic acid drugs. Background technique [0002] All-trans retinoic acid compounds such as retinoic acid (1) and acitretin (2) are more stable in structure than other retinoic acid compounds, have anti-keratosis effect, and can be used to treat acne, Various abnormal keratosis skin diseases such as psoriasis. Retinoic acid has the properties of anti-proliferation and induction of differentiation, and has been clinically used in the treatment and prevention of squamous cell carcinoma. The synthesis of retinoic acid reported in the current literature has the following several methods: US 3746730 discloses the industrial production method of retinoic acid, using vitamin A acetate as raw material, through hydrolysis, and then through silver oxide oxidation to directly obtain all-trans vitamin A Although this method has a short route, the raw material needs high-purity vitamin A acetate, which...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07C403/20
Inventor 徐广宇沈栋国刘彩
Owner HUNAN NORMAL UNIVERSITY
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com