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Method for forming double bonds between 1-position and 2-position during synthesis of finasteride and dutasteride

A technology of dutasteride and compound salt, which is applied in the field of drug synthesis, can solve the problems of difficult refining, product quality decline, long reaction time, etc., and achieve the effect of good product color, mild reaction conditions, economical and environmentally friendly process

Inactive Publication Date: 2016-06-08
赵建华 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Because the use equivalent of oxidizing reagent is quite large in the reaction, and m-chloroperoxybenzoic acid is very expensive again, the production cost is quite high
The price of peracetic acid is relatively low, but peracetic acid is an explosive product, and large-scale production has potential safety hazards
In these two patents at the same time, the solvent THF is not a good solvent for the reaction raw material iodide, saturated NaHCO 3 The addition of aqueous solution further reduces the solubility of iodides. The reaction is carried out in a heterogeneous system. The reaction time is long, and the raw materials are difficult to fully convert, resulting in a decline in the quality of the final product and difficulty in refining. This problem is more prominent when the scale of the reaction is enlarged.

Method used

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  • Method for forming double bonds between 1-position and 2-position during synthesis of finasteride and dutasteride
  • Method for forming double bonds between 1-position and 2-position during synthesis of finasteride and dutasteride
  • Method for forming double bonds between 1-position and 2-position during synthesis of finasteride and dutasteride

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Experimental program
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Effect test

Embodiment 1

[0034] The synthesis of embodiment 1 dihydrofinasteride iodide

[0035] Under the protection of nitrogen atmosphere, 30 g of dihydrofinasteride was dissolved in 300 ml of dry dichloromethane, and then 36 ml of dry N,N,N,N-tetramethylethylenediamine was added. The reaction mixture was cooled to 0°C, and 20.3 ml of trimethylchlorosilane was added. A white ammonium salt precipitate then precipitated out and the reaction mixture was stirred for an additional 20 minutes. The 24.4 g of iodine was added in three additions at 10-minute intervals. Stirring was continued for 1 hour at 0 to 5°C until the reaction of dihydrofinasteride was complete. The reaction was followed by 50 ml of 10% Na 2 SO 3The solution was quenched with 50 ml of saturated sodium chloride solution. After adding 50 ml of toluene to the separated organic phase, it was concentrated to 60 ml under reduced pressure at less than 40°C. 150 ml of petroleum ether was slowly added dropwise to the above stirred concen...

Embodiment 2

[0037] The synthesis of embodiment 2 dihydrofinasteride iodide

[0038] Under the protection of nitrogen atmosphere, 10.00 g of dihydrofinasteride was dispersed in 100 ml of dry toluene, and then 12.0 ml of dry N,N,N,N-tetramethylethylenediamine was added. The reaction mixture was cooled to 0°C, and 6.76 ml of trimethylchlorosilane was added. Dihydrofinasteride was gradually dissolved, and a white ammonium salt precipitate was precipitated out, and the reaction mixture was stirred for 30 minutes. 8.14 grams of iodine was added three times every 20 minutes. Stirring was continued at 0 to 5°C for 2 hours until the reaction of dihydrofinasteride was complete. The reaction was then quenched with 50 mL of 10% Na2SO3 solution. Stirring was continued for about 1 hour, and the product slowly precipitated out from the reaction mixture. Subsequently, 50 milliliters of petroleum ether was added dropwise to the reaction mixture to fully precipitate the product. Stirring was continued...

Embodiment 3

[0040] The synthesis of embodiment 3 dihydrodutasteride

[0041] Dissolve 16.65 g of 3-keto-4-aza-5α-androst-17β-carboxylate methyl ester in 250 ml of dichloromethane, and add 18.95 ml of boron tribromide dropwise under cooling with room temperature water (25°C) . Stirring was continued at room temperature for 20 minutes to obtain a clear brown solution. 19.5 ml of 2,5-bis(trifluoromethyl)aniline was added to the above solution under cooling with water at room temperature (25°C). The reaction was heated to 50 °C and stirred overnight. After the reaction solution was cooled to room temperature, 50 milliliters of water was slowly added, and the hydrogen bromide gas generated was introduced into Na 2 CO 3 in aqueous solution. Continue to add 200 ml of water until all solids are dissolved and two clear phases are obtained. After the dichloromethane organic phase of the lower layer was separated and washed with 200 ml of water and 200 ml of saturated brine, anhydrous Na 2 SO...

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Abstract

The invention provides a method for forming double bonds between the 1-position and the 2-position during synthesis of finasteride and dutasteride. According to the process, a dihydrogen finasteride iodide and a dihydrogen dutasteride iodide are oxidized by oxone for systhesis of finasteride and dutasteride, and the method has the characteristics that reaction operation is simple and convenient, raw materials are low in price and easy to obtain, and the yield and the purity are high. In particular, oxone is non-toxic, stable, easy to operate and more suitable for large-scale industrial production, and reagents which are harmful to the environment and high in price are avoided. The method can be further applied to forming of double bonds between the 1-position and the 2-position of an intermediate in other finasteride and dutasteride processes. The invention further provides a synthesis method of dihydrogen dutasteride; according to the method, a corresponding ester raw material has a one-pot reaction with 2,5-bis(trifluoromethyl)aniline under the activation of boron tribromide, and dihydrogen dutasteride with the yield of 93% is obtained.

Description

technical field [0001] The invention relates to a drug synthesis method for benign prostatic hyperplasia. In particular, it relates to a synthesis method of finasteride and dutasteride, and belongs to the technical field of drug synthesis. Background technique [0002] Finasteride (Finasteride), trade name Proscar (Proscar), Baofazhi (Propecia) are effective drugs for the treatment of senile benign prostatic hyperplasia (BPH) and male hair loss. The pathogenesis of this type of disease is closely related to dihydrotestosterone (DHT). As a type II 5α reductase inhibitor, finasteride can effectively inhibit the conversion of testosterone to dihydrotestosterone. Dutasteride, trade name Avodart, developed by GSK, has similar therapeutic effects but is used in lower doses. [0003] [0004] The process of producing finasteride and dutasteride from pregnenolone has been quite mature after decades of development. Processes starting from the cheaper and readily available 4-an...

Claims

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Application Information

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IPC IPC(8): C07J73/00
Inventor 赵建华樊怡林
Owner 赵建华
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