C00c2h5

j Haloperidol'8 0) Furethidine(81> In the phenylpiperidine series, which was then studied on a large scale, further analgesics were developed. Besides pethidine, which is still of therapeutic importance in spite of competition from newer analgesics belonging to the same or different groups, a series of phenylpiperidine derivatives has been developed, the most important of which are given in Table II. 3. Synthesis of .N-methyl-morphinan by Grewe Once the structure of morphine had been...

Ch2ch2ch3

(b) The anti-tussive activity of iV-aralkyl derivatives of (-f)-morphinans does not parallel the analgesic action of the corresponding ( )-isomers. The ( + )-isomers of the strongly analgesic ( )iV- 2-(2-furyl)-ethyl - and which are 60 and 45 times more strongly analgesic than ( )-3-hydroxy-iV-methyl morphinan, proved to be 3 to 5 times less effective as cough inhibitors than Dextromethorphan. This was equally true for their methyl ethers. (c) Substitution at position 2 and formation of an...

References

R.Grewe, Naturwissenschaften 33, 333 (1946). 2. R. Grewe, Angew. Chem. 59, 198 (footnote) (1947). 3. J.A.Barltrop, J. Chem. Soc. 399 (1947). 4. J.M.Gulland and R.Robinson, Mem. Manchester Phil. Soc. 69, 79 (1925). 5. C. Sch pf, Ann. Chem. 452, 211 (1927). 6. C.I.Wright and F.A.Barbour, J. Pharmacol. Exp. Therap. 53, 34 (1935). 7. L.F.Small, N.B.Eddy, E.Mosettig and N.Himmelsbach, U.S. Publ. Hlth. Rep. No. 138 (1938). 8. N.B.Eddy, Ann. N.Y. Acad. Sei. 51, 51 (1948). 9. C.K.Himmelsbach, J....

Info

'I'his greatly facilitated the isolation of this enantiomer in an optically pure form. In order to obtain an absolutely pure -antipode, the resolution had to be carried out at an earlier stage of the synthesis with 59 which has only one asymmetric carbon itom CJ 154 . This separation is achieved also with -tartaric acid. In this case, the less soluble tartrate is formed by the base which, after the usual cyclization with phosphoric acid, yields -3-hydroxy-iV-methyl-morphinan. These two methods...

Ci

E, H2SO, r v rV gt 1 H2 PI i _n - - jl _n - - i j ch3 - en r ch v v-r ch k s Chlorotetrahydroisoquinoline 78 is condensed with the appropriate benzyl cyanidc to yield 79 . The latter is transformed by a series of unambiguous reactions to 82 which, on treatment with phosphoric acid, yields iV-methyl-morphinan. This procedure is also applicable to the preparation of 3-hydroxy-iV-methyl-morpliinan R OH 83 and -tetrahydrodesoxycodeine 73 . As already indicated 3-hydroxy-iV-methyl-morphinan...

Cooh

88 95 96 97 94 Shortly afterwards it was discovered that this amine 94 which was easily obtainable in high yields could be used as starting material for the syntheses of several morphinans Roche 128 , Grewe 131 , Henecka 32-133 , Sasa-moto 34 - In fact, Schnider and Hellerbach 128 found that cyclohexe-nylethylamides e.g. 99 could easily be cyclized in good yields even when the reacting alicyclic double bond is not activated by any substituent0 35 , Amides of the structure 99 were obtained by...