New process for synthesizing tamibarotene

A technology of Tamibarotene and a new method, which is applied in the new process field of Tamibarotene synthesis, can solve the problems of easy generation of by-products, high unit consumption of solvents, and poor solubility of methyl anilbamoylbenzoate And other issues

Inactive Publication Date: 2014-03-26
SHANDONG LUBEI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] Though this method has adopted a new route, because the solubility of methyl p-aniscarbamoylbenzoate is very bad in the reaction, need to use a large amount of organic solvents when doing Friedel-Crafts reaction, cause the unit consumption of solvent to be too large, yield The efficiency is not very ideal, and NaOH is used for alkali hydrolysis, which is easy to produce by-products, resulting in difficult purification of products

Method used

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  • New process for synthesizing tamibarotene
  • New process for synthesizing tamibarotene
  • New process for synthesizing tamibarotene

Examples

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example 1

[0025] Preparation of methyl 4-[(4,5,6,7-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene)carbamoyl]benzoate (II)

[0026]

[0027] Dissolve 20.1g of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-amine and 19.4g of monomethyl terephthalate in 200mL of dichloromethane, and then add 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) and 33.6 grams each of triethylamine, stirred at room temperature for 24 hours, continued to add 100 mL of hydrochloric acid to the reactant and 500mL of water, separate the water layer, wash once with 500mL of water, once with 300mL of saturated sodium bicarbonate solution, once with saturated saline, dry over anhydrous magnesium sulfate, filter out the desiccant, and distill under reduced pressure to obtain a light yellow solid. Add the solid to 300 mL of ethanol, stir at 50° C. for 12 hours and filter to obtain 29.5 g of white solid.

example 2

[0029] Add 200mL of 10% K in 29.5 grams of compound (II) 2 CO 3 , heated to reflux for 30 minutes, cooled down after the reaction, adjusted the pH to about 2 with hydrochloric acid, and filtered to obtain a white solid. After the solid was dried, it was dissolved in 300 mL of ethanol, and 300 mL of water was slowly added dropwise to precipitate a white solid. After the solid was dried, 25.4 g of Tamibarotene was obtained. The purity of the product was 99.6%.

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Abstract

The invention discloses a synthetic method of tamibarotene, namely a medicament for treating leukemia and provides a new synthetic route. The synthetic method mainly comprises the following steps: carrying out condensation reaction on raw materials 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-amine and mono-methyl terephthalate to obtain 4-[(4,5,6,7-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl]methyl benzoate; further hydrolyzing the intermediate in potassium carbonate to obtain 4-[(5,5,8,8-tetramethyl-6,7-dihydronaphthalene-2-yl)carbamoyl]benzoic acid, namely tamibarotene. The synthetic route is simple and environment-friendly and is beneficial to industrial production.

Description

technical field [0001] The invention relates to a new process for synthesizing tamibarotene, which belongs to the technical field of synthesis. Background technique [0002] Tamibarotene is a fully synthetic retinoic acid compound developed for ATRA drug resistance, and it is a drug that has a significant ability to induce differentiation in patients with relapsed acute promyelocytic leukemia. This drug has shown a significant effect on APL relapsed after remission of ATRA, and its effectiveness in patients who have difficulty responding to ATRA is also expected. In vivo tests of Tamibarotene have shown anti-tumor activity and good tolerance, and the in vitro effectiveness is about 10 times higher than that of all-trans retinoic acid. This new type of anti-leukemia drug will have broad market application prospects. Tamibarotene was developed by Japan Toko Co., Ltd., and was first listed in Japan on June 13, 2005. [0003] [0004] There are mainly three kinds of synthet...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/65C07C231/12
Inventor 王克柳王美海
Owner SHANDONG LUBEI PHARMA
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