Method for synthesizing 6-methyl-17alpha-acetoxyl-19-norpregnane-4,6-diene-3,20-diketone

A technology of acetoxyl and norpregnant, applied in the field of drug synthesis, can solve problems such as difficulty in obtaining, and achieve the effects of simplified operation, reduced production cost and high yield

Active Publication Date: 2011-07-27
黄云生 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this starting material is very difficult to obtain. At home and abroad, it mainly relies on the semi-synthesis of tuber plant resources, and a total of 15 steps of reaction

Method used

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  • Method for synthesizing 6-methyl-17alpha-acetoxyl-19-norpregnane-4,6-diene-3,20-diketone
  • Method for synthesizing 6-methyl-17alpha-acetoxyl-19-norpregnane-4,6-diene-3,20-diketone
  • Method for synthesizing 6-methyl-17alpha-acetoxyl-19-norpregnane-4,6-diene-3,20-diketone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] 1. 17α-ethynylestradiol-3-methyl ether (2)

[0022] Put 60 grams of potassium tert-butoxide powder into a 3-liter reaction flask, add THF (1.4 L), pass acetylene gas into the reaction flask until saturated, cool to 0° C., and pass acetylene gas for 30 minutes. Add estrone alcohol-3-methyl ether (100g, 0.35mol), and stir the reaction solution at room temperature for 1 hour, add saturated aqueous ammonium chloride solution, separate the organic layer, extract the aqueous layer with tetrahydrofuran, combine the organic phases, and wash with saturated chlorine Wash with sodium chloride water, concentrate part of the organic solvent, pour it into ice-water, filter the precipitated solid, and obtain 105 g of 17α-ethynylestradiol-3-methyl ether after drying, the yield is 97%, and TLC shows one point, It can be directly used in the next reaction.

[0023] 2. 17α-ethynyl-17β-hydroxy-19-desmethylandrost-4-en-3-one (3)

[0024] Under the cooling of dry ice-acetone, 2kg of liquid...

Embodiment 2

[0036] 1. 17α-ethynylestradiol-3-methyl ether (2)

[0037] Put 60 grams of potassium tert-butoxide powder into a 3-liter reaction flask, add THF (1.4 L), pass acetylene gas into the reaction flask until saturated, cool to -10°C, and pass acetylene gas for 30 minutes , add estrone alcohol-3-methyl ether (100g, 0.35mol), the reaction solution was stirred at room temperature for 1 hour, added saturated ammonium chloride aqueous solution, the organic layer was separated, the aqueous layer was extracted with tetrahydrofuran, the combined organic phase was washed with saturated Wash with sodium chloride water, concentrate part of the organic solvent, pour into ice-water, filter the precipitated solid, and obtain 105 g of 17α-ethynylestradiol-3-methyl ether after drying, the yield is 96%, and TLC shows one point , which can be directly used in the next reaction.

[0038] 2. 17α-ethynyl-17β-hydroxy-19-desmethylandrost-4-en-3-one (3)

[0039] Under the cooling of dry ice-acetone, 2kg...

Embodiment 3

[0051] 1. 17α-ethynylestradiol-3-methyl ether (2)

[0052] Put 60 grams of potassium tert-butoxide powder into a 3-liter reaction flask, add THF (1.4 L), pass acetylene gas into the reaction flask until saturated, cool to -5°C, and then pass acetylene gas for 30 minutes , adding estrone alcohol-3-methyl ether (100g, 0.35mol), the reaction solution was stirred at room temperature for 1 hour, adding saturated aqueous ammonium chloride solution, the organic layer was separated, the aqueous layer was extracted with tetrahydrofuran, the combined organic phase was washed with saturated After washing with sodium chloride water, after concentrating part of the organic solvent, pour it into ice-water, filter the precipitated solid, and obtain 105 grams of 17α-ethynylestradiol-3-methyl ether after drying, the yield is 98%, and TLC shows one point , which can be directly used in the next reaction.

[0053] 2. 17α-ethynyl-17β-hydroxy-19-desmethylandrost-4-en-3-one (3)

[0054] Under the...

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Abstract

The invention relates to a method for synthesizing 6-methyl-17alpha-acetoxyl-19-norpregnane-4,6-diene-3,20-diketone. The method comprises the following steps: 1) reacting acetylene with estrone-3-methyl ether so as to obtain 17alpha-acetenyl estrone-3-methyl ether; 2) carrying out Birich reaction at a low temperature; 3) carrying out alkene etherification on the product obtained in the step 2); 4) carrying out a Vilsmeier reaction on the product obtained in the steps 3); 5) reacting the product obtained in the step 4) with benzene sulfenyl chloride; 6) reacting the product obtained in the step 5) with sodium methoxide and trimethyl phosphate; 7) reducing the formoxyl at the 6-position of the product obtained in the step 6); and 8) reacting the product obtained in the step 7) with Pd-C/cyclohexene, then reacting with acetic oxide so as to obtain the target product 6-methyl-17alpha-acetoxyl-19-norpregnane-4,6-diene-3,20-diketone. By using the method, the operation is simplified, and theproduction cost is reduced; and the reactions involved in the invention are simple to operate, and the yield is high.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular, the invention relates to a method for synthesizing 6-methyl-17α-acetoxy-19-norpregna-4,6-diene-3,20-dione. Background technique [0002] 6-Methyl-17α-acetoxy-19-norpregna-4,6-diene-3,20-dione is a new type of high-efficiency oral progestin, which has good contraceptive effect, small side effects and easy to use Convenience, safety and other features. 6-methyl-17α-acetoxy-19-norpregna-4,6-diene-3,20-dione was researched and developed by Theramex Company and was launched in France in 1985. In western countries, 6-methyl-17α-acetoxy-19-norpregna-4,6-diene-3,20-dione has been widely used as the fourth-generation contraceptive. In addition, 6-methyl-17α-acetoxy-19-norpregna-4,6-diene-3,20-dione has uterine displacement (Chinese Pharrnacological Bulletin 2004 Nov; 20(11): 1215-7 ), it has a good effect on reversing the multidrug resistance of breast cancer drug-resistant cell lines (Chin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J7/00
Inventor 黄云生夏秋黄华
Owner 黄云生
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