Title of Invention

A PROCESS FOR THE PRODUCTION OF y-KETOACETAL COMPOUNDS

Abstract The present invention provides a process for the production of a ?-ketoacetal compound wherein the desired product can be obtained through a simple procedure in high yield as a high purity product. [Means to solve the subject] The present invention is a process in which the reaction scheme is shown below: (wherein Ar is an aryl group; X is a halogen atom; Ra and Rb are alkyl groups or the like; W is an alkylene group).
Full Text [Field of the invention]
The present invention relates to a process for producing y-ketoacetal compounds.
[Background of the invention]
The y-ketoacetal compounds of general formula (A) shown below are known as
intermediates for producing a 4-methyl-l,2-diarylpyrroie derivative (Japanese Patent
Publication (Kokai) Number 2000-80078) which is known as a useful analgesic (see
U.S. patent number 5908858)
(wherein Ar represents an aryl group which may be optionally substituted with a
substituent(s), R' and R^ each independently represent a lower alkyl group or R' and
R^ taken together represent a trimethylene group or the like).
The process for producing said y-ketoacetal compounds, wherein nitromethane
(CH3NO2) and a base are used, is documented (Japanese Patent Publication (Kokai)
Number 2000-80078). Since nitromethane is apt to explode, the process must be
carefully carried out. There are hence some considerable problems in the process;
for example, the process for preparation of y-ketoacetal compounds, especially in a
large-scale production, becomes particularly complex in order to avoid explosions
occurring.
[Disclosure of the invention]
The inventors have investigated a process for the production of y-ketoacetal
compounds, found a process for production of them by using an enamine derivative,
but not nitromethane, and obtained the desired product with high purity by a simple
procedure with good yields, and thus completed the present invention.
The present invention relates to
(1) a process for the production of a compound of general formula (1) by
reacting a compound of general formula (2)
(wherein Ar represents a C6-C10 aryl group or a C6-C10 aryl group substituted with a
substituent(s) independently selected fiom Substituent group a; Substituent group a
consists of halogen atoms, C1-C6 alkyl groups, halog6nated C1-C6 alkyl groups,
hydroxyl groups, C1-C6 alkoxy groups, C1-C6 alkylthio groups, mercapto groups, Ci-
Ce alkylsulfonyl groups, and sulfamoyl groups; and X represents a halogen atom)
with a compound of general formula (3)
(wherein R' and R are the same or different and each represents independently a C1-
C6 alkyl group, a C1-C6 alkyl group substituted with a C1-C6 alkoxy group(s), or a C3-
C6 cycloalkyi group, or Ra and Rb taken together represent a C4-C8 alkylene group) in
an inert solvent and hydrolyzing the product with an acid to afford a compound of
general formula (4),
(wherein Ar has the same meaning as that indicated above), followed by reacting the
compound of general formula (4) with a compound of general formula (5)
HO-W-OH (5)
(wherein W represents a C1-C6 alkylene group) in the presence of an acid to give a
compound of general formula (1)
(wherein Ar and W have the same meanings as those indicated above).
Among the above processes, the preferred processes are:
(2) a process wherein Ar is a phenyl group or a phenyl group substituted with a
substituent(s) independently selected from Substituent group a,
(3) a process wherein Ar is a phenyl group or a phenyl group substituted with a
substituent(s) independently selected from the substituent group consisting of methyl,
methoxy, ethoxy and methylthio groups,
(4) a process wherein Ar is a 4-methylphenyl, 3-methylphenyl, 4-
methoxyphenyl, 4-ethoxyphenyl, 4-methylthiophenyl, 3,4-dimethylphenyl, or 3,4-
dimethoxyphenyl group,
(5) a process wherein X is a bromine atom or an iodine atom,
(6) a process wherein X is a bromine atom,
(7) a process wherein Ra and Rb are the same or difFerent and each represents
independently a C2-C5 alky! group, a C2-C5 alkyl group substituted with a C1-C4
alkoxy group(s), or a C4-C6 cycloalkyi group,
(8) ¦ a process wherein Ra and Rb are the same or different and each represents
independently an isopropyl, isobutyl, isopentyl, 2-methoxyethyl, 3-methoxypropyl, 2-
ethoxyethyl, cyclopentyl, or cyclohexyl group,
{9) a process wherein Ra and Rb" are both an isobutyl group,
(10) a process wherein W is a straight or branched chain C3-C5 alkylene group,
(11) a process wherein W is a straight chain C3-C5 alkylene group, and
(12) a process wherein W is a 2-methyltrimethylene or 2,2-dimethyltrimethylene
group.
Furthermore, the present invention provides
(13) a process for the production of a compound of general formula (7)
(wherein Ar represents a C6-C10 aryl group or a C6-C10 aryl group substituted with a
substituent(s) independently selected fkwn Substituent group a; Substituent group a
consists of halogen atoms, C1-C6 alkyl groups, halogenated C1-C6 alky I groups,
hydroxyl groups, C1-C6 alkoxy groups, C1-C6 alkylthio groups, mercapto groups, C\-
C6 alkylsulfonyl groups, and sulfamoyl groups; and Y represents a methyl or amino
group (preferably an amino group)) that includes a process for the production of a
compound of general formula (4) by reacting a compound of general formula (2)
(wherein Ar represents a C6-C10 aryl group or a C6-C10 aryl group substituted with a
substituent(s) independently selected from Substituent group a; Substituent group a
consists of halogen atoms, C1-C6 alkyl groups, halogenated C1-C6 alkyl groups,
hydroxyl groups, C1-C6 alkoxy groups, C1-C6 alkylthio groups, mercapto groups, C1-
C6 alkylsulfonyl groups, and sulfamoyl groups; and X represents a halogen atom)
with a compound of general formula (3)
(wherein Ra and Rb are the same or different and each represents independently a C1-
C6 alkyl group, a C1-C6 alkyl group substituted with a C1-C6 alkoxy group(s), or a C3-
C6 cycloalkyl group, or Ra and Rb taken together represent a C4-C8 alkylene group) in
an inert solvent and hydrolyzing the product with an acid to afford a compound of
general formula (4)
(wherein Ar has the same meaning as that indicated above), and that further includes a
process for the production of a compound of general formula (1) by reacting a
compound of general formula (4) with a compound of general formula (5)
HO-W-OH (5)
(wherein W represents a C1-C6 alkylene group) in the presence of an acid to afford a
compound of general formula (1)
(wherein Ar and W have the same meanings as those indicated above), and
(14) a process for the production of a compound of general formula (7)
(wherein Ar represents a C6-C10 aryl group or a C6-C10 aryl group substituted with a
substituent(s) independently selected from Substituent group a; Substituent group a
consists of halogen atoms, C1-C6 alkyl groups, halogenated C1-C6 alkyl groups,
hydroxyl groups, C1-C6 alkoxy groups, C1-C6 alkylthio groups, mercapto groups, C1-
C6 alkylsulfonyl groups, and sulfamoyi groups; and Y represents a methyl or amino
group (preferably an amino group)) by reacting a compound of general formula (2)
(wherein Ar represents a C6-C10 aryl group or a C6-C10 aryl group substituted with a
substituent(s) independently selected fix)m Substituent group a; Substituent group a
consists of halogen atoms, C1-C6 alkyl groups, halogenated C1-C6 alkyl groups,
hydroxyl groups, C1-C6 alkoxy groups, C1-C6 alkylthio groups, mercapto groups, C1-
C6 alkylsulfonyl groups, and sulfamoyl groups; and X represents a halogen atom)
with a compound of general formula (3)
(wherein Ra and Rb are the same or different and each represents independently a C1-
C6 alkyl group, a C1-C6 alkyl group substituted with a C1-C6 alkoxy group(s), or a C3-
C6 cycloalkyl group; or Ra and Rb taken together represent a C4-C8 alkylene group) in
an inert solvent; hydrolyzing the product with an acid to afford a compound of general
formula (4)
(wherein Ar has the same meaning as that indicated above); and reacting the
compound of general formula (4) with a compound of general formula (5)
HO-W-OH (5)
(wherein W represents a C1-C6 alkylene group) in the presence of an acid to afford a
compound of general formula (1)
(wherein Ar and W have the same meanings as those indicated above); followed by
reacting the compound of general formula (I) with a compound of general formula
(6)
(wherein Y represents a methyl or amino group (preferably an amino group)) to give a
compound of general formula (7).
The terms of "C6-C10 aryl group", "halogen atom", "Ci-Cg alkyl group", "halogenated
C1-C6 alkyl group", "C1-C6 alkoxy group", "C1-C6 alkylthio group", "C1-C6
alkylsulfonyl group", "C3-C6 cycloalkyl group", "C4-C8 alkylene group" and "C1-C6
alkylene group", which are used in this specification to specify the present invention,
are defined below.
The "C6-C10 aryl group" moiety of "C6-C10 aryl group" and "C6-C10 aryl group
substituted with a substituent(s) independently selected from Substituent group a" in
the definition of Ar is a phenyl or naphthyl group and preferably a phenyl group.
In addition, the "C6-C10 aryl group" described above may be optionally fused to a C3-
C10 cycloalkyl group (preferably C5-6 cycloalkyl group), for example, a fused aryl
group is a 5-indjmyl group.
The "C6-C10 aryl group substituted with a substituent(s) independently selected from
Substituent group a" in the definition of Ar is preferably a C6-C10 aryl group
substituted with one to four substituents independently selected from Substituent
group a, more preferably a C6-C10 aryl group substituted with one to three
substituents independently selected from Substituent group a, and still more
preferably a C6-C10 aryl group substituted with one or two substituents independently
selected from Substituent group a.
The "halogen atom" in the definitions of Substituent group a and X is a fluorine atom,
a chlorine atom, a bromine atom, or an iodine atom. The preferred halogen atom in
Substituent group a is a fluorine atom, a chlorine atom, or a bromine atom and still
more preferably a fluorine atom or a chorine atom. The preferred halogen atom in X
is a bromine atom or an iodine atom, particularly more preferably a bromine atom.
The "C1-C6 alkyl group" in the defmiticms of Substituent group a, Ra and R^ and the
alkyl moiety of the "C1-C6 alkyl group substituted with a C1-C6 alkoxy group(s)" in
the definitions of Ra and Rb' are each indq)endentiy a straight or branched chain alkyl
group such as a methyl, ethyl, propyl, isoprc^yl, butyl, isobutyl, s-butyl, tert-butyl,
pentyl, isopentyl, 2-methyIbutyl, nec^ntyl, 1-ethylpropyl, hexyl, isohexyl, 4-
methylpentyl, 3-methylpentyl, 2-methylpentyI, 1-methylpentyl, 3,3-dimethylbutyl,
2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-
dimethylbutyl, or 2-ethylbutyl group. The alkyl group in Substituent group a is
preferably a straight or branched chain C1-C4 alkyl group, more preferably a methyl,
ethyl, propyl, isopropyl, or butyl group, still more preferably a methyl, ethyl, or
propyl group, and most preferably a methyl group. The alkyl groups in Ra and R'
are preferably each independently a straight or branched chain C2-C5 alkyl group,
more preferably an ethyl, propyl, isopropyl, butyl, isobutyl, or isopentyl group, still
more preferably an isopropyl, isobutyl, or isopentyl group, and most preferably an
isobutyl group.
The "halogenated C1-C6 alkyl group" in the definition of Substituent group a is a
"C1-C6 alkyl group" as indicated above in which one or more hydrogen atoms are
substituted with a halogen atom(s) indicated above, and preferably a halogenated Ci-
C4 alkyl group, more preferably a trifluoromethyl, trichloromethyl, difluoromethyl,
dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl, 2,2,2-
trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, or 2,2-dibromoethyl group,
more preferably a trifluoromethyl, trichloromethyl, difluoromethyl, or fluoromethyl
group, and most preferably a trifluoromethyl group.
The "C1-C6 alkoxy group" in the defmition of Substituent group a and the "alkoxy
group moiety" of the "C1-C6 alkyl group substituted with a C1-C6 alkoxy group(s)" in
the definition of R^ and Rb* are each independently a "C1-C6 alkyl group" as indicated
above to which an oxygen atom is attached, preferably a straight or branched chain
C1-C4 alkoxy group, more preferably a methoxy, ethoxy, propoxy, isopropoxy, or
butoxy group, still more preferably a methoxy, ethoxy, or propoxy group, and most
preferably an ethoxy group.
The "C1-C6 alkylthio group" in the definition of Substituent group a is a "C1-C6 alkyl
group" as indicated above to which a sulfur atom is attached, preferably a straight or
branched chain C1-C4 alkylthio group, more preferably a methylthio, ethylthio,
propoylthio, isopropoylthio, or butyltfiio group, and still more preferably a methylthio,
ethylthio, or propylthio group.
The "C1-C6 alkylsulfonyl group" in the definition of Substituent group a is a "C1-C6
alkyl group" as indicated above to which a sulfonyl group (-SO2-) is attached,
preferably a straight or branched chain C1-C4 alkylsulfonyl group, more preferably a
methylsufonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, or butylsulfonyl
group, still more preferably a methylsulfonyl, ethylsulfonyl, or propylsulfonyl group,
and most preferably a methylsulfonyl group.
The "C3-C6 cycloalkyi groups" in the definitions of the Ra and Rb" are each
independently a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, preferably
a C4-C6 cycloalkyi group, and more preferably a cyclopentyl or cyclohexyl group.
The "C4-Cg alkylene group" that is formed by Ra and Rb" taken together is a
tetramethylene, I-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethylethyIene,
pentamethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1,2-
dimethyltrimethylene, hexamethylene, 2-methylpentamethylene, heptamethylene, or
2,4-dimethylpentamethylene group, preferably a straight or branched chain C4-C6
alkylene group, more preferably a tetramethylene or pentamethylene group, and still
more preferably a tetramethylene group.
The "C1-C6 alkylene group" in the definition of W is a straight or branched chain
alkylene group such as a methylene, ethylene, trimethylene, propylene,
tetramethylene, I-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethylethylene,
pentamethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1,2-
dimethyltrimethylene, or hexamethylene group, and preferably a straight or branched
chain C3-C5 alkylene group, more preferably a trimethylene, 2-methyltrimethylene, or
2,2-dimethyltrimethylene group, still more preferably a trimethylene or 2,2-
dimethyltrimethylene group, and most preferably a 2,2-dimethyltrimethylene group.
The definitions of Ar, X, W, and Substituent group a are as indicated above and
preferred Ar, X, W, and Substituent group a among these definitions are shown below.
Ar is preferably a phenyl group or a phenyl group substituted with a substituent(s)

independently selected from Substituent group a; more preferably a phenyl or a
phenyl group substituted with a substituent(s) independently selected from the
substituent group consisting of methyl, medioxy, ethoxy and methylthio groups; still
more preferably a phenyl group substituted with a substituent(s) independently
selected fix)m the substituent group consisting of methyl, methoxy, ethoxy and
methylthio groups; particularly more preferably a 4-methylphenyl, 3-methylphenyl,
4-methoxyphenyl, 4-ethoxyphenyl, 4-methyltfiiophenyl, 3,4-dimethylphenyl, or 3,4-
dimethoxyphenyl group; and most preferably a 4-ethoxyphenyl or 3,4-
dimethylphenyl group.
X is preferably a bromine atom or an iodine atom and most preferably a bromine
atom.
W is preferably a straight or branched chain C3-C5 alkylene group, more preferably a
straight chain C3-C5 alkylene group, still more preferably a trimethylene, 2-
methyltrimethylene, or 2,2-dimethyltrimethylene group, particularly more preferably
a trimethylene or 2,2-dimethyltrimethylene group, and most preferably a 2,2-
dimethyltrimethylene group.
Substituent group a preferably consists of C1-C4alkyl groups, C1-C4alkoxy groups,
and C1-C4 alkylthio groups, more preferably consists of methyl, methoxy, ethoxy and
methylthio groups, and most preferably consists of a methyl or ethoxy group.
[Mode for carrying out the invention]
The process for the production of a y-ketoacetal compound is carried out as shown
below.
(wherein Ar, Ra, Rb, X, and W have the same meanings as those indicated above).
The step la is a process for the production of a dioxo compound of formula (4) which
process comprises reacting a phenacyl halide compound of formula (2) with an
enamine compound of formula (3) in an inert solvent in the presence or absence of a
base, followed by hydrolyzing the reaction mixture using an acid to give the dioxo
compound of formula (4).
The inert solvent used in the step la is, for example, an aliphatic hydrocarbon such as
pentane, hexane, or heptane; an aromatic hydrocarbon such as benzene, toluene, or
xylene; a halogenated hydrocarbon such as dichloromethane, chloroform, carbon
tetrachloride, or dichloroethane; an ether such as diethyl ether, diisopropyl ether,
tetrahydrofuran, or dioxane; an alcohol such as methanol, ethanol, propanol,
isopropanol, butanol, s-butanol, isobutanol, or t-butanol; an aprotic polar solvent such
as N,N-dimethylformamide, N,N-dimethylacetamide, or dimethyl sulfoxide; a nitrile
such as acetonitrile, or an ester such as methyl acetate, or ethyl acetate. The
preferred solvent is an aprotic polar solvent or a nitrile and the more preferred one is
N,N-dimethylacetamide or acetonitrile.
The base used in step la is an organic amine such as pyridine, picoline, 4-(N,N-
dimethylamino)pyridine, triethylamine, tributylamine, diisopropylethylamine, or N-
methylpiperidine, and it is preferably triethylamine, tributylamine, or
diisopropylethylamine.
The reaction temperature is between -30°C and 200°C (preferably between 0°C and

100°C). The reaction time depends on the reaction temperature and the like and is
usually from 30 minutes to 30 hours (preferably from 1 hour to 20 hours).
After the reaction of a phenacyl halide compound of the formula (2) with an enamine
compound of the formula (3), a dioxo compound of the formula (4) is produced by
the addition of an acid to the reaction mixture. Hie acid used in the step la is an
inorganic acid such as hydrogen chloride, hydrobromic acid, sulfuric acid, perchloric
acid, or phosphoric acid; or an oi^ganic acid such as acetic acid, formic acid, oxalic
acid, methanesulfonic acid, para-toluenesulfonic acid, trifluoroacetic acid, or
trifluoromethanesulfonic acid, and it is preferably sulfuric acid, hydrogen chloride, or
para-toiuenesulfonic acid.
After the reaction the desired product in the step la is isolated from the reaction
mixture according to a conventional procedure.
For example, the desired product is precipitated by cooling the reaction mixture, or
the reaction mixture is appropriately neutralized, and when there are insoluble
materials in the reaction mixture, the materials are removed by filtration of the
reaction mixture; water is added to the reaction mixture; the mixture is extracted with
an organic solvent immiscible with water such as toluene; the extract is washed with
water, dried over anhydrous magnesium sulfate or the like and the solvent is removed
by distillation to give the desired product. The product thus obtained, if necessary,
can be further purified by a conventional procedure, for example, silica gel column
chromatography.
The dioxo compound of the formula (4) obtained in the step la may be used in the
next step (step 1 b) without purification.
The step lb is a process for the production of a compound of formula (1) which
process comprises reacting a dioxo compound of formula (4) with a glycol compound
of formula (3) in an inert solvent (which has the same meaning as that indicated in the
step la) in the presence of an acid (which has the same meaning as that indicated in
the step la) to give the compound of formula (1),
The reaction temperature is usually between -70°C and IOO°C, preferably between -
30°C and 60°C. The reaction time is usually from 10 minutes to 20 hours,
preferably from 30 minutes to 2 hours.
After the reaction the desired product in the step lb is isolated from the reaction

mixture according to a conventional procedure. For example, the desired product is
precipitated by cooling the reaction mixture, or the reaction mixture is appropriately
neutralized, and when there are insoluble materials in the reaction mixture the
materials are removed by filtration of the reaction mixture; water is added to the
reaction mixture; the mixture is extracted with an organic solvent immiscible with
water such as toluene; the extract is washed with water, dried over anhydrous
magnesium sulfate or the like and the solvent is removed by distillation to give the
desired product.
The product thus obtained, if necessary, can be further purified by a conventional
procedure, for example, silica gel column chromatography.
The starting materials of the present invention of the compounds of formulae (2), (3)
and (5) are known and the compounds of formulae (2) and (3) are, for example,
disclosed in the U.S. Patent number 5908858.
A 4-methyl-l,2-diarylpyrroIe derivative of the formula (7) can be prepared by
carrying out the following reaction using a compound of formula (1) obtained by the
procedure indicated above,

(wherein Ar and W have the same meanings as those indicated above, and Y
represents a methyl or amino group).
The step 2 is a process for the production of a 1,2-diarylpyrrole compound of formula
(7) which process comprises ring-closing of a compound of formula (1) with an
aniline compound of formula (6) by means of a coupling reaction with dehydration in
an inert solvent in the presence or absence of an acid to give a compound of formula
(7).
The solvent used in the step 2 is not particularly restricted provided that it has no

adverse effect on the reaction and can dissolve the starting material to some extent,
for example, it is an aliphatic hydrocarbon such as hexane, heptane or petroleum
ether; an aromatic hydrocarbon such as benzene, toluene, or xylene; a halogenated
hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, or
dichloroethane; an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, or
dioxane; an alcohol such as methanol, ethanol, propanol, isopropanol, or butanol; a
nitrile such as acetonitrile, an organic acid such as formic acid, acetic acid, or
propionic acid; or water or a mixture of these plural solvents. The preferred solvent
is a mixture of an alcohol and water and the more preferred one is a mixture of
propanol and water.
The acid used in step 2 is an inorganic acid such as hydrochloric acid or sulfuric acid;
or an organic acid such as acetic acid, trifluoroacetic acid, methanesulfonic acid,
para-toluenesuifonic acid, or trifluoromethanesulfonic acid, preferably an organic
acid, more preferably acetic acid or para-toluenesulfonic acid, and most preferably
para-toluenesulfonic acid. The amount of the acid used in step 2 is between 0.01 and
50 equivalents, preferably between 0.05 and 20 equivalents, and more preferably
between 0.1 and 10 equivalents.
The amount of the aniline compound of formula (6) is between 1 and 10 equivalents
for one equivalent of the compound of formula (1) and preferably between 1 and 3
equivalents.
The reaction temperature depends on the solvent used in the step 2. It is usually
between 0°C and 200°C and preferably between room temperature and 150°C. The
reaction time depends on the reaction temperature or the like and is usually from 10
minutes to 48 hours and preferably from 30 minutes to 15 hours.
In addition, the reaction of step 2 may be carried out with removal of water formed
during the reaction; however, usually it can be conducted without removal of the
water.
After the reaction of the step 2, the desired product is isolated from the reaction
mixture according to a conventional procedure. For example, the reaction mixture is
appropriately neutralized, and when there are insoluble materials in the reaction
mixture the materials are removed by filtration of the reaction mixture; water is added
to the reaction mixture and the mixture is extracted with an organic solvent
immiscible with water such as ethyl acetate; the extract is washed with water, dried

over anhydrous magnesium sulfate or the like and the solvent is removed by
distillation to give the desired product. The product thus obtained, if necessary, can
be further purified by a conventional procedure, for example, recrystallization,
reprecipitation, or silica gel column chromatography.
According to the process of the present invention a y-ketoacetal compound can be
obtained through a simple procedure and in high yield as a high-purity product
without using nitromethane.
[The best mode for carrying out the invention]
The present invention is exemplified by some examples shown below. However, it
can not be restricted by these examples.
Example
Example 1
3-(5,5-Dimethyl-1,3-dioxan-2-yl)-1 -(4-ethoxyphenyl)butan-1 -one
2-Bromo-I-(4-ethoxyphenyl)ethan-2-one (5.0 kg) and N,N-bis(2-methylpropyl)-l-
propenylamine (5.1 kg) were added to 20 liters of acetonitrile under an atmosphere of
nitrogen and the mixture was stirred at around 50°C for 1.5 hours. To the reaction
mixture were added successively 20 liters of water, 5.0 kg of concentrated sulfuric
acid, 3.2 kg of neopenty! glycol, and 0.5 kg of para-toluenesulfonic acid and the
mixture was stirred at around 50°C for 1.5 hours. After cooling the reaction mixture
to the room temperature, crystals precipitated. These crystals were isolated by
filtration to give 4.3 kg (yield 71%) of the title compound as white crystals.
'H-NMR spectrum (400 MHz, CDCl3)6 ppm: 0.71 (s, 3H), 1.03 (d, J=6.8Hz, 3H),
1.18 (s, 3H), 1.44 (t, J=7.0Hz, 3H), 2.42-2.52 (m, 1H), 2.78 (dd, J=16.6Hz, J=8.5Hz,
1H), 3.25 (dd, J=I6.6Hz, J=4.6Hz, 1H), 3.41 (dd, J=11.0Hz, J=3.7Hz, 2H), 3.57-3.63
(m, 2H), 4.10 (q, J=7.0Hz, 2H), 4.38 (d, J=3.7Hz, 1H), 6.91 (d, J=8.7Hz, 2H), 7.96 (d,
J=8.7Hz, 2H).
Example 2
3-(5,5-Dimethyl-1,3-dioxan-2-y I)-1 -(4-ethoxyphenyl)butan-1 -one
2-Bromo-l-(4-ethoxyphenyl)ethan-l-one (4.0 g) and N,N-bis(2-methylpropyl)-l-
propenylamine (4.0 g) were added to 16 ml of dimethylacetamide under an

atmosphere of nitrogen and the mixture was stirred between 50°C and 55°C for 2
hours. To the reaction mixture were added successively 1.6 g of para-
toluenesulfonic acid and 2.1 g of neopentyl glycol and the mixture was stirred
between 50°C and 60°C for 3 hours. After addition of 8 ml of water to the reaction
mixture and cooling the reaction mixture to the room temperature, crystals
precipitated. These crystals were isolated by filtration to give 3.7 g (yield 74%) of
the title compound as white crystals. The 'H-NMR spectrum of the product is
substantially identical with that of the product of Example 1.
Example 3
3-(5,5-Dimethyl-1,3-dioxan-2-yl)-1 -(4-ethoxyphenyl)butan-1 -one
2-Bromo-l-(4-ethoxyphenyl)ethan-l-one (4.0 g) and N,N-bis(2-methylpropyl)-l-
propenylamine (4.0 g) were added to 16 ml of dimethylformamide under an
atmosphere of nitrogen and the mixture was stirred between 50°C and 55°C for 2
hours. To the reaction mixture were added successively 1.6 g of para-
toluenesulfonic acid and 2.1 g of neopentyl glycol and the mixture was stirred
between 50°C and 60°C for 3 hours. After addition of 8 ml of water to the reaction
mixture and cooling the reaction mixture to the room temperature, crystals
precipitated. These crystals were isolated by filtration to give 3.7 g (yield 72%) of
the title compound as white crystals. The 'H-NMR spectrum of the product is
substantially identical with that of the product of Example 1.
Example 4
3-(5,5-Dimethyl-1,3-dioxan-2-yl)-1 -(3,4-dimethylphenyl)butan-1 -one
2-Bromo-l-(3,4-dimethylphenyl)ethan-l-one (220 g) and N,N-bis(2-methylpropyl)-l-
propenylamine (249 g) were added to 990 ml of dimethylformamide under an
atmosphere of nitrogen and the mixture was stirred at around 50°C for 2 hours.
After cooling the reaction mixture to I0°C, 990 ml of water, 170 g of neopentyl
glycol and 173 g of concentrated sulfuric acid were added successively to the reaction
mixture and the mixture was stirred at around 60°C for 2 hours. After cooling the
reaction mixture to the room temperature, crystals precipitated. These crystals were
isolated by filtration to give 262 g (yield 83%) of the title compound as white crystals.

1H-NMR spectrum (400 MHz, CDCl3)d ppm: 0.71 (s, 3H), 1.03 (d, J=6.8Hz, 3H),
1.18 (s, 3H), 2.31 (s,6H), 2.43-2.53 (m, 1H), 2.81 (dd, J=16.8Hz, J=8.5Hz, 1H), 3.26
(dd, J=16.7Hz, J=4.8Hz, 1H), 3.41 (dd, J=ll.lHz, J=4.3Hz, 2H), 3.58-3.63 (m, 2H),
4.39 (d, J=3.4Hz, 1H), 7.20 (d, J=7.6Hz, 1H), 7.72 (d, J=7.6Hz, 1H), 7.76 (s, 1H).
Example 5
3-(5,5-Dimethy!-1,3-dioxan-2-yl)-1 -(3,4-dimethylphenyi)butan-1 -one
2-Bromo-l-(3,4-dimethylphenyl)ethan-l-cme (6.2 g) and N,N-bis(2-methylpropyl)-l-
propenylamine (6.8 g) were added to 25 ml of acetonitrile under an atmosphere of
nitrogen and the mixture was stirred at around 50°C for 4 hours. After cooling the
reaction mixture to 10°C, 25 ml of water, 4.3 g of neopentyl glycol, 6.2 g of
concentrated sulfuric acid and 0.62 g of para-toluenesulfonic acid were added to the
reaction mixture and the mixture was stirred at around 60°C for 1 hour. After
cooling the reaction mixture to the room temperature, crystals precipitated. These
crystals were isolated by filtration to give 6.6 g (yield 84%) of the title compound as
white crystals.
The 'H-NMR spectrum of the product is substantially identical with that of the
product of Example 4.
[The possibility for utilization to industry]
According to the process of the present invention a y-k^toacetal compound can be
obtained through a simple procedure and in high yield as a high-purity product
without using nitromethane.
We Claim:
1. A process for the production of a compound of a formula (1) which
process comprises
(a) reacting a compound of a formula (2)
wherein Ar represents an unsubstituted C6-C10 aryl group or a C6-
C10 aryl group substituted with at least one substituent
independently selected from Substituent group a;
Substituent group a is selected from the group consisting of a
halogen atom, an unsubstituted C1-C6 alkyl group, a halogenated
C1-C6 alkyl group, a hydroxy 1 group, a C1-C6 alkoxy group, a C1-
C6 alkylthio group, a mercapto group, a C1-C6 alkylsulfonyl group
and a sulfamoyl group; and X represents a halogen atom,
with a compound of a formula (3)
wherein Ra and Rb are the same or different and each represents
independently an unsubstituted C1-C6 alkyl group; a C1-C6 aikyl
group substituted with at least one C1-C6 alkoxy group; or a C3-C6
cycloalkyl group; or Ra and Rb taken together represents a C4-C8
alkylene group,
in an inert solvent and hydrolyzing the resultant reaction product
with an acid to afford a compound of a formula (4)
wherein Ar has the same meaning as that indicated above; and
(b) reacting the compound of the formula (4) with a compound of a
formula (5)
HO-W-OH (5)
wherein W represents a C1-C6 alkylene group,
in the presence of an acid to afford the compound of the formula (1)
wherein Ar and W have the same meanings as those indicated above.
2. The process as claimed in claim 1, wherein Ar is an unsubstituted
phenyl group or a phenyl group substituted with at least one
substituent independently selected from substituent group a.
3. The process as claimed in claim 1, wherein Ar is an unsubstituted
phenyl group or a phenyl group substituted with at least one
substituent independently selected from the group consisting of a
methyl group, a methoxy group, an ethoxy group and a methylthio
group.
4. The process as claimed in claim 1, wherein Ar is a 4-methylphenyl
group, a 3-methylphenyl group, a 4-methoxyphenyl group, a 4-
ethoxyphenyl group, a 4-methylthiophenyl group, a 3,4-
dimethylphenyl group or 3,4-dimethoxyphenyl group.
5. The process as claimed in any one of claims 1 to 4, wherein X is a
bromine atom or an iodine atom.
6. The process as claimed in any one of claims 1 to 4, wherein X is a
bromine atom.
7. The process as claimed in claim 1, wherein R^ and Rb' are the same
or different and each represents independently an unsubstituted C2-
C5 alkyl group; a C2-C5 alkyl group substituted with at least one
C1-C4 alkoxy group; or a C4-C6 cycloalkyl group.
8. The process as claimed in claim 1, wherein Ra and Rb are the same
or different and each represents independently an isopropyl group,
an isobutyl group, an isopentyl group, a 2-methoxyethyl group, a
3-methoxypropyl group, a 2-ethoxyethyl group, a cyclopentyl
group, or a cyclohexyl group.
9. The process as claimed in claim 1, wherein R' and Rb' are both an
isobutyl group.
10. The process as claimed in claim 1, wherein W is a straight or
branched chain C3-C5 alkylene group.
11. The process as claimed in claim 1, wherein W is a straight chain
C3-C5 alkylene group.
12. The process as claimed in claim 1, wherein W is a 2-
methyltrimethylene group or 2,2-dimethyltrimethylene group.
13. The process as claimed in claim 1, wherein Ar is 4-ethoxyphenyl.
14. A process for the production of a compound of a formula (7)
wherein Ar represents an unsubstituted C6-C10 aryl group or a C6-
C10 aryl group substituted with at least one substituent
independently selected from substituent group a;
substituent group a is selected from the group consisting of a
halogen atom, a C1-C6 alkyl group, a halogenated C1-C6 alkyl
group, a hydroxy 1 group, a C1-C6 alkoxy group, a C1-C6 alkylthio
group, a mercapto group, a C1-C6 alkylsulfonyl group and-a

sulfamoyl group; and Y represents a methyl group or an amino
group,
which comprises:
(a) reacting a compound of a formula (2)

wherein Ar represents an unsubstituted C6-C10 aryl group or a C6-
C10 aryl group substituted with at least one substituent
independently selected from substituent group a;
Substituent group a is selected from the group consisting of a
halogen atom, a C1-C6 alkyl group, a halogenated C1-C6 alkyl
group, a hydroxyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio
group, a mercapto group, a C1-C6 alkylsulfonyl group and a
sulfamoyl group; and X represents a halogen atom,
with a compound of a formula (3)
wherein Ra and Rb are the same or different and each represents
independently an unsubstituted C1-C6 alkyl group; a C1-C6 alkyl
group substituted with at least one C1-C6 alkoxy group; or a C3-C6
cycloalkyl group; or Ra and Rb taken together represent a C4-C8
alkylene group,
in an inert solvent; hydrolyzing the resultant product with an acid
to afford a compound of a formula (4)

wherein Ar has the same meaning as that indicated above; and
(b) reacting the compound of the formula (4) with a compound of a
formula (5)
HO-W-OH (5)
wherein W represents a C1-C6 alkylene group, in the presence of an
acid to afford a compound of formula (1)
wherein Ar and W have the same meanings as those indicated
above; and
(c) reacting the compound of the formula (1) with a compound of a
formula (6)
wherein Y is a methyl group or an amino group to afford the
compound of the formula (7).
15. The process as claimed in claim 14, wherein Y is an amino group.


The present invention provides a process for the production of a ?-ketoacetal
compound wherein the desired product can be obtained through a simple procedure in
high yield as a high purity product.
[Means to solve the subject]
The present invention is a process in which the reaction scheme is shown below:
(wherein Ar is an aryl group; X is a halogen atom; Ra and Rb are alkyl groups or the
like; W is an alkylene group).

Documents:

00420-kolnp-2005-abstract.pdf

00420-kolnp-2005-claims.pdf

00420-kolnp-2005-correspondence.pdf

00420-kolnp-2005-correspondence_1.1.pdf

00420-kolnp-2005-correspondence_1.2.pdf

00420-kolnp-2005-correspondence_1.3.pdf

00420-kolnp-2005-description(complete).pdf

00420-kolnp-2005-form-1.pdf

00420-kolnp-2005-form-18.pdf

00420-kolnp-2005-form-2.pdf

00420-kolnp-2005-form-3.pdf

00420-kolnp-2005-form-5.pdf

00420-kolnp-2005-g.p.a.pdf

00420-kolnp-2005-international publication.pdf

00420-kolnp-2005-international search authority report.pdf

00420-kolnp-2005-priority document other.pdf

00420-kolnp-2005-priority document.pdf

420-KOLNP-2005-FORM-27.pdf

420-kolnp-2005-granted-abstract.pdf

420-kolnp-2005-granted-claims.pdf

420-kolnp-2005-granted-correspondence.pdf

420-kolnp-2005-granted-description (complete).pdf

420-kolnp-2005-granted-examination report.pdf

420-kolnp-2005-granted-form 1.pdf

420-kolnp-2005-granted-form 18.pdf

420-kolnp-2005-granted-form 2.pdf

420-kolnp-2005-granted-form 3.pdf

420-kolnp-2005-granted-form 5.pdf

420-kolnp-2005-granted-pa.pdf

420-kolnp-2005-granted-reply to examination report.pdf

420-kolnp-2005-granted-specification.pdf

420-kolnp-2005-granted-translated copy of priority document.pdf


Patent Number 239171
Indian Patent Application Number 420/KOLNP/2005
PG Journal Number 11/2010
Publication Date 12-Mar-2010
Grant Date 09-Mar-2010
Date of Filing 15-Mar-2005
Name of Patentee SANKYO COMPANY, LIMITED
Applicant Address 5-1, NIHONBASHI HONCHO 3-CHOME, CHUO-KU, TOKYO
Inventors:
# Inventor's Name Inventor's Address
1 REI OKAZAKI C/O. SANKYO COMPANY, LIMITED, 12-1 CHINOMIYA 1-CHOME, HIRATSUKA-SHI, KANA GAWA 254-0014
2 SHUNSHI KOJIMA C/O SANKYO COMPANY, LIMITED, 12-1 CHINOMIYA 1-CHOME, HIRATSUKA-SHI, KANA GAWA 254-0014
PCT International Classification Number C07D 319/06
PCT International Application Number PCT/JP2003/010471
PCT International Filing date 2003-08-19
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2003-131270 2003-05-09 Japan
2 2002-238786 2002-08-20 Japan