Patent GB-1469650-A (GB)
Title: Steroids of the oestrane series substituted in 7-position
IPC: C07J21/00
Filed: 1974-03-27
Abstract: 1469650 7-Substituted steroids of the estrane series AKZO NV 27 March 1974 [13 April 1973] 13621/74 Headings C2U and C2P Novel steroids have the formula wherein ring A and the bonding to the 6-position is in which R 5  is H or a free, esterified or etherified hydroxyl group; R 6  is H 2 O, H(#-OH), H(#- Oalkyl) or H(#-Oacyl); and the dotted lines indicate the presence of a #<SP>4</SP>-, #<SP>5</SP>- or #<SP>5(10)</SP>- double bond; R 1  is C 1-4  alkyl; R 2  is O or (α-Y)- (#-Z) in which Y is C 1-4  alkyl, alkenyl, alkynyl, alkadienyl, alkadiynyl or alkenynyl and Z is free, esterified or etherified hydroxyl; R 3  is H or free or esterified hydroxyl; R 4  is C 13  alkylene or alkylidene; and X is H, acyl, alkyl, aralkyl, cycloalkyl or heterocyclyl. Typical preparations are as follows (i) #<SP>4,6</SP>-estradiene-3,17-dione-17- ethyleneketal (from the free dione) with dimethyl sulphoxonium methylide gives 6,7 - methylene- #<SP>4</SP> - estrene - 3,17 - dione 17 - ethyleneketal (mixture of 6α, 7α and 6#, 7#-epimers), this is hydrolysed to the corresponding dione and this is reacted with methanol in the presence of BF 3  etherate to give 7α-methoxymethyl-#<SP>4</SP>-estrene- 3,17 - dione (I) which on hydrolysis gives the corresponding 7α-hydroxymethyl compound; (ii) (I) is converted to the corresponding 3-ethylenedithioketal, this is reduced to the corresponding 17#-ol and this to 7α-methoxymethyl-#<SP>4</SP>-estren- 17#-ol, which is then oxidized to the corresponding 17-one and this converted to 7α-methoxymethyl - 17α - ethynyl - #<SP>4</SP> - estren - 17#- ol; (iii) (I) is converted to 3-hydroxy-7α-methoxymethyl - #<SP>3,5</SP> - estradien - 17 - one 3 - acetate and this is treated with NBA to give 3-hydroxy-7α- methoxymethyl - #<SP>1,3,5(10)</SP> - estradien - 17 - one which may subsequently be reduced to the corresponding 17#-ol; (iv) 17#-hydroxy-#<SP>4,6</SP>-estradien-3-one 17-acetate is reacted with KCN in DMF containing NH 4 Cl to give 7α-cyano-17#- acetoxy - #<SP>4</SP> - estren - 3 - one, this is hydrolysed to the corresponding 17#-ol, this is converted to 3,3 - ethylenedioxy - 7α - cyano - #<SP>5</SP> - estren - 17#- ol, this to the 17#-tetrahydropyranylether, this is hydrolysed to the corresponding 7α-carboxylic acid, this is reduced to 3,3-ethylenedioxy-7α- hydroxymethyl - #<SP>5</SP> - estren - 17# - ol - 17 - THP ether and this is hydrolysed to 7α-hydroxymethyl - 17# - hydroxy - #<SP>4</SP> - estren - 3 - one or is reacted with methyl iodide to give 3,3-ethylenedioxy - 7α - methoxymethyl - #<SP>5</SP> - estren - 17# - ol 17-THP ether which is hydrolysed to the 17#- ol - #<SP>4</SP> - 3 - one; (v) 3 - hydroxy - #<SP>1,3,5(10)</SP>- estratriene - 7,17 - dione 3 - methyl ether 17,17- ethyleneketal is reacted with the Wittig reagent from methyltriphenylphosphonium bromide and NaH in DMSO to give 3-hydroxy-7,7 - methylene- #<SP>1,3,5(10)</SP> - estratrien - 17 - one 3 - methylether 17,17 - ethyleneketal, this is treated with LiACH 4  and BF 3  etherate in ether and then with aqueous KOH and H 2 O 2  to give 3-hydroxy- 7α - hydroxymethyl - #<SP>1,3,5(10)</SP> - estratrien - 17- one 3 - methylether 17,17 - ethyleneketal and the corresponding 7# - hydroxymethyl compound and these on hydrolysis give the corresponding 17- ones; in a similar manner is prepared 3-hydroxy - 7,7 - methoxymethylene - #<SP>1,3,5(10)</SP>- estratrien - 17 - one 3 - methylether 17,17- ethyleneketal, this is catalytically hydrogenated to give 3-hydroxy-7α-methoxymethyl-#<SP>1,3,5(10)</SP>- estratrien - 17 - one 3 - methylether 17,17 - ethyleneketal and the corresponding 7# - methoxymethyl compound and these on hydrolysis give the corresponding 17-ones; and (vi) 3-hydroxy-7α-methoxymethyl-#<SP>1,3,5(10)</SP>-estratrien - 17 - one is converted to 7α - methoxymethyl - #<SP>1,3,5,(10),16</SP> - estratetraene - 3,17 -diol diacetate, this is oxidized to 7α-methoxymethyl-16α,17α- epoxy - #<SP>1,3,5(10)</SP> - estratriene - 3,17# - diol diacetate and this is reduced to 7α-methoxymethyl- #<SP>1,3,5(10)</SP> - estratriene - 3,16α,17# - triol. In general free hydroxy groups in the products may be esterified and etherified and esterified and etherified hydroxy groups hydrolysed by standard procedures. In a further method not specifically exemplified, #<SP>4,6</SP> - 17# - hydroxyestradien - 3 - one, for example, is reacted with an alkoxy alkyl magnesium chloride or a lithiumdialkoxyalkyl copper to give a #<SP>4</SP>-7α- alkoxyalkyl - estradien - 3 - one. Methoxymethyltriphenylphosphonium chloride  is prepared from triphenylphosphine and methoxymethyl chloride. The novel steroids are stated to possess anabolic, androgenic, estrogenic, progestative, and ovulation- and gonad-inhibiting properties, and they may be made up into pharmaceutical compositions with suitable carriers.