Process for preparing piperidylidene dihydro-dibenzo(a,d)-cycloheptenes or aza-derivatives thereof
AssigneeSchering Corporation
InventorsDoris P. Schumacher, Bruce L. Murphy, Jon E. Clark
Life of this patent
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Abstract
A process for the preparation of piperidylidene-dihydro-dibenzo[a,d]cycloheptene or aza-derivatives thereof and intermediates in such process are disclosed.
Claims35
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.
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.
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.
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.
Dependencies are inferred from the claim text.