Patent GB-952484-A (GB)
Title: New alkaloid derivatives
Inventor: MEN JEAN LE
IPC: C07J75/00
Filed: 1961-02-08
Abstract: The invention comprises (1) compounds of the formula: <FORM:0952484/C2/1> (wherein P and Q each is a hydrogen atom or together they form a double bond; R is a hydrogen atom, an alkyl radical of at most 5 carbon atoms or an acetyl radical; Y is an acetyl radical or a hydrogen atom or, together with B, a bond with the 18-carbon atom; Z is a hydrogen atom or an acetyl radical or, together with A and when B is not a hydrogen atom, a second bond with the 18-carbon atom; A is a hydrogen atom or, together with Z, a double bond; B is a hydrogen atom, the radical OR2 (provided that Z is not a hydrogen atom or an acetyl radical when A is a hydrogen atom) R2 being a hydrogen atom or an alkyl radical, or, together with Y (provided that Z is not a hydrogen atom or an acetyl radical, when A is a hydrogen atom) a bond of the 18-carbon atom to the oxygen on the 20-carbon atom; T is a hydrogen atom, or together with S, a double bond; S is a hydrogen atom or together with T, forms a double bond or, together with X, is a =O, =NOH or ethylenedioxy radical; X is a hydroxyl group, an alkoxy radical of at most 5 carbon atoms, an acetoxy radical or, together with S, is a =O, =NOH or ethylenedioxy radical); and the preparation of paravallarine i.e. (20S)-3 b -N-methylamino-20-hydroxy -18- oie lactone (-->20)-pregna-5-ene, N-methyl-paravallarine, paravallaridine i.e. 16a -hydroxy-paravallarine, and N-methyl-paravallaridine wherein parts of the plant Paravallaris microphylla Pitard are crushed, reduced to powder and the powder is made alkaline, the mixture is extracted with an organic solvent which is immiscible with water, other than an alcohol having more than 5 carbon atoms, the bas alkaloids contained in the organic phase are converted into oxalates by treatment with a solution of oxalic acid in water, an alcohol or a ketone of at most 5 carbon atoms and the oxalates are filtered off and converted to the bases. This process may contain a further purification stage in which the alkaloids contained in the organic phase are extracted with a dilute mineral acid, the solution is made alkaline, and the precipitated alkaloids are dissolved in a solvent as described above and then converted to their oxalates.  The paravallaridine may be extracted from the other bases by benzene, the paravallaridine alone being insoluble. The remaining bases may then be separated by chromatography or fractional crystallization, for example in acetone or methyl ethyl ketone. Examples describe this process and also the following: paravallaridine, formic acid and formaldehyde give N-methyl-paravallaridine, which on acetylation gives the 16-acetate, on reduction with lithium aluminium hydride gives (20S) -3b -N-dimethylamino-16a , 18, 20-trihydroxy-pregna-5-ene from which a triacetate is prepared, and on catalytic hydrogenation gives the 4, 5-dihydro-derivative; paravallaridine is heated with acetic anhydride to give the diacetyl derivative this on partial hydrolysis gives the mono-N-acetyl compound, this on heating with alcoholic potash gives (20S)-3b -N-methyl-N-acetylamino-16a , 20-dihydroxy-18-oic pregn-5-ene and this with diazomethane gives the methyl ester; paravallaridine is catalytically hydrogenated to dihydroparavallaridine, this with acetic anhydride gives the diacetyl derivative, this on partial hydrolysis gives the N-mono-acetyl derivative, this on oxidation gives 16-oxo-N-acetyl-dihydroparavallarine (which gives an oxime), this is converted to the 16-ethylene ketal and this on lithium aluminium hydride reduction gives (20S)-3b -N-methyl-N-ethylamino-16-oxo-18, 20-dihydroxy-5a -pregnane; N-methyl-dihydroparavallaridine is (a) converted to the 16-acetate, (b) reduced to (20S)-3b -N-dimethyl-amino-16a , 18, 20-trihydroxy-5a -pregnane, and (c) oxidized to 16-oxo-N-methyl-dihydroparavallarine which on LiAlH4 reduction gives (20S) - 3b  - N - dimethylamino - 16b ,18,20 - tri -hydroxy -5a - pregnane or, without heating, 16-epi-N-methyl-dihydroparavallaridine; 16-oxo-N-acetyl-dihydroparavallarine is reduced with zinc amalgum to N-acetyl -D 15- dihydroparavallarine, this is hydrogenated to N-acetyl-dihydroparavallarine (which is also prepared by acetylation of dihydroparavallarine) or is reduced by LiAlH4 to (20S)-3b -N-methyl-N-ethylamino-18, 20-dihydroxy-5a -pregna-15-ene, either of which can be reduced to (20S) -3b -N-methyl-N-ethylamino-18, 20-dihydroxy-5a -pregnane; and 16-oxo-N-methyl-paravallarine gives on zinc amalgum reduction N-methyl-D 15-dihydroparavallarine which on catalytic hydrogenation gives N-methyl-dihydroparavallarine (also obtained by methylation of dihydroparavallarine. The conversion of paravallaridine to its hydrochloride is also described. Specification 913,602 is referred to.