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Green synthetic method of highly pure dutasteride

A dutasteride, high-purity technology, applied in the pharmaceutical field, can solve problems such as difficult complete recovery, and achieve the effect of improving purity and refining efficiency

Active Publication Date: 2015-11-04
大道隆达(北京)医药科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Although the above-mentioned synthetic route can avoid the side reaction of chlorination in the finished product stage, it uses the highly toxic oxidant 2,3-bis, which is difficult to completely recover, in the construction of 1,2-ene bonds as in the synthetic method of first oxidation and then amination. Chlorine-5,6-dicyano-1,4-benzoquinone (DDQ), which makes its environmental pollution and toxic substance residue problems can not be ignored

Method used

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  • Green synthetic method of highly pure dutasteride
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  • Green synthetic method of highly pure dutasteride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1 (preparation of iodide)

[0047] Add (5α, 17β)-N-[2,5-bis(trifluoromethyl)phenyl]-3-oxo-4-azandrost-17-carboxamide (amination) 3.56 in a 200-liter reactor Kg and dichloromethane 110Kg, stir, add 3.12Kg of tetramethylethylenediamine under cooling, continue to stir and cool down to -10°C, add 2.2Kg of trimethylchlorosilane dropwise, slowly warm up to room temperature and stir for 2 hours. Cool down to -20~-15°C, add 2.9Kg of iodine in batches, and keep warm until the reaction is complete. Under cooling, add 10% sodium bisulfite solution to quench the reaction, let stand to separate the layers, extract the water layer with dichloromethane, combine the organic phases and wash with 5% hydrochloric acid and purified water successively until neutral, anhydrous Dry over sodium sulfate and concentrate to dryness under reduced pressure. The resulting residue was added to acetonitrile, beaten at room temperature, cooled and crystallized, filtered, and dried under re...

Embodiment 2

[0050] Embodiment 2 (preparation of dutasteride)

[0051] Put 6.84Kg of potassium tert-butoxide and 60Kg of N,N-dimethylformamide (DMF) into a 200-liter reactor, stir to dissolve, lower the temperature to -20~-10°C, and add the compound prepared in Example 1 dropwise. The mixed solution of iodide 4.00Kg and DMF20Kg, and insulation reaction to complete. After cooling, add acetic acid dropwise to quench the reaction, add sodium chloride solution for crystallization, filter and dry to obtain crude dutasteride.

[0052] Dissolve the above crude product in dichloromethane, wash with potassium carbonate solution and saturated sodium chloride solution until neutral, concentrate to dryness under reduced pressure, add acetonitrile to dissolve the obtained concentrate, add 2.5Kg hydrochloric acid to stir crystallization, filter, Wash with purified water, add dichloromethane to redissolve the filter cake, wash with purified water until neutral, separate liquids, stir and dry the obtaine...

Embodiment 3

[0053] Embodiment 3 (small scale preparation of iodide)

[0054] Add 300g of amide, 230g of triethylamine and 6L of dichloromethane into a 20-liter reactor, stir, cool down to 0°C, control the temperature at -25°C to 15°C, add 185g of trimethylchlorosilane dropwise, complete the addition, and raise the temperature to 15°C ℃ ~ 35 ℃ stirring reaction is complete, then lower the temperature to -25 ℃, add 200g of iodine in batches, and react at -15 ℃ ~ 0 ℃. After the reaction was completed, sodium thiosulfate solution was added to quench the reaction, and the liquid was separated after standing. The organic phase was washed with dilute hydrochloric acid and purified water successively, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The resulting residue was added into acetonitrile, crystallized, filtered, and dried under reduced pressure to constant weight to obtain 347 g of iodide, yield 91%, purity: 98.6%

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Abstract

The invention discloses a new green industrial preparation method of highly pure dutasteride. The method is realized through a synthetic route represented by a figure shown in the specification. The preparation method is adopted to construct a steroid 1,2-olefinic bond in order to avoid raw materials being harmful to environment and having large toxicity, and use of a severely toxic oxidant DDQ is thoroughly avoided from a reaction principle; and the method has the advantages of high efficiency, high purity, greenization, clean industrialization, strong maneuverability and high yield, and the total yield of a two-step reaction is greater than 80%. An iodo intermediate is purified to easily control the quality of finished dutasteride, the purity of the obtained dutasteride product is not smaller than 99.5%, the content of any single impurity does not exceed 0.1%, and medicinal demands are completely met.

Description

technical field [0001] The invention relates to the technical field of pharmacy, and describes a new industrial preparation method of dutasteride, which is widely used as a 5α reductase inhibitor for treating moderate and severe benign prostatic hyperplasia and the like. Background technique [0002] Dutasteride (Dutasteride) is a new dual inhibitor of 5α reductase, it can inhibit both 5α reductase 1 and 5α reductase 2, it is a specific competitive inhibitor of the two enzymes, can Forms a stable enzyme complex with 5α-reductase, effectively inhibiting the conversion of testosterone to dihydrotestosterone (DHT). Therefore, it is used for the treatment of benign prostatic hyperplasia patients with moderate and severe symptoms, and reduces the risk of acute urinary retention (AUR) and surgery. The drug has been marketed in many countries around the world since it was approved by the FDA in 2002, and it is more efficient than finasteride. [0003] The chemical name of dutaste...

Claims

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Application Information

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IPC IPC(8): C07J73/00
CPCC07J73/005
Inventor 周华明孟令桥田玉涛刘宏斌朱琳周英
Owner 大道隆达(北京)医药科技发展有限公司
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