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The preparation method of etonogestrel and desogestrel intermediate

A technology of etonogestrel and desogestrel, applied in the directions of steroids, organic chemistry, etc., can solve problems such as inability to obtain target products, and achieve the effects of easy industrialization, mild reaction conditions, and simple operation.

Active Publication Date: 2020-09-04
SHANGHAI GONGTUO PHARMA & CHEM IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After experimental research and verification, it was found that this method has problems such as a large number of configuration inversions of raw materials during the 1,2 addition reaction and the inability to obtain the target product by enolization of raw materials.

Method used

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  • The preparation method of etonogestrel and desogestrel intermediate
  • The preparation method of etonogestrel and desogestrel intermediate
  • The preparation method of etonogestrel and desogestrel intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] The preparation of compound (3):

[0063] Pre-cool the system temperature to -50°C in a 500mL four-neck flask equipped with a thermometer, constant pressure dropping funnel, reflux condenser, and magnetic stirring in a dry nitrogen filled flask, then pass through barium oxide dry ammonia gas, and collect about 200mL After liquid ammonia, metal lithium particles (1.04 g; Fw: 6.94; 150.00 mmol) were gradually added in batches, and the system turned dark blue during the addition process. Then the compound of formula (2) (5.0g; Fw: 330.42; 15.13mmol) was dissolved in a mixed solvent of tetrahydrofuran and tert-butanol (50 ml of tetrahydrofuran, 10 ml of tert-butanol), and then the solution was slowly added dropwise to the system During the dropwise addition, the temperature of the system was maintained at -40°C. After the dropwise addition was completed, the system continued to stir for 0.5h.

[0064] After the reaction is complete, add solid ammonium chloride to the syste...

Embodiment 2

[0066] Preparation of compound (4):

[0067] Add 100 ml of methanol, 10.00 g of compound (3) and 5 ml of concentrated hydrochloric acid into a dry 250 mL three-neck flask equipped with a thermometer, a reflux condenser, and a magnetic stirrer filled with nitrogen, and then stir in the system at 20-25 °C for 1.5 h;

[0068] After the reaction is complete, add saturated sodium bicarbonate solution to the reaction system, adjust the pH to neutral, then add 100 milliliters of water, continue to stir until the crystals are completely precipitated, and then go through steps such as filtration, washing with water, and vacuum drying to obtain an off-white solid 9.04 grams, molar yield: 90%, HPLC content greater than 98.0%.

Embodiment 3

[0070] Preparation of compound (5):

[0071] Add 100 ml of methanol, compound (4) (10.00 g; Fw: 300.39; 33.30 mmol), tetrahydropyrrole (2.37 g; Fw: 71.12; 33.30mmol), then heated up to 50°C and stirred for 1.0h, a large amount of precipitation occurred;

[0072] Then the system was cooled to -20°C, and an aqueous solution of hydrobromic acid (5.61g, 48%, Fw: 80.91, 33.30mmol) was dissolved and slowly added dropwise to the reaction system;

[0073] After the dropwise addition, react at -20°C for 0.5h, then add 100ml of water, continue to stir until the crystals are completely precipitated, and then go through steps such as filtration, washing with water, and vacuum drying to obtain 13.67 grams of light yellow solid, molar yield: 94.5%, HPLC The content is greater than 97.0%.

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Abstract

The invention discloses a preparation method for an etonogestrel and desogestrel important intermediate. The preparation method is characterized in that the intermediate is prepared from a compound shown as a formula (2) which is taken as an initial raw material. The preparation method obtains the object product in high yield through five steps, and the whole process is mild in reaction condition,low in danger and simple in operation. The preparation method is much better than known literature processes no matter from respects of atomic economy, safety and price cost or the respect of storageand transportation, and the problems of high toxicity and non-stabilization of used reagents and intermediate products and severe pollution on environment of by-products can be avoided. The prepareddesogestrel and etonogestrel important intermediate (1) is mild in reaction condition, relatively complete in reaction, high in chemical selectivity and high in reaction yield, and solvents can be recycled, so that convenient industrial implementation can be realized. Reaction general formulas are shown as follows.

Description

technical field [0001] The invention relates to a new process for preparing desogestrel and etonogestrel intermediates. Background technique [0002] Desogestrel and etonogestrel are a new generation of powerful progestogens. They have strong affinity to progesterone receptors after metabolism in the human body, and have reliable ovulation inhibition effects. They have low affinity to androgen receptors, so they have only slight androgen Hormone and protein anabolic activity, no androgen activity, but strong anti-estrogen activity, no adverse effects on lipid metabolism, and little impact on human physiological metabolism. Desogestrel and etonogestrel are the third-generation new contraceptive drugs, and their structural formula is as follows: [0003] [0004] At present, in the existing technology, the key step is the key compound (1) (its chemical name is: 13β-ethyl-11-methylene-17β-hydroxyl-4-estren-3-one, another name is: 13β -Ethyl-11-methylene-estr-4(5)-en-3-one-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J1/00
CPCC07J1/00
Inventor 施彬建李得福杨文棋
Owner SHANGHAI GONGTUO PHARMA & CHEM IND
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