TECHNICAL FIELD
[0001] The present invention relates to a method for producing an N-substituted
sulfonamide compound with high purity by reacting a sulfonamide compound with a
halogenated organic compound. The method for producing N-substituted sulfonamide
10 compounds of the present invention involves a specific base, and thereby allows the
reaction to proceed faster than heretofore possible and affords high yield with little
byproducts, which makes the method of great usefulness in industry. Further,
N-substituted sulfonamide compounds obtained by the production method of the present
invention are useful as intermediates and active ingredients for drugs.
15
BACKGROUND ART
[0002] N-substituted sulfonamide compounds are useful in various fields as medicinal
and agrochemical products and organic materials, or as raw materials and intermediates
thereof. In particular, they have recently been reported to be useful as medicinal
20 products. Safe and convenient methods for their production have been desired (for
example, see Patent Documents 1 and 2).
[0003] In some methods presented so far, N-substituted sulfonamide compounds are
produced by reacting a sulfonamide compound with a halogenated organic compound in
the presence of sodium hydride (for example, see Patent Documents 1 and 2, and
25 Non-Patent Documents 1 to 5).
[0004] In other methods, N-substituted sulfonamide compounds are produced by
reacting a sulfonamide compound with a halogenated organic compound in the presence
of potassium carbonate (for example, see Patent Documents 3 and 4, and Non-Patent
Document 6).
30 [0005] Further, methods have been presented which produce an N-substituted
sulfonamide compound by reacting a sulfonamide compound with a halogenated
organic compound in the presence of sodium methoxide (for example, see Non-Patent
Document 7).
35 CITATION LIST
Patent Documents
[0006] Patent Document 1 : WO 20091086123
Patent Document 2: WO 20101059627
Patent Document 3: WO 200710678 17
Patent Document 4: Japanese Patent Application Publication No. 20 1 1-057633
5 Non-Patent Documents
[0007] Non-Patent Document 1 : Bioorganic & Medicinal Chemistry Letters, 200 1,
Vol. 1 1,757-760
Non-Patent Document 2: Tetrahedron Letters, 1986, Vol. 27, No. 50,
6083-6086
10 Non-Patent Document 3: J. Med. Chem., 1997, Vol. 40,2525-2532
Non-Patent Document 4: J. Chem. Soc. Perkin Trans. 1, 1985, 831-836
Non-Patent Document 5: J. Org. Chem., 2002, Vol. 67, 5250-5256
Non-Patent Document 6: Arzneimittel Forschung (Drug Research), 2008, Vol.
58, NO. 11, 585-591
15 Non-Patent Document 7: Chemistry of Heterocyclic Compounds, 2009, Vol.
45, NO. 4,436-444
SUMMARY OF THE INVENTION
Problem to be Solved by the Invention
20 [0008] Sodium hydride used in reactions similar to those described above generates
explosive hydrogen during the reaction, and bubbles vigorously and produces extreme
heat to make controlling of the reaction temperature difficult. In addition to being very
dangerous in reactions, sodium hydride has many safety problems when it is handled or
disposed of, such as the generation of bubbles or heat. Further, sodium hydride is a
25 strong base and acts on (reactive) functional groups of compounds having a complicated
structure such as medicinal products, possibly giving rise to the occurrence of side
reactions and consequent undesired impurities. Furthermore, sodium hydride is sold as
a 60% oil dispersion (a mixture in mineral oil) which entails troublesome pretreatments
such as the removal of oil. Thus, the production methods using sodium hydride are
30 less attractive in industry.
The other methods are also not satisfactory in terms of yield and are less
attractive in industry because of the risk that byproducts may be formed by the reaction
of the base with reactive functional groups such as esters.
[0009] In general, medicinal products have a risk of unexpected side effects caused by
35 trace impurities. To attain high quality of medicinal products, the synthesis thereof
strongly demands an efficient production method that has high selectivity and does not
have any impurities such as unreacted raw materials and byproducts. In particular, the
poorness in selectivity and yield in near final stages of the production increases the risk
that a large amount of impurities will remain, and therefore has a significant influence
on the purity of pharmaceutical ingredients. Thus, there has been a strong demand for
5 a safe, highly selective, and industrially advantageous method capable of producing
N-substituted sulfonamides with high purity.
[OO 101 It is therefore an object of the present invention to provide a simple and
industrially advantageous method which can produce N-substituted sulfonamide
compounds with high yield and high purity. Another object is to provide an
10 N-substituted sulfonamide compound having higher quality than before by such the
production method.
Means for Solving the Problems
[0011] The present inventors carried out extensive studies on basic compounds used in
15 the reaction between a sulfonamide compound and a halogenated organic compound.
As a result, the present inventors have found that cesium carbonate or potassium
carbonate allows the reaction to proceed quickly and with good selectivity, and have
developed an industrially advantageous method for the production of high-purity
N-sulfonamides which, by the use of such a base, can produce an N-substituted
20 sulfonamide with high yield and high purity in a safe manner with little side reactions,
thereby completing the present invention.
[0012] An aspect of the present invention resides in a method for producing
N-substituted sulfonamide compounds including a step of reacting a sulfonamide
compound of the general formula (1):
[OO 1 41 (wherein
R' and R2 are each independently an optionally substituted alkyl, alkenyl,
alkynyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl group) with a
30 halogenated organic compound of the general formula (2):
[00 151
[OO 1 61 (wherein
R3 is an optionally substituted alkyl, aralkyl or heteroarylalkyl group, and X is
a halogen atom) in the presence of cesium carbonate or potassium carbonate in an
5 organic solvent to produce an N-substituted sulfonamide compound of the general
formula (3):
[00 171
[0018] (wherein R1, R2 and R3 are the same as defined above).
10 Effect of the Invention
[OO 193 According to the present invention, an N-substituted sulfonamide compound of
the general formula (3) can be produced with high purity and in high yield selectively
from a sulfonamide compound of the general formula (1) and a halogenated organic
compound of the general formula (2) under mild conditions in a simple and industrially
15 advantageous manner.
MODE FOR CARRYING OUT THE INVENTION
[0020] An N-substituted sulfonamide compound of the general formula (3) according
to the present invention can be obtained by reacting a sulfonamide compound of the
20 general formula (1) with a halogenated organic compound of the general formula (2) in
the presence of cesium carbonate (Cs2C03) or potassium carbonate (K2C03) in an
organic solvent (see [Reaction formula 11 below, which illustrates only the reaction
using cesium carbonate).
[002 11
[Reaction formula I]
R'
I
O=S, cs2co3 I
+ R~-x - // NH
R3 + HX
0 I Solvent
R2 R*
25 (1) (2) (3) (7)
[0022] (In the formula, R', R2, R3 and X are the same as defined above.)
[0023] An N-substituted sulfonamide compound of the general formula (6) according
to the present invention can be obtained by reacting a sulfonamide compound of the
general formula (4) with a halogenated organic compound of the general formula (5) in
the presence of cesium carbonate (Cs2C03) or potassium carbonate (K2C03) in an
5 organic solvent (see [Reaction formula 1'1 below, which illustrates only the reaction
using cesium carbonate).
[0024]
[Reaction formula 1'1
R" a
I
[0025] (In the formula, Ria is defined the same as R', R4 is an optionally substituted
10 aryl or heteroaryl group, R5 is an alkyl group, and X' is defined the same as X.)
[0026] In the present invention, the following terms, alone or in combination with
other terms, have the meanings given below, unless otherwise stated.
[0027] "Alkyl group" means a monovalent group of linear or branched, saturated
aliphatic hydrocarbon. Typical examples include alkyl groups having 1 to 10 carbon
15 atoms, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group,
hexyl group, heptyl group, octyl group, nonyl group and decyl group (including various
isomers). Alkyl groups having 1 to 6 carbon atoms are preferable, with examples
including methyl group, ethyl group, propyl group, isopropyl group, butyl group,
isobutyl group and hexyl group. Alkyl groups having 1 to 4 carbon atoms are more
20 preferable, with examples including methyl group, ethyl group, propyl group, isopropyl
group, butyl group and isobutyl group.
[0028] "Alkenyl group" means a monovalent group of linear or branched, unsaturated
aliphatic hydrocarbon which includes at least one carbon-carbon double bond. Typical
examples include alkenyl groups having 2 to 10 carbon atoms, for example, vinyl group,
propenyl group, butenyl group, pentenyl group, hexenyl group, heptenyl group, octenyl
group, nonenyl group and decenyl group (including various isomers). Alkenyl groups
5 having 2 to 6 carbon atoms are preferable, with examples including vinyl group,
propenyl group, butenyl group, pentenyl group and hexenyl group. Alkenyl groups
having 2 to 4 carbon atoms are more preferable, with examples including vinyl group,
1 -propenyl group, 2-propenyl group, 1 -butenyl group and 2-butenyl group.
[0029] "Alkynyl group" means a monovalent group of linear or branched, unsaturated
10 aliphatic hydrocarbon which includes at least one carbon-carbon triple bond. Typical
examples include alkynyl groups having 2 to 10 carbon atoms, for example, ethynyl
group, propynyl group, butynyl group, pentynyl group, hexynyl group, heptynyl group,
octynyl group, nonynyl group and decynyl group (including various isomers). Alkynyl
groups having 2 to 6 carbon atoms are preferable, with examples including ethynyl
15 group, propynyl group, butynyl group, pentynyl group and hexynyl group. Alkynyl
groups having 2 to 4 carbon atoms are more preferable, with examples including
ethynyl group, 2-propynyl group, 3-butynyl group and 2-butynyl group.
[0030] "Cycloalkyl group" means a monovalent group of cyclic saturated aliphatic
hydrocarbon. Typical examples include cycloalkyl groups having 3 to 10 carbon
20 atoms, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group,
cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group and
cyclodecyl group. Cycloalkyl groups having 3 to 8 carbon atoms are preferable, with
examples including cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl
group, cycloheptyl group and cyclooctyl group. Cycloalkyl groups having 3 to 6
25 carbon atoms are more preferable, with examples including cyclopropyl group,
cyclobutyl group, cyclopentyl group and cyclohexyl group.
[003 11 "Aryl group" means a monovalent group of monocyclic or condensed
polycyclic aromatic hydrocarbon. Typical examples include aryl groups having 6 to
14 carbon atoms, for example, phenyl group, naphthyl group and anthryl group. Aryl
30 groups having 6 to 10 carbon atoms are preferable, with examples including phenyl
group, 1 -naphthyl group and 2-naphthyl group.
[0032] "Heteroaryl group" means a monovalent group of a monocyclic or condensed
polycyclic aromatic heterocyclic compound which includes at least one hetero atom
selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur
35 atom. Typical examples include 5- to 10-membered heteroaryl groups, for example,
pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, pyridyl group,
pyrimidinyl group, pyridazinyl group, indolyl group, quinolyl group; thienyl group,
benzothienyl group; fury1 group, benzofuranyl group; oxazolyl group, isoxazolyl group,
thiazolyl group, isothiazolyl group, oxadiazolyl group and thiadiazol yl group (including
various isomers). 5- to 6-membered heteroaryl groups are preferable, with examples
5 including 2-pyrrolyl group, 3-pyrrolyl group, 1 -pyrazolyl group, 1,2,4-triazol- 1 -yl group,
2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrimidinyl group, 4-pyridazinyl
group, 2-thienyl group, 3 -thienyl group, 2-fury1 group, 3 -fury1 group, 2-thiazolyl group
and 4-thiazolyl group.
[0033] "Aralkyl group" means an alkyl group substituted with an aryl group. Here,
10 "aryl group" and "alkyl group" are the same as defined above. Typical examples
include aralkyl groups having 7 to 14 carbon atoms, for example, benzyl group,
phenethyl group, phenylpropyl group, phenylbutyl group, naphthylmethyl group and
naphthylethyl group (including various isomers). Aralkyl groups having 7 to 10
carbon atoms are preferable, with examples including benzyl group, 1-phenethyl group,
1 5 2-phenethyl group, 3 -phenylpropyl group and 4-phenylbutyl group.
[0034] "Heteroarylalkyl group" means an alkyl group substituted with a heteroaryl
group. Here, "heteroaryl group" and "alkyl group" are the same as defined above.
Typical examples include 6- to 14-membered heteroarylalkyl groups, for example,
pyrrolylmethyl group, pyrrolylethyl group, imidazolylmethyl group, imidazolylethyl
20 group, p yrazol ylmethyl group, pyrazolylethyl group, triazol ylmethyl group,
triazolylethyl group, pyridylmethyl group, pyridylethyl group, pyrimidinylmethyl group,
pyrimidinylethyl group, pyridazinylmethyl group, pyridazinylethyl group,
indolylmethyl group, indolylethyl group, quinolylmethyl group, quinolylmethylethyl
group; thienylmethyl group, thienylethyl group, benzothienylmethyl group,
25 benzothienylethyl group; furylmethyl group, furylethyl group, benzofuranylmethyl
group, benzofuranylethyl group; oxazolylmethyl group, oxazolylethyl group,
isoxazolylmethyl group, isoxazolylethyl group, thiazolylmethyl group, thiazolylethyl
group, isothiazolylmethyl group, isothiazolylethyl group, oxadiazolylmethyl group,
oxadiazolylethyl group, thiadiazolylmethyl group and thiadiazolylethyl group
30 (including various isomers). 6- to 10-membered heteroarylalkyl groups are preferable,
with examples including 2-pyridylmethyl group, 3 -p yridylmethyl group,
2-pyrimidinylmethyl group, 5-pyrimidinylmethyl group, 2-indolylmethyl group,
5-indolylmethyl group, 2-benzofuranylmethyl group, 5-indolylmethyl group,
2-benzothienylmethyl group and 5-benzothienylmethyl group.
35 [0035] "Halogen atom" or "halo" means a fluorine atom, a chlorine atom, a bromine
atom or an iodine atom, preferably a chlorine atom, a bromine atom or an iodine atom,
and more preferably a chlorine atom or a bromine atom.
[0036] In the compounds of the general formulae (1) and (3), R' and R2 are each
independently an optionally substituted alkyl, alkenyl, alkynyl, c yclo alkyl, aryl,
heteroaryl, aralkyl or heteroarylalkyl group.
5 [0037] In the present invention, the phrase "optionally substituted" means, unless
otherwise stated, that the group mentioned after the phrase has at least one substituent or
has no substituents (that is, the group is unsubstituted). For example, an "optionally
substituted alkyl group" means a "substituted alkyl mmmgroup" or an "unsubstituted
alkyl group", wherein the "alkyl group" is the same as defined hereinabove. The
10 substituents are not particularly limited as long as they are inactive in the production
methods of the present invention and do not cause any chemical inconsistency in the
structure.
[0038] Examples of the substituents in the "optionally substituted alkyl groups", the
"optionally substituted alkenyl groups", the "optionally substituted alkynyl groups" and
15 the "optionally substituted cycloalkyl groups" in R' and R2 include halogen atoms;
hydroxyl groups; alkoxy groups having 1 to 10 carbon atoms; optionally substituted
amino groups; cyano groups; and nitro groups. Two or more of the substituents may
be the same as or different from one another.
[0039] Examples of the substituents in the "optionally substituted aryl groups", the
20 "optionally substituted heteroaryl groups", the "optionally substituted aralkyl groups"
and the "optionally substituted heteroarylalkyl groups" in R' and R2 include halogen
atoms; alkyl groups having 1 to 10 carbon atoms; alkenyl groups having 2 to 10 carbon
atoms; alkynyl groups having 2 to 10 carbon atoms; optionally substituted aryl groups;
optionally substituted heteroaryl groups; optionally substituted aralkyl groups;
25 optionally substituted heteroarylalkyl groups; alkoxy groups having 1 to 10 carbon
atoms; alkoxyalkoxy groups having 2 to 20 carbon atoms; acyl groups having 2 to 11
carbon atoms; alkoxycarbonyl groups having 2 to 11 carbon atoms;
alkoxycarbonylalkyl groups having 3 to 21 carbon atoms; alkoxycarbonylalkoxy groups
having 3 to 21 carbon atoms; aryloxy groups having 6 to 14 carbon atoms; aralkyloxy
30 groups having 7 to 14 carbon atoms; haloalkyl groups having 1 to 4 carbon atoms;
optionally substituted amino groups; cyano groups; and nitro groups. Two or more of
the substituents may be the same as or different from one another. Further, any two
substituents which are bonded to adjacent ring atoms may form a ring together with
such ring atoms.
35 [0040] Examples of the substituents in the "optionally substituted aryl groups", the
"optionally substituted heteroaryl group", the "optionally substituted aralkyl groups"
and the "optionally substituted heteroarylalkyl groups" in the examples of the
substituents described above include halogen atoms; alkyl groups having 1 to 10 carbon
atoms; alkenyl groups having 2 to 10 carbon atoms; alkynyl groups having 2 to 10
carbon atoms; alkoxy groups having 1 to 10 carbon atoms; haloalkyl groups having 1 to
5 4 carbon atoms; cyano groups; and nitro groups. Two or more of the substituents may
be the same as or different from one another.
[004 11 "Alkoxy group having 1 to 10 carbon atoms" in the present invention means a
group -OR (wherein R is any of the alkyl groups having 1 to 10 carbon atoms described
hereinabove). Examples of the alkoxy groups having 1 to 10 carbon atoms include
10 methoxy group, ethoxy group, propoxy group, butoxy group, pentyloxy group,
hexyloxy group, heptyloxy group, octyloxy group, nonyloxy group and decyloxy group
(including various isomers). Alkoxy groups having 1 to 6 carbon atoms are preferable,
with examples including methoxy group, ethoxy group, propyloxy group, isopropyloxy
group, butyloxy group, isobutyloxy group and hexyloxy group. Alkoxy groups having
15 1 to 4 carbon atoms are more preferable, with examples including methoxy group,
ethoxy group, propyloxy group, isopropyloxy group, butyloxy group and isobutyloxy
group.
[0042] Similarly, "alkoxyalkoxy group having 2 to 20 carbon atoms" means an alkoxy
group having 1 to 10 carbon atoms that is substituted with an alkoxy group having 1 to
20 10 carbon atoms. Here, "alkoxy group having 1 to 10 carbon atoms" is the same as
defined above. Alkoxyalkoxy groups having 2 to 8 carbon atoms are preferable.
Alkoxyalkoxy groups having 2 to 4 carbon atoms are more preferable, with examples
including methoxyrnethoxy group, methoxyethoxy group, ethoxymethoxy group and
ethoxyethoxy group.
25 [0043] Similarly, "acyl group having 2 to 11 carbon atoms" means a group -C(=O)-R
(wherein R is any of the alkyl groups having 1 to 10 carbon atoms described
hereinabove). Examples of the acyl groups having 2 to 11 carbon atoms include acetyl
group, propionyl group, butyryl group, valeryl group, hexanoyl group, octanoyl group
and decanoyl group (including various isomers). Alkoxycarbonyl groups having 2 to 7
30 carbon atoms are preferable. Alkoxycarbonyl groups having 2 to 5 carbon atoms are
more preferable, with examples including acetyl group, propionyl group, butyryl group,
isobutyryl group, valeryl group, isovaleryl group and pivaloyl group.
[0044] Similarly, "alkoxycarbonyl group having 2 to 11 carbon atoms" means a group
-C(=O)-OR (wherein R is any of the alkyl groups having 1 to 10 carbon atoms
3 5 described hereinabove). Examples of the alkoxycarbonyl groups having 2 to 1 1
carbon atoms include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl
group, butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group,
heptyloxycarbonyl group, octyloxycarbonyl group, nonyloxycarbonyl group and
dec ylox ycarbonyl group (including various isomers). Alkox ycarbonyl groups having
2 to 7 carbon atoms are preferable, with examples including methoxycarbonyl group,
5 ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group,
butoxycarbonyl group, t-butox ycarbonyl group and hex yloxy group. Alkoxycarbonyl
groups having 2 to 5 carbon atoms are more preferable, with examples including
methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group,
isopropoxycarbonyl group, butoxycarbonyl group and t-butoxycarbonyl group.
10 [0045] Similarly, "alkoxycarbonylalky1 group having 3 to 21 carbon atoms" means an
alkyl group having 1 to 10 carbon atoms that is substituted with an alkoxycarbonyl
group having 2 to 1 1 carbon atoms. Here, "alkoxycarbonyl group having 2 to 1 1
carbon atoms" and "alkyl group having 1 to 10 carbon atoms" are the same as defined
above. Alkoxycarbonylalkyl groups having 3 to 1 1 carbon atoms are preferable.
15 Alkyl groups having 1 to 4 carbon atoms that are substituted with an alkoxycarbonyl
group having 2 to 5 carbon atoms (namely, alkoxycarbonylalkyl groups having 3 to 9
carbon atoms) are more preferable, with examples including methoxycarbonylmethyl
group, ethoxycarbonylmethyl group, propoxycarbonylmethy1 group,
isopropoxycarbonylmethyl group, butoxycarbonylmethyl group,
20 t-butoxycarbonylmethyl group, methoxycarbonylethyl group, ethoxycarbonylethyl
group, propoxycarbonylethyl group, isopropoxycarbonylethyl group,
butoxycarbonylethyl group and t-butoxycarbonylethyl group.
[0046] Similarly, "alkoxycarbonylalkoxy group having 3 to 21 carbon atoms" means
an alkoxy group having 1 to 10 carbon atoms that is substituted with an alkoxycarbonyl
25 group having 2 to 1 1 carbon atoms. Here, "alkoxycarbonyl group having 2 to 1 1
carbon atoms" and "alkoxy group having 1 to 10 carbon atoms" are the same as defined
above. Alkoxycarbonylalkoxy groups having 3 to 1 1 carbon atoms are preferable.
Alkoxy groups having 1 to 4 carbon atoms that are substituted with an alkoxycarbonyl
group having 2 to 5 carbon atoms (namely, alkoxycarbonylalkoxy groups having 3 to 9
30 carbon atoms) are more preferable, with examples including methoxycarbonylmethoxy
group, ethoxycarbonylmethoxy group, propoxycarbonylmethoxy group,
isopropoxycarbonylmethoxy group, butoxycarbonylmethoxy group,
t-butoxycarbonylmethoxy group, methoxycarbonylethoxy group, ethoxycarbonylethoxy
group, propoxycarbonylethoxy group, isopropoxycarbonylethoxy group,
35 butoxycarbonylethoxy group and t-butoxycarbonylethoxy group.
[0047] Similarly, "aryloxy group having 6 to 14 carbon atoms" means a group -OR1
(wherein Rt is any of the aryls having 6 to 14 carbon atoms described hereinabove).
Examples of the aryloxy groups having 6 to 14 carbon atoms include phenoxy group,
naphthyloxy group and anthryloxy group. Aryloxy groups having 6 to 10 carbon
atoms are preferable, with examples including phenoxy group, 1 -naphthyloxy group and
5 2-naphthyloxy group.
[0048] Similarly, "aralkyloxy group having 7 to 14 carbon atoms" means a group
-OR" (wherein R" is any of the aralkyl groups described hereinabove). Typical
examples include aralkyloxy groups having 7 to 14 carbon atoms, for example,
benzyloxy group, phenethyloxy group, phenylpropyloxy group, phenylbutyloxy group,
10 naphthylmethyloxy group and naphthylethyloxy group (including various isomers).
Aralkyloxy groups having 7 to 10 carbon atoms are preferable, with examples including
benzyloxy group, 1 -phenethyloxy group, 2-phenethyloxy group, 3-phenylpropyloxy
group and 3-phenylbutyloxy group.
[0049] Similarly, "haloalkyl group having 1 to 4 carbon atoms" means an alkyl group
15 having 1 to 4 carbon atoms that is substituted with one or more halogen atoms. Here,
"halo" and "alkyl group having 1 to 4 carbon atoms" are the same as defined above.
Examples of the haloalkyl groups having 1 to 4 carbon atoms include fluoromethyl
group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group,
2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, 1,1,2,2,2-pentafluoroethylg roup and
20 perfluorobutyl group. Fluoroalkyl groups having 1 to 2 carbon atoms are preferable,
with examples including fluoromethyl group, difluoromethyl group, trifluoromethyl
group, 2-fluoroethyl group, 2,2-di fluoroethyl group, 2,2,2-trifluoroethyl group and
1,1,2,2,2-pentafluoroethyl group.
[0050] "Optionally substituted amino group" in the examples of the substituents
25 described above means an amino group or an amino group having one or two
substituents. Examples of the substituents include alkyl groups having 1 to 10 carbon
atoms; alkoxycarbonylalkyl groups having 3 to 20 carbon atoms; and acyl groups
having 2 to 10 carbon atoms. Two substituents may be the same as or different from
each other.
30 [005 11 In a preferred embodiment of the present invention, R' in the sulfonamide
compounds of the general formulae (1) and (3) is an optionally substituted aryl or
heteroaryl group. In a particularly preferred embodiment of the present invention, R'
in the sulfonamide compounds of the general formulae (1) and (3) is an optionally
substituted phenyl or pyridyl group.
35 [0052] Examples of the "optionally substituted aryl groups (in particular, phenyl
group)" in R' include aryl groups (in particular, phenyl group); and aryl groups (in
particular, phenyl group) substituted with one, two or three substituents selected from
the group consisting of halogen atoms, alkyl groups having 1 to 10 carbon atoms,
alkenyl groups having 2 to 10 carbon atoms, alkynyl groups having 2 to 10 carbon
atoms, optionally substituted aryl groups, optionally substituted heteroaryl groups,
5 optionally substituted aralkyl groups, optionally substituted heteroarylalkyl groups,
alkoxy groups having 1 to 10 carbon atoms, alkoxyalkoxy groups having 2 to 20 carbon
atoms, acyl groups having 2 to 1 1 carbon atoms, alkoxycarbonyl groups having 2 to 1 1
carbon atoms, alkoxycarbonylalkyl groups having 3 to 21 carbon atoms,
alkoxycarbonylalkoxy groups having 3 to 21 carbon atoms, aryloxy groups having 6 to
10 14 carbon atoms, aralkyloxy groups having 7 to 14 carbon atoms, haloalkyl groups
having 1 to 4 carbon atoms, optionally substituted amino groups, cyano groups and nitro
groups. Here, two or more of the substituents may be the same as or different from
one another. Any two substituents bonded to adjacent ring atoms may form a ring
together with such ring atoms.
15 [0053] "Optionally substituted aryl group (in particular, phenyl group)" in R' is
preferably an aryl group having 6 to 10 carbon atoms (in particular, a phenyl group); or
an aryl group having 6 to 10 carbon atoms (in particular, a phenyl group) substituted
with one, two or three substituents selected from the group consisting of halogen atoms,
alkyl groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, and
20 nitro groups. Two or more of the substituents may be the same as or different from
one another.
[0054] The optionally substituted aryl group in R' is more preferably a phenyl group, a
1-naphthyl group, a 2-naphthyl group, a 4-tolyl group, a 3-fluorophenyl group, a
4-fluorophenyl group, a 4-chlorophenyl group, a 4-methoxyphenyl group, a
25 3,4-dimethoxyphenyl group, a 3,4-methylenedioxyphenyl group or a 4-nitrophenyl
group, and is more preferably a phenyl group, a 3-fluorophenyl group or a
4-fluorophenyl group.
[0055] Examples of the "optionally substituted heteroaryl groups (in particular,
pyridyl group)" in by R' include heteroaryl groups (in particular, pyridyl group); and
30 heteroaryl groups (in particular, pyridyl group) substituted with one, two or three
substituents selected from the group consisting of halogen atoms, alkyl groups having 1
to 10 carbon atoms, alkenyl groups having 2 to 10 carbon atoms, alkynyl groups having
2 to 10 carbon atoms, optionally substituted aryl groups, optionally substituted
heteroaryl groups, optionally substituted aralkyl groups, optionally substituted
35 heteroarylalkyl groups, alkoxy groups having 1 to 10 carbon atoms, alkoxyalkoxy
groups having 2 to 20 carbon atoms, acyl groups having 2 to 11 carbon atoms,
alkoxycarbonyl groups having 2 to 1 1 carbon atoms, alkox ycarbonylalkyl groups
having 3 to 21 carbon atoms, alkoxycarbonylalkoxy groups having 3 to 21 carbon atoms,
aryloxy groups having 6 to 14 carbon atoms, aralkyloxy groups having 7 to 14 carbon
atoms, haloalkyl groups having 1 to 4 carbon atoms, optionally substituted amino
5 groups, cyano groups and nitro groups. Here, two or more of the substituents may be
the same as or different from one another. Any two substituents bonded to adjacent
ring atoms may form a ring together with such ring atoms.
[0056] The "optionally substituted heteroaryl group (in particular, pyridyl group)" in
R' is preferably a 5- to 10-membered heteroaryl group (in particular, a pyridyl group);
10 or a 5- to 10-membered heteroaryl group (in particular, a pyridyl group) substituted with
one, two or three substituents selected from the group consisting of halogen atoms, alkyl
groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, cyano
groups and nitro groups. Two or more of the substituents may be the same as or
different from one another.
15 [0057] The optionally substituted heteroaryl group in R' is more preferably a 2-pyridyl
group, a 3-pyridyl group, a 4-pyridyl group, a 2-pyrrolyl group, a 3 -pyrrolyl group, a
2-thienyl group, a 3-thienyl group, a 2-fury1 group, a 2-(3-methy1)pyridyl group, a
2-(4-methy1)pyridyl group, a 3-(2-methy1)pyridyl group, a 2-(3-fluoro)pyridyl group or
a 2-(3-nitro)pyridyl group, and is more preferably a 2-pyridyl group or a 3-pyridyl
20 group.
[0058] In a preferred embodiment of the present invention, R2 in the sulfonamide
compounds of the general formulae (1) and (3) is an optionally substituted aralkyl or
heteroarylalkyl group. In a particularly preferred embodiment of the present invention,
R2 in the sulfonamide compounds of the general formulae (1) and (3) is an optionally
25 substituted benzyl or benzo furanylmethyl group.
[005 91 Examples of the "optionally substituted aralkyl groups (in particular, benzyl
group)" in R~ include aralkyl groups (in particular, benzyl group); and aralkyl groups
(in particular, benzyl group) substituted with one, two or three substituents selected
from the group consisting of halogen atoms, alkyl groups having 1 to 10 carbon atoms,
30 alkenyl groups having 2 to 10 carbon atoms, alkynyl groups having 2 to 10 carbon
atoms, optionally substituted aryl groups, optionally substituted heteroaryl groups,
optionally substituted aralkyl groups, optionally substituted heteroarylalkyl groups,
alkoxy groups having 1 to 10 carbon atoms, alkoxyalkoxy groups having 2 to 20 carbon
atoms, aryloxy groups having 6 to 14 carbon atoms, aralkyloxy groups having 7 to 14
35 carbon atoms, haloalkyl groups having 1 to 4 carbon atoms, cyano groups and nitro
groups. Here, two or more of the substituents may be the same as or different from
one another. Any two substituents bonded to adjacent ring atoms may form a ring
together with such ring atoms.
[0060] The "optionally substituted aralkyl group (in particular, benzyl group)" in R2 is
preferably an aralkyl group having 7 to 10 carbon atoms (in particular, a benzyl group);
5 or an aralkyl group having 7 to 10 carbon atoms (in particular, a benzyl group)
substituted with one, two or three substituents selected from the group consisting of
halogen atoms, alkyl groups having 1 to 4 carbon atoms, optionally substituted aryl
groups, optionally substituted heteroaryl groups, alkoxy groups having 1 to 4 carbon
atoms, alkoxyalkoxy groups having 2 to 4 carbon atoms, aryloxy groups having 6 to 10
10 carbon atoms, aralkyloxy groups having 7 to 10 carbon atoms, haloalkyl groups having
1 to 4 carbon atoms, cyano groups and nitro groups. Two or more of the substituents
may be the same as or different from one another.
[0061] The "optionally substituted aralkyl group (in particular, benzyl group)" in R2 is
more preferably an aralkyl group having 7 to 10 carbon atoms (in particular, a benzyl
15 group); or an aralkyl group having 7 to 10 carbon atoms (in particular, a benzyl group)
substituted with an optionally substituted aryl group or an optionally substituted
heteroaryl group.
[0062] The optionally substituted aralkyl group in R2 is still more preferably a benzyl
group, a phenethyl group, a 3-phenylpropyl group or a 4-phenylbutyl group; a
20 biphenyl-4-ylmethyl group, a 2'-ethoxybiphenyl-4-ylmethyl group, a
3 ' -ethoxybiphenyl-4-ylmethyl group, a 4'-ethoxybiphenyl-4-ylmethyl group, a
2' -( 1 -propenyl)biphenyl-4-ylmethyl group, a 2' -( 1 -propenyl)biphenyl-4-ylmethyl group,
a 3 '-(I -propenyl)biphenyl-4-ylmethyl group, a 4'-(1 -propenyl)biphenyl-4-ylmethyl
group, a 2'-(1 -propynyl)biphenyl-4-ylmethyl group, a
25 3 ' -(1 -prop ynyl)biphenyl-4-ylmethyl group or a 4' -(1 -propynyl)biphenyl-4-ylmethyl
group; a 4-(thiazol-2-yl)benzyl group, a 3-(thiazol-2-y1)benzyl group, a
2-(thiazol-2-y1)benzyl group, a 4-(thiazol-4-y1)benzyl group, a
4-(4-methylthiazol-2-y1)benzyl group, a 4-(5-methylthiazol-2-y1)benzyl group, a
4-(4,5-dimethylthiazol-2-y1)benzylg roup, a 4-(5-fluorothiazol-2-y1)benzyl group, a
30 4-(5-chlorothiazol-2-y1)benzyl group, a 4-(4-trifluoromethylthiazol-2-y1)benzyl group, a
4-(5-trifluoromethylmethylthiazol-2-y1)benzyl group, a 4-((1 H)-pyrazol- 1 -yl)benzyl
group, a 3-((1 H)-pyrazol- 1 -yl)benzyl group, a 2-((1 H)-pyrazol- 1 -yl)benzyl group, a
4-(3-methyl-(1 H)-pyrazol- 1 -yl)benzyl group, a 4-(5-methyl-(1 H)-pyrazol- 1 -yl)benzyl
group, a 4-(oxazol- 1 -yl)benzyl group, a 3-(oxazol- 1 -yl)benzyl group, a
35 2-(oxazol- 1 -yl)benzyl group, a 4-(5-methyloxazol- 1 -yl)benzyl group or a
4-(4-methyloxazol- 1 -yl)benzyl group.
[0063] Examples of the "optionally substituted heteroarylalkyl groups (in particular,
benzofuranylmethyl group)" in R2 include heteroarylalkyl groups (in particular,
benzo furanylmethyl group); and heteroarylalkyl groups (in particular, benzo furanyl
group) substituted with one, two or three substituents selected from the group consisting
5 of halogen atoms, alkyl groups having 1 to 10 carbon atoms, alkenyl groups having 2 to
10 carbon atoms, alkynyl groups having 2 to 10 carbon atoms, optionally substituted
aryl groups, optionally substituted heteroaryl groups, optionally substituted aralkyl
groups, optionally substituted heteroarylalkyl groups, alkoxy groups having 1 to 10
carbon atoms, alkoxyalkoxy groups having 2 to 20 carbon atoms, acyl groups having 2
10 to 1 1 carbon atoms, alkoxycarbonyl groups having 2 to 1 1 carbon atoms,
alkoxycarbonylalkyl groups having 3 to 2 1 carbon atoms, alkoxycarbonylalkoxy groups
having 3 to 2 1 carbon atoms, aryloxy groups having 6 to 14 carbon atoms, aralkyloxy
groups having 7 to 14 carbon atoms, haloalkyl groups having 1 to 4 carbon atoms,
optionally substituted amino groups, cyano groups and nitro groups. Here, two or
15 more of the substituents may be the same as or different from one another. Any two
substituents bonded to adjacent ring atoms may form a ring together with such ring
atoms.
[0064] The "optionally substituted heteroarylalkyl group (in particular,
benzofuranylmethyl group)" in R2 is preferably a 6- to 10-membered heteroarylalkyl
20 group (in particular, a benzofuranylmethyl group); or a 6- to 1 0-membered
heteroarylalkyl group (in particular, a benzofuranylmethyl group) substituted with one,
two or three substituents selected from the group consisting of halogen atoms, alkyl
groups having 1 to 4 carbon atoms, optionally substituted aryl groups, optionally
substituted heteroaryl groups, alkoxy groups having 1 to 4 carbon atoms, alkox yalkox y
25 groups having 2 to 4 carbon atoms, aryloxy groups having 6 to 10 carbon atoms,
aralkyloxy groups having 7 to 10 carbon atoms, haloalkyl groups having 1 to 4 carbon
atoms, cyano groups and nitro groups. Two or more of the substituents may be the
same as or different from one another.
[0065] The optionally substituted heteroarylalkyl group in R2 is more preferably a
30 2-pyridylmethyl group, a 3-pyridylmethyl group, a 2-pyrimidinylmethyl group, a
5-pyrimidinylmethyl group, a 3-pyridazinylmethyl group, a 2-indolylmethyl group, a
5-indolylmethyl group, a 2-benzofuranylmethyl group, a 5-indolylmethyl group, a
2-benzothienylmethyl group, a 5-benzothienylmethyl group, a
6-fluoro-2-benzo furanylmethyl group, a 6-chloro-2-benzo furanylmethyl group, a
3 5 6-methoxy-2-benzo furanylmethyl group, a 6-fluoro-2-benzothienylmethylg roup, a
6-chloro-2-benzothienylmethylg roup, a 6-methoxy-2-benzothienylmethygl roup or a
6-phenyl-3 -p yridazinylmethyl group.
[0066] In the compound of the general formula (2), X is a halogen atom, preferably a
chlorine atom, a bromine atom or an iodine atom, and is more preferably a chlorine
atom.
5 [0067] In the compounds of the general formulae (2) and (3), R3 is an optionally
substituted alkyl, aralkyl or heteroarylalkyl group.
[0068] Examples of the substituents in the "optionally substituted alkyl groups" in R'
include halogen atoms; alkoxy groups having 1 to 10 carbon atoms; cyano groups; and
nitro groups. Two or more of the substituents may be the same as or different from
10 oneanother.
[0069] In a preferred embodiment of the present invention, R3 in the compounds of the
general formulae (2) and (3) is an optionally substituted aralkyl or heteroarylalkyl group.
In a particularly preferred embodiment of the present invention, R~ in the compounds of
the general formulae (2) and (3) is an optionally substituted benzyl or pyridylmethyl
15 group.
[0070] Examples of the substituents in the "optionally substituted aralkyl groups (in
particular, benzyl group)" and the "optionally substituted heteroarylalkyl groups (in
particular, pyridylmethyl group)" in R3 include halogen atoms; alkyl groups having 1 to
10 carbon atoms; alkenyl groups having 2 to 10 carbon atoms; alkynyl groups having 2
20 to 10 carbon atoms; optionally substituted aryl groups; optionally substituted heteroaryl
groups; optionally substituted aralkyl groups; optionally substituted heteroarylalkyl
groups; alkoxy groups having 1 to 10 carbon atoms; alkoxyalkoxy groups having 2 to
20 carbon atoms; acyl groups having 2 to 11 carbon atoms; alkoxycarbonyl groups
having 2 to 1 1 carbon atoms; alkoxycarbonylalkyl groups having 3 to 2 1 carbon atoms;
25 alkoxycarbonylalkoxy groups having 3 to 21 carbon atoms; aryloxy groups having 6 to
14 carbon atoms; aralkyloxy groups having 7 to 14 carbon atoms; haloalkyl groups
having 1 to 4 carbon atoms; optionally substituted amino groups; cyano groups; and
nitro groups. Here, two or more of the substituents may be the same as or different
from one another. Any two substituents bonded to adjacent ring atoms may form a
30 ring together with such ring atoms.
[0071] The "optionally substituted aralkyl group" in R3 is preferably an aralkyl group
having 7 to 14 carbon atoms (in particular, a benzyl group); or an aralkyl group having
7 to 14 carbon atoms (in particular, a benzyl group) substituted with one, two or three
substituents selected from the group consisting of halogen atoms, alkyl groups having 1
35 to 10 carbon atoms, alkoxy groups having 1 to 10 carbon atoms, alkoxycarbonylalkyl
groups having 3 to 2 1 carbon atoms, alkoxycarbonylalkoxy groups having 3 to 21
carbon atoms, haloalkyl groups having 1 to 4 carbon atoms, optionally substituted
amino groups, cyano groups and nitro groups. Two or more of the substituents may be
the same as or different from one another. Any two substituents bonded to adjacent
ring atoms may form a ring together with such ring atoms.
5 [0072] The "optionally substituted heteroarylalkyl group" in R3 is preferably a 6- to
14-membered heteroarylalkyl group (in particular, a pyridylmethyl group); or an aralkyl
group having 7 to 14 carbon atoms (in particular, a benzyl group) substituted with one,
two or three substituents selected from the group consisting of halogen atoms, alkyl
groups having 1 to 10 carbon atoms, alkoxy groups having 1 to 10 carbon atoms,
10 alkoxycarbonylalkoxy groups having 3 to 2 1 carbon atoms, haloalkyl groups having 1
to 4 carbon atoms, optionally substituted amino groups, cyano groups and nitro groups.
Two or more of the substituents may be the same as or different from one another.
Any two substituents bonded to adjacent ring atoms may form a ring together with such
ring atoms.
1 5 [0073] Examples of the "optionally substituted heteroarylalkyl groups" in R3 include
2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(3-methy1)furylmethyl group,
2-(4-methy1)furylmethyl group, 2-(3-ethy1)furylmethyl group, 2-(4-ethy1)furylmethyl
group, 2-(3-fluoro)furylmethyl group, 2-(3-ch1oro)furylmethyl group,
2-(3 -methox y) furylmethyl group, 2- (3 -nitro) furylmethyl group, 2-(3 -c yano) furylmethyl
20 group, 2-(3-methy1)pyridylmethyl group, 2-(4-methy1)pyridylmethyl group,
2-(3-ethy1)pyridylmethyl group, 2-(4-ethy1)pyridylmethyl group,
2-(3-fluoro)pyridylmethyl group, 2-(4-ch1oro)pyridylmethyl group,
2-(3-methoxy)pyridylmethyl group, 2-(3-nitro)pyridylmethyl group,
2-(3 -cyano)pyridylmethyl group, 2-(3,5 -dichloro)pyridylmethyl group,
25 3-(2-ch1oro)pyridylmethyl group, 2-(3-methy1)pyrrolylmethyl group,
2-(3-methy1)thienylmethyl group, 2-(6-methoxycarbonylmethylamino)pyridylmethyl
group, 2-(6-ethoxycarbonylmethylamino)pyridylmethyl group,
2-(6-propoxycarbonylmethylamino)pyridylmethyl group,
2-(6-isopropoxycarbonylmethylamino)pyridylmethyl group,
30 2-(6-t-butoxycarbonylmethylamino)pyridylmethyl group and
2-(6-hexyloxycarbony1methylamino)pyridylmethyl group, with
2-(3 -methyl)furylmethyl group, 2-(3 - fluoro) furylmethyl group,
2-(3 -methyl)p yridylmethyl group, 2-(3 - fluoro)p yridylmethyl group, 2-(3 -nitro)pyridyl
group, 2-(3 -cyano)p yridylmethyl group, 2-(3,5 -dichloro)pyridylmethyl group,
3 5 2-(6-methoxycarbonylmethylamino)pyridylmethyl group,
2-(6-ethox ycarbonylmethylamino)p yridylmethyl group,
2-(6-propoxycarbonylmethylamino)p yridylmethyl group,
2-(6-isopropoxycarbonylmethylamino)p yn'd group,
2-(6-t-butoxycarbonylmethylamino)p yridylmethyl group and
2-(6-hexyloxycarbony1methylamino)pyridylmethyl group being preferable.
5 [0074] The optionally substituted heteroarylalkyl group in R3 is more preferably
2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, a
2-(6-methoxycarbonylmethylamino)pyridylmethyl group, a
2-(6-ethoxycarbonylmethylamino)pyridylmethyl group, a
2-(6-propoxycarbonylmethylamino)pyridylmethyl group, a
10 2-(6-isopropoxycarbonylmethylamino)pyridylmethyl group, a
2- (6-t-butox ycarbonylmethylamino)p yridylmethyl group or a
2-(6-hexyloxycarbony1methylamino)pyridylmethyl group.
[0075] In a preferred embodiment of the present invention, the sulfonamide compound
of the general formula (1) is of the general forrnula (4):
(In the formula,
R'" is defined the same as R', and
R4 is an optionally substituted aryl or heteroaryl group.)
[0076] In a preferred embodiment of the present invention, the halogenated organic
20 compound of the general formula (2) is of the general formula (5):
(In the formula, R5 is an alkyl group, and X' is defined the same as X.)
[0077] In a preferred embodiment of the present invention, the N-substituted
sulfonamide compound of the general formula (3) is of the general forrnula (6):
(In the formula, R'", R4 and R5 are the same as defined above.)
[0078] In the general formulae (4) and (6), R'" is defined the same as R'.
[0079] In the general formulae (4) and (6), R4 is an optionally substituted aryl or
5 heteroaryl group.
[0080] Examples of the substituents in the "optionally substituted aryl groups" and the
"optionally substituted heteroaryl groups" in R4 include halogen atoms; alkyl groups
having 1 to 10 carbon atoms; alkenyl groups having 2 to 10 carbon atoms; alkynyl
groups having 2 to 10 carbon atoms; alkoxy groups having 1 to 10 carbon atoms;
10 haloalkyl groups having 1 to 4 carbon atoms; cyano groups; and nitro groups. Two or
more of the substituents may be the same as or different from one another.
[008 11 Examples of the "optionally substituted heteroaryl groups" in R4 include
thiazole group, oxazole group, benzothiazole group, benzopyridoxinethiazole group,
pyridoxinethiazole group, pyridine group, pyridazine group, pyrimidine group, pyrazine
15 group, triazine group, quinoline group, pyridobenzothiazole group and pyrazole group
(including various isomers), and further include 2-(4-methy1)thiazole group,
2-(5-methy1)thiazole group, 2-(5-fluoro)thiazole group, (1 H)- 1 -(3-methy1)pyrazole
group, 1 H- 1 -(5-methy1)pyrazole group, 2-(4-methy1)oxazole group and
2-(5-methy1)oxazole group.
20 The "optionally substituted heteroaryl group" in R4 is preferably a 2-thiazole
group, a 2-(4-methy1)thiazole group, a 2-(5-fluoro)thiazole group, a 1 H- 1 -pyrazole
group, a 1H-(3-methy1)pyrazole group or a 2-methoxythiazole group.
[0082] In the general formulae (5) and (6), R5 is an alkyl group, for example, an alkyl
group having 1 to 10 carbon atoms, and is preferably an alkyl group having 1 to 6
25 carbon atoms, for example, a methyl group, an ethyl group, an n-propyl group, an
isopropyl group, a t-butyl group or an n-hexyl group.
[0083] In the general formula (9, X' is defined the same as X.
[0084] The reaction in the present invention is carried out in the presence of cesium
carbonate or potassium carbonate. Cesium carbonate is more preferable.
[0085] In the present invention, cesium carbonate or potassium carbonate is preferably
used in an amount of 0.5 to 10 mol, more preferably 0.5 to 5 mol, and particularly
preferably 1 to 3 mol per 1 mol of the sulfonamide compound of the general formula (1)
or (4).
5 [0086] The cesium carbonate or the potassium carbonate used in the present invention
may be an anhydride or a hydrate, and is preferably an anhydride.
[0087] The purity of the cesium carbonate or the potassium carbonate used in the
present invention is not particularly limited, but is preferably not less than 95%, and
more preferably not less than 98%.
10 [0088] The reaction in the present invention is performed in the presence of an organic
solvent. The organic solvent used in the reaction of the present invention is not
particularly limited as long as it is inert in the reaction.
[0089] Examples of the organic solvents used in the present invention include alcohol
organic solvents such as methanol, ethanol, propanol, 2-propanol, butyl alcohol and
15 t-butyl alcohol; nitrile organic solvents such as acetonitrile and benzonitrile; amide
solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyridone,
dimethylimidazole and 1,3-dimethyl-2-imidazolidinoneh;a logenated organic solvents
such as methylene chloride, chloroform and 1,2-dichloroethane; aliphatic hydrocarbon
solvents such as pentane, hexane, heptane, octane, cyclopentane, cyclohexane and
20 cyclopentane; aromatic hydrocarbon solvents such as benzene, toluene and xylene; and
ether solvents such as diethyl ether, t-butyl methyl ether, diisopropyl ether,
tetrahydrofuran and 14-dioxane. Alcohol organic solvents, aromatic hydrocarbon
organic solvents, halogenated organic solvents and nitrile organic solvents are
preferable, and nitrile organic solvents are more preferable. Incidentally, these organic
25 solvents may be used singly, or two or more may be used in combination.
[0090] The organic solvent is preferably used in an amount of 2 to 200 mL, more
preferably 5 to 50 mL, and particularly preferably 5 to 20 mL per 1 g of the sulfonamide
compound of the general formula (1) or (4).
[0091] The reaction in the present invention is performed by, for example, mixing a
30 sulfonamide compound of the general formula (1) or (4), a halogenated organic
compound of the general formula (2) or (5), cesium carbonate or potassium carbonate,
and an organic solvent, and allowing the compounds to react together while performing
stirring. Here, the reaction pressure is not particularly limited, but normal pressure is
preferable.
35 [0092] In the reaction of the present invention, the reaction temperature is, for
example, -20 to 130°C, preferably 0 to 90°C, more preferably 30 to 90°C, and
particularly preferably 60 to 90°C.
[0093] The reaction system in the present invention is generally a solid-liquid
heterogeneous system. After the completion of the reaction, the product may be
recovered with high purity easily by filtering the system to remove cesium carbonate or
5 potassium carbonate, and subjecting the filtrate to concentration, extraction or
crystallization.
[0094] The production apparatus used in the reaction of the present invention is not
particularly limited. For example, use may be made of a usual production apparatus
including a reaction vessel, a heating (cooling) device and a distillation device (for
10 example, a Dean-Stark trap).
[0095] An N-substituted sulfonamide compound of the general formula (3) or (6) that
is obtained by the method of the present invention may be further purified by a usual
method such as distillation, separation, extraction, crystallization, recrystallization or
column chromatography.
15 [0096] In the production method of the present invention, the N-substituted
sulfonamide compound of the general formula (3) or (6) is obtained selectively by the
use of cesium carbonate or potassium carbonate. Thus, the compound contains an
extremely small amount of byproduced contaminants which arise from side reactions as
often experienced in the conventional production methods and are difficult to remove,
20 and thereby attains higher safety as a medicinal product.
[0097] Preferably, the N-substituted sulfonamide compound of the general formula (3)
or (6) that is obtained by the production method of the present invention has an HPLC
purity of not less than 99.5%, and the contents of any impurities present in the
compound are each less than 0.10%. More preferably, the HPLC purity is not less
25 than 99.9%.
[0098] Thus, the present invention may provide a high-purity N-substituted
sulfonamide compound of the general formula (3) or (6). The N-substituted
sulfonamide compound of the general formula (3) or (6) according to the present
invention has high purity; preferably, the HPLC purity thereof is not less than 99.5%
30 and the contents of any impurities present in the compound are each less than 0.10%.
More preferably, the HPLC purity is not less than 99.9%.
[0099] The present invention may provide a halogenated organic compound of the
general formula (5), and a hydroxyrnethyl compound that is a raw material for the
halogenated organic compound. Such compounds are of the general formula (9):
35 [OlOO]
(In the formula, R~ is an alkyl group, and x2 is a halogen atom or a hydroxyl
group.) In the general formula(9), R~ is analkyl group, for example, an alkyl group
having 1 to 10 carbon atoms, and is preferably an alkyl group having 1 to 6 carbon
5 atoms, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl
group, a t-butyl group or an n-hexyl group. x2 is a halogen atom, and is preferably a
chlorine atom or a bromine atom. Specific embodiments of the compounds of the
general formula (9) are disclosed in Examples below.
EXAMPLES
10 [O 10 11 Next, the present invention will be described in detail by presenting Examples,
but the scope of the present invention is not limited thereto.
[O 1021 The structure of target compounds obtained was identified by methods such as
IR and NMR spectral analysis. Further, the reaction yields (internal standard method)
and the chemical purities were measured using high-performance liquid
1 5 chromatography (HPLC) .
[0103] [Example 11
Synthesis of isopropyl
2- {[6-( {N-[4-(1 H-pyrazol- 1- yl)benzyl]pyridine-3-sulfonamido}methyl)pyridin-2-yl]a mi
20 no} acetate
[0104] A glass vessel having an internal volume of about 50 ml and equipped with a
stirrer, a thermometer and an upper cooling unit was loaded with 3.2 1 g (1 0.2 mmol) of
N-[4-(1 H-pyrazol- 1 -yl)benzyl]pyridine-3-sulfonamide, 2.43 g (1 0.0 mmol) of isopropyl
2- {[6-(chloromethy1)pyridin-2-yl1amino)acetate obtained in Example 6, 6.65 g (20.4
25 mmol) of cesium carbonate and 17.6 g of acetonitrile. The mixture was stirred while
performing heating at 80°C. The reaction was performed for 2 hours until the area
percentage of the raw material isopropyl
2- {[6-(chloromethy1)pyridin-2-yllamino} acetate in the high-performance liquid
chromatography analysis fell to 0.03% or less. The reaction was further carried out for
5 2 hours. The reaction conversions of isopropyl
2- {[6-(chloromethy1)pyridin-2-yla] mino}a cetate after 1 hour and 2 hours from the start
of the thermal stirring were 99.88% and 99.97%, respectively. After the completion of
the reaction, the reaction liquid was cooled to room temperature and was filtered
through Celite (trade name), and the residue was washed with acetonitrile. The filtrate
10 obtained was quantitatively analyzed by high-performance liquid chromatography, and
was found to contain 5.08 g of the target product (97.5% reaction yield). Next, the
reaction liquid was concentrated under reduced pressure until the weight of the liquid
became 7.85 g. After the addition of 42.8 g of toluene, the product was washed with
water three times. The resultant organic phase was combined with 3 1.5 ml(3 1.5
15 mmol) of 1 molIL hydrochloric acid. The mixture was stirred at room temperature for
20 minutes and was separated. The separated organic phase contained 0.17 g of the
target product (corresponding to 3.2% yield). To the aqueous phase were added 42.8 g
of toluene and 34.6 ml(34.6 mrnol) of a 1 mol/L aqueous sodium hydroxide solution.
The mixture was heated to 40°C and was stirred for 20 minutes. Hot filtration was
20 performed at 40°C, and thereafter the liquid was separated. The organic phase
obtained was washed with water two times. The organic phase was concentrated
under reduced pressure until the weight of the liquid became 8.97 g, and 7.40 g of
2-propanol was added. The mixture was heated to 60°C, then cooled gradually, stirred
at 33°C for 30 minutes, cooled slowly to not more than 5"C, and stirred at the
25 temperature for 1 hour. The solid precipitated was recovered by filtration, washed
with cold 2-propanol, and vacuum dried at 50°C to give 3.90 g of isopropyl
2- {[6-( {N- [4-(1 H-pyrazol- 1 -yl)benzyl] pyridine-3 -sulfonamido } methyllpyridin-2-yl] ami
nolacetate as a light brown solid (75.1% yield of isolation in terms of the raw material
isopropyl2- {[6-(chloromethy1)pyridin-2-yllamino} acetate). The high-performance
30 chromatography HPLC showed that the quantitative purity was 99.5% and the
compound contained 0.04% of the raw material
N-[4-(1 H-pyrazol- 1 -yl)benzyl]pyridine-3-sulfonamide. In the measurement by
high-performance liquid chromatography HPLC (260 nm wavelength), no impurities
having an area percentage of 0.1% or above were detected.
35 [O 1051 The properties of isopropyl
2- { [6-( {N- [4-(1 H-pyrazol- 1 -yl)benzyl] pyridine-3 -sulfonamido } methy1)pyridin-2-yl] ami
no) acetate obtained are described below.
EI-MS (mlz): 520 [MI.
CI-MS (mlz): 521 [M+l].
1 H-NMR (CDC13, 6 (ppm)): 1.24 (6H, d, J = 6.3 Hz), 3.82 (2H, d, J = 5.5 Hz), 4.3 1 (2H,
5 ~),4.64(2H,s),4.94(1H,t,J=5.5Hz),5.07(1H,sep,J=6.3Hz),6.26(1H,d,J=8.3
Hz), 6.41 (lH, dd, J = 7.2, 0.5 Hz), 6.46 (lH, dd, J = 2.5, 1.8 Hz), 7.25 (lH, dd, J = 8.3,
7.2 Hz), 7.32 (lH, ddd, J = 8.0,4.9, 0.8 Hz), 7.37-7.42 (2H, m), 7.62-7.66 (2H, m), 7.71
(lH, dd, J = 1.8, 0.6 Hz), 7.93 (lH, dd, J = 2.6, 0.6 Hz), 7.94 (lH, ddd, J = 8.0,2.4, 1.7
Hz),8.69(1H7dd, J=4.8, 1.6Hz), 8.98 (lH,dd, J=2.4,0.8Hz).
10 1 3 ~(CDC-13, 6~ (ppm~)): 2~1.8,4 3.7, 51.0, 51.1,68.9, 107.4, 107.7, 112.6, 119.2,
123.3, 126.7, 129.9, 133.8, 134.6, 137.3, 137.6, 139.8, 141.1, 148.0, 152.6, 153.2, 157.3,
170.5.
IR (KBr cm-I): 764 (C-H), 1161 (S=O), 1525 (C=N), 1737 (C=O), (298 1,2933) (C-H),
3437 (N-H).
15 Elemental analysis: Calcd: C, 59.80%; H, 5.31%; N, 16.07%
Found: C, 59.98%; H, 5.42%; N, 16.14%.
[0106] [Example21
Synthesis of isopropyl
20 2-( {6- [(N-benzylpyridine-3 -sulfonamido)methyl] pyridin-2-yl ) amino)acetate
[O 1071 A glass vessel having an internal volume of about 50 ml and equipped with a
stirrer, a thermometer and an upper cooling unit was loaded with 0.253 g (1.02 mmol)
of N-benzylpyridine-3-sulfonamide, 0.243 g (1 .OO mmol) of isopropyl
2- {[6-(chloromethy1)pyridin-2-yl] amino) acetate obtained in Example 6, 0.665 g (2.04
25 mrnol) of cesium carbonate and 1.76 g of acetonitrile. The mixture was stirred while
performing heating at 80°C. The reaction was performed for 2 hours until the area
percentage of the raw material isopropyl
2- {[6-(chloromethy1)pyridin-2-yl] amino) acetate in the high-performance liquid
chromatography analysis fell to 0.03% or less. The reaction was further carried out for
30 2 hours. The reaction conversions of isopropyl
2- {[6-(chloromethy1)pyridin-2-yl]amino}acetate after 1 hour and 2 hours from the start
of the thermal stirring were 99.81% and at least 99.99%, respectively. After the
completion of the reaction, the reaction liquid was cooled to room temperature and was
filtered through Celite (trade name), and the residue was washed with acetonitrile. The
5 filtrate obtained was quantitatively analyzed by high-performance liquid
chromatography, and was found to contain 0.430 g of the target product (94.5% reaction
yield). Next, the reaction liquid was concentrated under reduced pressure until the
weight of the liquid became 0.785 g. After the addition of 4.3 g of toluene, the product
was washed with water three times. During this process, an emulsion was formed.
10 Although this emulsion contained a portion of the target product, it was disposed of
together with the aqueous phase. The resultant organic phase was combined with 3.15
ml(3.15 rnmol) of 1 mol/L hydrochloric acid. The mixture was stirred at room
temperature for 20 minutes and was separated. To the aqueous phase were added 4.27
g of toluene and 3.46 ml(3.46 mmol) of a 1 mol/L aqueous sodium hydroxide solution.
15 The mixture was heated to 40°C and was stirred for 20 minutes. The liquid was
separated. The organic phase obtained was washed with water two times. The
organic phase was concentrated under reduced pressure until the weight of the liquid
became 0.239 g. In this manner, isopropyl
2-( (6- [(N-benzylpyridine-3 -sulfonamido)methyl] pyridin-21 amino)acetate was
20 obtained as a light brown solid (53.8% yield of isolation in terms of the raw material
isopropyl2- {[6-(chloromethy1)pyridin-2-yllamino} acetate). The high-performance
liquid chromatography HPLC showed that the quantitative purity was 98.0%. In the
measurement by high-p erformance liquid chromatography HPLC (260 nm wavelength),
no impurities having an area percentage of 0.1% or above were detected.
25 [O 1081 The properties of isopropyl
2-( (6- [(N-benzylp yridine-3 -sulfonamido)methyl] pyriin-21 amino)acetate obtained
are described below.
EI-MS (dz): 454 [MI.
CI-MS (dz): 455 [M+l].
30 1~-~~~(CDC13,6(ppm)):1.27(6H,d,J=6.3Hz),3.82(2H,d,J=5.4Hz),4.31(2H,
~),4.62(2H,s),4.73( lH, t, J=5.2Hz), 5.09(1H,sep, J=6.3 Hz),6.26(1H,d7J =8.1
Hz), 6.43 (lH, d, J = 6.9 Hz), 7.26-7.33 (7H, m), 7.90-7.93 (lH, m), 8.69 (lH, dd, J =
4.8, 1.6 Hz), 8.95 (lH, dd, J = 2.3, 0.7 Hz).
13c-N~(RC DC13, 6 (ppm)): 21.8,43.8, 51.1, 51.6, 69.0, 107.2, 112.6, 123.2, 127.9,
35 128.6, 128.8, 134.7, 135.6, 137.6, 137.7, 148.2, 152.5, 153.6, 157.3, 170.5.
IR (KBr cm-I): 1169 (S=O), 1724 (C=O), (2936,2984) (C-H), 3428 (N-H).
Elemental analysis: Calcd: C, 60.77%; H, 5.77%; N, 12.33%
Found: C, 61.03%; H, 5.85%; N, 12.15%.
[O 1091 [Example 31
5 Synthesis of isopropyl
2- { [6-( {N- [4-(1 H-p yrazol- 1 -yl)benzyl] pyridine-3 -sulfonamido } methy1)pyridin-2-yl] ami
no} acetate
[0110] A glass vessel having an internal volume of about 30 ml and equipped with a
stirrer, a thermometer and an upper cooling unit was loaded with 641 mg (2.04 mmol)
10 of N-[4-(1H-pyrazol- 1 -yl)benzyl]pyridine-3-sulfonamide, 485 mg (2.00 mmol) of
isopropyl2- {[6-(chloromethy1)pyridin-2-yllamino} acetate obtained in Example 6, 1.33
g (4.08 mmol) of cesium carbonate and 3.53 g of acetonitrile. The mixture was stirred
at 30°C. The reaction was performed for 26 hours until the area percentage of the raw
material isopropyl2- {[6-(chloromethy1)pyridin-2-yl]a mino}a cetate in the
15 high-performance liquid chromatography analysis fell to 0.3% or less. The reaction
was further carried out for 2 hours. After the completion of the reaction, the reaction
liquid was filtered, and the residue was washed with acetonitrile. The filtrate obtained
was quantitatively analyzed by high-performance liquid chromatography, and was
found to contain 991 mg of the target product (95.2% reaction yield).
20 [Olll] [Example41
Synthesis of isopropyl
2- {[6-( {N-[4-(1 H-pyrazol- 1 -yl)benzyl]pyridine-3 -sulfonamido } methy1)pyridin-2-yl] ami
no} acetate
[O 1 121 A glass vessel having an internal volume of about 50 ml and equipped with a
25 stirrer, a thermometer and an upper cooling unit was loaded with 3.21 g (10.2 mmol) of
N-[4-(1H-pyrazol- 1 -yl)benzyl]pyridine-3-sulfonamide, 2.43 g (1 0.0 mmol) of isopropyl
2- {[6-(chloromethy1)pyridin-2-yllamino} acetate obtained in Example 6,2.82 g (20.4
mmol) of potassium carbonate and 17.6 g of acetonitrile. The mixture was stirred
while performing heating at 80°C. The reaction was performed for 10 hours until the
area percentage of the raw material isopropyl
2- {[6-(chloromethy1)pyridin-2-ylaminolacetate in the high-performance liquid
chromatography analysis fell to 0.03% or less. The reaction conversion of isopropyl
2- {[6-(chloromethy1)pyridin-2-yllamino} acetate after 1 hour from the start of the
5 thermal stirring was 43.9%. After the completion of the reaction, the reaction liquid
was cooled to room temperature and was filtered through Celite (trade name), and the
residue was washed with acetonitrile. The filtrate obtained was quantitatively
analyzed by high-performance liquid chromatography, and was found to contain 5.00 g
of the target product (96.0% reaction yield). Next, the reaction liquid was
10 concentrated under reduced pressure until the weight of the liquid became 7.85 g.
After the addition of 42.77 g of toluene, the product was washed with water three times.
The resultant organic phase was combined with 3 1.5 ml(3 1.5 mmol) of 1 mol/L
hydrochloric acid. The mixture was stirred at room temperature for 20 minutes and
was separated. The separated organic phase contained 0.62 g of the target product
15 (corresponding to 1 1.8% yield). To the aqueous phase were added 42.77 g of toluene
and 34.6 ml(34.6 mmol) of a 1 mol/L aqueous sodium hydroxide solution. The
mixture was heated to 40°C and was stirred for 20 minutes. Hot filtration was
performed at 40°C, and thereafter the liquid was separated. The organic phase
obtained was washed with water two times. The organic phase was concentrated
20 under reduced pressure until the weight of the liquid became 8.97 g, and 7.40 g of
2-propanol was added. The mixture was heated to 60°C, cooled gradually, and, at the
temperature which caused a crystal to precipitate, stirred for 30 minutes. Thereafter,
the mixture was cooled slowly to not more than 5"C, and stirred at the temperature for 1
hour. The resultant slurry was filtered, and the residue was washed with cold
25 2-propanol and vacuum dried at 50°C to give 3.90 g of isopropyl
2- {[6-( {N- [4-(1 H-pyrazol- 1 -yl)benzyl]pyridine-3 -sulfonamido} methyllpyridin-2-yllami
nojacetate as a light brown solid (74.9% yield of isolation in terms of the raw material
isopropyl2- {[6-(chloromethy1)pyridin-2-yl]a mino}a cetate). The high-performance
chromatography HPLC showed that the quantitative purity was 99.0% and the
3 0 compound contained 0.1 1 % of the raw material
N-[4-(1 H-pyrazol- 1 -yl)benzyl]pyridine-3-sulfonamide.
[O 1 131 The properties of isopropyl
2- {[6-( {N-[4-(1H-pyrazol- 1- yl)benzyl]pyridine-3-sulfonamido}methyl)pyridin-2-yla]m i
no} acetate obtained are described below.
35 EI-MS (dz): 520 [MI.
CI-MS (dz): 521 [M+l].
1 H-NMR (CDC13, 6 (ppm)): 1.24 (6H, d, J = 6.3 Hz), 3.82 (2H, d, J = 5.5 Hz), 4.3 1 (2H,
~),4.64(2H,s),4.94( lH, t, J=5.5Hz),5.07(1H, sep, J=6.3Hz),6.26(1H,d, J=8.3
Hz), 6.41 (lH, dd, J = 7.2, 0.5 Hz), 6.46 (lH, dd, J = 2.5, 1.8 Hz), 7.25 (lH, dd, J = 8.3,
7.2 Hz), 7.32 (lH, ddd, J = 8.0,4.9, 0.8 Hz), 7.37-7.42 (2H, m), 7.62-7.66 (2H, m), 7.71
5 (lH, dd, J = 1.8,0.6 Hz), 7.93 (lH, dd, J = 2.6, 0.6 Hz), 7.94 (lH, ddd, J = 8.0,2.4, 1.7
Hz), 8.69 (lH, dd, J = 4.8, 1.6 Hz), 8.98 (lH, dd, J = 2.4, 0.8 Hz).
1 3 ~(CDC-13, 6~ (ppm~)): 2~1.8,4 3.7, 51.0, 51.1, 68.9, 107.4, 107.7, 112.6, 119.2,
123.3, 126.7, 129.9, 133.8, 134.6, 137.3, 137.6, 139.8, 141.1, 148.0, 152.6, 153.2, 157.3,
170.5.
10 IR (KBr cm-I): 764 (C-H), 1161 (S=O), 1525 (C=N), 1737 (C=O), (298 1,2933) (C-H),
3437 (N-H).
Elemental analysis: Calcd: C, 59.80%; H, 5.31%; N, 16.07%
Found: C, 59.98%; H, 5.42%; N, 16.14%.
[O 1 141 [Comparative Example 11
15 Synthesis of isopropyl
2- {[6-( {N-[4-(1 H-pyrazol- 1 -yl)benzyl]pyridine-3-sulfonamido}methyl)pyridin-2-yl]ami
no} acetate
[O 1 151 A glass vessel having an internal volume of about 50 ml and equipped with a
stirrer, a thermometer and an upper cooling unit was loaded with 3.2 1 g (1 0.2 mrnol) of
20 N-[4-(1H-pyrazol- 1 -yl)benzyl]pyridine-3-sulfonamide, 2.43 g (1 0.0 mmol) of isopropyl
2- {[6-(chloromethy1)pyridin-2-yllamino} acetate obtained in Example 6,2.16 g (20.4
mmol) of sodium carbonate and 17.6 g of acetonitrile. The mixture was stirred while
performing heating at 80°C. The reaction was performed for 110 hours until the area
percentage of the raw material isopropyl
25 2- {[6-(chloromethy1)pyridin-2-yllamino} acetate in the high-performance liquid
chromatography analysis fell to 0.05% or less. The reaction conversion of isopropyl
2- {[6-(chloromethy1)pyridin-2-yllamino} acetate after 1 hour from the start of the
thermal stirring was 0.92%. After the completion of the reaction, the reaction liquid
was cooled to room temperature and was filtered through Celite (trade name), and the
30 residue was washed with acetonitrile. The filtrate obtained was quantitatively
analyzed by high-performance liquid chromatography, and was found to contain 0.72 g
of the target product (1 3 3% reaction yield). Next, the liquid was concentrated under
reduced pressure until its weight became 7.85 g. After the addition of 42.6 g of
toluene, the product was washed with water three times. Tar components which had
35 separated during the washing with water were disposed of together with the aqueous
phase. The resultant organic phase was combined with 3 1.5 ml(3 1.5 mmol) of 1
mollL hydrochloric acid. The mixture was stirred at room temperature for 20 minutes
and was separated. To the aqueous phase were added 42.6 g of toluene and 34.6 ml
(34.6 mmol) of a 1 mol/L aqueous sodium hydroxide solution. The mixture was
heated to 40°C and was stirred for 20 minutes. Hot filtration was performed at 40°C,
5 and thereafter the liquid was separated. The organic phase obtained was washed with
water two times. The organic phase was concentrated under reduced pressure to give
0.764 of a dark brown viscous liquid containing isopropyl
2- {[6-( {N- [4-(1 H-p yrazol- 1 - yl)benzyl] pyridine-3 -sulfonamido } methy1)pyridin-2-yl] ami
no} acetate. The high-performance chromatography HPLC showed that the
10 quantitative purity was 60.2% and the net weight was 0.460 g (8.8% yield of isolation in
terms of the raw material isopropyl2- {[6-(chloromethy1)pyridin-2-yllamino} acetate).
[O 1 161 The properties of isopropyl
2- {[6-( {N- [4-(1 H-pyrazol- 1 - yl)benzyl] pyridine-3 -sulfonamido } methy1)pyridin-2-yl] ami
no} acetate obtained are described below.
15 EI-MS (dz): 520 [MI.
CI-MS (dz): 521 [M+l].
1 H-NMR (CDC13, 6 (ppm)): 1.24 (6H, d, J = 6.3 Hz), 3.82 (2H, d, J = 5.5 Hz), 4.3 1 (2H,
s),4.64(2H7 s),4.94(1H7 t, J=5.5 Hz), 5.07(1H7 sep, J=6.3 Hz), 6.26 (lH,d, J=8.3
Hz), 6.41 (lH, dd, J = 7.2, 0.5 Hz), 6.46 (lH, dd, J = 2.5, 1.8 Hz), 7.25 (lH, dd, J = 8.3,
20 7.2 Hz), 7.32 (lH, ddd, J = 8.0,4.9, 0.8 Hz), 7.37-7.42 (2H, m), 7.62-7.66 (2H, m), 7.71
(lH, dd, J = 1.8,0.6 Hz), 7.93 (lH, dd, J = 2.6, 0.6 Hz), 7.94 (lH, ddd, J = 8.0,2.4, 1.7
Hz), 8.69 (lH, dd, J = 4.8, 1.6 Hz), 8.98 (lH, dd, J = 2.4, 0.8 Hz).
1 3 ~(CD-C13~, 6 (p~pm))~: 21. 8,43.7, 51.0, 51.1, 68.9, 107.4, 107.7, 112.6, 119.2,
123.3, 126.7, 129.9, 133.8, 134.6, 137.3, 137.6, 139.8, 141.1, 148.0, 152.6, 153.2, 157.3,
25 170.5.
IR (KBr cm-I): 764 (C-H), 1 16 1 (S=O), 1525 (C=N), 1737 (C=O), (298 1,2933) (C-H),
3437 (N-H).
[0117] [Example 51
Synthesis of isopropyl2- {[6-(hydroxymethy1)pyridin-2-yllamino} acetate
30 [0118] A glass vessel having an internal volume of about 2 L and equipped with a
stirrer, a thermometer and an upper cooling unit was loaded with 948 g of 2-propanol
and 76.7 g of concentrated sulfuric acid. The mixture was heated to 75OC. There was
added dropwise, over a period of 40 minutes, a mixed solution of 135 g of t-butyl
2- {[(t-butoxycarbonyl)(6-hydroxymethylp y r i }aceta te synthesized by the
35 method described in Reference Example 3-(b) of Japanese Patent Application
Publication No. 20 1 1-57633, in 45 g of toluene and 3 1 1 g of 2-propanol. The resultant
mixture was stirred for 6 hours while performing heating at 78OC. After being cooled,
the liquid was vacuum concentrated at an internal pressure of 20 hPa and an external
temperature of 40°C until the weight of the liquid became 309 g. 677 g of toluene and
406 g of water were added, and the mixture was stirred at room temperature and was
5 separated. The aqueous phase obtained was added dropwise, over a period of 20
minutes, to a separately prepared mixed solution of 129 g of sodium hydrogencarbonate
in 8 12 g of water and 677 g of toluene. The resultant mixture was stirred at room
temperature for 1 hour and was separated. The aqueous phase was extracted with 338
g of toluene. The organic phases obtained were combined and washed with 426 g of a
10 5 wt% aqueous sodium chloride solution. Thus, an organic phase weighing 1370 g
was obtained. An approximately 1356 g portion was collected and concentrated until
the weight of the liquid became 113 g. Thereafter, the weight of the liquid was
adjusted to 300 g by the addition of toluene. To this solution, 190 g of n-heptane was
added. The mixture was heated to 45OC to dissolve the crystal and was thereafter
15 cooled to 35OC. A small amount of a seed crystal synthesized separately by the similar
process was added, and stirring was performed at 35°C for 1 hour. The amount of the
crystal increased gradually during the stirring. 365 g of n-heptane was added dropwise
over a period of 30 minutes. The internal temperature was lowered to 5OC in 40
minutes, and the mixture was stirred at the temperature for 30 minutes. The crystal
20 precipitated was recovered by filtration, washed with n-heptane and dried at 50°C under
reduced pressure to give 70.4 g of isopropyl
2- {[6-(hydroxymethy1)pyridin-2-yllamino} acetate as a white powder. The
high-performance chromatography HPLC showed that the quantitative purity was
94.3% and the net weight was 66.4 g (74.7% yield of isolation in terms of the raw
25 material t-butyl2- {[(t-butoxycarbonyl)(6-hydroxymethylpyri} acetate).
[O 1 1 91 The properties of isopropyl2- {[6-(hydroxymethy1)pyridin-2-yllamino} acetate
obtained are described below.
EI-MS (dz): 224 [MI.
CI-MS (dz): 225 [M+l].
30 'H-NMR (CDC13, G(ppm)): 1.27 (6H, d, J = 6.3 Hz), 3.76 (lH, s), 4.10 (2H, d, J = 5.5
Hz),4.59(2H7 s), 5.00 (lH, s), 5.10(1H7m),6 .36(1H7dd7J =8.2,0.6Hz),6.51 (lH,
dd, J = 7.3, 0.7 Hz), 7.41 (lH, ddd, J = 5.74, 3.88 Hz).
13c-NMR (CDC13, G(ppm)): 21.8,44.1, 63.5, 69.0, 106.6, 109.5, 138.0, 156.8, 156.9,
170.7.
35 IR (KBr cm-'): 416,469,531,559,731,785,826, 862,903,916,941,980, 1014, 1052,
1082,1106,1131, 1147, 1182,1217,1256,1276,1347, 1378, 1402, 1471, 1526 (C=N),
1582,1607,1687,1724 (C=O), 2878,2935 (C-H), 2983 (C-H), 3381 (N-H).
Elemental analysis: Calcd: C, 58.91%; H, 7.19%; N, 12.49%
Found: C, 58.99%; H, 7.17%; N, 12.48%.
[0120] [Example 61
5 Synthesis of isopropyl2- {[6-(chloromethy1)p yn'din-2-yl] amino) acetate
[O 12 11 At room temperature, 19.6 g of thionyl chloride was added dropwise over a
period of 20 minutes to a solution of 35.7 g of isopropyl
2- {[6-(hydroxymethy1)pyridin-2-yllamino) acetate obtained in Example 5 in 396 g of
methylene chloride. The mixture was stirred at room temperature for 1 hour. The
10 resultant reaction liquid was added dropwise to a mixture slurry of 37.8 g of sodium
hydrogencarbonate and 149 g of water. The mixture was stirred at room temperature
for 20 minutes and was separated. The organic phase was dehydrated by the addition
of 6.73 g of magnesium sulfate. The filtrate was concentrated to dryness at 50°C. In
this manner, 37.8 g of isopropyl2- {[6-(chloromethy1)pyridin-2-yllamino} acetate was
15 obtained as a light brown solid.
[O 1221 The properties of isopropyl2- {[6-(chloromethy1)pyridin-2-yllamino} acetate
obtained are described below.
EI-MS (dz): 242 [MI.
CI-MS (dz): 243 [M+l].
20 ' H - N M R ( C D C ~ ~ , ~ (1~.2~4~(6)H),:m ),4.10(2H,d,J=5.4Hz),4.48(2H,s),5.03
(lH,s), 5.10(1H,m),6.39(1H,d, J=8.3 Hz),6.76(1H,d, J=7.3 Hz), 7.43 (lH,dd, J
= 7.8, 7.8 Hz).
' 3 ~(CD-C13,~ 6 (pp~m)): ~21.8, 44.0,44.7, 68.9, 107.7, 112.2, 138.1, 154.6, 157.3,
170.7.
25 IR (KBr cm-I): 415,446,530,560,627,735,804,827,874,903,939,952,982, 1042,
1088, 1108, 1128, 1144,1167, 1180, 1219, 1269,1281, 1350, 1378,1400, 1420,1434,
1470,1525 (C=N), 1580,1613,1690,1728 (C=O), 2878,2934 (C-H), 2981 (C-H),
3379 (N-H).
Elemental analysis: Calcd: C, 54.44%; H, 6.23%; N, 1 1.54%
30 Found: C, 54.46%; H, 6.23%; N, 11.56%.
INDUSTRIAL APPLICABILITY
[O 1231 The present invention relates to a method for obtaining an N-substituted
sulfonamide compound with high purity by reacting a sulfonamide compound with a
halogenated organic compound. The method for producing N-substituted sulfonamide
35 compounds of the present invention involves a specific base, and thereby allows the
reaction to proceed faster than heretofore possible and affords high yield with little
byproducts, which makes the method of great usefulness in industry. Further,
N-substituted sulfonamide compounds obtained by the method of the present invention
have high purity and qualify for use as intermediates and active ingredients for drugs.
Amendment under Article 19(1)

CLAIMS
[Claim 1] A method for producing N-substituted sulfonamide
compounds comprising a step of reacting a sulfonamide compound of the general
formula 5 ula (1):
wherein
R1 and R2 are each independently an optionally substituted alkyl, alkenyl,
alkynyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl group
10 with a halogenated organic compound of the general formula (2):
wherein
R3 is an optionally substituted aralkyl or heteroarylalkyl group, and X is a
halogen atom
15 in the presence of cesium carbonate or potassium carbonate in an organic solvent to
produce an N-substituted sulfonamide compound of the general formula (3):
wherein R1, R2 and R3 are the same as defined above.
[Claim 2] The method for producing N-substituted sulfonamide compounds
20 according to Claim 1, wherein R1 is an optionally substituted aryl or heteroaryl group.
[Claim 3] The method for producing N-substituted sulfonamide compounds
according to Claim 1 or 2, wherein R1 is an optionally substituted phenyl or pyridyl
group.
[Claim 4] The method for producing N-substituted sulfonamide compounds
25 according to Claim 1, wherein R2 is an optionally substituted aralkyl or heteroarylalkyl
group.
[Claim 5] The method for producing N-substituted sulfonamide compounds
Amendment under Article 19(1)
- 34 -
according to Claim 1 or 4, wherein R2 is an optionally substituted benzyl or
benzofuranylmethyl group.
[Claim 6] The method for producing N-substituted sulfonamide compounds
according to Claim 1 or 5, wherein R3 is an optionally substituted benzyl or
pyridylmethyl 5 l group.
[Claim 7] The method for producing N-substituted sulfonamide compounds
according to Claim 1, wherein X is a chlorine atom, a bromine atom or an iodine atom.
[Claim 8] The method for producing N-substituted sulfonamide compounds
according to Claim 1 or 7, wherein X is a chlorine atom or a bromine atom.
10 [Claim 9] The method for producing N-substituted sulfonamide compounds
according to Claim 1, wherein the sulfonamide compound of the general formula (1) is
of the general formula (4):
wherein
15 R1a is defined the same as R1, and
R4 is an optionally substituted aryl or heteroaryl group.
[Claim 10] The method for producing N-substituted sulfonamide compounds
according to Claim 1, wherein the halogenated organic compound of the general
formula (2) is of the general formula (5):
20
wherein R5 is an alkyl group, and X1 is defined the same as X.
[Claim 11] The method for producing N-substituted sulfonamide compounds
according to Claim 1, wherein the N-substituted sulfonamide compound of the general
formula (3) is of the general formula (6):
Amendment under Article 19(1)
- 35 -
wherein R1a, R4 and R5 are the same as defined above.
[Claim 12] The method for producing N-substituted sulfonamide compounds
according to any of Claims 1 to 11, wherein the reaction temperature is 0 to 90°C.
[Claim 13] The method for producing N-substituted sulfonamide compound5 s
according to any of Claims 1 to 12, wherein the organic solvent is one or more organic
solvents selected from the group consisting of dimethylsulfoxide, dimethylformamide
and acetonitrile.
[Claim 14] The method for producing N-substituted sulfonamide compounds
10 according to any of Claims 1 to 13, wherein the organic solvent is acetonitrile.
[Claim 15] A method for producing N-substituted sulfonamide compounds
comprising a step of reacting a sulfonamide compound of the general formula (1):
wherein R1 and R2 are the same as defined above
15 with a halogenated organic compound of the general formula (2):
wherein R3 and X are the same as defined above
in the presence of cesium carbonate in an organic solvent to produce an N-substituted
sulfonamide compound of the general formula (3):
20
Amendment under Article 19(1)
- 36 -
wherein R1, R2 and R3 are the same as defined above.
[Claim 16] The method for producing N-substituted sulfonamide compounds
according to Claim 15, wherein the reaction temperature is 30 to 90°C.
[Claim 17] A high-purity N-substituted sulfonamide compound of the general
formula 5 ula (3):
wherein R1, R2 and R3 are the same as defined above.
[Claim 18] The high-purity N-substituted sulfonamide compound according to
Claim 17, wherein the HPLC purity of the N-substituted sulfonamide compound is not
10 less than 99.5% and the contents of any impurities present in the compound are each
less than 0.10%.
[Claim 19] A high-purity N-substituted sulfonamide compound obtained by the
production method described in any of Claims 1 to 14.
[Claim 20] A high-purity N-substituted sulfonamide compound obtained by the
15 production method described in any of Claims 1 to 16, the HPLC purity of the
N-substituted sulfonamide compound being not less than 99.9%.
[Claim 21] A high-purity N-substituted sulfonamide compound obtained by the
production method described in any of Claims 1 to 16, the HPLC purity of the
N-substituted sulfonamide compound being not less than 99.5%, the contents of any
20 impurities present in the compound being each less than 0.10%.
[Claim 22] A high-purity N-substituted sulfonamide compound of the general
formula (6):
wherein R1a, R4 and R5 are the same as defined above.
25 [Claim 23] A compound of the general formula (9):