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Details for Patent: 4,731,447

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Details for Patent: 4,731,447

Title: Process for preparing piperidylidene dihydro-dibenzo(a,d)-cycloheptenes or aza-derivatives thereof
Abstract:A process for the preparation of piperidylidene-dihydro-dibenzo[a,d]cycloheptene or aza-derivatives thereof and intermediates in such process are disclosed.
Inventor(s): Schumacher; Doris P. (Florham Park, NJ), Murphy; Bruce L. (Elizabeth, NJ), Clark; Jon E. (Highland Park, NJ)
Assignee: Schering Corporation (Kenilworth, NJ)
Filing Date:Mar 12, 1986
Application Number:06/839,016
Claims:1. A process for preparing a compound of formula I: ##STR25## said process comprising the steps of reacting a compound of formula II ##STR26## with a compound of formula III ##STR27## in the presence of base to produce a compound of formula IV ##STR28## reacting the compound of formula IV with a dehydrating agent to produce a compound of formula V ##STR29## reacting the compound of formula V with a compound of formula VI ##STR30## and hydrolyzing the product thereof to produce a compound of formula VII ##STR31## and reacting the compound of formula VII with a super acid having a Hammett acidity function of less than minus 12 to produce the compound of formula I, wherein:

a, b, c and d represent CH or one of a, b, c and d represents N and the others represent CH;

R.sup.1, R.sup.2, R.sup.3 and R.sup.4 may be the same or different and each independently represents hydrogen, alkyl having from 1 to 6 carbon atoms, halogen, nitro, alkoxy having from 1 to 6 carbon atoms or trifluoromethyl;

R.sup.5 represents an N-protecting group which does not prevent formation of the Grignard reagent of formula VI;

R.sup.6 represents a protecting group that will protect the N of the group CONHR.sup.6 in formula II from reaction with an alkylating agent; and

Z represents chloro, bromo or iodo.

2. A process according to claim 1, wherein R.sup.6 is a tertiary butyl group.

3. A process according to claim 2, wherein the compound of formula II is prepared by reacting a compound of formula VIII ##STR32## with a tertiary butyl compound in the presence of acid.

4. A process according to claim 1, wherein R.sup.5 is an alkyl, aryl or aralkyl group.

5. A process according to claim 1, wherein R.sup.5 is methyl.

6. A process according to claim 1, wherein the group R.sup.5 in formula VII is converted to --H or --COOR.sup.8 prior to reaction with the super acid having a Hammett acidity function of less than minus 12, wherein R.sup.8 represents C.sub.1 to C.sub.12 alkyl, substituted C.sub.1 to C.sub.12 alkyl, C.sub.2 to C.sub.12 alkenyl, substituted C.sub.2 to C.sub.12 alkenyl, phenyl, substituted phenyl, C.sub.7 to C.sub.10 phenylalkyl or C.sub.7 to C.sub.10 phenylalkyl wherein the phenyl moiety is substituted, or R.sup.8 is 2-, 3-, or 4-piperidyl or N-substituted piperidyl, wherein the substitutents on said substituted C.sub.1 to C.sub.12 alkyl and on said substituted C.sub.2 to C.sub.12 alkenyl are selected from amino or substituted amino and the substituents on said substituted amino are selected from C.sub.1 to C.sub.6 alkyl, the substituents on said substituted phenyl and on said substituted phenyl moiety of the C.sub.7 to C.sub.10 phenylalkyl are selected from C.sub.1 to C.sub.4 alkyl and halo, and the substituent on said N-substituted piperidyl is C.sub.1 to C.sub.4 alkyl.

7. A process according to claim 1, wherein the group R.sup.5 in formula I is converted to --H or --COOR.sup.8 after the reaction of the compound of formula VII with the super acid having a Hammett acidity function of less than minus 12, wherein R.sup.8 represents C.sub.1 to C.sub.12 alkyl, substituted C.sub.1 to C.sub.12 alkyl, C.sub.2 to C.sub.12 alkenyl, substituted C.sub.2 to C.sub.12 alkenyl, phenyl, substituted phenyl, C.sub.7 to C.sub.10 phenylalkyl or C.sub.7 to C.sub.10 phenylalkyl wherein the phenyl moiety is substituted, or R.sup.8 is 2-,3-, or 4-piperidyl or N-substituted piperidyl, wherein the substitutents on said substituted C.sub.1 to C.sub.12 alkyl and on said substituted C.sub.2 to C.sub.12 alkenyl are selected from amino or substituted amino and the substituents on said substituted amino are selected from C.sub.1 to C.sub.6 alkyl, the substituents on said substituted phenyl and on said substituted phenyl moiety of the C.sub. 7 to C.sub.10 phenylalkyl are selected from C.sub.1 to C.sub.4 alkyl and halo, and the substituent on said N-substituted piperidyl is C.sub.1 to C.sub.4 alkyl.

8. A process for preparing a compound of the formula Ia: ##STR33## said process comprising the step of reacting a compound of the formula VIIa ##STR34## with a super acid having a Hammett acidity function value of less than minus 12 to produce a compound of formula Ia, wherein:

a, b, c and d represent CH or one of a, b, c and d represents N and the others represent CH;

R.sup.1, R.sup.2, R.sup.3 and R.sup.4 may be the same or different and each independently represents hydrogen, alkyl having from 1 to 6 carbon atoms, halogen, nitro, alkoxy having from 1 to 6 carbon atoms or trifluoromethyl; and

R.sup.7 represents an N-protecting group, --H or --COOR.sup.8, wherein R.sup.8 represents C.sub.1 to C.sub.12 alkyl, substituted C.sub.1 to C.sub.12 alkyl, C.sub.2 to C.sub.12 alkenyl, substituted C.sub.2 to C.sub.12 alkenyl, phenyl, substituted phenyl, C.sub.7 to C.sub.10 phenylalkyl or C.sub.7 to C.sub.10 phenylalkyl wherein the phenyl moiety is substituted, or R.sup.8 is 2-, 3-, or 4-piperidyl or N-substituted piperidyl, wherein the substitutents on said substituted C.sub.1 to C.sub.12 alkyl and on said substituted C.sub.2 to C.sub.12 alkenyl are selected from amino or substituted amino and the substituents on said substituted amino are selected from C.sub.1 to C.sub.6 alkyl, the substituents on said substituted phenyl and on said substituted phenyl moiety of the C.sub.7 to C.sub.10 phenylalkyl are selected from C.sub.1 to C.sub.4 alkyl and halo, and the substituent on said N-substituted piperidyl is C.sub.1 to C.sub.4 alkyl.

9. A process according to claim 8, wherein the super acid is selected from HF/BF.sub.3, CF.sub.3 SO.sub.3 H or CH.sub.3 SO.sub.3 H/BF.sub.3.

10. A process according to claim 9, wherein the super acid is HF/BF.sub.3.

11. A process according to claim 10, wherein the reaction temperature is in the range of from about -50.degree. C. to about 5.degree. C.

12. A process according to claim 10, wherein the reaction temperature is in the range of from about -35.degree. C. to about -30.degree. C.

13. A process according to claim 10, wherein the volume/weight ratio of HF to the compound of formula VIIa in the reaction mixture is from about 30 to about 1.5.

14. A process according to claim 10, wherein the volume/weight ratio of HF to the compound of formula VIIa in the reaction mixture is from about 2.5 to about 1.5.

15. A process according to claim 13, wherein the weight/weight ratio of BF.sub.3, to the compound of formula VIIa in the reaction mixture is from about 15 to about 0.75.

16. A process according to claim 14, wherein the weight/weight ratio of BF.sub.3 to the compound of formula VIIa in the reaction mixture is from about 1 to about 0.75.

17. A process according to claim 8, wherein R.sup.2 and R.sup.3 are each independently selected from hydrogen or halo; R.sup.1 and R.sup.4 are hydrogen; d is N; a, b and c are CH; and R.sup.7 is methyl.

18. A process according to claim 8, wherein R.sup.7 in formula Ia is an N-protecting group.

19. A process according to claim 18, wherein R.sup.7 in formula Ia represents an alkyl group.

20. A process according to claim 18, wherein R.sup.7 is methyl.

21. A process according to claim 19, wherein the compound of formula Ia is reacted with a compound of formula X

to produce a compound of formula XI ##STR35## wherein Z is chloro, bromo or iodo.

22. A process according to claim 21, wherein one or both of R.sup.2 and R.sup.3 are halo; R.sup.1 and R.sup.4 are hydrogen; d is N; a, b and c are CH; and R.sup.7 is alkyl having from 1 to 6 carbon atoms.

23. A process according to claim 21, wherein R.sup.2 is chloro or fluoro; R.sup.1, R.sup.3 and R.sup.4 are hydrogen; d is N; a, b, and c are CH; and R.sup.7 is ethyl.

24. A process according to claim 21, further comprising the step of removing the group --COOR.sup.8 to produce a compound of formula XII ##STR36##

25. A process according to claim 24, wherein one or both of R.sup.2 and R.sup.3 are halo; R.sup.1 and R.sup.4 are hydrogen; d is N; and a, b and c are CH.

26. A process according to claim 24, wherein R.sup.2 is chloro or fluoro; R.sup.1, R.sup.3 and R.sup.4 are hydrocen; d is N; and a, b and c are CH.

27. A process according to claim 18, further comprising the step of removing the N-protecting group to produce a compound of formula XII ##STR37##

28. A process according to claim 27, wherein the compound of formula XII is reacting with a compound of formula X

to produce a compound of formula XI ##STR38## wherein Z is chloro, bromo or iodo.

29. A process for preparing a compound of formula XIII ##STR39## which process comprises reacting a compound of formula II ##STR40## with a compound of formula III ##STR41## in the presence of base to produce of compound of formula IV ##STR42## and reacting the compound of formula IV with a super acid having a Hammett acidity function of less than minus 12 to produce compound of formula XIII, wherein

a, b, c and d represent CH or one of a, b, c and d represents N and the others represent CH;

R.sup.1, R.sup.2, R.sup.3 and R.sup.4 may be the same or different and each independently represents hydrogen, alkyl having from 1 to 6 carbon atoms, halogen, nitro, alkoxy having from 1 to 6 carbon atoms or trifluoromethyl;

R.sup.6 represents a protecting group that will protect the N of the group --CONHR.sup.6 in formula II from reaction with an alkylating agent; and

Z is chloro, bromo or iodo.

30. A process for preparing a compound of formula XIII ##STR43## which process comprises reacting a compound of formula IV ##STR44## with a super acid having a Hammett acidity function of less than minus 12 to produce the compound of formula XIII, wherein

a, b, c and d represent CH or one of a, b, c and d represents N and the others represent CH;

R.sup.1, R.sup.2, R.sup.3 and R.sup.4 may be the same or different and each independently represents hydrogen, alkyl having from 1 to 6 carbon atoms, halogen, nitro, alkoxy having from 1 to 6 carbon atoms or trifluoromethyl;

R.sup.6 represents a protecting group that will protect the N of the group --CONHR.sup.6 in formula IV from reaction with an alkylating agent; and

Z is chloro, bromo or iodo.

31. A process according to claim 30, wherein R.sup.6 in formulae IV is a tertiary butyl group.

32. A process according to claim 29, wherein the compounds of formula II is prepared by reacting a compound of formula VIII ##STR45## with a tertiary butyl compound in the presence of acid.

33. A process according to claim 30, wherein the compound of formula IV is converted to a compound of formula XIV ##STR46## which compound is then converted to the compound of formula XIII.

34. A process according to claim 30, wherein R.sup.2 and R.sup.3 may be the same of different and each is selected from hydrogen or halo; R.sup.3 and R.sup.4 are hydrogen; d is N; and a, b and c are CH.

35. A process according to claim 30, wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are hydrogen; d is N; and a, b and c are CH.
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