Patent EA-003997-B1 (EA)
Title: Process for the synthesis of (1h)-benzo[c]quinolizin-3-ones derivatives
Inventor: GUARNA ANTONIO
IPC: C07D455/04
Filed: 1999-07-23
Abstract: 1. Process for the preparation of compounds of formula (I): wherein: R1, R2, R3, R4, R5, same or different, are chosen in the group consisting of: H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-9cycloalkyl, aryl, saturated or aromatic heterocycle, comprising one or more atoms of N, halogen, CN, azide, NRR', C1-8alkylamino, arylamino, C1-8alkyloxy, aryloxy, COOR, CONRR' wherein R and R', same or different, are chosen from the group consisting of: H, C1-8alkyl, C3-9cycloalkyl, aryl, saturated or aromatic heterocycle, comprising one or more atoms of N, arylC1-8alkyl; Q is chosen in the group consisting of: simple bond, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-9cycloalkyl, CO, CONR, NR, wherein R is as above defined; W is chosen in the group consisting of: H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-9cycloalkyl, trifluoromethyl, C1-8alkoxy, C1-8alkoxy- C1-8alkyl, aryl C1-8alkyl, aryl, aryloxy, arylamino, C1-8alkylcarbonyl, arylcarbonyl, arylcarboxyl, arylcarboxyamide, halogen, CN, NRR', C1-8alkylamino, saturated or aromatic heterocycle, comprising one or more atoms of N, wherein the groups alkyl, alkenyl, alkynyl, C3-9cycloalkyl, aryl, saturated or aromatic heterocycle, comprising one or more atoms of N, can be substituted by OR, phenyl, CN, NRR', COOR, CONRR', C1-8alkyl(where R and R' has over mentioned values); aryl being phenyl and naphthyl; n is an integer comprised between 1 and 4; and their pharmaceutically acceptable salts or esters, wherein a thioamide 3 (wherein R3 and R4 are as above defined) is N-alkylated with a vinyl ketone of formula 2: (wherein R1, R2 and R6 are as above defined) to give the corresponding compound 4: (wherein all the substituents are as above defined) which is methylated, at the sulfur atom to give the salt 5: (wherein all the substituents are as above defined) which is directly reacted with a base to give the desired compound I. 2 Process according to claim 1, wherein the reaction between the compounds 2 and 3 is conducted in an organic solvent, in the presence of a strong, but non-nucleophylic base. 3. Process according to claims 1 or 2, wherein the final step of cyclization is conducted in an organic solvent in the presence of a strong, but non-nucleophylic base. 4. Process according to claim 2, wherein the base is K2CO2/18-crown-6 or diazabicycloundecene (DBU). 5. Process according to claim 3, wherein the base is diazabicycloundecene (DBU). 6. Process according to claim 2, wherein the solvent is THF. 7. Process according to clams 1 and 3, wherein the methylating agent is dimethylsulfate and the solvent is toluene at refluxing temperature. 8. Process according to claim 7, wherein the overall reaction time is comprised between half-hour to one hour. 9. Process according to claims 1-8, wherein the compound of formula (I) are: 2,3,5,6-tetrahydro-(1H)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6-tetrahydro-(1H)-benzo[c]quinolizin-3-one; 2, 3,5,6-tetrahydro-8-methyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6-tetrahydro-4-methyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6-tetrahydro-1-methyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6-tetrahydro-4-methyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6-tetrahydro-4,8-dimethyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6-tetrahydro-1-methyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6-tetrahydro-1,4-dimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6-tetrahydro-6-methyl-(1H)-benzo(c]quinolizin-3-one; 8-chloro-2,3,5,6 tetrahydro-6-methyl-(1H)benzo[c]quinolizin-3-one; 2,3,5,6-tetrahydro-6,8-dimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6-tetrahydro-4,6-dimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6-tetrahydro-1,6-dimethyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6-tetrahydro-4,6-dimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6-tetrahydro-4,6,8-trimethyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6-tetrahydro-1,6-dimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6-tetrahydro-1,4,6-trimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6-tetrahydro-5-methyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6-tetrahydro-5-methyh(1H)-benzo[c)quinolizin-3-one; 2,3,5,6-tetrahydro-5,8-dimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6-tetrahydro-4,5-dimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6-tetrahydro-1,5-dimethyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6-tetrahydro-4,5-dimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6-tetrahydro-4,5,8-trimethyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6-tetrahydro-1,5-dimethyl-(1H)benzo[c]quinolizin-3-one; 2,3,5,6-tetrahydro-1,4,5-trimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6-tetrahydro-5,6-dimethyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6-tetrahydro-5,6-dimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6-tetrahydro-5,6,8-trimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6-tetrahydro-4,5,6-trimethyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6-tetrahydro-4,5,6-trimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6-tetrahydro-1,5,6-trimethyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6-tetrahydro-1,5,6-trimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6-tetrahydro-4,5,6,8-tetramethyl-(1H)-benzo[c]quinolizin-3-one.