Pregnenes—

ACTH = adrenocortico-trophic hormone T4 = thyroxine T3 = triiodothyronine E, = estradiol T = testosterone I7,20/IP = 17,20/1-dihydroxy-4-pregnen-3-one KT = Il-ketotestosterone VTG = vitellogenin. 

When applied to A -pregnenes, 17a,20-glycols are produced exclusively, because of rear-side attack by the reagent. 

Oxime 26 was prepared from 5,ll-dihydro-dibenzo[a,d]cyclohepten-10-one. The Hoch-Campbell reaction of 26 with 3-dimethylaminopropylmagnesium bromide produced aziridine 27 in 46% yield after acidic workup. Extension of the Hoch-Campbell reaction to steroids has also been reported. Thus, treatment of 3(3-hydroxy-5-pregnen-20-one oxime (28) with methylmagnesium iodide furnished a mixture of diastereomers, 20ot/20P,21-imino-20-methyl-5-pregnen-3P-ol (29) in a 50% combined yield and a 3 1 ratio. On the other hand, homo-adamantan-4-one oxime (30) was transformed to homo-adamantano[4,5-b]-2 -ethylaziridine (31) in 76% yield upon the action of... 

Preparation of 9a-Bromo-110,17a 1 Trihydroxy-16 -Methyl-4-Pregnene-3,20-Dione 21-Acetate To a mixture of 620 mg of 17a,21-dihydroxy-16/3-methyl-4,9(11 )-pregnadiene-3,20-dione 21-acetate and 330 mg of N-bromosuccinimide in 10 ml of dioxane and 3.2 ml of water cooled to 10°C was added 1.8 ml of cold 1 M aqueous perchloric acid. The mixture was stirred at 15°C for 3 hours. Excess N-bromosuccinimide was destroyed by addition... 

Preparation of 9, 11 -Epoxy-17a-21 -Dihydroxy-16 -Methyl-4-Pregnene-3 0-Dione 21-Acetate To a stirred solution of 100 mg of the 9a-bromo-11(3,17a,2Ttrihydroxy-16 3-methyl-4-pregnene-3,20-dione 21-acetate in 3 ml of tetrahydrofuran and 1 ml of methanol under nitrogen was added 1.02 ml of 0.215 N methanolic sodium methoxide. After 10 minutes at 25°C, 0.2 ml of acetic acid was added and the methanol removed in vacuo. The residue was acetylated with 1.00 ml of pyridine and 0.5 ml of acetic anhydride at 60°C for 70 minutes. The mixture was taken to dryness in vacuo, water added, and the product extracted into chloroform. The residue was crystallized from ether-acetone to give pure 9(3,11 (3-epoxy-17a,21-dihydroxy-16(3-methyl-4-pregnene-3,20-dione 21-acetate. 

Preparation of 9a-Fluoro-110,17a,21-Trihydroxy-160-Methyl-4-Pregnene-3,2O-Dione 21-Acetate To a solution of 200 mg of 9(3,11(3-epoxy-1 7a,21-dihydroxy-16(3-methyl-4-pregnene 3,20-dione 21-acetate in 2 ml of chloroform and 2 ml of tetrahydrofuran in a polyethylene bottle at -60°C was added 2 ml of a 2 1 (by weight) mixture of anhydrous hydrogen fluoride and tetrahydrofuran. After 4 hours at -10°C the mixture was cooled to -60°C and cautiously added to a stirred mixture of 30 ml or 25% aqueous potassium carbonate and 25 ml of chloroform kept at -5°C. The aqueous phase was further extracted with chloroform and the latter phase washed with water and dried over magnesium sulfate. The residue on crystallization from acetone-ether gave pure 9a-fluoro-11(3,17a,21-trihydroxy-16(3-methyl-4-pregnene-3,20-dione 21-acetate. 

Preparation of 9a-F uoro-11, 17a,21 -Trihydroxy-16 Methy -1,4-Pregnadiene-3,20-Dione 21-Acetate 100 mg of 9a-f uoro-11(3,17a,21-trihydroxy-16(3-methyl-4-pregnene-3,20-dione 21-acetate was treated with selenium dioxide to produce the corresponding 9a-fluoro-11(3, 17a,21-trihydroxy-16(3-methyl-1,4-pregnadiene-3,20-dione 21-acetate. Alternately, Bacillus sphaericus may be utilized. 

Chemical Name 17a,21-dihydroxv4-pregnene-3,11,20-trione-21-acetate Common Name —... 

A solution of 1.0 g of A -3,11-diketo-20-cyano-21-acetoxy-pregnene in 10 cc of benzene is treated with 1.0 g of osmium tetroxide and 0.43 g of pyridine. After standing at room temperature for 18 hours, the resulting solution is treated successively with 50 cc of alcohol, and with 50 cc of water containing 2.5 g of sodium sulfite. The mixture is stirred for 30 hours, filtered, and the filtrate acidified with 0.5 cc of acetic acid and concentrated to small volume in vacuo. The aqueous suspension is then extracted four times with chloroform, the chloroform extracts are combined, washed with water and concentrated to dryness in vacuo. Recrystallization of the residue from acetone gives 3,11,20-triketo-17(a)-21-dihydroxy-pregnane MP 227° to 229°C. This compound is then treated with acetic anhydride and pyridine for 15 minutes at room temperature to produce 3,11,20-triketo-17(a)-hydroxy-21-acetoxy-pregnane or cortisone acetate. 

The organic phase is dried over sodium sulfate and then concentrated to dryness. 1.62 g of the thus obtained crude 1,2a-methylene-6,7a-oxido-A -pregnene-17a-ol-3,20-dione-17-acetate are dissolved in 109 cc of glacial acetic acid. This solution is then saturated at room temperature with hydrogen chloride gas and stored for 20 hours. It is then diluted with methylene chloride and washed with water until neutral. 

Methyl-60 ,90fBacterium Bacillus lentus Valeric acid chloride... 

The above crude bromohydrin was mixed with 2.5 grams of potassium acetate and 60 cc of acetone and refluxed for 6 hours, at the end of which the acetone was distilled, water was added to the residue and the product was extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. Recrystallization of the residue from methanol furnished 800 mg of the 16,21-diacetate of 6o-fluoro-9(3,11(3-oxido-A -pregnene-16o,l7a,2l-triol-3,20-dione with MP 120° to 124°C by chromatography of the mother liquors on silica gel there was obtained 180 milligrams more of the same compound with MP 117° to 119°C. The analytical sample was obtained by recrystallization from methanol it showed MP 125° to 127°C. 

Chemical Name 21-Chloro-9tt-fluoro-A -pregnene-11/3,16CK,17CK-trlol-3,20[Pg.749]

IB) 21-Chloro-90i-fluoro- -pregnene-11 160l,170i-triol-3,2Q-d ane 16,17-acetonlde A solution of 200 mg of the acetonide 21-mesylate from part (A) and 900 mg of lithium chloride in 25 ml of dimethylformamide is kept at 100°C for 24 hours. The mixture is poured on ice, extracted with chloroform and the chloroform extract washed with water and dried over sodium sulfate. Evaporation of the solvent in vacuo furnishes the crystalline chloride, which after recrystallization from acetone-ethanol has a melting point about 276°C to 277°C. 

A solution of 0.144 g of the 3-ethy ene glycol ketal of 5Q ,1 1/3,17Q ,21-tetrahydroxy-6/3-fluoro-16Q -methylallopregnane-3,20-dione 21-acetate in 12 ml of chloroform and 0.1 ml of absolute alcohol was cooled to -10°C in an ice-salt bath and a stream of anhydrous hydrochloric acid was gently bubbled through the solution for 2.5 hours while the temperature was maintained between -5°Cand -15°C. The solution wasthen diiuted with 25 ml of chloroform, washed with dilute sodium bicarbonate and water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure at BO t or less to give 60 -fluoro-11/3, 170 ,21 -trihydroxy-16Q -methyl-4-pregnene-3,20-dione 21-acetate. 

Dihydroxy-11 3,1 7a-iodo-21 -dioxo-3,20-pregnene-4 Manufacturing Process... 

There are then added 285 g (0.603 mol) of dihydroxy-11 3,1 7a-iodo-21 -dioxo-3,20-pregnene-4 and the mixture is brought up to the acetone reflux for two hours. The solvent is eliminated by distillation under vacuum until there is obtained a syrupy residue which Is poured into 10 liters of iced water. The insoluble part is filtered and dried under vacuum. 

Pancuronium bromide 16a 1 -Diacetoxy-11/3,17a-dihydroxy-9a-fluoro-4-pregnene-3,20-dione Triamcinolone diacetate la 5-Diacetoxyprecholecalciferol Calcitrlol... 

---