Patent GB-832245-A (GB)
Title: Improvements in or relating to steroid compounds
IPC: C07J75/00
Filed: 1957-05-17
Abstract: The invention comprises 17,21-dibromo-3a -acetoxy - pregnane - 20 - one, 17,21 - dibromo - 3a  - hydroxy - pregnane - 11,20 - dione, 21 - bromo - 3a  - acetoxy - D 16 - pregnene - 20 - one, 21 - bromo - 3a - hydroxy - D 16 - pregnene - 11,20 - dione, 4 - bromo - 17b  - acetoxy - D 1 - etiocholene - 3 - one, 4b  - bromo - 17a  - hydroxy-21 - acetoxy - D 1 - pregnene - 3,11,20 - trione, 4,21 - dibromo - 17a  - hydroxy - D 1 - pregnene - 3,11,20 - trione, 2a ,4b ,17a ,21 - tetrabromo - pregnane - 3,20 - dione, 4b ,21 - dibromo - D 1,16 - pregnadiene - 3,20 - dione, 3a  - hydroxy - 21 - acetoxy - D 16 - pregnene - 11,20 - dione, 17b  - acetoxy - D 1 - etiocholene - 3 - one and 4b  - bromo - D 1,16 - pregnadiene - 3,20 - dione, and a process for the preparation of an unsaturated halogeno steroid by partially dehydrohalogenating a steroid containing at least two halogen atoms, of which one is attached directly to a nuclear carbon atom connected through a saturated linkage to a nuclear carbon atom having a hydrogen atom directly attached to it with lithium carbonate or with lithium halide in a liquid medium consisting of a disubstituted amide of an aliphatic carboxylic acid containing a total of up to 14 carbon atoms while stirring for a period of time and at a temperature such that at least one halogen atom directly attached to the ring is removed by dehydrogenation with simultaneous double bond formation between the adjoining nuclear carbon atoms from which the halogen and the hydrogen atoms have been removed, leaving at least one halogen atom in the resulting steroid.  The preferred conditions are: (a) the steriod reactant contains a bromine atom or bromine atoms as the nuclear halogen substituents; (b) the disubstituted amide is a dialkyl amide which preferably contains a total of up to 8 carbon atoms such as dimethyl or diethyl formamide or acetamide; (c) the lithium halide is the bromide, chloride or iodide, which may be formed by the reaction of lithium carbonate on the halogenated steroid reactant; (d) the quantities of lithium carbonate and lithium halide should be such that an excess of lithium carbonate is present throughout the reaction and the lithium halide is present in an amount of at least 1/10 of a molecule for each molecule of steroid reactant; (a) the dehydrohalogenation is effected at a temperature between 70 DEG  and 100 DEG  C.; and (f) the dehydrohalogenation is effected for a period between 20 and 60 minutes.  The di- or polybrominated steroid reactants used in the above process may contain other substituents in the A, B, C or D ring or in the side chain, particularly a carbonyl or hydroxy group or derivatives of these groups which may be easily converted to the carbonyl or hydroxy group, e.g. acetals, enic amines or enolic ethers in the case of reconversion to carbonyl groups, and esters or ether oxides in the case of reconversion to hydroxy groups.  The process is applicable to steroids of the normal and allo series, and the steroid may belong to the genin series, e.g. a hecogenin, the sterol series or degradation products thereof, e.g. androstanes, allopregnanes, bile acids, pregnanes or etiocholanes.  The process is particularly applicable to steroids of the general formula <FORM:0832245/IV (b)/1> wherein R and R1 are the same or different and represent hydrogen, or a hydroxy, keto or acyloxy group, where the acyl group contains up to 8 carbon atoms, and X, X1, X11 and X111 represent hydrogen or a halogen with the proviso that at least two of X, X1, X11 and X111 must be similar or dissimilar.  By means of the above process D 1-4-bromo-steroids may be produced from 2,4-dibromo-steroids; 4,21-dibromo- D 1,16-pregnadienes and 21-bromo- D 1,4,16-pregnatriene may be produced from 2,4,17,21 - tetra-brominated pregnanes; 4-bromo-17b -acetoxy-D 1-etiocholene-3-ones may be produced from 2,4 - dibromo - 17b  - acetoxy - etiocholanes - 3 - ones; and 17a -hydroxy-21-acetoxy- D 1-pregnene-3,11,20-trione may be produced from 2,4-dibromo - 17a  - hydroxy - 21 - acetoxy - pregnane-3,11,20-trione.  In the examples: 21-bromo - 3a  - acetoxy - D 16 - pregnene is prepared from 17,21 - dibromo - 3a  - acetoxy - pregnane - 20 - one; 21 - bromo - D 16 - pregnene-3,20-dione is prepared from 17,21-dibromo - pregnane - 3,20 - dione; 21 - bromo - 3a  - hydroxy - D 16 - pregnene - 11,20 - dione is prepared from 3a -hydroxy-17,21-dibromo-pregnane - 11,20 - dione; 17b  - acetoxy - D 1,4 - androstadiene-3-one and 4-bromo-17b -acetoxy-D 1-etiocholene-3-one are prepared from 2,4-dibromo - 17b  - acetoxy - etiocholone - 3 - one; the acetate of D 1-dehydrocortisone and 4b -bromo - 17a  - hydroxy - 21 - acetoxy - D 1 - pregnene - 3,11,20 - trione are prepared from 2a ,4b  - dibromo - 17a  - hydroxy - 21 - acetoxy - pregnane - 3,11,20 - trione; 4b ,21 - dibromo - 17a  - hydroxy - D 1 - pregnene - 3,11,20 - trione is prepared from 2(a  and b ), 4b ,21-tribromo-17a  - hydroxy - pregnane - 3,11,20 - trione; 4b ,21 - dibromo - D 1,16 - pregnadiene - 3,20 - dione is prepared from 2a ,4b ,17a ,21-tetra-bromo-pregnane-3,20-dione.  17,21-Dibromo-3a -acetoxy-pregnane-20-one is prepared by brominating 3a -acetoxy-pregnane-20-one.  3a  - Hydroxy - 17,21 - dibromopregnane - 11,20-dione is prepared by treating 17,21-dibromo-3a -acetoxy - pregnane - 11,20 - dione with sulphuric acid.  2a ,4b ,17a ,21 - Tetrabromo - pregnane - 3,20 - dione is prepared by brominating 17,21-dibromo-pregnane-3,20-dione in dioxane.  19-Nor-progesterone is prepared by treating 4b ,21-dibromo-pregnane-3,20-dione with sodium iodide in acetone to form 4b -bromo-21-iodo-D 1,16-pregnadiene-3,20-dione, treating this compound with sodium bisulphite to form 4b -bromo-D 1,16-pregnadiene-3,20-dione, dehydrobrominating this compound to form D 1,4,16-pregnatriene-3,20-dione and cracking and hydrogenating the double bond in the 16,17-position.  21 - Acetoxy - D 4 - pregnene - 3,11,20 - trione is prepared by treating 21-bromo-3a -hydroxy-D 16-pregnene-11,20-dione with sodium iodide in acetone to form 21-iodo-3a -hydroxy- D 16-pregnene-11,20-dione, treating this compound with potassium acetate to form 3a -hydroxy-21-acetoxy - D 16 - pregnene - 11,20 - dione, hydrogenating this compound to form 3a -hydroxy-21-acetoxy-pregnane-11,20-dione, oxidizing and brominating this compound by the method described in Specification 760,032 to form 4a -bromo - 21 - acetoxy - pregnane - 3,11,20 - trione, and dehydrobrominating this compound by a method normally used in steroidal chemistry.  17a  - Hydroxy - 21 - acetoxy - D 1 - pregnene - 3,11,20-trione is prepared by treating 4b ,21-di-bromo-17a -hydroxy- D 1-pregnene-3,11,20-trione with sodium iodide in acetone to form the corresponding 21-iodo compound and then with potassium acetate to form the corresponding 21-acetoxy compound, and debrominating this compound with zinc powder in acetic acid and acetone.  17b -Acetoxy-D 1-etiocholene-3-one is prepared by brominating 17b  - acetoxy - 4 - bromo - D 1-etiocholene-3-one with zinc powder in acetic acid. Specifications 760,362, 787,935, 816,909 and 828,601 also are referred to.