Patent GB-816922-A (GB)
Title: Manufacture of polyoxygenated steroids
IPC: C12P33/00
Filed: 1955-07-13
Abstract: Compounds of the pregnane series (as hereinafter defined) having in at least two of the positions 11, 17 and 21 one of the following substituents: in the 11-position an oxo or hydroxy group, in the 17-position a hydroxy group, and in the 21-position a hydroxy group, wherein a compound of the pregnane series which is saturated and unsubstituted in two or three of the 11-, 17- and 21-positions is subjected in any order of succession, but without interruption, to the action of enzymes from aerobic cultures of two or three fungi, each fungus being selected from a different one of the following groups:-(a) the order Mucroales (e.g. Cunninghamella blakesleena or Rhizopus nigricans) and the genera Curvularia (e.g. C. brachyspora or C. lunata), Aspergillus, Streptomyces and Coniothyrium; (b) the species Trichothecium roseum, Leptosphaeria maculans, Cucurbitaria laburni, Acrospeira levis, Lophotrichus hartinii, Melanospora parasitica, and Thielavia terricola; and (c) the species Ophiobolus herpotrichus and Sclerotinia fructicola, with the proviso that the fungi employed are those capable of oxygenating the starting material employed in the said saturated and unsubstituted positions.  The compounds of the pregnane series are defined as saturated and unsaturated 10,13-dimethyl-17-ethyl-cyclopentanophenanthrenes and higher and lower homologues thereof, e.g. the 19-nor-compounds. Double bonds may be present, for example, in the 1-, 4-, 5-, 6-, 7-, 9-, 11-, 14-, 15- and/or 16-positions, subject to the above requirement concerning the 11-, 17- or 21-position.  The configuration of the pregnane reactant may be that of pregnane, 5a -pregnane or 17a -pregnane or the corresponding racemates such as those obtained by total synthesis.  The pregnane reactants may be oxygenated in the 3- and 20-positions and, if desired, in the 18- and/or in one of the 11-, 17- and 21-positions, and functional derivatives of such compounds, e.g. the said positions may be substituted by free or functionally converted oxo or hydroxy groups, particularly ester, ether, thioether, thiol- and thionesters, acetal, mercaptal, ketal, and enol groups such as an enol ester or enamine, and hydrazone and semicarbazone groups. The pregnane reactants may contain further substituents, e.g. free or functionally converted hydroxyl or oxo groups, particularly in the 1-, 2-, 6-, 7-, 12-, 15-, 16- or 19-position, or halogen atoms, particularly in the 9-position. Particularly useful reactants are 11 : 21-saturated and 11 : 21-unsubstituted, 11 : 17-saturated and 11 : 17-unsubstituted, and 11 : 17 : 21-saturated and unsubstituted pregnanes.  Specific starting compounds mentioned are progesterone, 17a -progesterone, 16a -oxy-, 17a -oxy- and 18-oxy-progesterone, cortexone, 11-keto-progesterone, 11a - and 11b -oxy-progesterone, 9 : 11- and 11 : 12-dehydro-progesterone, 19-oxy-progesterone, 9-chloro- and 9-fluoro-11b -oxy-progesterone, 11b ,18-dioxy-progesterone, 11b  - oxy - 18 - oxo - progesterone, 9-chloro- and 9-fluoro-11b -oxy-18-oxo-progesterone, 11 : 18-dioxo-progesterone, 19-nor-progesterone, 19 - nor - 11b  - oxy - 18 - oxo - progesterone, pregenolone and D 1,4-pregnadienes such as 1-dehydro-progesterone, 1-dehydro-17a -hydroxy-progesterone, 1-dehydro-11-keto- (and 11-a - and b -hydroxy)-progesterone and functional oxo and hydroxy derivatives thereof.  Submerged cultures of the appropriate fungi grown under aerobic conditions, or filtrates or enriched enzyme preparations obtained therefrom may be used in the above process.  In the examples, the following compounds are prepared; corticosterone, aldosterone, 17a ,21-dioxy-progesterone, cortisone, hydrocortisone, 11a ,17a ,21 - trioxy - progesterone, 1 - dehydrohydrocortisone, and 1-dehydro-cortisone.  Specifications 723,881, 724,094, 724,141, 727,811, 732,364, 732,686, 741,477, 749,414, 749,943, 767,361, 805,602, 806,141 and 809,911 are referred to.