CN-121591596-B - Method for synthesizing midbody of idoxifene

CN121591596BCN 121591596 BCN121591596 BCN 121591596BCN-121591596-B

Abstract

The invention provides a method for synthesizing a midbody of idoxifene, belonging to the field of organic chemical synthesis. The preparation method comprises the steps of taking 4,4' -difluorobenzophenone as a starting material, firstly reacting with an aqueous alkali solution to obtain a compound 2, and then mixing the compound 2, the aqueous alkali solution and a phase transfer catalyst for reaction to obtain a compound 3, namely a doxifene intermediate. The method has the characteristics of short route, high total yield, high product purity, low cost and suitability for industrial production.

Inventors

Kuang Yulong
JIN HAIQUAN
GUO PENG

Assignees

爱斯特（成都）生物制药股份有限公司
广安爱斯特健康科技有限公司

Dates

Publication Date: 20260508
Application Date: 20260130

Claims (3)

1. A method of synthesizing a clomefene intermediate, comprising the steps of: (1) Mixing and reacting the compound 1 with an aqueous solution of a base to obtain a compound 2; (2) Mixing compound 2, alkali aqueous solution and N, N-dimethylethanolamine for reaction to obtain compound 3, namely a doxifene intermediate; In the step (1), the equivalent ratio of the compound 1 to the alkali is 1:4, the alkali is potassium hydroxide, the solvent of the reaction is dimethyl sulfoxide, and the temperature of the reaction is 70 ℃; In the step (2), the equivalent ratio of the compound 2 to the alkali to the N, N-dimethylethanolamine is 1:9:2.2, the alkali is potassium hydroxide, the solvent of the reaction is dimethyl sulfoxide, and the temperature of the reaction is 70 ℃.
2. The method according to claim 1, wherein after the reaction in the step (1) is finished, the method further comprises the following post-treatment steps of adding water to the reaction solution for quenching, adding an organic solvent for extraction, taking water to adjust the pH to be 2-3, filtering, and drying to obtain the compound 2.
3. The method according to claim 1, wherein after the reaction in the step (2) is finished, the method further comprises the following post-treatment steps of adding water to the reaction solution for quenching, adding an organic solvent for extraction, taking water to adjust the pH to be 6-7, filtering, precipitating, pulping, purifying and drying to obtain the compound 3, namely the midbody of the doxifene.

Description

Method for synthesizing midbody of idoxifene Technical Field The invention belongs to the field of organic chemical synthesis, and particularly relates to a method for synthesizing a midbody of clomefene. Background Since doxifene (Endoxifen) is a third generation Selective Estrogen Receptor Modulator (SERM), it is clinically used in the treatment of osteoporosis and vasomotor symptoms in postmenopausal women. The structure is that.4- (2- (Dimethylamino) ethoxy) phenyl-4' -hydroxyphenyl methanone is an important intermediate for the synthesis of doxifene. Literature （Bis-arylidene oxindoles as anti-breast-cancer agents acting via the estrogen receptor,DOI: 10.1002/cmdc.201400003） uses 4,4 '-dihydroxybenzophenone to react with dimethylaminoethyl chloride hydrochloride to give 4- (2- (dimethylamino) ethoxy) phenyl-4' -hydroxyphenyl methanone. The method reported in the literature has high requirements on raw material quality, low yield and purity, is not suitable for industrialization, and needs to be further improved. Therefore, the novel preparation method of the doxifene intermediate with simple development route, mild conditions and high-risk reagent avoidance becomes a technical problem to be broken through in industrialization of 4- (2- (dimethylamino) ethoxy) phenyl-4' -hydroxyphenyl ketone. Disclosure of Invention Aiming at the defects existing in the prior art, the invention aims to provide a method for synthesizing the midbody of the clomefene, which has higher yield and purity and low cost and is suitable for industrialization. The invention provides a method for synthesizing a midbody of clomefene, which comprises the following steps: (1) Mixing and reacting the compound 1 with an aqueous solution of a base to obtain a compound 2; (2) And mixing the compound 2, an aqueous solution of alkali and a phase transfer catalyst for reaction to obtain a compound 3, namely a midbody of the doxifene. In the step (1), the equivalent ratio of the compound 1 to the alkali is 1:2-8, the alkali is inorganic alkali, the solvent for the reaction is organic solvent, and the temperature of the reaction is 60-110 ℃. Further, in the step (1), the reaction time is 10 hours or more. Further, in the step (1), the equivalent ratio of the compound 1 to the base is 1:4-6, the base is selected from sodium hydroxide (NaOH), lithium hydroxide (LiOH), potassium hydroxide (KOH) or sodium hydride (NaH), the solvent for the reaction is selected from Tetrahydrofuran (THF), toluene (tolene), N-Dimethylformamide (DMF), N-Dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), sulfolane or dimethyl sulfoxide (DMSO), and the temperature of the reaction is 70-110 ℃. Further, in the step (1), the equivalent ratio of the compound 1 to the base is 1:4, the base is potassium hydroxide, the solvent of the reaction is dimethyl sulfoxide, and the temperature of the reaction is 70 ℃. Further, after the reaction in the step (1) is finished, the method further comprises the following post-treatment steps of adding water into the reaction liquid for quenching, adding an organic solvent for extraction, taking water to adjust the pH to be 2-3, filtering and drying to obtain the compound 2. Further, the organic solvent is methyl tertiary butyl ether. Further, in the step (2), the equivalent ratio of the compound 2 to the alkali to the phase transfer catalyst is 1:5-12:1-3, the alkali is an inorganic alkali, the solvent of the reaction is an organic solvent, and the temperature of the reaction is 60-110 ℃. Further, in the step (1), the reaction time is 20 hours or more. Further, in the step (2), the equivalent ratio of the compound 2 to the alkali to the phase transfer catalyst is 1:6-12:2.2, the alkali is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide or sodium hydride, the solvent for the reaction is selected from tetrahydrofuran, toluene, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, sulfolane or dimethyl sulfoxide, and the temperature of the reaction is 70-110 ℃. Further, in the step (2), the equivalent ratio of the compound 2 to the alkali to the phase transfer catalyst is 1:9:2.2, the alkali is potassium hydroxide, the solvent of the reaction is dimethyl sulfoxide, and the temperature of the reaction is 70 ℃. Further, after the reaction in the step (2) is finished, the method further comprises the following post-treatment steps of adding water into the reaction liquid for quenching, adding an organic solvent for extraction, taking water phase to adjust pH to be 6-7, filtering, precipitating, pulping, purifying and drying to obtain the compound 3, namely the midbody of the doxifene. Further, the organic solvent is methyl tertiary butyl ether. Compared with the prior art, the invention has the following beneficial effects: (1) The invention establishes a brand new synthetic route, can be completed in two steps, has a total yield of 42% and has a product purity of 99.56%; (2) The scheme of the invention greatly