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Preparation method of dutasteride

A dutasteride, temperature-maintaining technology, applied in steroids, organic chemistry, etc., can solve the problems of low reaction yield, unfavorable product purification, poor solubility, etc., to improve reaction yield, stable and controllable quality , the effect of mild reaction conditions

Active Publication Date: 2014-05-07
CHINA RESOURCES SAIKE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] After experimental verification, the disadvantage of this route is that the solubility of compounds (1) and (10) is all poor, and they are not easily soluble in conventional solvents such as alcohol solvents, ester solvents, and ether solvents. Carry out 1, The 2-position dehydrogenation and amidation reactions will affect the progress of the reaction, the raw materials are difficult to react completely, and the reaction yield is lower than 50%, which is not conducive to the purification of the product, and is not conducive to large-scale industrial production
[0009] The amidation methods of the existing technology are mainly the thionyl chloride method and the oxalyl chloride method. These methods are used in the preparation of dutasteride, which will lead to incomplete reaction of raw materials, low yield, and the solvent used in the reaction system Such as tetrahydrofuran, toluene, dichloromethane etc. are all poor to the dissolubility of compound (1) or (10), are unfavorable for the carrying out of reaction

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0038] Embodiment 1, formula (2) compound

[0039] Dissolve 5g of compound (1) in 50mL of pyridine, add 2mL of phosphorus oxychloride, keep the temperature below 40°C, react for 1h, add 5mL of 2,5-bis(trifluoromethyl)aniline, and react for 12h. Cool to room temperature, dilute with water, filter with suction, and dry. Dissolve dichloromethane, decolorize with activated carbon, filter with suction, spin off dichloromethane, and recrystallize from ethyl acetate to obtain 7.2 g of compound (2).

Embodiment 2

[0040] Embodiment 2, dutasteride

[0041]4.5g of compound (2) was dissolved in 90mL of toluene, 2.1g of DDQ was added, 10mL of BSTFA was added dropwise at room temperature, and the reaction was completed at room temperature for 8h after the dropwise reaction, and then the temperature was raised to 150°C for 18h. Cool, spin off toluene, add 50mL 5% sodium bisulfite aqueous solution and 70mL dichloromethane, stir, filter with suction, separate the dichloromethane, wash 3 times with 5% NaOH, wash 3 times with saturated saline, decolorize with activated carbon for 1 hour, and filter with suction , decolorized on silica gel for 1 h, filtered with suction, removed the solvent by spin, recrystallized from ethyl acetate, and recrystallized from acetonitrile again to obtain 3.2 g of dutasteride (3).

[0042] [M+H] + =529; [M+CH 3 CN+H] + =570;H 1 NMR (CDCl 3 )δ: 0.8(s, 3H, 18-CH 3 ), 1.0 (s, 3H, 19-CH 3 ), 2.35(t, 1H, 17-H), 3.35(q, 1H, 5α-H), 5.5(s, 1H, CONH), 5.8(d, J=1.5, 1H,...

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Abstract

The invention relates to a preparation method of dutasteride. The method comprises the following steps: preparing acyl chloride from a compound shown in the formula (1), performing an amidation reaction with 2,5-bis(trifluoromethyl)aniline to obtain a compound shown in the formula (2), and performing 1,2-dehydrogenation to obtain dutasteride shown in the formula (3). The preparation method provided by the invention has the following advantages: the reaction conditions are mild, the intermediate of each step can be purified easily, and the quality is stable and controllable; the yield is higher, and the cost is low; and the method is suitable for industrial production. The formula (1) is shown in the description.

Description

technical field [0001] The invention belongs to the field of medicines, and relates to a preparation method of a compound, in particular to a preparation method of dutasteride. Background technique [0002] Benign prostatic hyperplasia (benign prostate hyperplasia, BPH) is a common chronic disease in middle-aged and elderly men. Exhausted. The clinically used drugs for the treatment of BPH mainly include finasteride and dutasteride. Dutasteride is a dual inhibitor of type I and type II 5α-reductase. Its therapeutic effect is better than that of finasteride, and its side effects are lower. It is expected to become a good drug for the treatment of BPH. The chemical name of dutasteride is: N-[2,5-bis(trifluoromethyl)phenyl]-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide , the structural formula is (3). [0003] There are many synthetic methods of dutasteride, first seen in the patent WO9507927A1, wherein the first route is shown as follows: with pregnenone acid (4) as the sta...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J73/00
Inventor 孙洁王俊杨琰
Owner CHINA RESOURCES SAIKE PHARMA
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