PROCESS OF A QUATERNARY AMMONIUM SALT USING PHOSPHATE
The present invention relates to a novel process for preparing quaternary ammonium salt derivatives.
1 - 17 . (canceled)
18 . A composition containing a compound of formula (8):
or an acid addition salt thereof and by-product (R)
wherein
B is carbonyl group or sulfonyl group,
R 5a , R 5b , R 5c , and R 5d are independently hydrogen atom or C 1-4 alkyl group, alternatively R 5a and R 5b , or R 5a and R 5c may be taken together to form a hydrocarbon ring, or R 5a and R 5c may be taken together to form an aromatic hydrocarbon ring, wherein the hydrocarbon ring may be bridged with C 1-4 alkylene or oxygen atom wherein the C 1-4 alkylene and the hydrocarbon ring may be substituted with at least one C 1-4 alkyl,
q is 0 or 1, and
Y is a substituent of the following formula (3a) or (3b):
wherein R 3 is independently methylene or oxygen atom; R 4 is independently C 1-6 alkyl group, C 1-6 alkoxy group, or hydroxy group; m and n are independently 0, 1, 2, or 3; and p is 1 or 2, and
Z is ═N—R 1 or ═CH—R 2 wherein R 1 is C 1-6 alkyl group, C 3-7 cycloalkyl group, C 5-7 cycloalkenyl group, C 6-10 aryl group, or 5- to 10-membered monocyclic or bicyclic heteroaryl group; R 2 is C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 alkylthio group, C 3-7 cycloalkyl group, C 3-7 cycloalkyloxy group, C 3-7 cycloalkylthio group, C 5-7 cycloalkenyl group, C 5-7 cycloalkenyloxy group, C 5-7 cycloalkenylthio group, C 6-10 aryl group, C 6-10 aryloxy group, C 6-10 arylthio group, 5- to 10-membered monocyclic or bicyclic heteroaryl group, 5- to 10-membered monocyclic or bicyclic heteroaryloxy group, or 5- to 10-membered monocyclic or bicyclic heteroarylthio group,
prepared by a process comprising the following steps (i) and (ii):
step (i)
a process for preparing a quaternary ammonium salt of formula (4):
wherein X is halogen atom, C 1-6 alkylsulfonyloxy group, or C 6-10 arylsulfonyloxy group, and Y and Z are as defined above,
comprising reacting a compound of formula (1):
wherein Z is as defined above
with 1 to 2 mole of a compound of formula (2):
wherein X and Y are as defined above, per one mole of the compound of formula (1)
in the presence of 1 to 5 mole of a phosphate per one mole of the compound of formula (1) and 0.01 to 0.1 part by weight of water per one part by weight of the phosphate; and
step (ii)
a process for preparing the compound of formula (8)
comprising reacting the quaternary ammonium salt (4) prepared in step (i) with a compound of formula (7):
wherein B, R 5a , R 5b , R 5c , R 5d and q are as defined above,
in the presence of a solid inorganic base selected from an alkali metal carbonate, an alkali earth metal carbonate and/or an alkali metal bicarbonate
wherein the production rate of the by-product (R) in step (ii) is about 3% or less, wherein the by-product (R) is produced by the reaction of the unreacted compounds of formula (1) and formula (2) with the potassium carbonate in step (ii), and the by product (R) has a carbonate part therein.
19 . The composition of claim 18 , wherein the production rate is about 0.019% or less.
20 . The composition of claim 18 , wherein X is independently C 1-6 alkylsulfonyloxy group, or C 6-10 arylsulfonyloxy group.
21 . The composition of claim 18 , wherein X is methanesulfonyloxy group.
22 . The composition of claim 18 , wherein Y is the substituent of formula (3a).
23 . The composition of claim 18 , wherein m is 2 and n is 0.
24 . The composition of claim 18 , wherein Z is ═N—R 1 .
25 . The composition of claim 18 , wherein R 1 is 5- to 10-membered monocyclic or bicyclic heteroaryl group.
26 . The composition of claim 18 , wherein R 1 is 1,2-benzisothiazol-3-yl.
27 . The composition of claim 18 , wherein the phosphate is dibasic potassium phosphate.
28 . The composition of claim 18 , wherein the phosphate is 1 to 3 mole per one mole of the compound of formula (1).
29 . The composition of claim 18 , wherein the amount of water is 0.01 to 0.05 part by weight per one part by weight of the phosphate.
30 . The composition of claim 18 , which further comprises the following step (iii) after the reaction of step (ii):
step (iii)
adding a solvent to the product in step (ii) to obtain the compound of formula (8) as a crystal,
wherein the solvent is an aliphatic hydrocarbon solvent and/or an alcohol solvent.
31 . The composition of claim 30 , wherein the solvent in step (iii) is an alcohol solvent.
32 . The composition of claim 31 , wherein the alcohol solvent is methanol, ethanol and/or isopropanol.
33 . The composition of claim 18 , wherein the solid inorganic base in step (ii) is a potassium carbonate.
34 . The composition of claim 18 , wherein B is carbonyl group.
35 . The composition of claim 18 , wherein R 5a and R 5c are taken together to form a hydrocarbon ring which may be bridged with C 1-4 alkylene, and R 5b and R 5d are hydrogen atom.
36 . The composition of claim 18 , wherein formula (1) is the following formula (1a):
37 . The composition of claim 18 , wherein formula (2) is the following formula (2a):
38 . The composition of claim 18 , wherein formula (4) is the following formula (4a):
39 . The composition of claim 18 , wherein formula (7) is the following formula (7b):
40 . The composition of claim 18 , wherein formula (2) is the following:
41 . The composition of claim 18 , wherein formula (7) is the following:
42 . The composition of claim 18 , wherein the compound of formula (8) is (3aR,4S,7R,7aS)-2-{[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)-piperazin-1-ylmethyl]cyclohexyl-methyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione.
43 . A process for preparing the composition of claim 18 .
44 . A process for preparing a compound of formula (8):
or an acid addition salt thereof
wherein
B is carbonyl group or sulfonyl group,
R 5a , R 5b , R 5c , and R 5d are independently hydrogen atom or C 1-4 alkyl group, alternatively R 5a and R 5b , or R 5a and R 5c may be taken together to form a hydrocarbon ring, or R 5a and R 5c may be taken together to form an aromatic hydrocarbon ring, wherein the hydrocarbon ring may be bridged with C 1-4 alkylene or oxygen atom wherein the C 1-4 alkylene and the hydrocarbon ring may be substituted with at least one C 1-4 alkyl,
q is 0 or 1, and
Y is a substituent of the following formula (3a) or (3b):
wherein R 3 is independently methylene or oxygen atom; R 4 is independently C 1-6 alkyl group, C 1-6 alkoxy group, or hydroxy group; m and n are independently 0, 1, 2, or 3; and p is 1 or 2, and
Z is ═N—R 1 or ═CH—R 2 wherein R 1 is C 1-6 alkyl group, C 3-7 cycloalkyl group, C 5-7 cycloalkenyl group, C 6-10 aryl group, or 5- to 10-membered monocyclic or bicyclic heteroaryl group; R 2 is C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 alkylthio group, C 3-7 cycloalkyl group, C 3-7 cycloalkyloxy group, C 3-7 cycloalkylthio group, C 5-7 cycloalkenyl group, C 5-7 cycloalkenyloxy group, C 5-7 cycloalkenylthio group, C 6-10 aryl group, C 6-10 aryloxy group, C 6-10 arylthio group, 5- to 10-membered monocyclic or bicyclic heteroaryl group, 5- to 10-membered monocyclic or bicyclic heteroaryloxy group, or 5- to 10-membered monocyclic or bicyclic heteroarylthio group,
comprising reacting the quaternary ammonium salt (4) prepared according to claim 1 with a compound of formula (7):
wherein B, R 5a , R 5b , R 5c , R 5d , and q are as defined above,
in the presence of a solid inorganic base.
45 . The process of claim 44 , wherein B is carbonyl group.
46 . The process of claim 44 , wherein R 5a and R 5c are taken together to form a hydrocarbon ring which may be bridged with C 1-4 alkylene, and R 5b and R 5d are hydrogen atom.
47 . The process of claim 44 , wherein formula (7) is the following formula (7b):
48 . The process of claim 44 , wherein the compound of formula (8) is (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione.
49 . The process of claim 44 , wherein formula (7) is the following: