Process for synthesis of a 2-thioalkyl pyrimidine
A method for preparing a compound of Formula 1 and compounds therefrom, comprising treating a compound of Formula 2 with a compound of Formula 3 and reacting the resulting intermediate of Formula 4 with a compound of Formula 5 (or a salt thereof). The compound of Formula 1, prepared by the above method, can be used to prepare a compound of Formula 8 wherein R 2 , R 3 , R 4 , m and r are as defined in the specification.
1 . A method for preparing a compound of Formula 1
wherein
R 1 is C 1 -C 4 alkyl; and
R 2 is halogen, or C 1 -C 4 alkyl;
the method comprising treating a compound of Formula 2
wherein
R 2 is halogen, or C 1 -C 4 alkyl; and
X is Cl or OH
in the presence of a halogenating agent and a compound of Formula 3
wherein
R A and R B are each independently C 1 -C 4 alkyl; or
R A and R B are taken together to be —(CH 2 ) 4 —, —(CH 2 ) 5 — or —CH 2 CH 2 OCH 2 CH 2 — to provide an intermediate of Formula 4
wherein
R 2 is halogen, or C 1 -C 4 alkyl; and
R A and R B are each independently C 1 -C 4 alkyl; or
R A and R B are taken together to be —(CH 2 ) 4 —, —(CH 2 ) 5 — or —CH 2 CH 2 OCH 2 CH 2 —; and
Hal − is chloride ion or bromide ion; and
treating the intermediate of Formula 4 in the presence of a base with an acid salt of a compound of Formula 5
wherein R 1 is C 1 -C 4 alkyl.
2 . The method of claim 1 wherein R 1 is C 1 -C 2 alkyl; and each R A and R B is methyl.
3 . The method of claim 2 wherein R 1 is methyl and R 2 is halogen.
4 . The method of claim 3 wherein R 2 is chlorine.
5 . The method of claim 1 wherein X is Cl.
6 . The method of claim 1 further comprising preparing a compound of Formula 6
wherein
R 1 is C 1 -C 4 alkyl; and
R 2 is halogen, or C 1 -C 4 alkyl
by treating a compound of Formula 1 with an oxidant.
7 . The method of claim 6 further comprising preparing a compound of Formula 8
wherein
R 2 is halogen, or C 1 -C 4 alkyl;
each R 3 is independently halogen, cyano, amino, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 2 -C 4 alkoxycarbonyl, C 2 -C 4 alkylcarbonyloxy, C 2 -C 4 alkoxyalkyl or C 1 -C 4 haloalkyl;
each R 4 is independently halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy or SCF 3 ;
m is 0, 1, 2 or 3; and
r is 0, 1 or 2;
by treating the compound of Formula 6
wherein
R 1 is C 1 -C 4 alkyl; and
R 2 is halogen, or C 1 -C 4 alkyl
in the presence of a second base with a compound of Formula 7
wherein
R 2 is halogen, or C 1 -C 4 alkyl;
each R 3 is independently halogen, cyano, amino, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 2 -C 4 alkoxycarbonyl, C 2 -C 4 alkylcarbonyloxy, C 2 -C 4 alkoxyalkyl or C 1 -C 4 haloalkyl;
each R 4 is independently halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy or SCF 3 ;
m is 0, 1, 2 or 3; and
r is 0, 1 or 2.
8 . The method of claim 7 wherein
m is 0 or 1;
r is 0 or 1;
R 2 is halogen;
R 3 is halogen, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl, wherein when m is 1, R 3 is attached to the remainder of Formula 7 and Formula 8 at the 3-position; and
R 4 is C 1 -C 4 haloalkyl, wherein when r is 1, R 4 is substituted on the remainder of Q at the 3′-position.
9 . The method of claim 8 wherein R 2 and R 3 are both chlorine.
10 . The method of claim 8 wherein R 4 is C 1 fluoroalkyl.
11 . The method of claim 7 wherein the compound of Formula 8 is selected from the group consisting of
2-[2-(3-bromo-5-isoxazolyl) phenoxy]-5-chloropyrimidine,
5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]phenoxy]pyrimidine,
5-chloro-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]phenoxy]pyrimidine,
5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-fluorophenoxy]pyrimidine,
5-bromo-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-fluorophenoxy]pyrimidine,
5-chloro-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine,
5-chloro-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]-3-fluorophenoxy]pyrimidine,
5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine,
5-bromo-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine,
5-bromo-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine and
5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-bromophenoxy]pyrimidine.
12 . The method of claim 11 wherein the compound of Formula 8 is 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine.
13 . A method for preparing a compound of Formula 8,
wherein
R 2 is halogen, or C 1 -C 4 alkyl;
each R 3 is independently halogen, cyano, amino, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 2 -C 4 alkoxycarbonyl, C 2 -C 4 alkylcarbonyloxy, C 2 -C 4 alkoxyalkyl or C 1 -C 4 haloalkyl;
each R 4 is independently halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy or SCF 3 ;
m is 0, 1, 2 or 3; and
r is 0, 1 or 2;
comprising treating a compound of Formula 2
wherein
R 2 is halogen, or C 1 -C 4 alkyl; and
X is Cl or OH
in the presence of a halogenating agent and a compound of Formula 3
wherein
R A and R B are each independently C 1 -C 4 alkyl; or
R A and R B are taken together to be —(CH 2 ) 4 —, —(CH 2 ) 5 — or —CH 2 CH 2 OCH 2 CH 2 — to provide an intermediate of Formula 4
wherein
R 2 is halogen, or C 1 -C 4 alkyl; and
R A and R B are each independently C 1 -C 4 alkyl; or
R A and R B are taken together to be —(CH 2 ) 4 —, —(CH 2 ) 5 — or —CH 2 CH 2 OCH 2 CH 2 —;
treating the intermediate of Formula 4 with an acid salt of a compound of Formula 5
wherein R 1 is C 1 -C 4 alkyl;
in the presence of a base to prepare a compound of Formula 1
wherein
R 1 is C 1 -C 4 alkyl;
R 2 is halogen, or C 1 -C 4 alkyl;
treating the compound of Formula 1 with an oxidant to provide a compound of Formula 6
wherein
R 1 is C 1 -C 4 alkyl; and
R 2 is halogen, or C 1 -C 4 alkyl; and
treating the compound of Formula 6 in the presence of a second base with a compound of
wherein
each R 3 is independently halogen, cyano, amino, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 2 -C 4 alkoxycarbonyl, C 2 -C 4 alkylcarbonyloxy, C 2 -C 4 alkoxyalkyl or C 1 -C 4 haloalkyl;
each R 4 is independently halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy or SCF 3 ;
m is 0, 1, 2 or 3; and
r is 0, 1 or 2.
14 . The method of claim 13 wherein
R 1 is C 1 -C 2 alkyl; and
each R A and R B is methyl.
15 . The method of claim 14 wherein R 1 is methyl and R 2 is halogen.
16 . The method of claim 13 wherein
m is 0 or 1;
r is 0 or 1;
R 2 is halogen;
R 3 is halogen, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl, wherein when m is 1, R 3 is attached to the remainder of Formula 7 and Formula 8 at the 3-position; and
R 4 is C 1 -C 4 haloalkyl; wherein when r is 1, R 4 is at the 3′-position.
17 . The method of claim 16 wherein R 2 and R 3 are both chlorine.
18 . The method of claim 16 wherein R 4 is C 1 fluoroalkyl.
19 . The method of claim 13 wherein the compound of Formula 8 is selected from the group consisting of
2-[2-(3-bromo-5-isoxazolyl) phenoxy]-5-chloropyrimidine,
5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]phenoxy]pyrimidine,
5-chloro-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]phenoxy]pyrimidine,
5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-fluorophenoxy]pyrimidine,
5-bromo-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-fluorophenoxy]pyrimidine,
5-chloro-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine,
5-chloro-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]-3-fluorophenoxy]pyrimidine,
5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine,
5-bromo-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine,
5-bromo-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine and
5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-bromophenoxy]pyrimidine.
20 . The method of claim 19 wherein the compound of Formula 8 is 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine.