U.S. patent application number 14/041657 was filed with the patent office on 2014-01-30 for process of a quaternary ammonium salt using phosphate.
Invention is credited to Nobuyuki AE, Yuji Fujiwara.
Application Number | 20140031548 14/041657 |
Document ID | / |
Family ID | 44816341 |
Filed Date | 2014-01-30 |
United States Patent
Application |
20140031548 |
Kind Code |
A1 |
AE; Nobuyuki ; et
al. |
January 30, 2014 |
PROCESS OF A QUATERNARY AMMONIUM SALT USING PHOSPHATE
Abstract
The present invention relates to a novel process for preparing
quaternary ammonium salt derivatives.
Inventors: |
AE; Nobuyuki; (Osaka,
JP) ; Fujiwara; Yuji; (Osaka, JP) |
Family ID: |
44816341 |
Appl. No.: |
14/041657 |
Filed: |
September 30, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13093985 |
Apr 26, 2011 |
8586737 |
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14041657 |
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61327804 |
Apr 26, 2010 |
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Current U.S.
Class: |
544/368 |
Current CPC
Class: |
A61P 25/18 20180101;
C07D 417/14 20130101; A61P 25/24 20180101; C07D 487/10
20130101 |
Class at
Publication: |
544/368 |
International
Class: |
C07D 417/14 20060101
C07D417/14 |
Claims
1-17. (canceled)
18. A composition containing a compound of formula (8):
##STR00029## or an acid addition salt thereof and by-product (R)
wherein B is carbonyl group or sulfonyl group, R.sup.5a, R.sup.5b,
R.sup.5c, and R.sup.5d are independently hydrogen atom or C.sub.1-4
alkyl group, alternatively R.sup.5a and R.sup.5b, or R.sup.5a and
R.sup.5c may be taken together to form a hydrocarbon ring, or
R.sup.5a and R.sup.5c may be taken together to form an aromatic
hydrocarbon ring, wherein the hydrocarbon ring may be bridged with
C.sub.1-4 alkylene or oxygen atom wherein the C.sub.1-4 alkylene
and the hydrocarbon ring may be substituted with at least one
C.sub.1-4 alkyl, q is 0 or 1, and Y is a substituent of the
following formula (3a) or (3b): ##STR00030## wherein R.sup.3 is
independently methylene or oxygen atom; R.sup.4 is independently
C.sub.1-6 alkyl group, C.sub.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
.dbd.N--R.sup.1 or .dbd.CH--R.sup.2 wherein R.sup.1 is C.sub.1-6
alkyl group, C.sub.3-7 cycloalkyl group, C.sub.5-7 cycloalkenyl
group, C.sub.6-10 aryl group, or 5- to 10-membered monocyclic or
bicyclic heteroaryl group; R.sup.2 is C.sub.1-6 alkyl group,
C.sub.1-6 alkoxy group, C.sub.1-6 alkylthio group, C.sub.3-7
cycloalkyl group, C.sub.3-7 cycloalkyloxy group, C.sub.3-7
cycloalkylthio group, C.sub.5-7 cycloalkenyl group, C.sub.5-7
cycloalkenyloxy group, C.sub.5-7 cycloalkenylthio group, C.sub.6-10
aryl group, C.sub.6-10 aryloxy group, C.sub.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):
##STR00031## wherein X is halogen atom, C.sub.1-6 alkylsulfonyloxy
group, or C.sub.6-10 arylsulfonyloxy group, and Y and Z are as
defined above, comprising reacting a compound of formula (1):
##STR00032## wherein Z is as defined above with 1 to 2 mole of a
compound of formula (2): ##STR00033## 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): ##STR00034## wherein B, R.sup.5a, R.sub.5b, R.sup.5c, R.sup.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.sub.1-6 alkylsulfonyloxy group, or C.sub.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 .dbd.N--R.sup.1.
25. The composition of claim 18, wherein R.sup.1 is 5- to
10-membered monocyclic or bicyclic heteroaryl group.
26. The composition of claim 18, wherein R.sup.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.sup.5a and R.sup.5c are
taken together to form a hydrocarbon ring which may be bridged with
C.sub.1-4 alkylene, and R.sup.5b and R.sup.5d are hydrogen
atom.
36. The composition of claim 18, wherein formula (1) is the
following formula (1a): ##STR00035##
37. The composition of claim 18, wherein formula (2) is the
following formula (2a): ##STR00036##
38. The composition of claim 18, wherein formula (4) is the
following formula (4a): ##STR00037##
39. The composition of claim 18, wherein formula (7) is the
following formula (7b): ##STR00038##
40. The composition of claim 18, wherein formula (2) is the
following: ##STR00039##
41. The composition of claim 18, wherein formula (7) is the
following: ##STR00040##
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-yl-
methyl]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): ##STR00041##
or an acid addition salt thereof wherein B is carbonyl group or
sulfonyl group, R.sup.5a, R.sup.5b, R.sup.5c, and R.sup.5d are
independently hydrogen atom or C.sub.1-4 alkyl group, alternatively
R.sup.5a and R.sup.5b, or R.sup.5a and R.sup.5c may be taken
together to form a hydrocarbon ring, or R.sup.5a and R.sup.5c may
be taken together to form an aromatic hydrocarbon ring, wherein the
hydrocarbon ring may be bridged with C.sub.1-4 alkylene or oxygen
atom wherein the C.sub.1-4 alkylene and the hydrocarbon ring may be
substituted with at least one C.sub.1-4 alkyl, q is 0 or 1, and Y
is a substituent of the following formula (3a) or (3b):
##STR00042## wherein R.sup.3 is independently methylene or oxygen
atom; R.sup.4 is independently C.sub.1-6 alkyl group, C.sub.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 .dbd.N--R.sup.1 or .dbd.CH--R.sup.2
wherein R.sup.1 is C.sub.1-6 alkyl group, C.sub.3-7 cycloalkyl
group, C.sub.5-7 cycloalkenyl group, C.sub.6-10 aryl group, or 5-
to 10-membered monocyclic or bicyclic heteroaryl group; R.sup.2 is
C.sub.1-6 alkyl group, C.sub.1-6 alkoxy group, C.sub.1-6 alkylthio
group, C.sub.3-7 cycloalkyl group, C.sub.3-7 cycloalkyloxy group,
C.sub.3-7 cycloalkylthio group, C.sub.5-7 cycloalkenyl group,
C.sub.5-7 cycloalkenyloxy group, C.sub.5-7 cycloalkenylthio group,
C.sub.6-10 aryl group, C.sub.6-10 aryloxy group, C.sub.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):
##STR00043## wherein B, R.sup.5a, R.sup.5b, R.sup.5c, R.sup.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.sup.5a and R.sup.5c are
taken together to form a hydrocarbon ring which may be bridged with
C.sub.1-4 alkylene, and R.sup.5b and R.sup.5d are hydrogen
atom.
47. The process of claim 44, wherein formula (7) is the following
formula (7b): ##STR00044##
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-ylme-
thyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione.
49. The process of claim 44, wherein formula (7) is the following:
##STR00045##
Description
TECHNICAL FIELD
[0001] The present invention relates to a pro{grave over (c)}ess
for preparing quaternary ammonium salt derivatives.
BACKGROUND ART
[0002] An imide derivative or a salt thereof whose typical example
is a compound of formula (8) mentioned later or an acid addition
salt thereof is known to be useful as a medicament for treating
schizophrenia, senile psychiatric disorder, bipolar disorder,
neurosis, etc. (Patent Reference 1). And, some processes for
preparing an imide derivative of the following formula (I):
##STR00001##
wherein A is optionally substituted C.sub.2-4 alkylene group or
other, D is carbonyl group or other, Y is optionally substituted
C.sub.1-2 alkylene group, Z is optionally substituted imino group
or other are also reported. For example, Patent Reference 2
discloses a process for preparing the imide derivative of the
above-mentioned formula (I) which comprises reacting a compound of
formula (II):
##STR00002##
wherein A is optionally substituted C.sub.2-4 alkylene group or
other, and D is carbonyl group or other, and a quaternary ammonium
salt of formula (III):
##STR00003##
wherein Y is optionally substituted C.sub.1-2 alkylene group, Z is
optionally substituted imino group or other, X.sup.- is a
counteranion in the presence of a solid inorganic base and
water.
[0003] In addition, Patent Reference 3 discloses that the compound
of formula (III) can be prepared by reacting a compound of formula
(IV):
##STR00004##
wherein Z is optionally substituted imino group or other, and a
compound of formula (V):
##STR00005##
wherein X is a group which can become the above counteranion
X.sup.- after cleavage, and Y is optionally-substituted C.sub.1-2
alkylene group in the presence of potassium carbonate whose
specific surface area is less than 1.8 m.sup.2/g.
[0004] Furthermore, Patent Reference 4 discloses a process for
preparing the compound of formula (III) which comprises reacting
the compound of formula (IV) and the compound of formula (V) in an
organic solvent in the presence of potassium carbonate whose mean
particle size (50% D) is not more than 200 .mu.m.
[0005] However, these processes have some problems on the preparing
processes, for example, the product of formula (I) contains a
by-product (hereinafter, referred to as "by-product (R)"), or the
reaction time of the preparing processes is unstable. Such
by-product (R) might cause the quality loss of the imide compound
of formula (I), hence it is necessary to remove the by-product
through a purification. Thus, it has been desired to further reduce
the producing of by-product (R) and stabilize the reaction time
from the viewpoint of the yield of the product and the production
cost.
PRIOR ART
[Patent Reference]
[0006] [Patent Reference 1] JP 2800953 B [0007] [Patent Reference
2] JP 2003-160583 A [0008] [Patent Reference 3] JP 2006-169155 A
[0009] [Patent Reference 4] JP 2006-169154 A
DISCLOSURE OF INVENTION
Problem to be Solved by the Invention
[0010] Under the situation, the present inventors have extensively
studied to reduce the producing of by-product (R) and then have
found that the cause of producing by-product (R) is potassium
carbonate which is used in the reaction of compound (IV) and
compound (V) as a base. And, the inventors have further extensively
studied other bases instead of potassium carbonate which has been
understood as an optimal base in the reaction process and then have
found that the producing of by-product (R) can be reduced by using
dibasic potassium phosphate with a small amount of water as a base
instead of potassium carbonate in the reaction between the
following compound of formula (1) and the following compound of
formula (2), and the improved process enable the reaction time to
be stabilized. Based upon the new findings, the present invention
has been completed.
Means to Solve the Problem
[0011] The present inventions are as follows.
Term 1:
[0012] A process for preparing a quaternary ammonium salt of
formula (4):
##STR00006##
wherein
[0013] X is halogen atom, C.sub.1-6 alkylsulfonyloxy group, or
C.sub.6-10 arylsulfonyloxy group, and X.sup.- is a counteranion
thereof,
[0014] Y is a substituent of the following formula (3a) or
(3b):
##STR00007##
[0015] wherein R.sup.3 is independently methylene or oxygen atom;
R.sup.4 is independently C.sub.1-6 alkyl group, C.sub.1-6 alkoxy
group, or hydroxy group; m and n are independently 0, 1, 2, or 3;
and p is 1 or 2, and
[0016] Z is .dbd.N--R.sup.1 or .dbd.CH--R.sup.2 wherein R.sup.1 is
C.sub.1-6 alkyl group, C.sub.3-7 cycloalkyl group, C.sub.5-7
cycloalkenyl group, C.sub.6-10 aryl group, or 5- to 10-membered
monocyclic or bicyclic heteroaryl group; R.sup.2 is C.sub.1-6 alkyl
group, C.sub.1-6 alkoxy group, C.sub.1-6 alkylthio group, C.sub.3-7
cycloalkyl group, C.sub.3-7 cycloalkyloxy group, C.sub.3-7
cycloalkylthio group, C.sub.5-7 cycloalkenyl group, C.sub.5-7
cycloalkenyloxy group, C.sub.5-7 cycloalkenylthio group, C.sub.6-10
aryl group, C.sub.6-10 aryloxy group, C.sub.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,
[0017] comprising reacting a compound of formula (1):
##STR00008##
wherein Z is as defined above
[0018] with 1 to 2 mole of a compound of formula (2):
##STR00009##
wherein X is independently selected from the above-defined ones,
and Y is as defined above, per one mole of the compound of formula
(1)
[0019] 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.
Term 2:
[0020] The process of Term 1 wherein X is independently C.sub.1-6
alkylsulfonyloxy group, or C.sub.6-10 arylsulfonyloxy group.
Term 3:
[0021] The process of Term 2 wherein X is methanesulfonyloxy
group.
Term 4:
[0022] The process of any one of Terms 1 to 3 wherein Y is the
substituent of formula (3a).
Term 5:
[0023] The process of Term 4 wherein m is 2 and n is 0.
Term 6:
[0024] The process of any one of Terms 1 to 5 wherein Z is
.dbd.N--R.sup.1.
Term 7:
[0025] The process of Term 6 wherein R.sup.1 is 5- to 10-membered
monocyclic or bicyclic heteroaryl group.
Term 8:
[0026] The process of Term 7 wherein R.sup.1 is
1,2-benzisothiazol-3-yl.
Term 9:
[0027] The process of any one of Terms 1 to 8 wherein the phosphate
is dibasic potassium phosphate.
Term 10:
[0028] The process of any one of Terms 1 to 9 wherein the phosphate
is 1 to 3 mole per one mole of the compound of formula (1).
Term 11:
[0029] The process of any one of Terms 1 to 10 wherein the amount
of water is 0.01 to 0.05 part by weight per one part by weight of
the phosphate.
Term 12:
[0030] The process of any one of Terms 1, 9 to 11 wherein
[0031] the compound of formula (1) is
##STR00010##
[0032] the compound of formula (2) is
##STR00011##
and
[0033] the quaternary ammonium salt of formula (4) is
##STR00012##
Term 13:
[0034] A process for preparing a compound of formula (8):
##STR00013##
wherein
[0035] B is carbonyl group or sulfonyl group,
[0036] R.sup.5a, R.sup.5b, R.sup.5c, and R.sup.5d are independently
hydrogen atom or C.sub.1-4 alkyl group, alternatively R.sup.5a and
R.sup.5b, or R.sup.5a and R.sup.5c may be taken together to form a
hydrocarbon ring, or R.sup.5a and R.sup.5c may be taken together to
form an aromatic hydrocarbon ring, wherein the hydrocarbon ring may
be bridged with C.sub.1-4 alkylene or oxygen atom wherein the
C.sub.1-4 alkylene and the hydrocarbon ring may be substituted with
at least one C.sub.1-4 alkyl,
[0037] q is 0 or 1, and
[0038] Y and Z are as defined in Term 1,
[0039] comprising reacting the quaternary ammonium salt (4)
prepared according to any one of claims 1 to 12 with the following
compound (7):
##STR00014##
wherein B, R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, and q are as
defined above, in the presence of a solid inorganic base.
Term 14:
[0040] The process of Term 13 wherein B is carbonyl group.
Term 15:
[0041] The process of Term 13 or 14 wherein R.sup.5a and R.sup.5b
are taken together to form a hydrocarbon ring which may be bridged
with C.sub.1-4 alkylene, and R.sup.5b and R.sup.5d are hydrogen
atom.
Term 16:
[0042] The process of Term 15 wherein Compound (7) is the following
compound of formula (7b):
##STR00015##
Term 17:
[0043] The process of any one of Terms 13 to 16 wherein Compound
(8) is
(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)-piperazin-1-ylm-
ethyl]cyclohexyl-methyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione.
Effect of the Invention
[0044] According to the present invention, the production of
by-product (R) can be held down because the reaction does not
include potassium carbonate. In addition, the reaction is carried
out with a small amount of water, thereby unfavorable variation of
the reaction time caused by such heterogeneous reaction medium can
be stabilized. Accordingly, the present reaction can be steadily
carried out (i.e. shortening the reaction time and enhancing the
transformation rate) and make it possible to prepare quaternary
ammonium salt (4) in stably high quality, particularly with an
industrial advantage.
BEST MODE FOR CARRYING OUT THE INVENTION
[0045] Hereinafter, the present invention is further illustrated.
The number additionally-described in each "substituent" such as
"C.sub.1-6" means the number of carbons contained therein. For
example, "C.sub.1-6 alkyl" means an alkyl group having 1 to 6
carbon atoms.
[0046] The number of substituents defined in an "optionally
substituted" or "substituted" group is not limited as long as the
substitution is possible, and the number may be one or more. Each
substituent used herein may be applied as a part of other
substituent or a substituent of other substituent, unless otherwise
indicated.
[0047] The term "halogen atom" used herein includes, for example,
fluorine atom, chlorine atom, bromine atom and iodine atom, and
preferably fluorine atom or chlorine atom.
[0048] The term "C.sub.1-6 alkyl group" used herein means a
straight or branched chain saturated hydrocarbon group having 1-6
carbon atoms, and the preferable one is "C.sub.1-4 alkyl group".
The "C.sub.1-6 alkyl group" includes, for example, methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl,
1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and
2-ethylbutyl.
[0049] The term "C.sub.3-7 cycloalkyl group" used herein means a
cyclic saturated hydrocarbon group having 3-7 carbon atoms, and the
preferable one is "C.sub.3-6 cycloalkyl group". The "C.sub.3-7,
cycloalkyl group" includes, for example, cyclopropyl, cyclobutyl,
cyclopentyl, and cyclohexyl.
[0050] The term "C.sub.6-10 aryl group" used herein means an
aromatic hydrocarbon group having 6-10 carbon atoms, and the
preferable one is "C.sub.6 aryl group" (i.e. phenyl). The
"C.sub.6-10 aryl group" includes, for example, phenyl, 1-naphthyl
and 2-naphthyl.
[0051] The term "C.sub.1-6 alkoxy group" used herein means a
C.sub.1-6 alkyloxy group, wherein the C.sub.1-6 alkyl moiety is
defined as the above-mentioned "C.sub.1-6 alkyl", and the
preferable one is "C.sub.1-4 alkoxy group". The "C.sub.1-6 alkoxy
group" includes, for example, methoxy, ethoxy, propoxy, isopropoxy,
butoxy, isobutoxy, sec-butoxy, and tert-butoxy.
[0052] The term "C.sub.3-7 cycloalkoxy group" used herein means a
C.sub.3-7 cycloalkyloxy group, wherein the C.sub.3-7 cycloalkyl
moiety is defined as the above-mentioned "C.sub.3-7 cycloalkyl".
The "C.sub.3-7 cycloalkoxy group" includes, for example,
cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and
cyclohexyloxy.
[0053] The "C.sub.6-10 aryl" moiety in the term "C.sub.6-10 aryloxy
group" used herein is defined as the above-mentioned "C.sub.6-10
aryl", and the preferable "C.sub.6-10 aryloxy group" is "C.sub.6
aryloxy" (i.e. phenyloxy). The "C.sub.6-10 aryloxy group" includes,
for example, phenoxy, 1-naphthyloxy and 2-naphthyloxy.
[0054] The "C.sub.1-6 alkyl" moiety in the term "C.sub.1-6
alkylthio group" used herein is defined as the above-mentioned
"C.sub.1-6 alkyl", and the preferable "C.sub.1-6 alkylthio group"
is "C.sub.1-4 alkylthio group". The "C.sub.1-6 alkylthio group"
includes, for example, methylthio, and ethylthio.
[0055] The "C.sub.3-7 cycloalkyl" moiety in the term "C.sub.3-7
cycloalkylthio group" used herein is defined as the above-mentioned
"C.sub.3-6 cycloalkyl". The "C.sub.3-7 cycloalkylthio group"
includes, for example, cyclopropylthio, cyclobutylthio,
cyclopentylthio, and cyclohexylthio.
[0056] The "C.sub.6-10 aryl" moiety in the term "C.sub.6-10
arylthio group" used herein is defined as the above-mentioned
"C.sub.6-10 aryl". The "C.sub.6-10 arylthio group" includes, for
example, phenylthio, 1-naphthylthio and 2-naphthylthio.
[0057] The "C.sub.1-6 alkyl" moiety in the term "C.sub.1-6
alkylsulfonyloxy group" used herein is defined as the
above-mentioned "C.sub.1-6 alkyl", and the preferable "C.sub.1-6
alkylsulfonyloxy group" is "C.sub.1-4 alkylsulfonyloxy group".
[0058] The "C.sub.1-6 alkylsulfonyloxy group" includes, for
example, methylsulfonyloxy, and ethylsulfonyloxy.
[0059] The "C.sub.6-10 aryl" moiety in the term "C.sub.6-10
arylsulfonyloxy group" used herein is defined as the
above-mentioned "C.sub.6-10 aryl". The "C.sub.6-10 arylsulfonyloxy
group" includes, for example, phenylsulfonyloxy,
1-naphthylsulfonyloxy and 2-naphthylsulfonyloxy.
[0060] The "heteroaryl group" used herein includes, for example, a
5- to 10-membered monocyclic or multi-cyclic aromatic group having
one or more heteroatoms (e.g. 1 to 4 heteroatoms)
independently-selected from nitrogen, sulfur, and oxygen atom. The
"multi-cyclic heteroaryl group" preferably includes a bicyclic or
tricyclic one, and more preferably a bicyclic one. The
"multi-cyclic heteroaryl group" also includes a fused cyclic group
of the above-mentioned monocyclic heteroaryl group with the
above-mentioned aromatic ring group (e.g. benzene) or non-aromatic
ring group (e.g. cyclohexyl). The "heteroaryl group" includes, for
example, the following groups.
##STR00016## ##STR00017##
[0061] The bond used herein which is connected to the middle of a
bond in a ring compound is meant to be attached to any possible
position of the ring. For example, the heteroaryl group of the
following formula:
##STR00018##
means 2-furyl group, or 3-furyl group.
[0062] In case that "heteroaryl group" is a multiple-cyclic group,
for example, in case of the following group:
##STR00019##
it means 2-benzofuryl group, or 3-benzofuryl group, and
additionally, it may mean 4-, 5-, 6- or 7-benzofuryl group.
However, in case that a multiple-cyclic heteroaryl group which is
composed by fusing an aromatic ring and non-aromatic ring (e.g.
piperidine), only the positions in the aromatic ring have the bond.
For example, the "multiple-cyclic heteroaryl group" such as the
following group:
##STR00020##
means to be bound on 2-, 3-, or 4-position.
[0063] The "heteroaryl" moiety in the term "heteroaryloxy group"
used herein is defined as the above-mentioned "heteroaryl group".
The "heteroaryloxy group" includes, for example, pyridyloxy.
[0064] The "heteroaryl" moiety in the term "heteroarylthio group"
used herein is defined as the above-mentioned "heteroaryl group".
The "heteroarylthio group" includes, for example, pyridylthio.
[0065] The "C.sub.5-7 cycloalkenyl group" used herein includes a
cycloalkenyl group having 5-7 carbon atoms such as cyclopentenyl
group, cyclohexenyl group, and cycloheptenyl group.
[0066] The "C.sub.5-7 cycloalkenyloxy group" used herein includes a
group composed of the above-mentioned cycloalkenyl group and oxygen
atom, such as cyclopentenyloxy group.
[0067] The "C.sub.5-7 cycloalkenylthio group" used herein includes
the above-mentioned cycloalkenyloxy group wherein the oxygen atom
is replaced by sulfur atom, such as cyclohexylthio group.
[0068] The "C.sub.1-4 alkylene" used herein has 1-4 carbon atoms
and includes, for example, methylene, ethylene, and
trimethylene.
[0069] The "C.sub.1-3 alkylene" used herein has 1-3 carbon atoms
and includes, for example, methylene, ethylene, and
trimethylene.
[0070] The "hydrocarbon ring" used herein is a cyclic alkane having
3-7 carbon atoms such as C.sub.3-7 cycloalkane, or a cyclic alkene
having 5-7 carbon atoms such as C.sub.5-7 cycloalkene. The cyclic
alkane having 3-7 carbon atoms includes, for example, cyclopropane,
cyclobutane, cyclopentane, cyclohexane, cycloheptane. The cyclic
alkene having 5-7 carbon atoms includes, for example, cyclopentene,
cyclohexene, and cycloheptene.
[0071] The "aromatic hydrocarbon ring" used herein means a ring
containing the above-mentioned "C.sub.6-10 aryl" moiety.
[0072] The compound of formula (2) (hereinafter, abbreviated as
"Compound (2)") includes, for example, 1,4-dibromobutane,
1,4-dichlorobutane, 1,4-diiodobutane,
1,4-dimethanesulfonyloxybutane,
1,4-di(p-toluenesulfonyloxy)-butane, 2-hydroxy-1,3-dibromopropane,
2-hydroxy-1,3-dichloropropane,
2-hydroxy-1,3-dimethanesulfonyloxypropane,
1,2-bis(bromomethyl)cyclohexane,
1,2-bis(methanesulfonyl-oxymethyl)cyclohexane,
1,2-bis(bromomethyl)cyclopentane,
1,2-bis(methanesulfonyloxymethyl)cyclopentane,
2,3-bis(bromomethyl)-bicyclo[2.2.1]heptane,
2,3-bis(methane-sulfonyloxymethyl)-bicyclo[2.2.1]heptane,
4,5-bis(bromo-methyl)-1-cyclohexene,
4,5-bis(methanesulfonyloxymethyl)-1-cyclohexene, and
2,3-bis(bromomethyl)-7-oxabicyclo[2.2.1]-hept-5-ene.
[0073] The "counteranion" includes, for example, halogen ion (e.g.
chlorine ion), sulfate ion, hydrogensulfate ion, phosphate ion,
hydrogenphosphate ion, dihydrogenphosphate ion, C.sub.1-6
alkylsulfonate ion (e.g. methanesulfonate ion), C.sub.6-10
arylsulfonate ion (e.g. p-toluenesulfonate ion), and hydroxide
ion.
[0074] The "by-product which is produced by the reaction with a
potassium carbonate of the compound having a carbonate part
therein" (by-product (R)) is all-inclusive term of by-products
having at least one carbonate parts therein. In the present
specification, these by-products are expressed as "by-product (R)",
and the producing rates of by-product (R) in the examples mentioned
below are used as an evaluation of the present invention.
[0075] In the compound of formula (1) (hereinafter, abbreviated as
"Compound (1)"), C.sub.1-6 alkyl group, C.sub.3-7 cycloalkyl group,
C.sub.5-7 cycloalkenyl group, C.sub.6-10 aryl group, and 5- to
10-membered monocyclic or bicyclic heteroaryl group in "R.sup.1";
and C.sub.1-6 alkyl group, C.sub.1-6 alkoxy group, C.sub.1-6
alkylthio group, C.sub.3-7 cycloalkyl group, C.sub.3-7
cycloalkyloxy group, C.sub.3-7 cycloalkylthio group, C.sub.5-7
cycloalkenyl group, C.sub.5-7 cycloalkenyloxy group, C.sub.5-7
cycloalkenylthio group, C.sub.6-10 aryl group, C.sub.6-10 aryloxy
group, C.sub.6-10 arylthio group, 5- to 10-membered monocyclic or
bicyclic heteroaryl group, 5- to 10-membered monocyclic or bicyclic
heteroaryloxy group, and 5- to 10-membered monocyclic or bicyclic
heteroarylthio group in "R.sup.2" may be further optionally
substituted with the same or different one to three substituents
selected from the group consisting of C.sub.1-4 alkyl, C.sub.1-4
alkoxy, C.sub.1-4 alkylthio and halogen atom.
[0076] Compound (1) includes, for example, 4-phenylpiperazine,
4-(2-methoxyphenyl)piperazine, 4-cyclohexylpiperazine,
4-(2-pyridinyl)piperazine, 4-(2-pyrimidinyl)piperazine,
4-(2-quinolyl)piperazine, 4-(4-quinolyl)piperazine,
4-(1,2-benzisothiazol-3-yl)piperazine,
4-(4-fluorophenyl)piperidine, 4-[(4-fluorophenyl)thio]-piperidine,
4-(3-chlorophenyl)piperazine, 4-(1,2-benzisoxazol-3-yl)piperidine,
4-(5-benzofuranyl)piperazine, 4-(1-naphthyl)piperazine,
4-[bis(4-fluorophenyl)methylene]-piperidine,
4-(3-isoquinolyl)piperazine, 4-(8-quinolyl)-piperazine,
4-(7-benzofuranyl)piperazine, and
4-(5-fluoro-1,2-benzisoxazol-3-yl)piperidine. The preferable
example is 4-(1,2-benzisothiazol-3-yl)piperazine.
[0077] Compound (1) can be prepared according to, for example, JP
63 (1988)-83085 A, J. Med. Chem., 28761 (1985), and J. Med. Chem.,
32, 1024 (1989). And, Compound (1) may include an addition acid
salt thereof (1) such as a hydrochloride and a sulfate thereof.
[0078] As Compound (2) used herein, a commercially available
compound may be used. In case that Compound (2) has a chiral
carbon(s), i.e. it has an optical isomer, the compound herein may
be a single optical isomer, a racemic compound thereof, or a
mixture of optical isomers in a certain ratio.
[0079] A preferable example of Compound (2) includes a compound of
the following formula:
##STR00021##
wherein Ms means methanesulfonyl group.
[0080] In the reaction between Compound (1) and Compound (2) in the
present invention, the amount of Compound (2) used herein is
generally 1 mole to 2 mole per one mole of Compound (1). The upper
limit amount of Compound (2) used herein is not limited, but, in
case that the amount is too much, the process cost increases.
[0081] The present invention is directed to the reaction between
Compound (1) and Compound (2) using dibasic potassium phosphate
with a small amount of water as a base instead of potassium
carbonate. The improved process can make the reaction time
stabilized and the producing of by-product (R) reduced to prepare a
quaternary ammonium salt (4):
##STR00022##
wherein X, Y and Z are as defined in the above Term 1 (hereinafter,
abbreviated as "quaternary ammonium salt (4)") in stably high
quality.
[0082] The "phosphate" used in the reaction between Compound (1)
and Compound (2) includes, for example, an alkali metal phosphate
such as potassium phosphate and sodium phosphate; an alkali earth
metal salt such as calcium phosphate; and an alkali metal
hydrogenphosphate such as dibasic sodium phosphate and dibasic
potassium phosphate; preferably dibasic potassium phosphate. Such
phosphate may be used alone or as a mixture of two or more kinds of
such phosphates. And, such phosphate may be an anhydrous form or a
hydrate thereof.
[0083] The amount of the phosphate used herein is generally 1.0
mole or more per one mole of Compound (1), and the upper limit
amount is not limited, but, in case that the amount is too much,
the process cost increases. Accordingly, the amount of the
phosphate used is practically 3 mole or less per one mole of
Compound (1). And, in case of using an acid addition salt of
Compound (1), it is preferable to add an additional appropriate
amount of a base to neutralize the acid addition salt. Such base
used is generally dibasic potassium phosphate.
[0084] The reaction of the present invention is carried out in the
coexistence of water, i.e. in the presence of generally 0.01 to 0.1
part by weight, preferably 0.01 to 0.05 part by weight of water per
one part by weight of the phosphate. When using a hydrate of
dibasic potassium phosphate, the amount of water used herein may be
decided considering the water of the hydrate. The water may
initially exist in the reaction medium or an appropriate amount of
water may be added thereto in mid-course. Or, the water may be
added to Compound (1) and/or Compound (2) beforehand.
[0085] In addition, the reaction of the present invention may be
carried out in the coexistence of a phase-transfer catalyst such as
tetra-n-butyl ammonium hydrogen sulfate, tetra-n-butyl ammonium
bromide, and benzyl triethyl ammonium chloride. The amount of the
phase-transfer catalyst used herein is generally 0.01 to 0.5 mole
per one mole of the amount of Compound (1).
[0086] In case of using an acid addition salt of Compound (1), it
is preferable to add an additional appropriate amount of
hydrochloric acid to neutralize the acid addition salt.
[0087] The solvent used herein includes, for example, an alcohol
solvent such as methanol, and ethanol; an aprotic polar solvent
such as acetonitrile, and N,N-dimethylformamide; aromatic carbon
ring solvent such as toluene, and xylene; which can be used alone
or in a mixture of two or more kinds of the solvents and the amount
of the solvent used is not limited.
[0088] The reaction temperature is generally 60 to 180.degree. C.,
preferably 90 to 150.degree. C.
[0089] After the reaction is completed, for example, the reaction
mixture or a part of the reaction mixture can be concentrated and
then filtrated to give a mixture of quaternary ammonium salt (4)
and a phosphate. In addition, the reaction mixture containing
quaternary ammonium salt (4) and a phosphate may be used in the
reaction mentioned below without taking out quaternary ammonium
salt (4) from the mixture.
[0090] Quaternary ammonium salt (4) thus prepared includes, for
example, chloride, bromide, iodide, hydroxide, sulfate,
hydrogensulfate, phosphate, hydrogenphosphate,
dihydrogen-phosphate, methanesulfonate, and p-toluenesulfonate of
[0091] 7-cyclohexyl-2-hydroxy-7-aza-4-azoniaspiro[3.5]-nonane,
[0092] 8-phenyl-8-aza-5-azoniaspiro[4.5]decane, [0093]
8-(2-methoxyphenyl)-8-aza-5-azoniaspiro[4.5]decane, [0094]
8-(2-pyridinyl)-8-aza-5-azoniaspiro[4.5]decane, [0095]
8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4.5]decane, [0096]
8-(2-quinolyl)-8-aza-5-azoniaspiro[4.5]decane, [0097]
8-(4-quinolyl)-8-aza-5-azoniaspiro[4.5]decane, [0098]
8-(1,2-benzisothiazol-3-yl)-8-aza-5-azoniaspiro-[4.5]decane, [0099]
4'-(1,2-benzisothiazol-3-yl)octahydro-spiro[2H-isoindole-2,1'-piperaziniu-
m], [0100]
4'-[(4-fluorophenyl)thio]octahydro-spiro[2H-isoindole-2,1'-pipe-
ridinium], [0101]
4'-(2-pyrimidinyl)octahydro-spiro[2H-isoindole-2,1'-piperazinium],
[0102]
4'-(4-fluorophenoxy)octahydro-spiro[2H-isoindole-2,1'-piperidinium],
[0103]
4'-(1,2-benzisoxazol-3-yl)octahydro-spiro[2H-isoindole-2,1'-piperi-
dinium],
4'-(6-fluoro-1,2-benzisoxazol-3-yl)-octahydro-spiro[2H-isoindole--
2,1'-piperazinium], [0104]
4'-(2-pyridinyl)octahydro-spiro[2H-isoindole-2,1'-piperazinium],
[0105]
4'-(3-chlorophenyl)octahydro-spiro[2H-isoindole-2,1'-piperazinium],
[0106]
4'-(5-benzofuranyl)octahydro-spiro[2H-isoindole-2,1'-piperazinium]-
, [0107]
4'-(1-naphthyl)octahydro-spiro[2H-isoindole-2,1'-piperazinium],
[0108]
4'-[bis(4-fluorophenyl)methylene]octahydro-spiro[2H-isoindole-2,1'-
-piperidinium], [0109]
4'-(2-methoxyphenyl)octahydro-spiro[2H-isoindole-2,1'-piperazinium],
4'-(3-isoquinolyl)octahydro-spiro[2H-isoindole-2,1'-piperazinium],
[0110]
4'-(8-quinolyl)octahydro-spiro[2H-isoindole-2,1'-piperazinium],
[0111]
4'-(1,2-benzisothiazol-3-yl)tetrahydro-spiro-[cyclopenta[c]pyrrole-2(1H),
1'-piperazinium], [0112]
4'-(1,2-benzisothiazol-3-yl)octahydro-spiro[4,7-methano-2H-isoindole-2,1'-
-piperazinium], [0113]
4'-(1,2-benzisothiazol-3-yl)-1,3,3a,4,7,7a-hexahydro-spiro[2H-isoindole-2-
,1'-piperazinium], [0114]
4'-(1,2-benzisothiazol-3-yl)-1,3,3a,4,7,7a-hexahydro-spiro[4,7-epoxy-2H-i-
soindole-2,1'-piperazinium], or [0115]
4'-(7-benzofuranyl)octahydro-spiro[2H-isoindole-2,1'-piperazinium].
[0116] By reacting the resulting quaternary ammonium salt (4) and a
compound of formula (7):
##STR00023##
wherein the symbols are as defined in the above Term 13
(hereinafter, abbreviated as "Compound (7)") in the presence of a
solid inorganic base, an imide compound of formula (8):
##STR00024##
wherein the symbols are as defined in the above Term 13
(hereinafter, abbreviated as "imide compound (8)") can be
prepared.
[0117] Compound (7) includes a compound of the following formula
(7a):
##STR00025##
wherein -L- is a single or double bond, E is C.sub.1-3 alkylene
optionally substituted with C.sub.1-4 alkyl or oxygen atom,
R.sup.5e is hydrogen atom or C.sub.1-4 alkyl group, and B is as
defined in the above formula (7).
[0118] Compound (7) includes, for example, succinimide,
2,6-piperidine-dione, 4,4-dimethyl-2,6-piperidine-dione,
8-azaspiro[4.5]decane-7,9-dione, perhydroazepin-2,7-dione,
maleimide, phthalimide, tetrahydrophthalimide,
cis-1,2-cyclohexane-dicarboximide,
trans-1,2-cyclohexane-dicarboximide,
cis-1,2-cyclohex-4-ene-dicarboximide,
trans-1,2-cyclohex-4-ene-dicarboximide,
cis-4-methyl-1,2-cyclohexane-dicarboximide,
trans-4-methyl-1,2-cyclohexane-dicarboximide,
cis-1,2-dimethyl-1,2-cyclohexane-dicarboximide,
trans-1,2-dimethyl-1,2-cyclohexane-dicarboximide,
cis-4,5-dimethyl-1,2-cyclohexane-dicarboximide,
trans-4,5-dimethyl-1,2-cyclohexane-dicarboximide,
cis-3,6-dimethyl-1,2-cyclohexane-dicarboximide,
trans-3,6-dimethyl-1,2-cyclohexane-dicarboximide,
bicyclo[2.2.1]heptane-2,3-di-exo-carboximide,
bicyclo[2.2.1]heptane-2,3-di-endo-carboximide,
bicyclo[2.2.1]hept-5-ene-2,3-di-exo-carboximide,
bicyclo[2.2.1]hept-5-ene-2,3-di-endo-carboximide,
bicyclo-[2.2.2]octane-2,3-di-exo-carboximide,
bicyclo[2.2.2]octane-2,3-di-endo-carboximide,
bicyclo[2.2.2]oct-5-ene-2,3-di-exo-carboximide,
bicyclo[2.2.2]oct-5-ene-2,3-di-endo-carboximide,
bicyclo[2.2.2]oct-7-ene-2,3-di-exo-carboximide,
bicyclo[2.2.2]oct-7-ene-2,3-di-endo-carboximide,
hexahydro-4,7-methano-1,2-benzisothiazol-3(2H)-one-1,1-dioxide,
3,6-epoxy-1,2-cyclohexane-dicarboximide, and
spiro[bicyclo[2.2.2]octane-2,3'-pyrrolidine]-2',5'-dione.
[0119] A preferable example of Compound (7) includes a compound of
the following (7b):
##STR00026##
[0120] Compound (7b) can include its optical isomers, thus the
compound used herein may be one of the optical isomers or a mixture
of the optical isomers. A preferable example of Compound (7)
includes a compound of the following formula:
##STR00027##
or a salt thereof.
[0121] Compound (7) can be prepared, for example, by reacting a
corresponding carboxylic anhydride compound and ammonia (for
example, JP-1(1989)-199967 A).
[0122] The solid inorganic base (salt) includes, for example, an
alkali metal carbonate such as potassium carbonate, and sodium
carbonate; an alkali earth metal salt such as calcium carbonate,
and magnesium carbonate; and an alkali metal bicarbonate such as
sodium bicarbonate, and potassium bicarbonate; preferably an alkali
metal carbonate, in particular, potassium carbonate. Such solid
inorganic base may be used alone or as a mixture of two or more
kinds of bases. And, such solid inorganic bases may be an anhydrous
form or a hydrate thereof.
[0123] The amount of the solid inorganic base used herein is
generally 0.7 mole or more, preferably 0.9 mole or more per one
mole of the amount of Compound (1) or quaternary ammonium salt (4).
The upper limit amount of the solid inorganic base used herein is
not limited, but, in case that the amount is too much, the process
cost increases. Accordingly, the practical amount of the solid
inorganic base is 3 mole or less, preferably 2.7 mole or less per
one mole of the amount of Compound (1) or quaternary ammonium salt
(4).
[0124] The amount of Compound (7) used herein is generally 0.7 mole
or more per one mole of the amount of Compound (1) or quaternary
ammonium salt (4). The upper limit amount of Compound (7) used
herein is not limited, but, in case that the amount is too much,
the process cost increases. Accordingly, the practical amount of
Compound (7) is 2.5 mole or less per one mole of the amount of
Compound (1) or quaternary ammonium salt (4).
[0125] The reaction of the present invention is generally carried
out in the presence of a solvent. The solvent used herein includes,
for example, aromatic hydrocarbons such as toluene, xylene,
mesitylene, chlorobenzene, and dichlorobenzene. The amount of such
solvent used herein is generally 3 parts by weight or more,
preferably 5 parts by weight or more per one part by weight of the
total amount of Compound (1) or quaternary ammonium salt (4). The
upper limit amount of the solvent used herein is not limited, but,
in case that the amount is too much, the volumetric efficiency is
turned down. Accordingly, the practical amount of the solvent is 20
parts by weight or less per one part by weight of the amount of
Compound (1) or quaternary ammonium salt (4).
[0126] The reaction of the present invention is preferably carried
out in the coexistence of water, i.e. in the presence of generally
0.05 to 3 mole, preferably 0.1 to 1.5 mole of water per one mole of
the amount of Compound (1) or quaternary ammonium salt (4). When
using a hydrate of solid inorganic base, the amount of water used
herein may be decided considering the water of the hydrate. The
water may initially exist in the reaction medium or an appropriate
amount of water may be added thereto in mid-course. Or, the water
may be added to Compound (7) and/or quaternary ammonium salt (4)
beforehand.
[0127] In addition, the reaction of the present invention may be
carried out in the coexistence of a phase-transfer catalyst such as
tetra-n-butyl ammonium hydrogen sulfate, tetra-n-butyl ammonium
bromide, and benzyl triethyl ammonium chloride. The amount of the
phase-transfer catalyst used herein is generally 0.01 to 0.5 mole
per one mole of the amount of Compound (2) or quaternary ammonium
salt (4).
[0128] The reaction temperature is generally 80 to 180.degree. C.,
preferably 95 to 150.degree. C.
[0129] The reaction of quaternary ammonium salt (4) and Compound
(7) is generally carried out by contacting and mixing quaternary
ammonium salt (4), Compound (7) and a solid inorganic base, and the
addition order of the substances is not limited. The solid
inorganic base may be added thereto in separated amounts or in a
lump, but it is preferable in a lump.
[0130] The reaction mixture containing imide compound (8) is
obtained after the reaction, and the mixture can be treated by
adding water thereto, mixing it, standing still in a whole,
separating it with a separating funnel, optionally treating the
organic layer with active carbon, and concentrating the organic
layer to give imide compound (8). Alternatively, imide compound (8)
can be obtained as a crystal by cooling the above-mentioned organic
layer or the partially-concentrated organic layer, or adding
another solvent which is comparatively insoluble for imide compound
(8) to the organic layer. The solvent which is comparatively
insoluble for imide compound (8) includes, for example, an
aliphatic hydrocarbon solvent such as pentane, hexane, and heptane,
and an alcohol solvent such as methanol, ethanol, and
isopropanol.
[0131] In addition, imide compound (8) can be also obtained from
the reaction mixture containing imide compound (8) by removing out
insoluble precipitates with a filter and concentrating the
filtrate. Further, imide compound (8) can be obtained as a crystal
by cooling the reaction mixture or the partially-concentrated
reaction mixture, or adding another solvent which is comparatively
insoluble for imide compound (8) to the organic layer.
[0132] The obtained imide compound (8) may be further purified by a
conventional purification such as recrystallization and
chromatography. In addition, imide compound (8) can be obtained as
an inorganic acid addition salt such as hydrochloride, sulfate,
hydrobromide, and phosphate; or an organic acid addition salt such
as acetate, oxalate, citrate, malate, tartrate, maleate, and
fumarate.
[0133] The imide compound (8) prepared herein includes, for
example, [0134]
2-[4-(4-phenyl-1-piperazinyl)butyl]hexahydro-1H-isoindole-1,3(2H)--
dione, [0135]
2-[4-(4-phenyl-1-piperazinyl)butyl]hexahydro-4,7-methano-1H-isoindole-1,3-
(2H)-dione, [0136]
2-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]-hexahydro-1H-isoindole-1,3-
(2H)-dione, [0137]
2-[9-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]-hexahydro-4,7-methano-1H-i-
soindole-1,3(2H)-dione, [0138]
2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]meth-
yl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione
(2-[2-[4-(1,2-benzisothiazol-3-yl)-piperazin-1-ylmethyl]cyclohexylmethyl]-
hexahydro-4,7-methano-2H-isoindole-1,3-dione), [0139]
2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]meth-
yl]hexahydro-4,7-methano-1,2-benz-isothiazole-3(2H)-one-1,1-dioxide,
[0140]
2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohex-
yl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione, [0141]
2-[[2-[[4-(2-pyrimidinyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahyd-
ro-4,7-methano-1H-isoindole-1,3(2H)-dione, [0142]
2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]meth-
yl]-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione, [0143]
8-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]meth-
yl]-8-azaspiro[4,5]decane-7,9-dione, [0144]
1-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]meth-
yl]-4,4-dimethyl-2,6-piperidine-dione, [0145]
2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]meth-
yl]hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione, [0146]
1'-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]met-
hyl]-spiro[bicyclo[2.2.2]octane-2,3'-pyrrolidine]-2',5'-dione,
[0147]
2-[[2-[([4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]met-
hyl]hexahydro-3a,7a-dimethyl-1H-isoindole-1,3(2H)-dione, [0148]
2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]meth-
yl]-3a,4,7,7a-tetrahydro-4,7-ethano-1H-isoindole-1,3(2H)-dione,
[0149]
2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]meth-
yl]hexahydro-4,7-ethano-1H-isoindole-1,3(2H)-dione, [0150]
2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]meth-
yl]-1H-isoindole-1,3(2H)-dione, [0151]
2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]meth-
yl]-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione, [0152]
2-[[2-[[4-[(4-fluorophenyl)thio]-1-piperidyl]-methyl]cyclohexyl]methyl]he-
xahydro-4,7-methano-1H-isoindole-1,3(2H)-dione, [0153]
2-[[2-[[4-[(4-fluorophenyl)thio]-1-piperidyl]-methyl]cyclohexyl]methyl]he-
xahydro-1H-isoindole-1,3(2H)-dione, [0154]
2-[[2-[[4-(4-fluorophenoxy)-1-piperidyl]methyl]-cyclohexyl]methyl]hexahyd-
ro-4,7-methano-1H-isoindole-1,3(2H)-dione, [0155]
2-[[2-[[4-(4-fluorophenoxy)-1-piperidyl]methyl]-cyclohexyl]methyl]hexahyd-
ro-1H-isoindole-1,3(2H)-dione, [0156]
2-[[2-[[4-(1,2-benzisoxazol-3-yl)-1-piperidyl]-methyl]cyclohexyl]methyl]h-
exahydro-4,7-methano-1H-isoindole-1,3(2H)-dione, [0157]
2-[[2-[[4-(1,2-benzisoxazol-3-yl)-1-piperidyl]-methyl]cyclohexyl]methyl]h-
exahydro-1H-isoindole-1,3(2H)-dione, [0158]
2-[[2-[[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidyl]methyl]cyclohexyl]-
methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione, [0159]
2-[[2-[[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidyl]methyl]cyclohexyl]-
methyl]hexahydro-1H-isoindole-1,3(2H)-dione, [0160]
2-[[2-[[4-(2-pyridinyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-
-4,7-methano-1H-isoindole-1,3(2H)-dione, [0161]
2-[[2-[[4-(2-pyridinyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-
-1H-isoindole-1,3(2H)-dione, [0162]
2-[[2-[[4-(2-pyrimidinyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahyd-
ro-4,7-methano-1H-isoindole-1,3(2H)-dione, [0163]
2-[[2-[[4-(2-pyrimidinyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahyd-
ro-1H-isoindole-1,3(2H)-dione, [0164]
2-[[2-[[4-(3-chlorophenyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahy-
dro-4,7-methano-1H-isoindole-1,3(2H)-dione, [0165]
2-[[2-[[4-(3-chlorophenyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahy-
dro-1H-isoindole-1,3(2H)-dione, [0166]
2-[[2-[[4-(5-benzofuranyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahy-
dro-4,7-methano-1H-isoindole-1,3(2H)-dione, [0167]
2-[[2-[[4-(5-benzofuranyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahy-
dro-1H-isoindole-1,3(2H)-dione, [0168]
2-[[2-[[4-(1-naphthyl)-1-piperazinyl]methyl]cyclohexyl]methyl]hexahydro-4-
,7-methano-1H-isoindole-1,3(2H)-dione, [0169]
2-[[2-[[4-(1-naphthyl)-1-piperazinyl]methyl]cyclohexyl]methyl]hexahydro-1-
H-isoindole-1,3(2H)-dione, [0170]
2-[[2-[[4-[bis(4-fluorophenyl)methylene]-1-piperidyl]methyl]cyclohexyl]me-
thyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione, [0171]
2-[[2-[[4-[bis(4-fluorophenyl)methylene]-1-piperidyl]methyl]cyclohexyl]me-
thyl]hexahydro-1H-isoindole-1,3(2H)-dione, [0172]
2-[[2-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexah-
ydro-4,7-methano-1H-isoindole-1,3(2H)-dione, [0173]
2-[[2-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexah-
ydro-1H-isoindole-1,3(2H)-dione, [0174]
2-[[2-[[4-(3-isoquinolyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahyd-
ro-4,7-methano-1H-isoindole-1,3(2H)-dione, [0175]
2-[[2-[[4-(3-isoquinolyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahyd-
ro-1H-isoindole-1,3(2H)-dione, [0176]
2-[[2-[[4-(8-quinolyl)-1-piperazinyl]methyl]cyclohexyl]methyl]hexahydro-4-
,7-methano-1H-isoindole-1,3(2H)-dione, [0177]
2-[[2-[[4-(8-quinolyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro--
1H-isoindole-1,3(2H)-dione, [0178]
2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclopentyl]met-
hyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione, [0179]
2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclopentyl]met-
hyl]hexahydro-1H-isoindole-1,3(2H)-dione, [0180]
2-[[3-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]bicyclo[2.2.1]h-
ept-2-yl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,
[0181]
2-[[3-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]bicyclo[2.2.1]h-
ept-2-yl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione, [0182]
2-[([2-[[4-(7-benzofuranyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexah-
ydro-4,7-methano-1H-isoindole-1,3(2H)-dione, [0183]
2-[[2-[[4-(7-benzofuranyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahy-
dro-1H-isoindole-1,3(2H)-dione, [0184]
2-[[3-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]-7-oxabicyclo[2-
.2.1]hept-5-ene-2-yl]methyl]-hexahydro-4,7-methano-1H-isoindole-1,3(2H)-di-
one, [0185]
2-[[3-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]-7-oxabicyclo[2-
.2.1]hept-5-ene-2-yl]methyl]-hexahydro-1H-isoindole-1,3(2H)-dione,
[0186]
2-[[6-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]-3-cyclohexen-1-
-yl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione, and
[0187]
2-[[6-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]-3-cyclohexen-1-
-yl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione.
[0188] In case that the optically active compound (7) and/or the
optically active quaternary ammonium salt (4) are used in the
reaction, the optically active corresponding imide compound (8) can
be obtained.
[0189] In addition, the present invention includes the following
process:
##STR00028##
wherein the symbols described in the scheme are as defined in Terms
1 and 13 mentioned above.
EXAMPLE
[0190] Hereinafter, the present invention is illustrated in more
detail by the following Example and Comparative Example, but it
should not be construed to be limited thereto. The analyses in the
examples were done by high-performance liquid chromatography
(LC).
Example 1
[0191] To a mixed solution of 4-(1,2-benzisothiazol-3-yl)piperazine
[Compound (A)] (20.0 g, 91.2 mmol),
(1R,2R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane [Compound (B)]
(32.9 g, 109.5 mmol), and toluene (280 g) were added dibasic
potassium phosphate (47.7 g, 273.9 mmol), water (1.4 g, 77.8 mmol)
and tetra-n-butyl ammonium hydrogen sulfate (1.2 g, 3.5 mmol). The
mixture was stirred under reflux for 15 hours (water (0.5 g) was
added in mid-course) to give a reaction mixture containing
4'-(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydro-spiro[2H-isoindole-2,1'--
piperazinium]methanesulfonate [Compound (C)].
Example 2
[0192] To the reaction mixture containing Compound (C) which was
obtained in the above Example 1 were added
(3aR,4S,7R,7aS)-hexahydro-4,7-methano-2H-isoindole-1,3-dione
[Compound (D)] (22.6 g, 136.8 mmol), potassium carbonate (15.1 g,
109.3 mmol) and toluene (44 g). Then, the toluene (44 g) was
distilled out from the mixture, water (0.82 g) was added thereto,
and the resulting mixture was reacted under reflux for 8 hours.
Then, the reaction mixture was cooled to room temperature, and
water (400 g) was added to the mixture. The mixture was separated
with a separating funnel, and the toluene layer was washed with
2.3% (W/W) brine (350 g). Further, active carbon (1.8 g) was added
to the toluene solution, and the mixture was stirred for 1 hour.
The active carbon was removed by filtration to give a toluene
solution containing
(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
(2-[[(1R,2R)-2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]methy-
l]cyclohexyl]-methyl]hexahydro-(3aS,4R,7S,7aR)-4,7-methano-1H-isoindole-1,-
3(2H)-dione) [Compound (E)] (341.4 g). The yield of Compound E was
94.3% The yield of Compound (E) was calculated based on the
analytical result that the content of the compound in the toluene
solution was 12.4% (w/w) (which was calculated by LC absolute
calibration curve method). And, the production rate of by-product
(R) was 0.013% (which was calculated with the following formula
(a)).
Production rate of by - product derived from carbonate = Total LC
area of by - product derived from carbonate Total LC area of
detected peaks except solvent .times. 100 ( a ) ##EQU00001##
Example 3
[0193] To a mixture of Compound (A) (20.0 g, 91.2 mmol), Compound
(B) (32.9 g, 109.5 mmol) and toluene (280 g) was added dibasic
potassium phosphate (23.8 g, 136.6 mmol), water (0.95 g, 52.8 mmol)
and tetra-n-butyl ammonium hydrogen sulfate (1.2 g, 3.5 mmol). The
mixture was stirred under reflux for 14 hours to give a reaction
mixture containing Compound (C).
Example 4
[0194] To the reaction mixture containing Compound (C) which was
obtained in the above Example 3 were added Compound (D) (22.6 g,
136.8 mmol) and potassium carbonate (15.1 g, 109.3 mmol), and the
mixture was stirred under reflux for 6 hours. Then, the reaction
mixture was cooled to room temperature, and water (400 g) was added
to the mixture. The mixture was separated with a separating funnel,
and the toluene layer was washed with 2.3% (WW) brine (350 g).
Further, active carbon (1.8 g) was added to the toluene solution,
and the mixture was stirred for 1.5 hours. The active carbon was
removed by filtration to give a toluene solution containing
Compound (E) (415.4 g). The yield of Compound E was 88.6%. The
yield of Compound (E) was calculated based on the analytical result
that the content of the compound in the toluene solution was 9.6%
(w/w) (which was calculated by LC absolute calibration curve
method). And, the production rate of by-product (R) was 0.019%
(which was calculated with the above formula (a)).
Comparative Example 1
[0195] To a mixture of Compound (A) (140.1 kg, 638.8 mol), Compound
(B) (230.3 kg, 766.7 mol) and toluene (2272 kg) was added potassium
carbonate (53.0 kg, 383.5 mol), the toluene (312 kg) was removed by
heating, and then the mixture was reflux-dehydrated for 5 hours.
Then, the reaction mixture was cooled to 70.degree. C. or lower,
and potassium carbonate (26.5 kg, 191.7 mol) and tetra-n-butyl
ammonium hydrogen sulfate (8.7 kg, 25.6 mol) were added to the
mixture. The mixture was refluxed for 10 hours to give the reaction
mixture containing Compound (C).
Comparative Example 2
[0196] To the reaction mixture containing Compound (C) which was
obtained in the above Comparative Example 1 were added toluene
(309.6 kg), Compound (D) (158.3 kg, 958.3 mol) and potassium
carbonate (105.9 kg, 766.2 mol), and then the toluene (308 kg) was
removed by heating. Then, the reaction mixture was cooled to
70.degree. C. or lower, and water (5.7 kg) was added to the
mixture. The mixture was refluxed for 4 hours. The reaction mixture
was cooled, and water (2819 kg) was added to the mixture. The
mixture was separated with a separating funnel, and the toluene
layer was washed with 2.3% (w/w) brine (2466 kg). Further, active
carbon (12.5 kg) was added to the toluene solution, and the mixture
was stirred for 1 hour. The active carbon was removed by filtration
and washed with toluene to give a toluene solution containing
Compound (E) (2562 kg). The yield of Compound (E) was 87.7%. The
yield of Compound (E) was calculated based on the analytical result
that the content of the compound in the toluene solution was 10.8%
(w/w) (which was calculated by LC absolute calibration curve
method). And, the production rate of by-product (R) was 9.83%
(which was calculated with the above formula (a))
Comparative Example 3
[0197] To a mixture of Compound (A) (90.0 kg, 410.4 mol), Compound
(B) (147.9 kg, 492.4 mol) and toluene (1460 kg) were added
potassium carbonate (34.0 kg, 246.0 mol) and water (636 g), the
toluene (298 kg) was removed by heating, and then the mixture was
reflux-dehydrated for 34 hours. Then, the reaction mixture was
cooled to 70.degree. C. or lower, and potassium carbonate (17.0 kg,
123.0 mol) and tetra-n-butyl ammonium hydrogen sulfate (5.6 kg,
16.5 mol) were added to the mixture. The mixture was refluxed for
12 hours to give the reaction mixture containing Compound (C). And,
the production rate of by-product (R) was 3.02% (which was
calculated with the above formula (a)).
Comparative Example 4
[0198] To the reaction mixture containing Compound (C) which was
obtained in the above Comparative Example 3 were added toluene (198
kg), Compound (D) (101.7 kg, 615.7 mol) and potassium carbonate
(68.1 kg, 492.7 mol), and then the toluene (198 kg) was removed by
heating. Then, the reaction mixture was cooled to 70.degree. C. or
lower, and water (3.7 kg) was added to the mixture. The mixture was
refluxed for 3 hours. The reaction mixture was cooled, and water
(1803 kg) was added to the mixture. The mixture was separated with
a separating funnel, and the toluene layer was washed with 2.3%
(w/w) brine (1578 kg). Further, active carbon (8.0 kg) was added to
the toluene solution, and the mixture was stirred for 1 hour. The
active carbon was removed by filtration and washed with toluene to
give a toluene solution containing Compound (E) (1625 kg). The
yield of Compound (E) was 90.1%. The yield of Compound (E) was
calculated based on the analytical result that the content of the
compound in the toluene solution was 11.2% (w/w) (which was
calculated by LC absolute calibration curve method). And, the
production rate of by-product (R) was 3.08% (which was calculated
with the above formula (a)).
[0199] Each reaction time, product yield, and by-product yield in
the above examples and comparative examples is shown in the
following table.
TABLE-US-00001 dibasic potassium Potassium Compound (B) phosphate
carbonate Reaction time Product yield By-product (R) Process (mol)
(mol) (mol) (hr) (%) (%) Example 1 (A) 1.2 3.0 -- 15 Example 2 (B)
-- 1.2 8 94 0.013 Example 3 (A) 1.2 1.5 -- 14 Example 4 (B) -- 1.2
6 89 0.019 Comparative (A) 1.2 -- 0.9 15 Example 1 Comparative (B)
-- 1.2 4 88 9.83 Example 2 Comparative (A) 1.2 -- 0.9 46 3.02
Example 3 Comparative (B) -- 1.2 3 90 3.08 Example 4 Process (A):
Compound (A) + Compound (B) --> quaternary ammonium salt (C)
Process (B): quaternary ammonium salt (C) + Compound (D) -->
imide compound (E)
[0200] According to the results of Examples 1 and 3, the process of
the present invention can make the reaction time for preparing
quaternary ammonium salt (4) shortened, i.e. the reaction times in
all the examples could be steadily shortened in 15 hours. In
addition, the production of by-product (R) could be drastically
held down by the present invention. Accordingly, the process of the
present invention is an industrially useful manufacturing method
which is also for practical preparation.
INDUSTRIAL APPLICABILITY
[0201] The process of the present invention is a process for
preparing quaternary ammonium salt (4) in steady reaction time and
in steady quality, thus it has some merits, in particular for the
industrial purpose.
* * * * *