Gestodene

Gestodene(SHB 331;WL 70) is a progestogen hormonal contraceptive.Target: Estrogen Receptor/ERRGestodene is androgenically neutral, meaning that contraceptive pills containing gestodene do not exhibit the androgenic side effects (e.g. acne, hirsutism, weight gain) often associated with second-generation contraceptive pills, such as those containing levonorgestrel. When 40 micrograms of gestodene was taken, six out of seven women did not ovulate, and one out of seven had a cycle with lutea

Method 1: Use 18-methylestro-4-ene-3, 17-dione as raw material. In a 20L glass fermentor, 15L sterile solution is filled. The composition of the solution is as follows: 3% glucose, 1% corn flour, 0.2% sodium nitrate, 0.1% potassium dihydrogen phosphate, 0.2% dipotassium hydrogen phosphate, 0.05% magnesium sulfate, 0.002% ferrous (II) sulfate and 0.05% Potassium chloride. Implanted 250 ml of Penicillium (ATCC 10490) cultured in shaking flasks for 72 h, and cultured at 30° C. with stirring and blowing air for 24 h. Under sterile conditions, 1.8L of this culture solution was transferred to a 50L fermentor containing 30L of the same composition as the above sterile solution. After culturing for 12h, 120g of Tween-80 salt of 18-methylestro-4-ene-3, 17-dione was suspended in a solution of 2L of distilled water, and cultured for another 70h under the same conditions. It is then extracted with methyl isobutyl ketone, and the extract is concentrated in vacuo. After the residue was reacted with activated carbon, it was recrystallized from ethyl acetate to obtain 97.8 g of compound (I) with a yield of 77.2% and a melting point of 179.9°C. 250 g (827 mmol) of compound (I) was dissolved in 704 ml of pyridine, and at 0° C. and 10 min, 77.5 ml of methanesulfonyl chloride was added dropwise, and the reaction was carried out for 3.5 hours. Add 350 ml of dimethylformamide and 283 g of anhydrous sodium acetate, and stir at room temperature for 20 h under an argon atmosphere. The reaction solution was poured into ice water, and the deposited precipitate was collected by filtration, washed with water, and dried in vacuo. The obtained 212 g of crude product was dissolved in 1500 ml of ethyl acetate and 0.4 ml of pyridine, and 21.0 g of activated carbon was added to decolorize. Concentrate to 420mL and place at 0°C for crystallization. Filtration yielded 188 g of compound (II), yield 80%, melting point 156.9°C (recrystallized from acetone-hexane). To a mixed solution of 240 ml of tetrahydrofuran and 60 ml of hexane, pass human acetylene at -70°C for 15 min. Under the protection of argon, a solution of 180 ml (288 mmol) 15% n-butyllithium (hexane solution) in 180 ml tetrahydrofuran was added dropwise. After 10 minutes, a solution of 30.0 g (106 mmol) of compound (II) in 210 ml of tetrahydrofuran was added. Under -70 ℃ and stirring, continue to pass acetylene for 1h. 150ml of methanol and 45ml of concentrated hydrochloric acid were added, and after stirring at room temperature for 1h, 375ml of water was added. After concentration in vacuo, the crystals were placed at 0°C. Filter, wash with water, and dry. Chromatography with 0-50% ethyl acetate/hexane and recrystallization with ethyl acetate gave 18.4 g of gestodene, yield 56%, melting point 198°C. Method 2: 18-methyl estradiol-4-ene-3, 17-dione is also used as the raw material. In the same way as method 1, the hydroxyl group is introduced through fermentation to obtain the compound (I). 100 g (330 mmol) of compound (I) was dissolved in 350 ml of pyridine, and 200 ml of acetic anhydride was added dropwise. After the completion of the reaction for another hour. The reaction solution was poured into ice water, and the deposited precipitate was collected by filtration, washed with water until neutral, and dried under vacuum at 50°C to obtain 109.3 g of compound (III) in 96% yield. After recrystallization from acetone-hexane, the melting point was 165.5°C. 48.0 g (139 mmol) of the compound (III) and 4.8 g of pyridine tosylate salt were dissolved in 400 ml of 2, 2-dimethoxypropane and stirred under reflux for 6 h. Slowly cool to -20°C. After 4h, the crystals were collected by filtration, washed with a small amount of cold methanol several times, and dried in vacuo to obtain 42.0g of compound (IV) in 84% yield. After recrystallization from acetone-hexane, the melting point is 194°C. To a solution of 200 ml (320 mmol) of n-butyl lithium (15% hexane solution) in 400 ml of anhydrous tetrahydrofuran, pass acetylene at 0°C for 30 min. The lithium acetylene solution thus obtained was added dropwise to a solution of 20.0 g (56 mmol) of compound (IV) in 500 ml of anhydrous tetrahydrofuran under the protection of argon at 0°C. Slowly add 80ml of semi-concentrated hydrochloric acid and stir at 0°C for 10min. Extract with ethyl acetate, wash the extract with water, dry, and decolorize with activated carbon. Use about. 50ml of methanol was recrystallized to obtain 13.0g of pregnenedione, yield. 75%, melting point 197°C. Method 3: Use ketal or thioketal on the 3-position carbonyl group in compound (I), react with lithium acetylide or magnesium acetylene bromide to introduce acetylene, and then remove the ketal to obtain gestodene. 18-Methylestrone-4-ene-3, 17-dione is introduced into the hydroxyl group at the 15 position through selective oxidation; it reacts with 2, 2-dimethylpropanediol to form a ketal at the 3 position to protect it; React with trimethylsilyl chloride or acetic anhydride to form trisiloxy or acetoxy at the 15th position; then react with acetylene magnesium bromide to introduce an ethynyl group at the 17th position, and then hydrolyze and dehydrate under the action of oxalic acid to obtain pregnancy Dienone. It can also be dehydrated to form olefinic bonds before introducing ethynyl groups. 7.5g of magnesium and 24ml of bromoethane are reacted in 140ml of tetrahydrofuran to obtain ethylmagnesium bromide. Then 300 ml of tetrahydrofuran was added, and acetylene was passed into the reaction solution for about 40 minutes under cooling in an ice bath. 5g of 18-methyl-3, 3-(2, 2-dimethyl-1, 3-propylenedioxy)-5, 15- and -5(10), 15-estradiene- A solution of 17-one in 200 ml of tetrahydrofuran. After the addition, stir at room temperature for 2h. Carefully add ammonium chloride solution and dilute with ether. The separated organic layer was continuously washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Chromatography with silica gel and 2.5% to 2.9% acetone/hexane yielded 3.1g of 17α-ethynyl-18-methyl-3, 3-(2, 2-dimethyl-1, 3-propylenediene Oxygen)-5, 15- and -5(10), 15-estradiene-17β monool. The compound was stirred vigorously with 70 ml methanol, 14 ml water and 2.3 g oxalic acid for 40 min. After the reaction solution was diluted with ether, it was washed with water until neutral and dried. Recrystallized with acetone-hexane to obtain 1.4g of gestodene, melting point 154 ℃.

Estrogens and progestins are female hormones. They are produced by the body and are necessary for the normal sexual development of the female and for the regulation of the menstrual cycle during the childbearing years. Gestodene is a progestogen hormonal