Patent SE-313304-B (SE)
Inventor: KIRK D
IPC: C07J41/00
Filed: 1963-12-20
Abstract: The invention comprises 3-enol ethers of 3-oxo-D  4-6-aminomethyl steroids having in rings A and B of the steroid nucleus the structure <FORM:0941121/C2/1> (wherein R1 is alkyl, hydroxyalkyl, cycloalkyl or aralkyl and R11 is an alkyl group of at most 6 carbon atoms and R111 an alkyl group of at most 6 carbon atoms or phenyl, or -NR11R111 represents piperidino, pyrrolidino or morpholino) and their addition compounds with acids and boranes; and their preparation by treating a corresponding 6-unsubstituted-3-OR1-3, 5-diene conditions to give a corresponding 6-CH\sLNR 11 R111\sLN iminium intermediate and then reducing this. The Vilsmeier reagent is formed from a formylated secondary amine and an acid halide such as phosphorus halides, thionyl chloride, phosgene or oxalyl chloride, and the amine constituent of this reagent provides the groups R11 and R111 in the products.  The reduction may be effected with the hydrides and organometallic hydrides of boron and aluminium, such as metal borohydrides, boranes and their complexes with bases and substituted borohydrides or the aluminium anologues thereof; and it may result in the production of borane complexes, particularly when excess of reducing agent is used.  Hydroxyalkyl enol ether starting materials may be formed in situ from the corresponding 3-ethylenedioxy- D 5-steroids and enol ether starting materials of 19-nor-steroids may be formed in situ from the corresponding 3-ethers of oestra-2,5(10)-dien-3-ols.  The process may be applied to derivatives of androstane, 19-nor-androstane, 9b ,10a -androstane, pregnane, 19-nor - pregnane, 9b , 10a  - pregnane, cholestane, spirostane, ergostane and stigmastane which may contain hydroxy groups which may be protected e.g. by acylation or, for corticoid side chains, formation of the bis-methylenedioxy derivatives or the 17,21-cyclic carbonates or acetonides, and which if not protected may be formylated in the reaction or replaced by halogen, 16-hydroxymethyl groups, 16a , 17a -alkylenedioxy, carbonyl, carbalkoxy, cyano, alkyl, alkenyl, methylene, ethylidene and 16,17-cyclomethylene groups, lactone and spirolactone residues such as -O.CO.CH2CH2- at position 17, etheric groups at position 16, and bridging positions 18 and 20, spiroketal moieties such as are present in 25D-spirost-4-en-3-one, chlorine, bromine or fluorine atoms e.g. in rings C or D or in the side-chain, unsaturated linkages e.g. at positions 9(11), 11, 14, 16 or 17(20), or epoxy groups.  The lastnamed may be converted to halohydrins corresponding to the halides used in the reagent (which may undergo further reaction with replacement of the hydroxy group by halogen), or they may react directly with the reagent to give acylated halohydrins, but these products may be reconverted to the required epoxides by treatment with alkali.  16b -Methyl-16a , 17a -epoxypregnan-20-ones are converted directly, however, into 17a -hydroxy-16-methylenepregnan-20-ones.  Reduction of the iminium intermediates may be accompanied by reduction of other groups, but this may be minimised by the use of borane compounds, giving borane complexes of the products.  These may be reconverted to the free bases by treatment with a strong base e.g. piperidine. Examples describe the preparation of many 6-aminomethyl-steroids and their derivatives, and the use of testololactone as a starting material is also referred to.  Enol ether starting materials are prepared from the corresponding 3-oxo- D  4-steroids and, for example, methyl or ethyl orthoformate.  Groups R1 may be interchanged.  17a -Hydroxy-21-methylpregn-4-ene-3, 11, 20-trione is prepared by reacting cortisone acetate 3-ethylene ketal with ethylmagnesium iodide to give 20-ethyl-3, 3-ethylenedioxy-17a , 20, 21-trihydroxypregn-5-en-11-one and then treating this with sodium metaperiodate followed by sodium metabisulphite and acetic acid. Specifications 929,983, 941,122, U.S.A. Specifications 2,705,712, 2,742,485 and German Specification 1,068,256 are referred to.