US2824100A - Process for preparation of steroid substances - Google Patents

Description

United I amples J. A. C. 'S., 1947, 69, 2404).

PROCESS FOR PREPARATION OF STEROID SUBSTANCES Alan Gibson Long, Greenford, and John Selwyn Hunt, South Ruislip, England, assignors to G. N. R. 1). Patent Holdings Limited, London, England, a British company No Drawing. Application June 22, 1954 Serial No. 438,593

Claims priority, application Great Britain June 29, 1953 12 Claims. (Cl. 260--239.'S5)

This invention is concerned with the preparation of new steroid substances namely such steroids of the allo atent series as have a keto group in the 3-position and a bromine atom in the 4-position.

It is well known that the bromination of S-keto steroids of the normal series (i. e. steroids in which rings A and B are fused in the cis-configuration) gives rise to 3-keto- 4-bromo-steroids which may be readily dehydrohalogenated to give A -3-keto compounds (cf. Butenandt and Wolff, Ber., 1935, 68, 2091, and Ruzicka et al., Helv. Chim. Acta, 1938, 21, 866; McGuckin and Kendall, J. Ann. Chem. Soc., 1952, 74, 5811). A number of important physiological substances, ex-

of which are cortisone, progesterone and testosterone possess the A -3-keto system and such compounds have frequently been prepared from steroids having the normal configuration by the above series of reactions.

However it is not always convenient to use normal steroids in such synthetic work and often normal steroids suitable as starting materials are not readily available; many readily available steroids are of the allo configuration (rings A and B fused in the trans configuration). However monobromination of allo steroids has hitherto led to a 2-bromo intermediate which on dehydrobromination gives mainly A -3-ketone (cf. Djerassi and Scholz, Thus alternative methods have had to be adopted to generate the 3-keto-A system from allo steroids which methods have been complicated and give rise to relatively poor yields. One such method involving the formation of a 2:4-dibromo intermediate has been described by Rosenkranz et al. (J. A. C. 8., 1950, 72, 4077, and Nature, 1951, 168, 28) but which whilst reasonably successful for allosteroids having a stable side-chain in the 17-position has been found by us, when applied 'to 2:4-dibromo-4:S-dihydroallocortisone monoacetate to give only small yields (10-15% of final lated compounds may be preparedin reasonable yield from the more readily available steroids of the allo series.

We have .now been successful in preparing 3-keto-4- tbromo allo steroids which, as wezhave found, are readily .dehydrobrominated to 3-keto-A -steroids. 'Nosteroids of theallo series having aketogroup in the 3-position and :abromine atominthe 4-.position have yet been described and ;.thus these compounds represent .new compounds which .we have found to have great .utility in synthetic workin the steroid field, particularly where the C17 .side chainl-is relativelyzunstable asin the synthesis of cortisone and related substances.

@urnew compounds are prepared by the reduction of 2:4-dibromo-3-ketoallosteroids to remove one atom of bromine thereby producing a mixture of 2-bromo-3- ketones and 4-bromo-3-ketones. In a preferred method of operation the conditions of reduction are so selected as to give a greater proportion of 4-bromo compound than 2-bromo compound. The desired 4-bromo compound can be separated from the mixture of isomers in many cases by simple crystallisation; it may be readily dehydrobrominated to the corresponding 3-lreto-A -compound.

Our new process thus enables 3-keto-A steroids to be prepared from 3-ketoallosteroids in a more convenient manner than hitherto.

According to the invention we provide a process for the preparation of allo steroids which have, in ring A, a-single bromine atom in the 4-position and a keto-group in the 3-position in which a 3-keto-2:4-dibromoallosteroid is reduced to remove one atom equivalent of bromine and the 3-keto-4-bromo allo steroid is separated from the resulting mixture.

Ring A of the steroid nucleus is, as is well-known, the ring formed by the carbon atoms marked 1, 2, 3, 4, 5 and 10.

Many reducing agents may be used in the process according to the invention it being remembered that reducing agents which under the conditions employed would reduce the 3-keto group are unsuitable.

Examples of reducing agents which can be used in the present process are chromous salts, such as chromous chloride, chromous acetate, titanous chloride, titanous sulphate, hydrogen iodide (for example generated by the reaction of sodium iodide and oxalic acid); reduction by means of a zinc copper couple, for example by heating in methanol, may also be used. The reducing agents which would cause reduction of the B-keto group will in many cases be obvious and include for example lithium aluminium hydride. Such a wide range of reducing agents is capable of use according to the invention that it is impossible to specify all suitable reagents. In doubtful cases preliminary tests will show whether any particular reducing agent is suitable.

The reduction reaction is conveniently carried out in the presence of a polar organic solvent, for example methanol, ethanol, acetone or acetic acid. Where a neutral solvent is employed a trace of acid, for example, hydrogen chloride is advantageously added. Another organic solvent, for example chloroform may, if desired, be added to solubilise the steroid starting material. The exact nature of the solvent to be employed of course depends to some extent on the particular reducing agent to be used.

We prefer to ensure that approximately one atom equivalent of bromine is reduced from the starting ma terial by selection of approximately the correct quantity of reducing agent to effect this; the quantity of reducing agent required is not necessarily the theoretical quantity and in the case of chromous chloride we have found that approximately 100% of this quantity is required. In any given case therefore the approximate quantity of reducing agent required for removal of one atom equivalent of bromine can only be determined by preliminary test.

As to whether one atom equivalent of bromine has been removed is conveniently determined by elemental analysis of the reduction product. When further the suitability of a particular reducing agent is in doubt the product may also be tested for the presence of a keto group whilst the infra-red spectrum will in general show the presence or absence of the e-bromo ketone structure.

The specific rotation of the reaction mixture may also be employed to indicate whether the reaction has proceeded in satisfactory manner. Thus in the application of the process to 2:4-dibromo-4:S-dihydroallocortisone mon'oacetate the following are the rotations of the starting material and products:

2:4-dibromo compound [d] +85 (chloroform) 2-bromo compound [a] +133 (chloroform) 4-bromo compound [a] -{-56 (chloroform) Thus the efliciency of the reduction may be roughly gauged by observing the reduction in the specific rotation of the reaction mixture; the greater the decrease the larger will be the amount of 4-bromo compound present.

These tests accompanied by the elemental analysis will thus enable the suitability of any particular reducing agent to be determined and the conditions which require to be used to remove one atom equivalent of bromine from the starting material. Observation of the specific rotation will also indicate the best conditions to yield the greatest proportion of 4-isomer.

We have found further that by adopting conditions which tend to slow down the rate of the reduction reaction, the percentage of the desired 4-bromo isomer as opposed to the Z-isomer is increased. Thus when carrying out the reduction with chromous chloride at room temperature the proportions of the two isomers in the mixture is approximately 1:1 whereas if the reduction is carried out at -45 C. the proportion of 4-isomers to 2-isomers in the reaction mixture may be approximately The separation of the desired 4-bromo isomer from the mixture resulting from the reduction may be effected in any convenient manner. The 4- and Z-bromo isomers may be distinguished by the differences in specific rotation or alternatively by dehydrobromination, the former giving rise to the 3keto-A -structure and the latter to the 3-keto-A. structure. These may be differentiated by their ultra violet absorption maxima which are in the region of 238 and 230 m respectively. The exact position of these two maxima is, however, to some extent dependent on other groupings present in the molecule. In general the desired 4-isomer can frequently be separated by simple crystallisation.

The 4-bromo-3-ketoallosteroids may be dehydrohalogenated to 3-keto-A -steroids in any desired manner, for example by treatment with semicarbazide (cf. McGuckin and Kendall, J. A. C. S., 1952, 74, 5871), 2:4-dinitr-ophenylhydrazine dimethylformamide or tertiary organic i amines such as collidine.

As stated above the herein described process is particularly useful in the synthesis of cortisone and related substances and thus the process is especially applicable to 2:4-dibromo-3-ketoallosteroids which may or may not have a keto group in the 11- or 12-positions and one of the following side chains in the 17- position:

( CHzOR CHzOB 4 new compounds, in particular such steroids as have one of the above-stated side-chains in the l7-position with or without a keto group in the 11- or 12-positions. For the purposes of illustration we. give an example of one such compound, its structure and physical characteristics as observed by us:

4 -br0m0-1 7 -hydroxy-21 -ace tarry-3:1 1 :20-

triketoallopregnane OHz.OOC.CHs

IE Br M. P. 204-206 (dec.) [a] +56 (chloroform) When recrystallised from ethyl acetate this substance is obtained as an ethyl acetate solvate showing M. P. 199- 201 (dec.) and [u] +49.5 (chloroform).

It will be understood that the foregoing physical characteristics are given for the purpose of illustration and were determined for the purest material we have been EXAMPLE 1 4-bromo-3-ket0ch0lestane 2:4-dibromo-3-ketocholestane (2 g.) was dissolved in acetone (40 ml.) and 0.6 M chromous chloride solution (1.5 mole) was added, a stream of nitrogen being passed through the reaction mixture. The reaction was left for 5 minutes at 20 and then poured into water. The solid (1.51 g.; 88%) that separated was filtered off, desiccated and twice recrystallised from ethyl acetate-hexane, from which crystals (0.33 g.; 19%) of 4-bromo-3-ketocholestane, M. P. 150-152", [a] +8 (chloroform), separated. Found: Br 16.5%, C H OBr requires Br 17.2%. The compound in CS solution showed an ab sorption maximum at 1731 cm. (due to the a-bromoketone system). 7

EXAMPLE 2 21 -ace toxy-4-bromo-1 7 a-h ydr0xy-3 :1 1 :2 O-rriltetoallopregnane A solution of 2l-acetoxy-2:4-dibromo-17u-hydroxy- 3:11:20-triketoallopregnane (7.9 g.) in a mixture of acetone (40 ml.) and methanol ml.) was cooled to 35 by the addition of solid carbon dioxide; concentrated hydrochloric acid (1.5 ml.) was added, followed by a 1.4 N solution of chromous chloride in 0.1 N hydrochloric acid (16.75 ml.; 1.7 mol. equivalents). The reaction mixture was kept at --35 for 15 minutes and allowed to warm to 0 over 30 minutes. It was then poured into water (800 ml.) and the precipitate that formed was collected, washed with water and dried in vacuo over phosphorus pentoxide. The crude product (5.85 g., M. P. 146-150 (dec.)), [a] -[73.5 (chloroform), contained 16.5% of bromine. It was crystallised once from tertbutanol-methylene chloride, twiceufrom ethyl acetate-isopropyl ether and twice from ethyl acetate. The optical rotation and melting point did not change during the last two recrystallisations, and the final product 21-acetoxy-4'bromo-17ot-hydroxy-3 11 :ZO-triketoallopregnane (ethylacetate solvate)was obtained as colourless rods (1.2 g.; 15%) M. P. 199-201 (dec.), [u1 +49.5 (c. 1.2% in chloroform). (Found: C,

H, BI. C23H21O6B1'.CH3CO2C2H5 requires C, 56.7; H, 6.9; Br. 14.0%.)

The weight loss (ethyl acetate) at 100/ 1 mm. in 4 hours was 14.2%; C H O BnCl-I CO C H requires 15.4%. In accordance with this is the optical rotation of the unsolvated form [a] |-61 (c. 0.8 in chloroform). (Calc. for the loss of CH CO C H of crystallisation [a] +59.) The infra-red absorption spectrum (bromoform) showed bands at 1744 and 1232 cm.- (21-acetate): 1722 cm." (ZO-carbonyl and CO-CHBr--);

1702 cm. (ll-carbonyl). (Found: Br. 15.53. C H O Br requires Br, 16.53%.)

EXAMPLE 3 (a) Cortisone acetate-S-semicarbazone (Cf. McGuckin and Kendall, J. Amer. Chem. Soc., 1952, 74, 5811.)

To a solution of the solvated 21-acetoxy-4-bromo-17ahydroxy-3:11:ZO-triketoallopregnane (820 mg.) in a mixture of dry alcohol-free chloroform (21 ml.) and tert.- butanol (36 ml.) was added finely ground semicarbazide base (215 mg). The air in the flask was displaced by carbon dioxide and the reaction mixture agitated for 5 minutes. A yellow colour developed within 15 minutes and disappeared after another 5 minutes. After standing for 1.5 hours, the solvents were distilled under reduced pressure. The residue was stirred with ethanol (10.5 ml.) and water (7.2 ml.) and the solid material collected, washed with water and dried in vacuo at 100 giving cortisone acetate-3-semicarbazone (624 mg; 96%) M. P. 194-8 [a] +260 (tert.-butanol: c. 0.64%). Light absorption in alcoholic solution, A max. 270.5 m, (27600).

(b) Cortisone acetate (Cf. McGuckin and Kendall, loc. cit.)

The crude cortisone acetate-3-sernicarbazone (510 mg.) was added to a mixture of acetic acid (15.5 ml.), water (5.5 ml.) and 1.12 N aqueous pyruvic acid (2 ml.). Air was displaced by carbon dioxide and the flask warmed to 40 for 15 minutes with agitation until all the solid had dissolved. After standing at room temperature for 18 hours, the solution was treated with water (25 ml.) and extracted with choloform (3X50 ml.). The combined extracts were washed with dilute sodium bicarbonate solution until the washings were alkaline, with N-hydrochloric acid (3X25 ml.) and finally with water until the washings were neutral. After dehydration over magnesium sulphate the chloroform was distilled and the residue crystallised from ether-acetone giving cortisone acetate (340 mg.; 78%), M. P. 238-240", lotl +2l2 (c. 1.06% in chloroform). Light absorption in alcohol solution, A max. 238 m (614900). Infra-red absorption in bromoform showed bands at 1742 and 1232 cm.- (21-acetate); 1724 (20-carbonyl) 1704 (ll-carbonyl); 1662 and 1616 cm.-

The spectrum was identical with that of an authentic specimen. (Found: C, 68.8; H, 7.5. Calc. for C H O C, 68.6; H, 7.5%.)

EXAMPLE 4 A solution of 20:40t-dlb1'0mO-3-l tOCllStan6 (20 g.) in anhydrous alcohol-free chloroform (175 ml.) was diluted with acetic acid (370 ml.). An atmosphere of nitrogen was maintained, and chromous acetate (20 g.; 73% pure; 2.3 mole equiv.) was added to the vigorously stirred solution. After 30 minutes, the green solution was diluted with water, the chloroform layer separated, and the aqueous phase extracted twice with chloroform. The combined chloroform phases were washed with water, dilute sodium bicarbonate solution, again with water, dehydrated (MgSO and evaporated to dryness. The residue (16.7 g.), [a] ]-13 (c, 1.5) (found: Br, 13.1%), was fractionally crystallised from methyl acetate, giving 4ot-bromo-3-ketocholestane (3.63 g.; 20%) as rods, M. P. 1446, [a] i0 (c, 1.4), A max. 229 m (c162) and 283 m (e25),

cs, max.

at 1730 cm.

(.CO.CB1'; equatorial Br) characteristic peaks occur at 1168, 828 and 730 cmr which distinguish the spectrum from that of the 2-bromo isomer, which had characteristic peaks at 1308, 1185, 1120, 956, 814, 748 and 700 cmf (Found: C, 69.3; H, 9.75; Br, 16.45. C H OBr requires C, 69.6; H, 9.7;

Second crops (2.1 g.; 13%) had M. P. -136", [a] +4 (c, 1.4). Further crops (5.7 g.; 30%) had [a] +lZ to +20".

EXAMPLE 5 The requisite amount of chromous acetate was added with stirring, over 5 minutes, to a solution of 21-acetoxy- 2:4-dibron1o-17a hydroxy 3:11:20 triketoallopregnane (107 g.) in glacial acetic acid (1 1.) under nitrogen.

r The temperature of the reaction mixture was kept at 20 by means of external cooling. After 45 minutes the crystalline material that had separated was collected, washed with dilute acetic acid, and finally with water and dried (12.7 g.). Recrystallisation from ethyl acetate gave 21 acetoxy-4bromo-17ot-hydroxy-3:111:20-triketoallopregnane (ethyl acetate solvate) as colourless rods (11.2 g.; 10.3%) M. P. 206208 (dec.), [ac] ]-47 (c, 1.3% in chloroform). (Found: C, 57.0; H, 6.9; Br,

14.0. C H O BLCH CO C H requires C, 56.7; H, 6.9;

Recrystallisation of this solvate from pure benzene afforded the solvent-free compound M. P. 204-206 (dec.), [u] -}56 (c, 0.86% in chloroform). The infra-red absorption spectrum (bromoform) showed bands at 1745 and 1234 cm.- (ZI-acetate); 1726 (3111.5 (20-carbonyl and --COCHBr-); 1708 cm.- (11- carbonyl). (Found: C, 57.35; H, 6.5; Br, 16.3; C H O Br requires C, 57.15; H, 6.5; Br, 16.5%.)

Dilution of the filtrate with water, extraction with methylene chloride, washing with dilute sodium bicarbonate solution and evaporating to dryness, gave a crystalline residue which, after two crystallisations from ethyl acetate, afforded a further quantity of the solvated 4- bromosteroid (26.26 g; 24%), M. P. 197200 (dec.) [a] +54 (c., 0.9% in chloroform).

EXAMPLE 6 In all the experiments covered by the following table the 2z4-dibromoallodihydrocortisone acetate was dissolved in the appropriate solvent at the specified temperature. In the first four experiments a small amount of mineral acid was added to act as a proton source. After the reaction had proceeded for the time indicated the products were isolated either by precipitation from the reaction mixture with water or by extraction of the reaction mixture with a suitable solvent (e. g. methylene chloride). The optical rotations quoted are those :for the crude product and taken in conjunction with the bromine analysis are adequate indications of a satisfactory result.

(c., 1.02% in dioxan).

behydrobromination of 4-br0mo-4 :S-dihydroallocortisone acetate The 4-bromo-3-ketone (1.4 g.) was heated in refluxing dimethylforrnamide (60 ml.) in the presence of lithium carbonate (2 g.) for 45 minutes. Isolation with methylene chloride yielded a solid which was reacetylated in acetic anhydride-pyridine at 20 for 60 minutes. Isolation in the usual way gave a solid (684 mg.) (Mnax. 238 m which was heated with Girard P reagent (650 mg.) in acetic acid in ethanol ml.) under reflux for 45 minutes. Aqueous formaldehyde (60%; 1 ml.) was added to the cooled solution which was kept at 20 for 20 minutes. The solution was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. Evaporation of the organic layer yielded crude 4:5-dihydroallocortisone acetate (0.094 g.).

The bicarbonate solution was acidified to pH 1 with cone. hydrochloric acid and then left at 20 for 4 hours cortisone acetate (0.460 g.) (\max. 237;

slowly separated from solution. Crystallisation from acetone gave cortisone acetate (cf. acetone solvate) as needles, which, after drying at 130/4 hours, had M. P.

238-240", Amax. 236 m lli... [a] -|216.

EXAMPLE 8 1 7a:12-dihydroxyallopregnane-3 :11 :20-tri0ne (Cf. MattoX and Kendall, J. Biol. Chem., 188, 287.)

A suspension of 2l-acetoxy-17a-hydroxya11opregnane- 3:11:20-trione (1 g.) in a mixture of chloroform (10 ml.), methanol (35 ml), water (3.4 m1.) and concentrated hydrochloric acid (2.1 ml.) was allowed to stand at room temperature for 87 hours with occasional swirling. The steroid had completely dissolved after the first 45 hours. Water (120 ml.) was added and the mixture was left overnight at 0, causing the separation of crystals from the lower (chloroform) phase. These crystals were collected, washed with dilute sodium bicarbonate solution and water and dried in vacuo over phosphorus pentoxide yielding 17a:21'dihydroxyallopregnane-3:11:

-20-trione (0.805 g.; 89.5%), M. P. 210222. Recrystallisation from acetone raised the M. P. to 217-221". [a] +78 (c., 0.41% in chloroform), [a] +80.5,

The infra-red absorption spectrum (Nujol) showed bands at 3500 cm.- (hydroxyl),

"TABLE 2:4-d1- Conditions Product bromo allocortisone Time, Wt... [12]]: Percent acetate Reducing agent Molec.equtv. Solvent Temp. hrs. Acid added g. ge grgas. B1

1 ortooocnm +nBEorBr, 2 Acetic ccm 20 0.5 HBr in acetic 0.80 +12 11.2

ml.). acid (6.8 N; 1.05 mL; 4 mol.). 1 Ti2(SO4)a,0.95N 2 Acetone (5 ml.) 20 2 HCl 0.5 ml. 10 0.88 +74 17.2

' and methanol N. 15 ml.). 1 Tlz(S04)a,0-95N 2 do 0 23 do 0.80 +74 17.0 0.5 TlClz,0-74N 2-.. Methanol (20 ml.), 20 0.5 CHllmLIN-.. 0.12 +75 methylene chloride (10 m 1 Nazszol 2 Aqgoeouls acetone 20 0.25 Nil 0.56 +75 16.2

0.5 HI1.e.[NaI+(O0OH)c] NaI, 3; (CO-21302, 2-. Acetone (50 ml.) Reflux" 0.5 0.35 +83 16.7 2.8 Zn/Cu counle 1 Mehhanol 20 5 1.7

EXAMPLE 7 1706 cm.- (ketones). (Found: C, 69.4; H, 8.31.

C H O requires C, 69.6; H, 8.3%.)

EXAMPLE 9 1 7on2]-dihydr0xyallopregnone-3:11 :ZO-trione 3 :20-bisethylene ketal (Cf. Antonucci, Bernstein, Heller, Lenhard, Littel and William, J. Org. Chem., 1953, 18, 70.)

To a mixture of dry benzene (36 ml.) and ethylene glycol (3 ml.) in which p-toluenesulphonic acid monohydrate (10 mg.) was dissolved, was added 17aZ2l-dihydroxyallopregnane-3:11:20-trione (1 g.). The mixture was refluxed for 15 hours, the steroid attaining solution during the first hour. Water, which co-distilled with the benzene was collected by means of a water trap. The cooled reaction mixture was poured into dilute sodium bicarbonate solution and the benzene phase separated. The aqueous phase was extracted twice with benzene and the combined benzene phases washed with water and evaporated. The residue was dissolved in ether (15 ml.) and on standing crystals of 17a:21-dihydroxyallopregnane-3:11:20-trione 3:20-bis-ethylene ketal rapidly separated. After cooling the mixture at 0 for 1 hour the crystals were collected (0.74 g.; 60%) M. P. 172-179. Recrystallisation from acetone gave needles (0.63 g.; 51%) M. P. 184186. [Ot:| +36 (c., 1% in chloroform). The infra-red absorption spectrum (Nujol) showed bands at 3430 GEL-1 (hydroxyl), 1680 cm.- (ketone) and 1100 and 1188 cmr (ether). (Found: C, 66.7; H, 8.4. (3 11 0; requires C, 66.6; H, 8.5%.)

EXAMPLE 10 21 acetoxy 17ct-hydr0xyall0pregnane-3:11:20-trione 20- ethylene ketal 17a:21-dihydroxyallopregnane-3 11 :20-trione 3 :20-bisethylene ketal (3 g.) was dissolved in dry pyridine 10 ml.) and acetic anhydride (5 ml.). After standing 20 'hours at room temperature the solvents were distilled under reduced pressure. The crystalline residue was dissolved in acetone ml.), water (18 ml.) and 2 N hydrochloric acid (1.5 ml.) were added, and the solution was allowed to stand at room temperature for 20 hours, after which time crystals had separated. Water (1 l.) was added and the crystalline precipitate collected, washed with water and dried, giving plates of 21-acetoxy-17ahydroxy allopregnane 3: 11 :20-trione ZO-ethylene ketal (2.805 g.; 94%) M. P. 240-247". Recrystallisation from acetone gave 2.415 g. (82%), M. P. 245-250", [al +53.5 (c, 0.77% in chloroform). The infra-red absorption spectrum (Nujol) showed bands at 3620 cm.- (hydroxyl), 1744 and 1234 cm." (acetate) and 1708 cm.- (ketones). (Found: C, 67.2; H, 8.0. C H O requires C, 66.9; H, 8.0%.)

EXAMPLE 11 3:11:20-tri0ne 20-ethylene ketal To 'a solution of 21-acetoxy-l7a-hydroxyallopregnane 3:11:20-trione 20-ethylene ketal g.) in a mixture of dry, freshly distilled, methylene chloride (75 ml.) and dry ether ml.), was added, with stirring, over 17 minutes, a solution of bromine (4.04 g.; 2.3 mol.) in methylene chloride (45 ml.). The temperature was kept at 20 by external cooling. Water was added, and the methylene chloride phase separated, washed with dilute sodium bicarbonate solution, water, dehydrated (MgSO and the solvents distilled at room temperature to small bulk. n-l-lexane was added and distillation continued to dryness. The residue of crude 21-acetoxy-2a:4a-dibromol7a-hydroxyallopregnane-3:11:ZO-trione 20-ethylene ketal (7.7 g.) (found: Br, 31.0. CH34O7BY2 requires Br, 26.4%) was dissolved in a mixture of glacial acetic acid (150 ml.), dry alcohol-free chloroform (40 ml.) and methylene chloride (25 ml.), and cooled to 5 by the addition of pieces of solid carbon dioxide. While under carbon dioxide, and with stirring, 1.15 N aqueous chromous chloride (22.8 ml.; 2.4 mol.) was added over 15 minutes, the temperature of the reaction mixture being kept at -5 by additional solid carbon dioxide. The mixture was allowed to stand for a further 15 minutes and poured into water. The chloroform-methylene chloride layer was separated, and the aqueous phase extracted with fresh methylene chloride. The chloroform-methylene chloride phases were combined and washed with water, dilute sodium bicarbonate solution, water, dehydrated (MgSO and evaporated to dryness. The residue (5.85 g.) had M. P. 190-208. [a] +34.5 (-c., 0.44% 'in chloroform). (Found: Br, 16.2. C H O Br requires Br, 15.2%.) It was crystallised from chloroform to give needles of 21-acetoxy-4a-brorno-17ot-hydroxyallopregnane- 3:11:20-trione 20-ethylene ketal. (1.5 g.; 26%) M. P. 240-242" (decomposition) [M +26.6 (c., 0.3% in chloroform). A specimen recrystallised from ethyl ace- --tate had .M. P. 240-244 (decomposition) [M +23.7;

:;(c., 0.55% in chloroform). The infra-red spectrum (Nujol) showed bands at 3600 cmr (hydroxyl); 1744 and 1226 cm.- (21-acetate); 1726 cm.-

and 1696 cmr (ketone). (Found: c, 57.1; H, 6.65; .Br, 15.2. C H O Br requires C. 56.9; H, 6.7; Br,

EXAMPLE 12 21 acetoxy 17o: hydr0xy-pregn-4-ene-3:11:20-rri0ne ZO-ethylene ketal To a solution of 21 acetoxy-4a-bromo-Not-hydroxyallopregnane-3z11:20-trione ZO-ethylene ketal (100 mg.) in a mixture of dry alcohol-free chloroform (20 ml.) and t-butano1 .(26 ml.) under carbon dioxide, was added semi- "carbazide base mg.). The solution was allowed to stand with occasional swirling for 2 hours, during which "time the characteristic transient yellow colour appeared.

After evaporation of the solvents under reduced pressure, the residue was triturated with dilute alcohol, filtered and washed with water. The crude undried 21-acetoxy-17uhydroxy 3 semicarbazono-pregni-ene-11:20-dione 20- ethylene ketal was suspended in acetic acid (4 ml.), water (2 ml.) and 1.13 N aqueous pyruvic acid (0.2 ml.), warmed under carbon dioxide to 40 with swirling until solution was attained, and then allowed to stand at room temperature for 21 hours. Water was added and the mixture extracted with methylene chloride. The extract was washed with water, dilute sodium bicarbonate solution, water, N-hydrochloric acid and finally with water until the washings were neutral. The residue from the dehydrated (MgSO extract, crystallised from acetone- ;ther as rhombs of 21-acetoxy-17m-hydroxy-preguA-ene 10 v3:-11:20-trione 20-ethylene ketal (50 mg; 59%) M. P. 204 -209", M11324 +l52 (0., 0.87% in chloroform).

x323 237.5 mg e 15,300. (Antonucci etal.,1oc. cit. give M. P. 212-215 [aJ +153 (chloroform);

or 16,700.) The infra-red absorption spectrum (Nujol) showed bands at 1740 and 1230 cm. (21-acetate), 1699 cm.- (ketone), 1668 and 1618 cm." (me-unsaturated ketone).

We claim:

1. A process for the preparation of compounds selected from the group consisting of compounds having the general formulas and where X is selected from the group consisting of in which R is selected from the group consisting of a hydrogen atom and an acyl group derived from a lower alkanoic acid having 2-5 carbon atoms and n is a number greater than one and less than 4 and Y is selected from the group consisting of hydrogen and oxygen atoms, comprising reacting the corresponding 2:4-dibromo compound with a reducing agent incapable of reducing the B-keto group under conditions of the reaction to remove one atom equivalent of bromine and form a mixture of :4-monobromo and 2-monobromo compounds and separating said =4-monobromo compound from said mixture.

2. A process as claimed in claim 1 in which a chromous salt is employed as reducing agent.

3. A process as claimed in claim 1 employing a reducing agent selected from the group consisting of chromous chloride, chromous acetate, stannous chloride, titanous chloride, titanous sulphate, hydrogen iodide and a zinc-copper couple.

4. A process as claimed in claim 1 in which the reduction is carried out in the presence of a polar organic solvent.

5. A process as claimed in claim 4 in which the solvent is selected from the group consisting of methanol, ethanol, acetone and acetic acid.

6. A process for the preparation of 3-keto-A steroids which comprises dehydro-halogenating compounds 59* aeaaiob 'lected from the group consisting of compounds having the general formulas igj j I;

and

a Br where X is selected from the group consisting of OHQOR CH3 0 I c0 00 C (0111)..

l l c--OR 0-0R 0 and CHCHzCHr-CH:CH(CH3)Q in which R is selected from the group consisting of a hydrogen atom and an acyl group derived from a lower alkanoic acid having 2-5 carbon atoms and n is a number greater than one and less than 4 and Y is selected from the group consisting of hydrogen and oxygen atoms.

7. A process as claimed in claim 6 in which the dehydrohalogenation is effected by treatment with an agent selected from the group consisting of semi-carbazide, 2:4-dinitrophenylhydrazine, dimethylformamide and collidine.

8. A process as claimed in claim 1, in which there is employed approximately the correct quantity of said reducing agent to reduce one atom equivalent of bromine from the starting material.

9. A process as claimed in claim 1 in which the reaction is carried out at a low temperature to favor production of the 4-monobromo isomer.

10. A process as claimed in claim 2 in which there is employed an amount of said chromous salt equal to 85-100% of the theoretical quantity required to reduce one atom equivalent of bromine from the starting material.

11. A process as claimed in claim 4 in which said polar organic solvent is made acid in reaction.

12. A process for the preparation of B-lceto-A steroids comprising reacting with a reducing agentincapable-of reducing under the conditions of the reaction the 3-keto group, a compound selected from the group consisting of Y l-X Br \J E Br and -----x Br fi Br where X is selected from the group consisting of CHaOR I IO 00 C\ /(CH:),. 0 --0R JJ-OR 0 and,

CHCH2CH2CH2CH(CH3)I 5 References Cited in the file of this patent UNITED STATES PATENTS Levin Mar. 2, 1954 Levin Apr. 6, 1954 OTHER REFERENCES Rosenkranz: Jour. Am. Chem. Soc., 72, 1046, 4077 s0 1950 Fieser et a1.: Natural Products Related to Phenanthrene, 3rd ed., pp. 262-3, 450-51 (1949).

Claims (1)

1. A PROCESS FOR THE PREPARATION OF COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING THE GENERAL FORMULAS

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