Preparation method of selective estrogen receptor degradation agent and intermediate thereof

A technology of selecting and reducing agents, applied in organic chemistry and other fields, can solve the problems of complex post-processing and low atom utilization rate, and achieve the effect of simple post-processing, high atom utilization rate, and easy-to-obtain raw materials

Active Publication Date: 2020-09-11
SHANGHAI HAOYUAN CHEMEXPRESS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In addition, from intermediate A 1 LSZ-102 is obtained through four steps of bromination, demethylation, Suzuki, and hydrolysis. In the demethylation step, there are some ester hydrolysis by-products. The post-treatment is complicated and the utilization rate of atoms is low.

Method used

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  • Preparation method of selective estrogen receptor degradation agent and intermediate thereof
  • Preparation method of selective estrogen receptor degradation agent and intermediate thereof
  • Preparation method of selective estrogen receptor degradation agent and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] (E)-tert-butyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (Intermediate A 1 ) preparation

[0106]

[0107] Intermediate A of this example 1 The preparation route is as shown above, and preparation method comprises the steps:

[0108]a. Dissolve 60g of compound 1 in 1L N,N-dimethylacetamide, cool in ice water to about 0°C, slowly add 14.6g of sodium hydrogen in batches, remove the ice-water bath, react at about 30°C for 30min, drop Add 51.7g of compound 2 and react at 30°C for 2h. Pour the reaction solution into 400mL of 1M hydrochloric acid aqueous solution, extract 3 times with ethyl acetate, combine the organic phases, wash 3 times with water in turn, wash with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate, and column chromatography to obtain pure product Compound 3 (83 g, 83%).

[0109] b. Dissolve 65g of Compound 3 in a mixed solvent of 240mL of water and 1.2L of ethanol, add 60g of iron pow...

Embodiment 2

[0118] (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy ) phenyl) the preparation method of acrylic acid (LSZ-102)

[0119]

[0120] The preparation route of LSZ-102 (SER degradation agent) of the present embodiment is as shown above, and preparation method comprises the following steps:

[0121] e, the 28g compound A 1 Added into 500mL THF, then added 13.6g N-bromosuccinimide, reacted at room temperature for 3h, concentrated to remove THF, and separated by column chromatography to obtain pure compound 7-1 (31g, 94%).

[0122] f. Dissolve 32.9g of compound 7-1 in 350mL of dichloromethane, under argon protection, cool to 0°C, slowly add 156.5mL of 1M boron tribromide in dichloromethane solution dropwise, stir at room temperature for 18h, and pour the reaction solution slowly into 1L saturated aqueous sodium bicarbonate solution, stirred evenly, extracted three times with tertiary methyl ether, combined the organic phases, washed with 1...

Embodiment 3

[0130] (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (Intermediate A 2 ) preparation

[0131]

[0132] Intermediate A of this example 2 The preparation route is as shown above, and preparation method comprises the steps:

[0133] d. Dissolve 50g of compound 5 in 1L of N,N-dimethylformamide, add 78.8g of compound 6-2, 65g of triethylamine, and 8.5g of bis(triphenylphosphine)palladium chloride, under argon protection, for 1 liter to 80°C, stirred for 4 hours, filtered to remove inorganic salts and palladium catalysts, diluted the mother liquor with 1.5 L of water, extracted three times with ethyl acetate, combined the organic phases, washed three times with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, Concentrate and separate by column chromatography to obtain pure product LSZ-102 intermediate compound A 2 (37.8g, 85%).

[0134] Compound A 2 : ESI-MS: m / z C 19 h 16 o 4 S[M+H] + Calculated: 341.1; ...

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Abstract

The invention relates to a benzothiophene-based selective estrogen receptor degradation agent (LSZ-102) and a preparation method of an intermediate thereof t. The preparation method of the LSZ-102 comprises the following steps: a, performing substitution reaction on a compound 1 and a compound 2 to obtain a compound 3; b, performing reduction reaction on the compound 3 and a reducing agent to obtain a compound 4; c, performing iodination reaction on the compound 4 and an iodinating agent to obtain a compound 5; d, carrying out Heck reaction on the compound 5 and a compound 6 to obtain an LSZ-102 intermediate compound A; e, carrying out bromination reaction on the compound A and a brominating agent to obtain a compound 7; f, carrying out dealkylation reaction on the compound 7 to obtain a compound 8; and g, carrying out Suzuki coupling reaction on the compound 8 and a compound 9 to obtain the compound LSZ-102. The method disclosed by the invention is low in starting material price, short in reaction route, mild in reaction conditions of each step, simple and convenient to operate, high in yield and suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of organic compound synthesis, in particular to a preparation method of a benzothiophene-based selective estrogen receptor degradation agent (LSZ-102) and an intermediate thereof. Background technique [0002] LSZ-102 is a potent, orally bioavailable selective estrogen receptor degrader (SERD), CAS: 2135600-76-7, chemical name (E)-3-(4-((2-( 2-(1,1-Difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid. A series of benzothiophene-containing compounds such as LSZ-102 have demonstrated oral bioavailability and clinical utility for the treatment of estrogen receptor alpha (ERα)-positive breast cancer. The structure of LSZ-102 is as follows: [0003] [0004] The LSZ-102 compound and its preparation method are published in WO2014130310A1. The synthesis method of LSZ-102 is as follows: [0005] [0006] Intermediate A shown above 1 Obtained through six steps of oxidation, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/64
CPCC07D333/64
Inventor 郑保富高强周治国张宏伟
Owner SHANGHAI HAOYUAN CHEMEXPRESS
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