Patent GB-1206303-A (GB)
Title: Fluorene compounds and preparation thereof
IPC: C07C47/548
Filed: 1968-02-21
Abstract: 1,206,303. Fluorene compounds. RICHARDSON-MERRELL Inc. 21 Feb., 1968 [21 Feb., 1967], No. 8524/68. Heading C2C. The invention comprises novel compounds of the Formula (I) where Z is defined as at (a) and X, X<SP>1</SP>, Y and n are defined as below and a process for preparing a fluorene compound of the Formula (I) wherein each of X and X<SP>1</SP> is hydrogen or X and X<SP>1</SP> together form a bond between the carbon atoms to which they are attached; Y is n is 0 or 1; Z is (a) pyridyl or N-(lower alkyl containing 1 to 4 carbon atoms) piperidyl having its open bond at a ring carbon atom or piperidyl having its open bond at a ring carbon atom; or a pharmacologically acceptable acid addition salt thereof, comprises reacting a correspondng compound in which -Y-(CH 2 ) n -Z is -CN, with a hetero-organometallic compound Q- (CH 2 ) n -Z wherein Q is lithium or sodium, and if desired, reducing a compound obtained wherein Y is with sodium borohydride or lithium aluminium hydride to obtain a compound wherein Y is and, if desired, selectively hydrogenating a compound obtained wherein Z is pyridyl to the compound wherein Z is piperidyl, if desired, after first obtaining the quaternary N-methyl pyridinium compound which is hydrogenated to the compound wherein Z is N-methylpiperidyl and, if desired, obtaining an acidaddition salt of a free base product obtained; in the case of compounds as defined above but where Y is and Z is (b) piperidyl having its open bond at the nitrogen atom, the process comprises condensing a corresponding compound wherein Y is and Z is -Br with piperidine, if desired, reducing the compound obtained wherein Y is with sodium borohydride or lithium aluminium hydride to obtain a compound wherein Y is and, if desired, obtaining an acid-addition salt of a free base obtained. 3 - Chloromethyl - 1 - methylpiperidine is obtained by making an aqueous solution of the hydrochloride strongly basic with sodium hydroxide pellets and extracting with ether. α - Fluoren - 9 - yl - p - tolunitrile is prepared by hydrogenation of α-fluoren-9-ylidene-p-tolunitrile in dimethylformamide in the presence of a palladium-on-charcoal catalyst, under 50 p.s.i. hydrogen pressure. α - Fluoren - 9 - ylidene - p - tolualdehyde is prepared by treating α-fluoren-9-ylidene-ptolunitrile with anhydrous stannous chloride and dry hydrogen chloride gas to give an imidochloride-tin complex which is decomposed by heating on a steam bath. 4<SP>1</SP> - Fluoren - 9 - ylidenylmethylacetophenone is prepared by treating α-fluoren-9-ylidene-ptolunitrile with methyl magnesium iodide. 2 - {p - [1 - (9 - fluorenyl) - 2 - (2 - pyridyl)- ethyl]-phenacyl}-pyridine is produced as a byproduct in the production of 2-[p-(fluoren-9- ylidenylmethyl)-phenacyl]-pyridine from α-fluoren-9-ylidene-p-tolunitrile and α-picolyl lithium. p - (Fluoren - 9 - ylidenylmethyl) - phenacyl bromide is prepared by treating 4<SP>1</SP>-fluoren-9- ylidenylmethylacetophenone with cupric bromide in the chloroform-ethyl acetate solution. The use of 4-picolyl sodium and 3-picolyl sodium to alkylate α-fluoren-9-ylidene-p-tolunitrile gives 4-{p-[1-(9-fluorenyl)-2-(4-pyridyl)- ethyl] - phenacyl} - pyridine and 3 - {p - [1 - (9- fluorenyl) - 2 - (3 - pyridyl) - ethyl] - phenacyl}- pyridine respectively. Treatment with 4- picolyl sodium of α-fluoren-9-ylidene-p-tolualdehyde gives α - {p - [1 - (9 -fluorenyl) - 2 - (4 - pyridyl) - ethyl] - phenyl} - 4 - pyridineethanol as a mixture of two diastereoisomeric pairs. Pharmaceutical compositions having anticoagulant activity and containing compounds of the Formula (I) wherein each of X and X<SP>1</SP> is hydrogen or X and X<SP>1</SP> taken together form a bond between the carbon atoms to which they are attached; Y is n is 0 or 1; and Z is pyridyl, or N-(lower alkyl having 1 to 4 carbon atoms) piperidyl having its open bond at a ring carbon atom, or piperidyl having its open bond at either ring-carbon atom or the nitrogen atom, but not at the nitrogen atom when Y is or pharmaceutically acceptable acid addition salts thereof, are administered orally or parenterally in association with a suitable pharmaceutical carrier.