Patent GB-843216-A (GB)
Title: Improvements in or relating to steroid compounds
IPC: C12P33/00
Filed: 1955-08-03
Abstract: The invention comprises cyclopentanophenanthrene compounds of the general formula <FORM:0843216/IV(b)/1> wherein X represents H2, O or (H1OH), R represents H or OR1, R1 being H or an ester radical derived from an inorganic or organic acid, and Y represents O or an additional bond between carbon atoms 16 and 17, and the preparation thereof by dehydrogenating the corresponding 3-keto-4-pregnene or 3-hydroxy (or acyloxy)-5-pregnene with a culture of a micro-organism of the family Corynebacteriacae e.g. of the genus Corynebacterium, or by treating the corresponding 3-keto-4 : 16(17)-pregnadiene or 3-hydroxy (or acyloxy)-5 : 16(17)-pregnadiene with a peracid or hydrogen peroxide in the presence of an alkali metal base to form the corresponding 16,17-oxido-3-keto-4-pregnene or 16,17-oxido-3-hydroxy (or acyloxy)-5-pregnene respectively and then dehydrogenating as above.  In the latter process, the two steps may be carried out in the reverse order.  The micro-organism is preferably of the genus Corynebacterium e.g., C. simplex or C. hoagii.  The group R is may be a sulphate, phosphate polyphosphate, or a formyloxy group, an alkanoyloxy group containing up to 8 carbon atoms e.g. an alkanoyloxy group derived from acetic, propionic, butyric, valeric, and caproic acids, a substituted alkanoic or aromatic acid such as cyclohexyl and cyclopentyl acetic, propionic and butyric acids and benzoic acid. Suitable reactants for use in the two stage process are 4,16-pregnadiene-3,20-dione, 5,16-pregnadiene-3-ol-20-one or a 3-ester thereof, 5,16-pregnadiene-3,11-diol-20-one or a 3-ester thereof, 5,16-pregnadiene-3,21-diol-20-one or a 3- or 21-ester thereof, 5,16-pregnadiene-3,11,21-triol-20-one or a 3- or 21-ester thereof, 4,16-pregnadiene-3,11,20-trione, and 4,16-pregnadiene-21-ol-3,11, 20-trione or a 21-ester thereof.  The dehydrogenating culture is capable not only of introducing a 1-double bond but also of oxidising a 3-hydroxyl group to a 3-keto group with simultaneous shifting of the 5(6) double bond to the 4(5) position, and under certain conditions is capable of oxidising a 20-hydroxy group to a 20-keto group and hydrolysing a 21-ester group which may be subsequently hydrolysed as required.  Thus the above processes facilitate the conversion of 16-dehydropregnenolone and 16-dehydroprogesterone and their esters into 1-dehydrocortisol and 1-dehydrocortisone respectively and their esters.  The conversion involves the following steps:-(a) formation of the 3-keto-4-pregnene system (in the case of 16-dehydropregnenolone); (b) introduction of a 17 a -hydroxy via the 16,17-epoxide; (c) introduction of a 21-hydroxy group by the action of a culture of a micro-organism of the genus Ophiobolus; (d) introduction of an 11 a -hydroxy group such as by the action of a culture of a micro-organism of the species Rhizopus arrhizus or Rhizopus nigricans, or of an 11 b -hydroxy group with the aid of a culture of a micro-organism of the species Curvularia lunata; and (e) the introduction of the 1-double bond by the method referred to above. Step (a) may be accomplished by the Oppenauer oxidation, by careful oxidation with chromic oxide at room temperature or below, or by the action of a culture of the dehydrogenating micro-organism.  Step (b) may be carried out using a per-acid such as perphthalic or perbenzoic acid to form the 16,17-epoxide which is then treated with hydrogen iodide in admixture with acetic acid and acetic anhydride to form a 16-iodo-17 a -hydroxy-compound, and the iodine atom is then removed by refluxing in a lower aliphatic alcohol such as ethanol, containing a small amount of an organic acid such as acetic acid, in the presence of Raney nickel.  Compounds containing an 11 a  or b -hydroxy group may be oxidised to the corresponding 11-keto-compound.  The various conversions which may be applied to 16-dehydropregnenolone and 16-dehydroprogesterone are summarized as follows:- <FORM:0843216/IV(b)/2> Most of these steps are completely independent of each other so that the sequence of operations can be changed in a variety of ways, thus 16-dehydropregnenolone, 16,17-epoxy-5-pregnen-3-ol-20-one, 16-dehydroprogesterone and 16,17-epoxy-4-pregnene-3,20-dione may be 11 a  or b -hydroxylated and 21-hydroxylated and then converted to the 3-keto-1,4-diene system, and these three sequences can be carried out in any order. It does not matter at what point the 16,17-epoxide ring is opened up by means of hydriodic acid to form the 17 a -hydroxy group or at what point the 11-hydroxy group is oxidised to the 11-keto group provided that during these reactions any hydroxy groups at the 3- and 21-positions are protected by ester groups which can be subsequently removed.  In an example, 5,16-pregnadiene-3-ol-20-one is treated with a culture of micro-organisms of the species Ophiobulus herbatrichus to form 5,16-pregnadiene-3,21-diol-20-one, the diol is diacetylated to form 5,16-pregnadiene-3,21-diol-20-one, 3,21-diacetate, the diacetate is treated with a culture of micro-organisms of the species Corynebacterium simplex to form 1,4,16-pregnatriene-21-ol-3,20-dione, the pregnatriene is treated with perbenzoic, peracetic or perphthalic acid or hydrogen peroxide in the presence of sodium or potassium hydroxide, to form 16,17-epoxy-1,4-pregnadiene-21-ol-3,20-di-one, the 16,17-epoxy compound is treated with hydrogen iodide to form 16-iodo-1,4-pregnadiene-17 a ,21-diol-3,20-dione, the 16-iodo compound is treated with Raney nickel to form 1,4-pregnadiene-17 a ,21-diol-3,20-dione, the diol is treated with a culture of micro-organisms of the species Curvularia lunata to form 1,4-pregnadiene-11 b , 17 a ,21-triol-3,20-dione which is then oxidised to 1,4-pregnadiene-17 a ,21-diol-3,11,20-trione.  If in the example, the initial step of hydroxylation at the 21-position is omitted, 1,4,16-pregnatriene-3,20-dione and 16,17-epoxy-1,4-pregnadiene-3,20-dione may be prepared, and the latter compound may be hydroxylated at the 11-position to form 16,17-epoxy-1,4-pregnadiene-11 (a  or b )-ol-3,20-dione, also 5,16-pregnadiene-3,11 (a  or b )-diol-20-one or a 3-ester thereof may be used as the starting material and, omitting the 21-hydroxylation step, 1,4,16-pregnatriene-3,11,20-trione and 16,17-epoxy-1,4-pregnadiene-3,11,20-triene and their esters may be prepared.  In addition, if 5,16-pregnadiene-3,21-diol-20-one or a 3- or 21-ester thereof is used as the starting material, 1,4, 16-pregnatriene-21-ol-3,20-dione and 16,17-epoxy-1,4-pregnadiene-21-ol-3,20-dione are prepared, if 5,16-pregnadiene-3,11 (a  or b ), 21-triol-20-one or a 3- or 21-ester thereof is used as the starting material, 1,4,16-pregnatriene-11 (a or b ), 21-diol-3,20-dione and 16,17-epoxy-1,4-pregnadiene-11 (a  or b ), 21-diol-3,20-dione are prepared, and if 4,16-pregnadiene-21-ol-3,11,20-trione or a 21-ester thereof is used as starting material, 1,4,16-pregnatriene-21-ol-3,11,20-trione and 16,17- epoxy-1,4-pregnadiene-21-ol-3,11,20-trione are obtained.