Patent GB-1373305-A (GB)
Title: 8-benzofurylmethyl-1,3,8-triazaspiro 4,5 decanes process for their manufacture and pharmaceutical preparations containing them
IPC: C07C45/71
Filed: 1971-12-31
Abstract: 1373305 Benzofurylmethyl - triazaspirodecanes; organomercury compound CIBAGEIGY AG 31 Dec 1971 [8 Jan 1971 24 Sept 1971] 61004/71 Headings C2C and C2J Novel compounds I in which Ph is 1,2-phenylene; R 1 , R 2  and R 3  are H or 1-7 C alkyl; alkl and alk 2  are 2-7 C alkylene separating the N from the spiro C by 2 ring C atoms; R 4  is H, 1-7 C alkyl, 2-7 C alkenyl or alkynyl, 3-7 C cycloalkyl or cycloalkenyl, 3-7 C cycloalkyl-1-7 C alkyl, 3-7 C cycloalkenyl-1-7 C alkyl or H-Ph-CnH 2n -; n is 0 or 1-4; R 5  is 2H, H and 1-7 C alkyl, or oxo; and R 6  is H or 1-7 C alkyl or hydroxyalkyl; and their acyl derivatives, N-oxides and quaternary ammonium salts are prepared by reaction of a compound III in which X is a reactive esterified OH group with a compound IV followed where necessary by acylation, salt formation or N-oxide formation and/or by resolution. Intermediates isolated are (1) 2 - bromomethyl - 5 - fluoro - 2,3 - dihydro - benzofuran, prepared by reaction of 4-fluorophenol with allyl bromide to give I-allyloxy-4-ftuorobenzene, heating this under N 2  to give 2-allyl-4-fluorophenol, acetylating this to give 1-acetoxy-2- allyl - 4 - fluorobenzene, brominating this to give 1,2 - dibromo - 3 - (2 - acetoxy - 5 - fluorophenyl)propane and cyclizing this with NaOCH 3 ; (2) 2 - bromomethyl - 4 or 6 - methoxy - 2,3- dihydrobenzofuran, prepared similarly to the intermediate (1), starting from 3-methoxyphenol; (3) 2-bromomethyl-2-methyl-5-methoxy- 2,3-dihydrobenzofuran, prepared by reaction of 4-methoxy phenol with 3-chloro-2-methyl-propene to give 4-methallyloxyanisole, refluxing this in N,N-dimethylaniline to give 2-methallyl-4- methoxyphenol, reacting this with mercuric chloride to give 5-methoxy-2-methyl-2,3-dihydro- 2 - benzofurylmethyl - mercuric chloride and brominating this; (4) 4-oxo-1,3,8-triazaspiro- (4,5)-decane, prepared by reaction of 1-benzyl-4- piperidone with KCN and CH 3 COONH 4  to give 4 - amino - 1 - benzyl - hexahydro - isonicotinonitrile, hydrolysing this to 4-amino-1-benzylhexahydronicotinamide, reacting this with formamide to give 8-benzyl-4-oxo-1,3,8-triazaspiro- (4,5)decane and hydrogenation of this; (5) 1-2- (tosyloxymethyl) - 5 - methoxy - 2,3 - dihydrobenzofuran, prepared by reaction of dl-5- methoxy - 2,3 - dihydro - 2 - benzofurancarboxylic acid with l-amphetamine to resolve the acid into its d and I salts with amphetamine, isolating the free d and l acids from the salts by treatment with 6NHCl, reducing the l-acid to l - 2 - hydroxymethyl - 5 - methoxy - 2,3 - dihydrobenzofuran and reacting this with tosyl chloride; (6) 3 - methyl - 2,4 - dioxo - 1,3,8 - triazaspiro- (4,5)decane, prepared by hydrogenation of 8- benzyl - 3 - methyl - 2,4 - dioxo - 1,3,8 - triazaspiro(4,5)decane; (7) 2-bromomethyl-5-acetyl- 2,3-dihydrobenzofuran, prepared by reaction of 4-hydroxyacetophenone with allyl bromide to give 4-allyloxyacetophenone, heating this under N 2  to give, after acetylation, 4-acetoxy-3-allylacetophenone, brominating this to give 1,2- dibromo - 3 - (2 - acetoxy - 5 - acetylphenyl)- propane, and cyclizing this using NaOCH 3 ; and (8) l - 2 - (d - 10 - camphorsulphonyloxymethyl) - 5 - methoxy - 2,3 - dihydrobenzofuran, prepared by reacting dl-2-bromomethyl-5-methoxy - 2,3 - dihydro - benzofuran, with benzoic acid to give dl - 2 - benzoyloxymethyl - 5 - methoxy - 2,3 - dihydro - benzofuran hydrolysing this with KOH to give dl-2-hydroxymethyl-5- methoxy-2,3-dihydrobenzofuran and reacting this with d-10-camphorsulphonyl chloride. Pharmaceutical compositions useful as analgesics and CNS depressants comprise a compound I together with a suitable diluent or carrier.