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Method for preparing novel androgen receptor antagonist

A technology of solvents and compounds, applied in the field of drug synthesis, can solve problems such as unsuitable for industrial production, unsuitable for industrial production, and expensive

Inactive Publication Date: 2018-06-29
LIANYUNGANG RUNZHONG PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The defect of route 1 is: (1) the starting material 3-butyn-2-ketone (compound 10) of preparing compound 7 does not have a large amount of off-the-shelf supply in the market, and small quantity custom-made is expensive, is not suitable for industrialized production; (2) compound The preparation process of 11 requires indium trichloride as a catalyst, and indium trichloride is a transition metal, which is used to treat wastewater after industrial production and seriously pollutes the environment
[0022] The disadvantages of routes 2 and 3 are: (1) difficult preparation of starting material compound 11; (2) KRED enzyme, as a biological enzyme, is not suitable for industrial production; (3) compound 9 and compound 16a or compound 16b to prepare compound 12a or compound The synthetic yield of 12b is extremely low, only reaching 0.026%
[0023] The process synthesis of reported ODM-201, formula Ia compound and formula Ib compound is not suitable for industrialized production, and the present invention aims to provide a new ODM-201 and its optical isomer formula Ia compound and formula Ib suitable for industrialized production Compound preparation method

Method used

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  • Method for preparing novel androgen receptor antagonist
  • Method for preparing novel androgen receptor antagonist
  • Method for preparing novel androgen receptor antagonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0134] Example 1: (R)-3-((tert-butyldimethylsilyl)oxy)butanoic acid methyl ester

[0135]

[0136] Add (R)-3-hydroxybutyric acid methyl ester (compound of formula Xa) (20g, 0.17mol), imidazole (23g, 0.34mol), anhydrous dichloromethane 350mL into a 500mL three-necked flask in sequence, replace with nitrogen three times, and cool down the system To 0°C, TBSCl (30.5 g, 0.2 mol) was slowly added dropwise, and the mixture was stirred at room temperature for 3 h after the drop was completed. After the reaction was completed, the reaction solution was poured into 300 mL of ice water to quench, the organic layer was washed three times with water and saturated brine three times, dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated under reduced pressure and evaporated to dryness to obtain 38 g of the title compound with a yield of 96 %.

Embodiment 2

[0137] Example 2: (R)-3-((tert-butyldimethylsilyl)oxy)butyraldehyde

[0138]

[0139] Add (R)-3-((tert-butyldimethylsilyl)oxy)methyl butyrate (15g, 64mmol) and 375mL of anhydrous dichloromethane successively into a 500mL three-necked flask, replace with nitrogen three times, and cool the system to -78°C, slowly drop into DIBAL-H (67.7mL, 1.0mol / L dissolved in n-hexane, 67mmol), and stir for 1h after dropping. After the reaction, add 15mL methanol to quench the reaction, then pour the reaction solution into 200mL saturated sodium potassium tartrate aqueous solution, stir, add 300mL diethyl ether to extract three times, wash the organic layer three times with water, wash three times with saturated saline, anhydrous sodium sulfate Dry, filter, and concentrate the organic phase under reduced pressure to obtain 12 g of the title compound, with a yield of 92%.

Embodiment 3

[0140] Example 3: (5R)-5-((tert-butyldimethylsilyl)oxy)-2-diazo-3-hydroxy-hexanoic acid ethyl ester

[0141]

[0142] Add (R)-3-((tert-butyldimethylsilyl)oxy)butyraldehyde (10g, 49mmol), ethyl diazoacetate (8.9g, 78mmol) and 300mL of anhydrous THF to a 500mL three-necked flask in sequence , replaced with nitrogen three times, the system was cooled to -78°C, and LIHMDS (74mL, 1.0mol / L dissolved in THF, 74mmol) was slowly added dropwise, and stirred for 1h after the drop was completed. After the reaction was completed, add 100 mL saturated ammonium chloride aqueous solution to quench the reaction, stir to room temperature, extract the solution three times with 300 mL ethyl acetate, combine the organic layers, wash three times with saturated saline, dry over anhydrous sodium sulfate, filter on silica gel, and concentrate under reduced pressure 13 g of the title compound were obtained with a yield of 83.3%.

[0143] ESI-MS(m / z):317[M+H] + ;

[0144] 1 H-NMR (400MHz, CDCl 3...

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Abstract

The invention relates to a method for preparing a novel androgen receptor antagonist. The method mainly comprising the following step: performing a cyclization reaction on a compound of formula V as shown in the description, thereby obtaining a compound of formula VI as shown in the description. The method has the characteristics of being easy in raw material obtaining, high in atom utilization rate, mild in reaction condition and simple and convenient in aftertreatment; in addition, by controlling stereo-chemical configuration of initial raw materials, ODM-201 and single isomer thereof can bedirectionally synthesized, and the method is simple and controllable in process and applicable to industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a preparation method of a novel androgen receptor antagonist, in particular to a preparation method of ODM-201 and its intermediate. Background of the invention [0002] Androgen receptor (AR) belongs to the nuclear receptor superfamily, which has many members, but there are only five types in vertebrates, namely progesterone receptor, estrogen receptor, androgen receptor, sugar Corticosteroid receptors and mineralocorticoid receptors. AR contains 918 amino acid residues, which constitute three important structural domains, namely DNA binding domain (DNAbinding domain, DBD), ligand binding domain (ligand binding domain, LBD) and nitrogen terminal binding domain (N-terminal binding domain). domain, NTD). [0003] Under normal circumstances, AR exists in the cytoplasm and binds to heat body protein (Hsp90). When androgen (testosterone or dihydrotestosterone) appears, AR will releas...

Claims

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Application Information

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IPC IPC(8): C07F7/18C07D231/14
CPCC07B2200/07C07D231/14C07F7/1892C07F7/1804
Inventor 潘听听夏春光杨玉雷张爱明
Owner LIANYUNGANG RUNZHONG PHARMA CO LTD
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