Novel Chemical Process For the Synthesis of Quinoline Compounds
Disclosed is a novel, simplified and economic process for making 3-phenylsulphonyl quinolines with an amine group at position 8 of the quinoline ring system, including 3-phenylsulfonyl-8-piperazin-1-yl-quinoline in particular, in the absence of a palladium catalyst. Also disclosed is the crystallization of polymorphic forms of 3-phenylsulfonyl-8-piperazin-1-yl-quinoline.
1 - 13 . (canceled)
14 . A process for the preparation of a compound of formula (I):
or a salt thereof, which comprises reacting a compound of formula (II):
with a compound having the formula R 1 R 2 NH, in the presence of a base and a solvent; wherein:
R 1 and R 2 independently represent hydrogen or C 1-6 alkyl, or R 1 and R 2 together with the nitrogen atom to which they are attached form an optionally substituted 4 to 7 membered monocyclic heterocyclyl group which can optionally contain 1 or 2 further heteroatoms selected from O, N and S; and
Ph represents an optionally substituted phenyl group.
15 . A process according to claim 14 , wherein the compound of formula (I) is 3-phenylsulfonyl-8-piperazin-1-yl-quinoline, and wherein the process comprises reacting 8-fluoro-3-phenylsulfonylquinoline with an excess of piperazine in the presence of potassium carbonate and n-propanol at a temperature between about 95° C. and about 105° C.
16 . A process according to claim 14 , further comprising reacting a compound of formula (III):
wherein R 3 represents iodine or bromine; with HSO 2 Ph, or a salt thereof, in the presence of a diamine ligand, a metal catalyst, a base and a polar aprotic solvent.
17 . A process according to claim 16 , wherein the compound of formula (II) is 8-fluoro-3-phenylsulfonylquinoline, and wherein the process comprises reacting 8-fluoro-3-iodoquinoline with HSO 2 Ph sodium salt in the presence of N,N′-dimethylethylenediamine, CuI, diisopropylethylamine and dimethylsulfoxide at a temperature between about 90° C. and about 105° C.
18 . A process according to claim 16 , which further comprises reacting 8-fluoroquinoline, with an iodinating or brominating agent, which can act as a source of electrophilic iodine or bromine, in the presence of a solvent.
19 . A process according to claim 18 , which comprises reacting 8-fluoroquinoline with N-iodosuccinimide or N-bromosuccinimide in the presence of acetic acid at a temperature between about 75° C. and about 85° C.
20 . A process according to claim 14 , which comprises:
(i) reacting 8-fluoroquinoline with an iodinating or brominating agent, which can act as a source of electrophilic iodine or bromine, in the presence of a solvent to produce a compound of formula (III) and optionally adding a reducing agent once the reaction is completed;
(ii) reacting the compound of formula (III) with HSO 2 Ph or a salt thereof, in the presence of a diamine ligand, a metal catalyst and a polar aprotic solvent to produce a compound of formula (II); and
(iii) reacting the compound of formula (II) with a compound of formula R 1 R 2 NH in the presence of a base and a solvent to produce the compound of formula (I), or a salt thereof.
21 . A process according to claim 20 , wherein the compound of formula (I) is 3-phenylsulfonyl-8-piperazin-1-yl-quinoline, said process comprising:
(i) reacting 8-fluoroquinoline with N-iodosuccinimide or N-bromosuccinimide in the presence of acetic acid at a temperature between about 75° C. and about 85° C. to produce 8-fluoro-3-iodoquinoline, and then adding sodium sulphite solution once the reaction is completed;
(ii) reacting 8-fluoro-3-iodoquinoline with benzene sulfinic acid sodium salt in the presence of N,N′-dimethylethylenediamine, CuI, diisopropylethylamine and dimethylsulfoxide at a temperature between about 90° C. and about 105° C. to produce 8-fluoro-3-phenylsulfonylquinoline; and
(i) reacting 8-fluoro-3-phenylsulfonylquinoline with an excess of piperazine in the presence of potassium carbonate and n-propanol at a temperature between about 95° C. and about 105° C. to produce 3-phenylsulfonyl-8-piperazin-1-yl-quinoline.
22 . A process according to claim 21 , further comprising the step of dissolving 3-phenylsulfonyl-8-piperazin-1-yl-quinoline in ethyl acetate, optionally filtering the 3-phenylsulfonyl-8-piperazin-1-yl-quinoline solvent mixture, and then allowing the 3-phenylsulfonyl-8-piperazin-1-yl-quinoline to recrystallize.
23 . A process according to claim 21 , further comprising the step of dissolving 3-phenylsulfonyl-8-piperazin-1-yl-quinoline in isopropanol, optionally filtering the 3-phenylsulfonyl-8-piperazin-1-yl-quinoline solvent mixture, and then allowing the 3-phenylsulfonyl-8-piperazin-1-yl-quinoline to recrystallize.
24 . A process according to claim 21 , further comprising the step of dissolving 3-phenylsulfonyl-8-piperazin-1-yl-quinoline ethanol, optionally filtering the 3-phenylsulfonyl-8-piperazin-1-yl-quinoline solvent mixture, and then allowing the 3-phenylsulfonyl-8-piperazin-1-yl-quinoline to recrystallize.
25 . A compound of formula (II)
wherein Ph represents an optionally substituted phenyl group or a salt thereof.
26 . A compound according to claim 25 , which is 8-fluoro-3-phenylsulfonylquinoline, or a salt thereof.
27 . A compound of formula (III)
wherein R 3 represents iodine or bromine or a salt thereof.
28 . A compound according to claim 27 , which is 8-fluoro-3-iodoquinoline, or a salt thereof.