Patent GB-811867-A (GB)
Title: Dehydro-compounds of the steroid series and process of making same
IPC: C07J75/00
Filed: 1956-05-24
Abstract: The invention comprises D 1,4-3,20-dioxopregnadienes of the general formula: <FORM:0811867/IV (b)/1> wherein R represents H or OH, R1 represents OH or OAc in which Ac represents the acyl radical of a carboxylic acid containing from 1 to 12 carbon atoms, X represents an alkyl radical containing from 1 to 5 carbon atoms, Y represents O or H(OH) and Z represents H or a halogen atom; D 1,4,9(11)-3,20-dioxopregnatrienes of the general formula: <FORM:0811867/IV (b)/2> where R and X have the above significance; D 1,4 - 3 - oxo - 9a  - halo - androstadienes of the general formula: <FORM:0811867/IV (b)/3> wherein R represents O, H(OH) or a CH3(b OH), Z represents a halogen atom and g  has the above significance; D 1,4 - 3,20 - dioxo - 12a  - halopregnadienes of the general formula: <FORM:0811867/IV (b)/4> wherein R represents H or OH, and Y and Z have the above significance; D 1,4,6-3,11,20-trioxo - 9a  - fluoro - 17a ,21 - dihydroxy - pregnatriene; D 1,4,6 - 3,20 - dioxo - 9a  - fluoro - 11b ,17a ,21-trihydroxy-pregnatriene; D 1,4,9(11) 3 - oxo - spirostatriene; D 1,4 - 3 - oxo - 9,11b -oxido - 22a  - spirostadiene; D 1;4 - 3 - oxo - 9a -chloro - 11b  - hydroxy - 22a  - spirostadiene; and selenium compounds of the formul : <FORM:0811867/IV (b)/5> <FORM:0811867/IV (b)/6> and <FORM:0811867/IV (b)/7> and a process for the preparation of D 1-, D 4- or D 1,4-dehydro compounds of the steroid series by treating a 3-oxo compound of the steroid series which is saturated in at least one of the a -positions relatively to the 3-oxo group with selenium dioxide or selenious acid.  The dehydrogenation may be carried out in an aqueous or non-aqueous solvent in an open or closed vessel-preferably in the presence of a tertiary alcohol such as tert.-butyl or -amyl alcohol.  The dehydrogenation is accelerated by the presence of an inorganic or organic acid such as acetic, propionic or benzoic acid, and the organic acid may also serve as the reaction solvent.  If water is present in the reaction mixture, the addition of acid other than selenious acid is not necessary to accelerate the reaction. Suitable reaction solvents are dioxane, glacial acetic acid, acetic anhydride, methanol, ethanol, isopropanol, a polyvalent alcohol such as ethylene glycol, benzene, toluene, hexane, ethyl ether, dibutyl ether, tetrahydrofuran, ethylene glycol mono-ethyl ether, carbon tetrachloride, anisole, pyridine, ethyl acetate, and acetonitrile, and mixtures thereof.  The quantity of selenium dioxide used for the dehydrogenation is preferably adapted to the number of double bonds which have to be introduced, i.e. somewhat more than one molar equivalent of SeO2 for each double bond is required, and excess of the dehydrogenating agent can be eliminated after the reaction, e.g. by means of lead acetate, sulphur dioxide or other reducing agent. Thus D 4-3-keto compounds may be formed from 5b -3-ketones saturated in ring A, D 1-5a -3-keto compounds may be formed from 5a -3-ketones saturated in ring A, and D 1,4-3-keto compounds may be formed from 5a (or b )-3-ketones saturated in ring A or from D 1- or D 4-3-ketones. The starting compounds may be of any steric configuration and may be racemates, e.g. the starting compounds may be 3-ketones of the cholestane, 5a ,22a -spirostane, furostane, cholane, norcholane, bisnorcholane, pregnane or androstane series.  They may be saturated or may contain double bonds, e.g. in the 1- or 4-position and also in the 5-, 6-, 9(11)-, 11- or 16-position, and may contain further substituents such as oxy, oxo, oxymethyl, formyl, carboxyl or alkyl groups e.g. methyl or epoxy groups or halogen atoms-particularly in the 2-, 9-, 11-, 12-, 17-, 18-, 20- or 21-position.  Particularly useful starting compounds for the dehydrogenation process are progesterone, 9(11)-dehydro - 17a  - oxy - progesterone, 11a ,17a -dioxy - progesterone, corticosterone, 11 - desoxycorticosterone, cortisone, hydrocortisone, 11-epi-hydrocortisone, aldosterone, 18-oxy-corticosterone, 11 - epi - corticosterone, 18 - oxy- and 18-oxo-cortexone, 17a -oxy-cortexone, compounds unsaturated in the 4- and 6-positions, e.g. D 4,6 - 17a ,21 - dihydroxy - 3,11,20 - trioxopregnadiene, D 4,6 - 11b ,17a ,21 - trihydroxy - 3,20 - dioxo - pregnadiene, D 4,6 - 11b ,17a ,21-trihydroxy 9a -fluoro (chloro and bromo)-3,20-dioxo-pregnadiene and D 4,6-17a ,21-dihydroxy 9a -fluoro (chloro and bromo)-3,11,20-trioxopregnadiene, allopregnane- and pregnane-3,20-diones, e.g. pregnane- and allopregnane-3,11,20-trione-17a ,21-diol and pregnane- and allopregnane - 3,20 - dione - 11b ,17a ,21-triol; the corresponding 9a - and 12a -halogen derivatives of all these compounds, e.g. 9a -fluoro- and 12a -fluoro- and -chloro-derivatives such as 9a -fluoro - cortisone, D 4 - 3,20 - dioxo - 11b  - oxy-12a  - fluoro - pregnene and 3,20 - dioxo - 11b , 17a  - dioxy - 12a  - fluoro - pregnane; 2 - alkyl derivatives and 9 : 11b -epoxides such as 2-methyl - hydrocortisone, 2 - methyl - 9a  - fluorohydrocortisone, D 4 - 9 : 11b  - oxido - 3,20 - diketo - 17a  - oxy - pregnene and 9 : 11b -oxido - 3,20 - diketo - 17a  - oxy - pregnane; D 4 - 3 : 17 - dioxo - androstene, the D 4 - 3 - oxo - 17b  - oxy - androstenes which may bear in the 17-position on alkyl group such as a methyl group or an ethinyl group and/or in the 9a -position a halogen atom particularly 9a  - fluoro - 11b  - oxy - 17a  - methyl - testosterone and 17a -ethinyl- and 17a -methyl-testosterone.  In the starting compounds the oxy groups may be esterified with an aliphatic, aromatic or heterocyclic carboxylic acid, e.g. acetic, trimethyl-acetic or benzoic acid, or a furane carboxylic acid. The starting compounds may also contain an etherified hydroxyl group, e.g. the tetrahydropyranyloxy-, benzoyloxy- or triphenylmethoxy group.  Oxo groups other than the 3-oxo group may be in the ketalized form especially a ketalized oxo group derived from a bivalent alcohol, e.g. the ethylenedioxy group.  An 11-hydroxy group in the product may be oxidized to an 11-keto group.  The products of the above process may be converted into esters, ethers, enol esters and enol ethers. In the esters and enol esters, the acid residues may be those of any desired organic or inorganic acid, e.g. an aliphatic, alicyclic, araliphatic, aromatic or heterocyclic carboxylic acid, e.g. formic, acetic, a chloracetic, trifluoro-acetic, propionic, trimethyl-acetic, b -cyclopentylpropionic, benzoic, phenyl-acetic, cyclohexyl - acetic, g  - cyclohexyl - butyric, b -phenyl-propionic, an hydrohalic or phosphoric acid.  If desired, any ester or other groups in the products may be converted into the free groups, e.g. by chemical or enzymatic hydrolysis.  The D 1,4-3-oxo-9,11b -oxido-pregnadienes, -spirostadienes and -ondrostadienes obtained by the process of the invention, or by a subsequent treatment of D 1,4,9(11)-3-oxopregnatrienes, -spirostatrienes, or -androstatrienes respectively with N-bromo-acetamide to form a 9a -bromo-11b -hydroxy compound and then with silver oxide, can be converted by the action of a hydrohalic acid especially hydrofluoric or hydrochloric acid into the corresponding 9a  - halogen - 11b  - oxy - compounds, e.g. 1 - dehydro - 9a  - fluoro (and chloro)-hydrocortisone may be prepared from 1-dehydro - 9,11b  - oxido - 17a  - oxy - cortexone. In the reactions to prepare dehydro compounds, D 1,4 - 3 - oxo - selenium steroids may be formed in addition to the dehydro compounds.  The selenium derivatives have the following basic structure <FORM:0811867/IV (b)/8> In the examples D 1-17a ,21-dihydroxy-3,11,20-trioxo - allopregnene - 21 - acetate, 1,9(11)-dehydro - 17a  - oxy - progesterone, D 1,4,9(11)-3,20 - dioxo - 17a  - oxy - 21 - acetoxy - pregnatriene, D 1,4,9(11) - 2 - methyl - 3,20 - dioxo-17a  - oxy - 21 - acetoxy - pregnatriene, D 1,4,9(11) 3 - oxo - 22a - spirostatriene, D 1,4,6 - 17a ,21-dihydroxy - 3,11,20 - trioxo - pregnatriene, D 1,7,6- 17a ,21 - dihydroxy - 9a  - fluoro - 3,11,20-trioxo - pregnatriene, D 1,4,6 - 11b ,17a ,21 - trihydroxy - 9a  - fluoro - 3,20 - dioxo - pregnatriene, and D 1,4,6 - 11b ,17a ,21 - trihydroxy - 3,20-dioxo-pregnatriene, and a large number of D 4- and D 1,4-compounds are prepared.  3,11,20 - Trioxo - 9a  - chloro (and fluoro)-17a  - oxy - 21 - acetoxy - pregnane and -allopregnane and the corresponding 2-methyl-derivatives are prepared by treating D 9,(11)-3,20-dioxo - 17a  - oxy - 21 - acetoxy - pregnane and -allopregnane and the corresponding 2-methyl-derivatives with N-bromoacetamide to form 3,20 - dioxo - 9a  - bromo - 11b ,17a  - oxy - 21-acetoxy - pregnane and - allopregnane and the corresponding 2 - methyl - derivatives, treating these compounds with pyridine and silver oxide and then with acetic anhydride to form 3,20-dioxo - 9,11b  - oxido - 17a  - oxy - 21 - acetoxy - pregnane and -allopregnane and the corresponding 2-methyl-derivatives, treating these compounds with hydrogen chloride or hydrogen fluoride, and oxidizing the resulting 3,20-dioxo-9a  - chloro (or fluoro) - 11b ,17a  - dioxy - 21 - acetoxy - pregnane and - allopregnane and the corresponding 2-methyl-derivatives.  D 4 - 2 - Methyl - 3,20 - dioxo - 9,11b  - oxido-17a  - oxy - 21 - acetoxy - pregnene is prepared by treating D 4,9(11) - 2 - methyl - 3,20 - dioxo - 17a  - oxy - 21 - acetoxy - pregnadiene with N-bromo-acetamide to form D 4-2-methyl-3,20-dioxo - 9a  - bromo - 11b ,17a  - dioxy - 21 - acetoxy-pregnene, and treating this compound with pyridine and silver oxide and then with acetic anhydride.  D 9(11) - 2 - Methyl - 3,20 - dioxo - 17a  - oxy-21 - acetoxy - allopregnene is prepared by hydrogenating 2 - methyl - cortisolacetate and treating the resulting 2-methyl-3,20-dioxo-17a -21-acetoxy-allopregnane with phosphorus oxychloride in pyridine.