Patent IE-36653-B1 (IE)
Title: 17-hydroxy-7-(lower alkoxy) carbonyl-3-oxo-17alpha-pregn-4-ene-21-carboxylic acidgamma-lactones and congeners
IPC: C07D/
Filed: 1972-08-24
Abstract: 1368005 7-Carboxy steroids and related compounds G D SEARLE & CO 24 Aug 1972 [25 Aug 1971] 39401/72 Heading C2U Novel steroids have the formulµ wherein Z is H, alkali metal, alkaline earth metal/2, ammonium or alkyl; Z<SP>1</SP> is H, alkali metal, alkaline earth metal/2 or ammonium when Z is alkyl and is identical to Z when Z is H, alkali metal, alkaline-earth metal/2 or ammonium; the #<SP>1</SP> double bond is optional; the wavy line indicates the alternative α and # configurations; and X is oxygen, and it may also be sulphur when Z is alkyl and #<SP>1</SP> is absent in (Ia). They are prepared by (a) contacting 4α,7α - carbonyl - 5 - cyano - 17 - hydroxy - 3- oxo - 5#,17α - pregnane - 21 - carboxylic acid γ-lactone with an alkali metal alkoxide to afford a mixture of 7α and 7# compounds (Ia) wherein X is O, Z is alkyl and #<SP>1</SP> is absent, which may be separated by conventional procedures; (b) contacting an active acylating derivative of a compound (Ia) wherein X is O and Z is H, particularly a novel compound of the formula with an alkanol to give compounds (Ia) wherein X is O and Z is alkyl, the acylating derivatives (II) being prepared from the corresponding 7- carboxylic acids (Ia) and alkyl chloroformates in the presence of a tertiary amine; (c) dehydrogenating a compound (Ia) wherein X is O, Z is alkyl and #<SP>1</SP> is absent to give the corresponding #<SP>1,4</SP> compound, using, for example, 2,3-dichloro - 5,6 - dicyano - 1,4 - benzoquinone; (d) reacting a compound (Ia) wherein X is O and Z is alkyl or H with, respectively, one or two equivalents of a base, e.g. KOH, in an aqueous medium, to give the corresponding mono- or bis-metal salt (Ib) followed, when required, by brief exposure to a proton source to give the corresponding mono- or di-carboxylic acid (Ib); (e) hydrolysing under alkaline conditions a compound (Ia) wherein X is O and Z is alkyl followed by mineral acid treatment to give a compound (Ia) wherein X is O and Z is H; (f) contacting a starting material as defined in (b) above with an alkane thiol to give a compound (Ia) wherein X is S, Z is alkyl and #<SP>1</SP> is absent; (g) contacting a starting material as defined in (a) above with KOH in methanol followed by alkaline hydrolysis and subsequent mineral acid treatment to give a corresponding 7α compound (Ia) wherein X is O, Z is H and #<SP>1</SP> is absent; (h) contacting a compound (Ia) or (Ib) wherein X is O, Z is H or alkyl and Z<SP>1</SP> is H which contains at least one acid hydrogen with an appropriate quantity of a base in an aqueous medium to give a corresponding mono- or bis-metal salt of a compound (Ia) or (Ib); or (i) contacting a compound (Ia) wherein X is O and Z is H or a compound (Ib) wherein X is O, Z is H or alkyl and Z<SP>1</SP> is H with excess ammonia to give a corresponding ammonium salt. 4α,7α - Carbonyl - 5 - cyano - 17 - hydroxy - 3- oxo - 5#,17α - pregnane - 21 - carboxylic acid γ-lactone is prepared by heating 17-hydroxy-3- oxo - 17α - pregna - 4,6 - diene - 21 - carboxylic acid γ-lactone with an alkali metal cyanide under slightly basic conditions in a solvent followed by heating the resulting 7α,4-aminomethylidyne - 5 - cyano - 17 - hydroxy - 3 - oxo- 5#,17α - pregnane - 21 - carboxylic acid γ- lactone with very dilute aqueous mineral acid (see Specification 1,368,006). The novel steroids of the Formulµ (Ia) and (Ib) are diuretic and blood pressure-lowering agents. They may be made up into pharmaceutical compositions with suitable carriers.
[GB1368005A]