Patent GB-1143661-A (GB)
IPC: C07J75/00
Abstract: 1,143,661. 18 - Alkyl - steroids. SYNTEX CORP. 18 March, 1966 [19 March, 1965; 18 Feb., 1966], No. 12155/66. Heading C2U. The invention comprises (1) a process for the preparation of an 18 - (C 1-3  alkyl) - 20 - hydroxypregnane (including ring - unsaturated and 19- nor compounds) in which an 18,20 - lactone of a 20 - hydroxy - pregnan - 18 - oic acid is reacted with an excess over 1 mole of a C 1-3  alkylmagnesium halide to give the corresponding 18 - (C 1-3  alkyl) - 20 - hydroxy - 18 - one steroid and this is converted to the required product by reaction with an excess over 1 mole of hydrazine hydrate to give the 18 - hydrazone and treatment of this with a strong base; and (2) novel steroids of the partial structure (wherein R<SP>1</SP> is C 1-3  alkyl; Z<SP>11</SP> is a single or double bond or #-oxido between C-9 and C-11; and Y<SP>11</SP> is hydrogen, α- or #- hydroxy, α- or #-acyloxy or oxo, but is H when Z<SP>11</SP> is oxido or a double bond). These processes and products are described in detail, as are the following preparations of starting materials and processing of final products. 18 - Alkyl - progesterones and - 19 - nor - progesterones are prepared by the process (wherein R is CH 3  or H; and there is a #<SP>5(10)-</SP> double bond, when R<SP>5</SP> is absent, or there is a #<SP>5</SP> double bond, when R<SP>5</SP> is CH 3 ). The first stage is an Oppenauer oxidation and the second an oxidation with Jones' reagent. The intermediate #<SP>4</SP> - 3 - one can also be prepared by hydrolysis of the corresponding #<SP>5</SP> - 3 - ketal. 17α - Hydroxy and acyloxy - 18 - alkyl - progesterones are prepared by the following process: (wherein R<SP>6</SP> is H or acyl; and Ac is acetyl), the reaction steps being successively acylation, oxidation, bromination, debromination using Nal in methyl ethyl ketone, dehydrobromination with CaCO 3  in dimethyl formamide, epoxidation, reaction with HBr and catalytic hydrogenation (one stage), 17 - acylation, hydrolysis in the 3 - position, and Oppenauer oxidation (and, if required, hydrolysis in the 17α - position, and, if desired, re-esterification); or by the following process: (wherein Z<SP>1</SP> is a single or double bond; R<SP>4</SP> is acyl; R<SP>7</SP> is acyloxy or cycloethylenedioxy, being the latter when Z<SP>1</SP> is a double bond, R is H or CH 3  being CH 3  when Z<SP>1</SP> is a double bond and also being CH 3  when R<SP>7</SP> is acyloxy) the reaction steps being oxidation e.g. with Jones' reagent or CrO 3  in pyridine, reaction with an alkali metal tertiary alkoxide in the presence of oxygen gas, catalytic hydrogenation, and, when R<SP>7</SP> is acyloxy, acylation to the 3,17- diacylate, partial hydrolysis to the 3#-ol and Oppenauer oxidation (one stage), or, when R<SP>7</SP> is cycloethylenedioxy, hydrolysis followed by 17-acylation. 18-Alkyl-corticoids are prepared by the following process: (wherein X is F, Cl or Br) the reaction steps being introduction of a 21 - OH group via the 21-iodo and 21-acetoxy compounds by standard procedures, hydrolysis to the #<SP>4</SP> - 3 - one, and conversion to the 9α - halo - 11# - hydroxy products by known methods. Starting materials of the general formula (wherein R<SP>4</SP> is H or acyl) are prepared by oxidizing a #<SP>5</SP>-pregnene-3#,19-diol-20-one 3-acylate to a 10# - carboxy - A<SP>5</SP> - pregnen - 3# - ol - 20 - one 3 - acylate, heating this in pyridine to give a 19 - nor - #<SP>5(10)</SP> - pregnen - 3# - ol - 20 - one 3 - acylate, reducing this to the corresponding 3,20 - diol and converting this to the required 18,20 - lactone (by the method described in Helv. Chim. Acta. 45, 1317-1343, 1962), which may be hydrolysed to the 3#-ol. 3 - Cycloethylenedioxy - 19 - nor - #<SP>5</SP> - pregnen- 18 - oic acid 18,20 - lactone is prepared by reducing 3 - Cycloethylenedioxy - 19 - nor - #<SP>5</SP> - pregnen - 20 - one (prepared from 19-norprogesterone) to the 20#-ol and converting this to the 18,20 - lactone by the method referred to above. 3 - Cycloethylenedioxy - #<SP>5,9(11)</SP> - pregnadien - 18 - oic acid 18,20 - lactone is prepared by warming 3 - cycloethylenedioxy-18-iodo-18,20- oxido - #<SP>5</SP>'<SP>9(11)</SP> - pregnadiene with pyridine, CrO 3 , silver chromate and water.