DE1183500B - Process for the production of alpha, beta-methylene ketones of the steroid series - Google Patents

Description

Process for the production of α, ß-methylene ketones of the steroid series Among the ac, ß-methylene ketones of the steroid series, some representatives are therapeutic valuable properties known. Examples include 1,2a-methylene-d4, g-pregnadien-17oc-ol-3,20-dione-17-acetate, 1,2ca-methylen-d4-pregnen-17a-ol-3,20-dione-17-acetate, 1,2a-methylene-6-chloro-d4 # e-pregnadien-17a-ol-3,20-dione- 17-acetate, 16,17a-methylen-d4-pregnen-3,20-dione, 1,2oc-methylen-androstan-17ß-ol-3-one, 1,2oc-methylen-d4-androsten-17ß-ol-3-one and their 17-acetates.

For the preparation of such compounds, however, only technically unsatisfactory methods were available, such as, for. B. the processes of German patents 1 096 353, 1 072 991, 1 107 663 and 1096 902. These methods were based either on the addition of diazomethane to the corresponding α, ß-unsaturated ketones, followed by nitrogen elimination from the pyrazolines formed in this way, or on the splitting off of hydrogen halide from the corresponding ß-halomethyl ketones.

In the implementation of α, ß-unsaturated ketones, especially benzalacetophenone with dimethylsulfonium methylide (Tetrahedron Letters [1962], pp. 661 and 662) or with dimethylsulfoxonium methylide (Journ. Am. Chem. Soc., 84 [1962], pp. 867 and 868) recently a new method for the direct x, ß-methylenation of oc, ß-unsaturated Known ketones.

However, these methods appeared to target x; ß-unsaturated steroid ketones not to be easily transferable, as it is expressly stated in the latter work d 4-Cholestenon against Dimethylsulfoxoniummethylid had proven resistant.

It has now been found that, surprisingly, α, ß-unsaturated steroid ketones, which still carry a hydrogen atom on the ß-carbon atom, in particular the d 1-3-keto steroids and the d 18-20-keto steroids those observed with d 4-cholestenone Do not show resistance to the new methylenating agents mentioned. they react rather surprisingly smooth - with formation of the corresponding a, ß-methylene ketones, in particular the 1,2a-methylene-3-keto steroids or the corresponding 16,17a-methylene-20-keto steroids.

The reaction is carried out in such a way that one of the trimethylsulfonium or. Trimethylsulfoxonium salts (such as the halides, perchlorates, methyl sulfates) goes out, they in Dimethylsulfoxyd with bases, such as. B. potassium or sodium tertiary butoxide, Potassium or sodium methylate or ethylate or sodium hydride in solvents such as Dimethyl sulfoxide or dimethylformamide, to the sulfonium methylide or to the sulfoxonium methylide converts and this without isolation at temperatures of -40 to 100 ° C, preferably Reacts with the α, ß-unsaturated ketone at room temperature.

Example 1 3 g of trimethylsulphonium iodide are dissolved in 30 ml of absolute dimethylsulphoxide 0.4 g of sodium hydride are added under nitrogen and stirring. After 15 minutes it will be 3 g of d 1-5a-androsten-17β-ol-3-one acetate were added. It will be 1 hour at room temperature and stirred at 50 ° C for 1 hour. Excess sodium hydride is destroyed with alcohol. After pouring into ice water, filtering off, washing and drying, the precipitate becomes recrystallized from methanol-water and from ethyl acetate. 0.4 g of loc, 2a-methylen-5a-androstan-17ß-ol-3-one is obtained from m.p. 183.5 to 184/185 ° C.

Beisp.e, 12 1 g of trimethylsulfoxonium chloride in 20 ml of dimethylsulfoxide is mixed with 0.11 g of sodium hydride, kept under nitrogen for 15 minutes and then 1 g of 16,17-dehydropregnenolone is added. The mixture is stirred at room temperature for 1 hour and then at 50 ° C. for 1 hour. After adding methanol. poured into ice water, filtered off, washed and dried. 1.04 g of crude product-; 182/188 to 199 ° C. After recrystallization from methanol, 0.45 g of 16a, 17a-methylen-ds-pregnen-3ß-ol-20-one with a melting point of 205 ° to 207 ° C. are obtained.

Example 3 1 g of trimethylsulfoxonium iodide in 10 ml of dimethylsulfoxide is mixed with 0.11 g of sodium hydride, stirred for 15 minutes under a stick and then 1 g of androsta-1,4,6-trien-17β-ol-3-one is added. 1 hour will be. Room temperature and then stirred at 50 ° C for one hour. After adding methanol, it is poured into ice water, filtered off, washed and dried. After recrystallization from ethyl acetate-hexane, 0.6 g of la, 2a-methylenandrosta-4,6-dien-17β-ol-3-one with a melting point of 164 / 164.5 to 165.5 ° C. are obtained.

For analysis, the following is recrystallized from the same solvent: 170.5 / 171 to 172 ° C.

By working up the mother liquors, the yields can be as Incidentally, also in the preceding examples - still increase significantly.

EXAMPLE 4 1.3 g of trimethylsulfoxonium iodide are dissolved in 15 ml of dimethylsulfoxide and 0.13 g of sodium hydride are added under nitrogen. The mixture is stirred for 15 minutes under nitrogen and 1.85 g of d4 # 18-pregnadien-21-ol-3,20-dione acetate are added. The mixture is stirred for 3 hours at room temperature and 1 hour at 50 ° C., mixed with methanol, poured into ice water, the precipitate is filtered off, washed with water, dried and chromatographed on 100 g of silica gel. 501, ethyl acetate in methylene chloride elutes 16,17a-methylene-21, acetoxyprogesterone. After recrystallization from ethyl acetate, 0.41 g with a melting point of 154.5 / 155 to 156 ° C. is obtained.

Example s 2.6 g of trimethylsulfoxonium iodide are dissolved in 40 ml of dimethylsulfoxide dissolved and treated with 0.22 g of sodium hydride under nitrogen. The mixture is stirred for 15 minutes under nitrogen and then 3.3 g of d 1-5a-androsten-17ß-ol-3-one acetate are added. The mixture is stirred for a further 5 hours under nitrogen at room temperature, poured into ice water, the precipitate is filtered off, washed with water, dried and crystallized from hexane. 3 g of 1,2a-methylene-5a-androstane-17flol-3-one acetate are obtained. For analysis it is recrystallized from diisopropyl ether: mp 138.5 to 140.degree.

Example 6 0.66 g of trimethylsulfoxonium iodide are dissolved in 10 ml of dimethylsulfoxide, 57 mg of sodium hydride are added under nitrogen and the mixture is stirred at room temperature for 15 minutes. 1.02 g of 2-bromo-d 1-5a-androstan-17ß-ol-3-one acetate are added and the mixture is stirred for 5 hours at room temperature under nitrogen: it is precipitated with ice water, filtered off, washed with water and dried . 1.05 g of 2-bromo-1,2-methylene-5α-androstane-17β-ol-3-one acetate are obtained. For analysis, it is recrystallized from methanol and 0.46 g with a melting point of 162 to 163 ° C. is obtained. 30% sodium amide in benzene was added and the mixture was stirred at room temperature for 15 minutes. 3.3 g of 1-5α-androsten-17β-ol-3-one = acetate are added and the mixture is stirred for 5 hours at room temperature under nitrogen: it is precipitated with ice water and filtered off; washes with water and dries. By recrystallization. 1 g of 1,2α-methylene-5α-androstane-17β-ol-3-one acetate with a melting point of 128 ° to 113 ° C. is obtained from hexane. For analysis, it is recrystallized again from isopropyl ether and a product identical to that obtained in Example 6 is obtained. Example ? 2.6 g of trimethylsulfoxonium iodide are dissolved in 50 ml of dimethylsulfoxide under nitrogen. mixed with 0.29 g of sodium hydride and stirred for 15 minutes at room temperature. 3.1 g of 16-dehydroprogesterone are added and the mixture is stirred for 5 hours at room temperature under nitrogen. Then it is precipitated with ice water, filtered off, washed with water and dried. 3.2 g of crude 16,17a-methylene progesterone with a melting point of 176 ° to 180 ° C. were obtained. For analysis, it is recrystallized from ethyl acetate and 2.0 g of 16a, 17a-methylene progesterone with a melting point of 187.5 to 188 ° C. are obtained.

Example 8 2.6 g of trimethylsulfoxonium iodide are added in 50 ml of dimethylsulfoxide dissolved, under nitrogen with 0.6 ml Example 9 990 mg of trimethylsulfoxonium iodide dissolved in 20 ml of dimethyl sulfoxide, treated with 75 mg of sodium hydride under nitrogen and stirred until completely dissolved, about 15 minutes. 991 mg of d 1-5a-pregnen-1 are used 7ca-ol-3,20-dione is added and the mixture is stirred for 5 hours at room temperature under nitrogen. Then pour ice water, filter off, wash with water and dry. To Recrystallization from ethyl acetate gives 0.63 g of 1,2a-methylene-5a-pregnan-17nc-ol-3,20-dione from 227 to 237 ° C. For analysis, recrystallize from methanol-ethyl acetate: M.p. 233 to 237.5 ° C.

EXAMPLE 10 1.17 g of trimethylsulfoxonium iodide are dissolved in 25 ml of dimethylsulfoxide, 0.15 g of sodium hydride is added under nitrogen and the mixture is stirred until it is completely dissolved (about 20 minutes). 1.64 g of 2-chloro-d 1-5a-androsten-17ß-ol-3-one acetate are added and the mixture is stirred for 5 hours at room temperature under nitrogen. It is precipitated with ice water, filtered off, washed with water and dried. After recrystallization from methanol, 1.31 g of 2β-chloro-1,2oc-methylene-5oc-androstane 17β-ol-3-one acetate with a melting point of 168 ° to 169 ° C. are obtained. For analysis, it is recrystallized a second time from methanol, mp 170.5 to 171.5 ° C.

Example 11 3.12 g of trimethylsulfoxonium iodide are dissolved in 70 ml of dimethylsulfoxide, under. Nitrogen mixed with 0.32 g of sodium hydride and stirred until completely dissolved (about 20 minutes). 3.6 g of 17a-methyl-d 1-5a-androsten-17ß-ol-3-one are added and the mixture is stirred for 5 hours at room temperature under nitrogen: it is precipitated with ice water, filtered off, washed with water and dried. After recrystallization of beers from ethyl acetate, 2.45 g of 1,2α-methylene-17ac-methyl-sca-androstan-17β-ol-3-one with a melting point of 195 ° to 197 ° C. are obtained.

For analysis, it is recrystallized again from ethyl acetate, mp 201 up to 202 ° C.

Example 12 260 mg of trimethyl sulfoxonium iodide are dissolved in 5 ml of diethyl sulfoxide dissolved, treated with 58 mg of sodium hydride under nitrogen and guided for about 20 minutes, until everything is resolved. 330 mg of 21-methylen-A5-pregnen-3ß-ol-20-one are used added and stirred for 5 hours at room temperature under nitrogen: It is precipitated with acidified Ice water (acetic acid), filtered off, washed with water and dried. One cleans by chromatography on silica gel. 5 ° / s ethyl acetate eluted in methylene chloride 100 mg 21,21-Ethylendä-pregnen-3ß-ol-20-one. After recrystallization from ethyl acetate a melting point of 164 ° to 165 ° C. is obtained. The 21,21-ethylene-A5-pregnen-3ß-ol-20-one can be used for further processing z. B. after O p p e n a u e r in the usual way oxidize to the 3,20-diketone, the methylene group introduced according to the process not bother.

Example 13 330 mg of trimethylsulfoxonium iodide are dissolved in 15 ml of dimethylsulfoxide, add 36 mg of sodium hydride under nitrogen and stir in for about 20 minutes Nitrogen: 385 mgd 1-cholesten-3-one are added and the mixture is stirred for 6 hours under nitrogen. It is poured into acetic ice water, filtered off, washed with water, dried and after recrystallizing twice from methanol, 120 mg of 1,2a-methylen-5oc-cholestan-3-one are obtained from 81 to 83 ° C.

Example 14 1.59 g of trimethylsulfoxonium iodide are dissolved in 30 ml of dimethylsulfoxide dissolved and treated with 173 mg of sodium hydride under nitrogen. Mix about 20 Minutes under nitrogen, adds 1.8 g of 2-methylenetestosterone, stirs another 5 Hours under nitrogen, pour into 400 ml of acetic ice water, filtered off, washed with water, dried and chromatographed on 100 g of silica gel. With 10 ° / o Ethyl acetate in methylene chloride, 0.7 g of 2,2-ethylene testosterone are eluted. To Recrystallization from ethyl acetate-hexane melts the substance at 148.5 to 149.5 ° C.

EXAMPLE 15 412 mg of trimethylsulfoxonium iodide are dissolved in 7 ml of dimethylsulfoxide, and 46 mg of sodium hydride are added to this solution under a nitrogen atmosphere. The mixture is stirred for about 25 minutes under nitrogen, 500 mg of 19-Nord 1-androsten-17β-ol.3-one acetate are added, the mixture is stirred for 5 hours at room temperature under nitrogen and worked up by precipitation of water (acetic acid). It is washed with water, dried and chromatographed on 80 g of silica gel. 50% methylene chloride in benzene elutes 370 mg of 1,2a-methylene-19-nor-5a-androstane-17ß-ol-3-one acetate. After recrystallization from ethyl acetate, the methylene compound melts at 149.5 to 151 ° C. EXAMPLE 16 286 mg of trimethylsulfoxonium iodide are dissolved in 5 ml of dimethyl sulfoxide, 52 mg of sodium hydroxide powder are added to this solution under nitrogen, the mixture is stirred for about 20 minutes and 330 mg of d 1-5α-androsten-17β-ol-3-one acetate are added. The mixture is stirred for 5 hours under nitrogen, precipitated with acetic ice water, filtered off, washed with water, dried and 320 mg of a UV-transparent crude product is obtained. 70 ° / 0 1,2a-methylen-5a-androstane-17β-ol-3-one-acetate and 5 ° / 0 1,2a-methylen-5a-androstane-17β-ol-3-one can be isolated by chromatography .

EXAMPLE 17 246 mg of trimethylsulfoxonium iodide are dissolved in 5 ml of dimethylsulfoxide, 29 mg of sodium hydride are added to this solution under nitrogen, the mixture is stirred for about 20 minutes and 342 mg of 2-methylenetestosterone acetate (prepared from 2-methylenetestosterone by acetylenes) are added. The mixture is stirred for 5 hours under nitrogen and precipitated with ice-water in acetic acid. It is filtered off, washed with water, dried and 230 mg of crude 2,2-ethylene testosterone acetate is obtained. After recrystallization from isopropyl ether, the compound melts at 195.5 to 196.5 ° C.

Claims (1)

Claim: Process for the production of α, ß-methylene ketones the steroid series, d u r g e k e n n -z e i c h n e t that one a, ß-unsaturated Steroid ketones that still have a hydrogen atom on the ß-carbon atom, especially d 1-3-ketosteroids and d 'g-20-ketosteroids, with dimethylsulfonium methylide or Dimethylsulfoxoniummethylid converts.