TECHNICAL FIELD
[0001]
The present invention relates to a method for producing a 3-hydroxypropan-l-
10 one compound, a 2-propen-l-one compound and an isoxazoline compound which are
useful for functional materials such as medical drugs, agricultural chemicals or
electronic materials or production intermediates thereof.
BACKGROUND ART
[0002]
Methods for producing an isoxazoline compound from a l,3-bis(substituted
phenyl)-3-substituted-2-propen-l-one compound and hydroxylamine as raw materials
have been known in, for example, Non-patent Documents 1 to 6.
20 [0003]
Several methods for producing a l,3-bis(substituted phenyl)-3-substituted-3-
hydroxypropan-1-one compound from an aromatic ketone compound and a
substituted acetophenone compound as starting raw materials have been known (for
example, Patent Document 1 and Non-patent Documents 7 to 15).
25 [0004]
Moreover, methods for producing a l,3-bis(substituted phenyl)-3-substituted-
2-propen-l-one compound from a l,3-bis(substitutedphenyl)-3-substituted-3-
hydroxypropan-1-one compound as a raw material have been known in, for example,
Non-patent Documents 10 and 11.
30 [0005]
Furthermore, methods for producing a l,3-bis(substituted phenyl)-3-
substituted-2-propen-l-one compound from an aromatic ketone compound and a
2
substituted acetophenone compound as starting raw materials in one step have been
known in, for example, Non-patent Documents 18 to 20.
[0006]
[Patent Document 1]
5 WO 2007/074789 pamphlet
[Non-patent Document 1]
Farmaco, Edizione Scientifica(1971)J 591-596
[Non-patent Document 2]
Zeitschrift fuer Naturforschung, Teil B: Anorganische Chemie, Organische
10 Chemie (1977), 443-446
[Non-patent Document 3]
Bulletin des Societes Chimiques Beiges (1987), 293-302
[Non-patent Document 4]
Journal of Heterocyclic Chemistry (1998), 989-990
15 [Non-patent Document 5]
Synthetic Communication (1999), 3237-3250
[Non-patent Document 6]
Archives of Pharmacal Research (2004), 885-892
[Non-patent Document 7]
20 Zhumal Organicheskoi Khimii, vol. 26, No. 10, 2205-2208 (1990)
[Non-patent Document 8]
Journal of Fluorine Chemistry, vol. 113, 105-109 (2002)
[Non-patent Document 9]
Organic Letters vol. 7, No. 22, 5103-5105 (2005)
25 [Non-patent Document 10]
Journal of Organic Chemistry, vol, 71, 3822-3828 (2006)
[Non-patent Document 11]
Chinese Journal of Chemistry, vol. 23, 584-588 (2005)
[Non-patent Document 12]
30 Synthesis, No. 17, 2901-2905 (2005)
[Non-patent Document 13]
Tetrahedron Letters, vol. 38, 8727-8730 (1997)
[Non-patent Document 14]
Tetrahedron, vol. 58, 8263-8268 (2002)
3
[Non-patent Document 15]
Organic Process Research and Development, vol. 8, 18-21 (2004)
[Non-patent Document 16]
Tetrahedron, Vol. 58, No. 39, 7775-7780 (2002)
5 [Non-patent Document 17]
Tetrahedron Letters, vol. 46, 8913-8915 (2005)
[Non-patent Document 18]
Journal of Organic Chemistry, Vol. 71, No. 9, 3545-3555 (2006)
[Non-patent Document 19]
10 Journal of Fluorine Chemistry, Vol. 125 No. 1, 91-94 (2004)
[Non-patent Document 20]
Journal of Molecular Catalysis A: Chemical, Vol. 181, 179487 (2002)
DISCLOSURE OF THE INVENTION
15
[Problems to be Solved by the Invention]
[0007]
The reaction conditions described in Non-patent Documents 1 to 4 and 6 are
the reactions in which alcoholic solvents such as ethanol are used to react basic
20 compounds such as sodium hydroxide, potassium hydroxide, barium hydroxide and
pyridine. In recent synthetic examples, methods of reacting the basic compound in an
alcoholic solvent are common methods used for producing an isoxazoline compound
from a l,3-bis(substituted phenyI)-3-substituted-2-propen-l-one compound and
hydroxylamine as raw materials, as far as the present inventors have known.
25 However, yields are moderate in many cases of these reaction examples. In addition,
although these methods require a liquid separation operation in order to remove
overused hydroxylamine, these methods do not provide industrial satisfaction due to
the difficulty in recovery, the increase in environmental load and the increase in cost
when alcoholic solvents are used. Non-patent Document 5 describes the method of
30 using pyridine as a solvent and a base. However, this method provides low yield of
around 50%, and pyridine also has difficulty in recovery similar to alcohol.
Moreover, Non-patent Document 5 describes the reaction example in which
methylene chloride is used as a solvent. However, this reaction example has
4
limitation of equipment and the like in industrial production, because microwave
irradiation is required.
[0008]
As described above, in related art methods, there is no method of producing an
5 isoxazoline compound in low-polarity solvents as represented by toluene which are
recovered easily from a l,3-bis(substituted phenyl)-3-substituted-2-propen-l-one
compound and hydroxylamine as raw materials, so that there is room for
improvement.
[0009]
10 In the reaction condition described in Non-patent Document 7, since n-butyl
lithium which is expensive and requires careful handling is used as a base, this
reaction is not satisfactory in industrial processes. In the reaction condition described
in Non-patent Document 8, an aromatic ketone compound is required to be converted
into imine once and then is made to react. After the reaction, the imine part is
15 required to be reconverted. Therefore, this reaction leads to an increase in production
cost and waste materials, and is not satisfactory as an industrial production method.
In the reaction conditions described in Non-patent Documents 9 to 11, proline is used
as a catalyst. The yields in these descriptions are comparatively high. However,
since solvents which have difficulty in recovery or halogen-based solvents are
20 required, the reaction is not satisfactory in an industrial production method. In the
reaction conditions described in Non-patent Documents 12 and 13, the reaction leads
to an increase in production cost and waste materials because titanium tetrachloride is
used stoichiometrically, and has a problem of equipment and the like in industrial
production because the reaction requires ultra cold temperature of-78°C. In the
25 reaction conditions described in Non-patent Document 14, the reaction is conducted
in water by adding a surfactant. This reaction is required to be effected after an
aromatic ketone compound is converted into a silyl ether. This leads to an increase in
production cost and waste materials, and the reaction is not satisfactory as an
industrial production method. In the reaction conditions described in Non-patent
30 Document 15, the reaction is also conducted in water. However, the amount of water
to be used is very large, and this reaction is not satisfactory for industrial production
in volume efficiency.
[0010]
5
In the reaction conditions described in Non-patent Document 16, a
dehydration agent and a base are used in a solvent amount. In the reaction conditions
described in Non-patent Document 17, solvents are used in some cases, but the
solvents used are halogen-based organic solvents. These reactions are not satisfactory
5 in industry, because the reactions described in both documents have large
environmental loads and increased costs.
[0011]
In the reaction conditions described in Non-patent Document 18, one of the
starting raw materials is converted into a phosphorus ylide, and this ylide is reacted
10 with another starting raw material. Therefore, this reaction is not satisfactory in
production cost. In the reaction conditions described in Non-patent Document 19,
raw materials are reacted with each other using a transition metal catalyst. However,
this reaction is difficult to use in industry, because a tin compound which has anxiety
of toxicity is required to be used. In the reaction conditions described in Non-patent
15 Document 20, a solid catalyst which can be recovered and reused is used. However,
the reaction is not satisfactory in industry, because the conversion ratio is low.
[0012]
As described above, in related art methods, there is no method for producing a
l,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-l-one compound from an
20 aromatic ketone compound and a substituted acetophenone compound as raw
materials with water which is harmless for the environment and creatures as a solvent
without using expensive reagents and with good volume efficiency. In addition, a
method for production characterized in that a reaction is conducted in the presence of
a base in a low-polarity solvent as represented by toluene which is recovered easily
25 and the equilibrium reaction is distributed to the target product side by generating
slurry has not been known, so that there is room for improvement.
[0013]
In addition, there is no method for producing a l,3-bis(substituted phenyl)-3-
substituted-2-propen-l-one compound from a l,3-bis(substitutedphenyl)-3-
30 substituted-3-hydroxypropan-l-one compound as a raw material in a low-polarity
solvent as represented by toluene which is recovered easily by using a dehydration
agent and a base, and a method for producing a 1,3-bis(substituted phenyl)-3-
substituted-2-propen-l-one compound from an aromatic ketone compound and a
substituted acetophenone compound as starting raw materials in one step has also not
been known, so that there is room for improvement.
[Means for Solving the Problems]
[0014]
5 As a result of an intensive investigation for achieving the above-described
objects, the present inventors have discovered a method for producing a 1,3-
bis(substituted phenyl)-3-substituted-3-hydroxypropan-l-one compound from an
aromatic ketone compound and a substituted acetophenone compound as raw
materials by conducting the reaction in the presence of a base in water which is
10 harmless or in a low-polarity solvent as represented by toluene which is recovered
easily and distributing the equilibrium reaction to the target product side by
generating slurry, and have accomplished the present invention.
[0015]
In addition, the present inventors also have discovered a method for producing
15 a l,3-bis(substituted phenyl)-3-substituted-2-propen-l-one compound from a 1,3-
bis(substituted phenyl)-3-substituted-3-hydroxypropan-l-one compound as a raw
material in a low-polarity solvent as represented by toluene which is recovered easily
by using a dehydration agent and a base, and moreover a method for producing a 1,3-
bis(substituted phenyl)-3-substituted-2-propen-l-one compound from an aromatic
20 ketone compound and a substituted acetophenone compound as starting raw materials
in one step, and have accomplished the present invention.
[0016]
Furthermore, the present inventors also have discovered a method for
producing an isoxazoline compound from l,3-bis(substituted phenyl)-3-substituted-2-
25 propen-l-one compound and hydroxyiamine as raw materials in low-polarity solvents
as represented by toluene which are recovered easily, and have accomplished the
present invention.
[0017]
Namely, the present invention is:
30 [1] a method for producing an isoxazoline compound represented by Formula (1):
(1)
7
(where R1, R2, X, A1, A2, A3, A4, A5, A6 and A7 represent the same meaning as
described below), includes reacting a l,3-bis(substituted phenyl)-3-substituted-2-
propen-1-one compound represented by Formula (2):
X R1 O
A if ir A ,n-.
i* ll 13 II <2)
^A7 X ^A4 R2
5 (where R1 represents a C1-C6 haloalkyl or C3-C8 halocycloalkyl;
each of A1, A2, A3 and A4 independently represents N or C-Y;
each of A5, A6 and A7 independently represents N or C-X;
X represents a hydrogen atom, a halogen atom, cyano, nitro, -SF5, C1-C6 alkyl,
CrC6 haloalkyl, hydroxy (Ci-C6) haloalkyl, C|-C6 alkoxy (Ci-C6) haloalkyl, CrC6
10 haloalkoxy (CrC6) haloalkyl, C3-Cg halocycloalkyl, -OR3, -OS02R3 or -S(0)rR3; and
each X may be the same as or different from each other;
R3 represents a C1-C6 alkyl, C1-C4 alkoxy (C1-C4) alkyl, Ci-Cg haloalkyl or Ci-
C3 haloalkoxy (C1-C3) haloalkyl;
R2 represents a C1-C6 alkyl, a halogen atom, cyano, nitro, -NIHb, -N(R5)R4, -
15 OH, -OR3, benzyloxy, -OSO2R3, phenylsulfonyloxy, phenylsulfonyloxy substituted
by (Z)pi, -C(O)0H, -C(0)OR3, -C(0)NH2, -C(0)N(RIb)Rla, -C(S)N(Rlb)Rla, -L-Q, -
L-N(R,c)Rld, -S(0)r-L2-Q2 and a substituent selected from D-1 to D-50;
Y represents a hydrogen atom, a halogen atom, cyano, nitro, C1-C4 alkyl, QC4
haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Ci-C6 alkylthio, Ci-C6 halo alky lthio,
20 CrC6 alkyisulfonyl, CrC6 haloalkylsulfonyl, -NH2, or -N(R5)R4
5 and each Y may be
the same as or different from each other;
two adjacent Ys may form A8=A9-A10=A1! together;
each of A8, A9, A10 and A1' independently represents N or C-Yl;
Y1 represents a hydrogen atom, a halogen atom, cyano, nitro, C1-C4 alkyl, Ci-
25 C4 haloalkyl, C1-C4 alkoxy, d-C4 haloalkoxy, d-C6 alkylthio, CrC6 haloalkylthio,
CrC6 alkyisulfonyl, Ci-C6 haloalkylsulfonyl, -NH2, or -N(R5)R4, and each Y1 may be
the same as or different from each other;
R4 represents a Ci-C6 alkyl, -CHO, CrC6 alkylcarbonyl, C]-C6
halo alkyl carbonyl, C1-C6 alkoxycarbonyl, Cj-C6 alkylthiocarbonyl, C1-C6
30 alkoxythiocarbonyl, CrC6 alkyldithiocarbonyl, Ci-C6 alkyisulfonyl or C,-C6
haloalkylsulfonyl;
R5 represents a hydrogen atom or Ci-C6 alkyl;
8
RIa represents a Ct-C6 alkyl, Ci-Ce alkyl optionally substituted by R8, C3-C6
cycloalkyl which may be ring-condensed by benzene ring, C3-Q alkenyl, C3-C6
haloalkenyl, C3-C6 alkynyl, -N(Rn)R10, -C(0)OR9, -C(0)NH2, -C(0)NHR9, -
C(R7)=NOR6, phenyl, phenyl substituted by (Z)pU D-5, D-7, D-10, D-ll, D-12, D-14,
5 D-15, D-18, D-31, D-32, D-42, D-43, D-45, D-46, D-48, E-l, E-2, E-3, E-4 or E-7;
RIb represents a hydrogen atom, C1-C6 alkyl, Q-C4 alkoxy (C1-C4) alkyl,
cyano (CrC6) alkyl, C3-C6 alkynyl, -C(0)R9 or -C(O)0R9,
or represents that Rlb may form a 3-7 membered ring with a nitrogen atom to
be bonded, by forming a C2-C6 alkylene chain together with RLa, and this alkylene
10 chain may contain one oxygen atom, sulfur atom or nitrogen atom in this case;
L represents -C(R2a)(R2b>, -C(R2a)(R2b)CH2-, -CH2C(R2a)(R2b)- or -N(R2c)-;
Q represents a hydrogen atom, a halogen atom, cyano or nitro;
Rlc represents a hydrogen atom, -C(0)R3a, -C(0)OR3a, -C(0)SR3a, -
C(0)N(R3b)R3a, -C(S)N(R3b)R3a or -S(0)2R3a;
15 RId represents a hydrogen atom, Ci-Cg alkyl, Q-Ce haloalkyl, C1-C4 alkoxy
(C1-C4) alkyl, C1-C4 haloalkoxy (CrC4) alkyl, C1-C4 alkylthio ( O Q ) alkyl, C1-C4
alkylsulfonyl (C1-C4) alkyl, cyano (Ci-Ce) alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl
(C1-C4) alkyl, C3-C6 alkenyl, C3-C6 alkynyl, -C(0)R3c, -C(0)OR3c, -C(0)SR3c, Q-Q;
haloalkylthio or Ci-Ce alkylsulfonyl,
20 or represents that Rlc may form a 5-7 membered ring with a nitrogen atom to
be bonded, by forming a C4-C6 alkylene chain together with R , and this alkylene
chain may contain one oxygen atom, sulfur atom or nitrogen atom in this case and
may be optionally substituted by a Ci-Ce alkyl group, -CHO group, CpCe
alkylcarbonyl group, Ct-Ce haloalkylcarbonyl group, Ci-Ce alkoxycarbonyl group,
25 Ci-Ce halo alkoxycarbonyl group, Cj-Ce alkylaminocarbonyl group, Ci-Cg
haloalkyl amino carbonyl group, oxo group or thioxo group;
R2a represents a hydrogen atom, cyano, Q-Ce alkyl, C^Ce haloalkyl, Ci-Cg
alkoxycarbonyl, -C(0)NH2 or -C(S)NH2;
R represents a hydrogen atom or Ci-Ce alkyl, or represents that R may
30 form a 3-6 membered ring with a carbon atom to be bonded, by forming a C2-C5
alkylene chain together with R2a, and this alkylene chain may contain one to three
oxygen atom(s), sulfur atom(s) or nitrogen atom(s) in this case;
R2c represents a hydrogen atom, Ci-Ce alkyl, Ci-Ce haloalkyl, Cj-Ce
alkylcarbonyl, Ci-C6 haloalkylcarbonyl or C1-C6 alkoxycarbonyl;
9
R3a represents a Ci-Ce alkyl, Ci-Ce haloalkyl, (C1-C4) alkyl optionally
substituted by R4a, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, E-l, E~2, E-4, C2-C6
alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, phenyl, phenyl substituted by (V)pi, D-3,
D-4, D-12 to D-14, D-42 or D-43;
5 R3b represents a hydrogen atom or Ci-Ce alkyl;
R3c represents a hydrogen atom, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6
cycloalkyl (C1-C4) alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl or C3-C6 alkynyl, or
represents that R3c may form a 5-7 membered ring with a nitrogen atom, carbon atom,
oxygen atom or sulfur atom to be bonded, by forming an ethylene chain or benzene
10 ring bonded at an ortho-position together with R3a;
R a represents a halogen atom, cyano, nitro, C3-C6 cycloalkyl, C1-C4 alkoxy,
Ci-C6 alkoxycarbonyl, S(0)rR5a, D-42 or D-43;
R5a represents a CVC4 alkyl;
V represents a halogen atom, cyano, nitro, Ci-Ce alkyl, CpCe haloalkyl, -OH,
15 Ci-Ce alkoxy, CpCe haloalkoxy, Ci-Ce alkylsulfonyloxy, Ci-Ce halo alkyl sulfonyloxy,
Ci-C6 alkylthio, Ci-C6 halo alkylthio, CrC6 alkylsulfmyl, Cj-Ce haloalkylsulfmyl, Ct-
Q alkylsulfonyl, Ci-C6 haloalkylsulfonyl, -NH2, Ci-C6 alkylamino, di(Ci-C6 alkyl)
amino, Ci-Ce alkoxycarbonyl, -C(0)NH2, Ci-Ce alkylaminocarbonyl, CpCe
haloalkylaminocarbonyl, di(Ci-C6 alkyl) aminocarbonyl, -C(S)NH2, -S(0)2NH2, Q-
20 C6 alkylaminosulfonyl or di(Ci-C6 alkyl) aminosulfonyl, and each V may be the same
as or different from each other when p 1 represents an integer of 2 or more;
moreover, when two Vs are adjacent, the two adjacent Vs may form a 5-
membered ring or a 6-membered ring with carbon atoms bonding to each of the two
Vs by forming -OCH20- or -OCH2CH20-, and hydrogen atoms bonding to each
25 carbon atom forming the ring may be optionally substituted by halogen atoms in this
case;
R6 represents a Ci-Ce alkyl or C1-C6 haloalkyl;
R7 represents a hydrogen atom or Ci-C6 alkyl;
R8 represents a halogen atom, cyano, amino, C3-C6 cycloalkyl, C3-C6
30 halocycloalkyl, Ci-C6 alkoxy, CrC6 haloalkoxy, CrC6 alkylthio, CrC6 haloalkylthio,
Ci-C6 alkylsulfmyl, Ci-C6 haloalkylsulfinyl, CrC6 alkylsulfonyl, CrC6
haloalkylsulfonyl, -C(0)R14, -C(0)OR14, -C(0)NH2, -C(0)N(R15)R14, -C(S)NH2, -
C(S)N(R15)RM, -C(R7)=NOH, -C(R7)=NOR6, phenyl, phenyl substituted by (Z)pi, D-l
to D-50 or E-l to E-8;
D-1 to D-50 represent aromatic heterocyclic rings represented by the
following structural formulae:
(Z)p3 (fV (Z)P4
D-1 D-2 D-3 D-5
P< (Z)p4 (Z)p4 p3
D-21
R 12 • 12
N-N' (Z)p4 /j—N' J—N !*-* ^ M -v** (Z*)p
(Z)p4
D-12
( Z ) P . Jb
D-17
R12
N
IS-22
D-13
D-18
R"
D-23
(Z)p4
D-14
flfci
-4?
D-19
R12
N - ^ / ( Z ) p <
D-24
D-15
P*
D-42 D-43 D-44 D-45 D-46
Z represents a halogen atom, cyano, nitro, amino, C1-C6 alkyl, (Ci-Cg) alkyl
optionally substituted by R16, C1-C6 haloalkyl, Q-Ct alkoxy, C1-C6 haloalkoxy, C1-C6
alkylthio, C1-C6 haloalkylthio, Ci-C6 alkylsulfinyl, Cj-C6 haloalkylsulfmyl, Ci-Ce
5 alkylsulfonyl, CrC6 haloalkylsulfonyl, C,-C6 alkoxycarbonyl, -C(0)NH2, -C(S)NH2,
-S(0)2NH2, -C(0)N(R18)R17, -C(S)N(RI8)R17
5 Ci-C6 alkylaminosulfonyl or di(CrC6
alkyl) aminosulfonyl, and each Z may be the same as or different from each other
when pi, p2, p3 or p4 represents an integer of 2 or more;
E-l to E-8 represent saturated heterocycles represented by the following
10 structural formulae:
12
(0)r
(RI5)q3 (R13)q3 (R%
E-l E-2 E-3 E-4
0 43 X7) A7J
E-5 E-6 E-7 E-8
R9 represents a Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkoxy (CrC4) alkyl, Cr
C6 alkylthio (C]-C4) alkyl, C3-C8 cycioalkyl, C3-C6 alkenyl or C3-C6 alkynyl;
R10 represents a Ci-C6 haloalkyl, -C(0)R14, -C(0)OR14, phenyl, phenyl
substituted by (Z)pi, D-3, D-4, D-18, D-42, D-45, D-46, D-48 or D-49;
R11 represents a hydrogen atom, Ci-Cg alkyl or C3-C6 alkynyl;
R12 represents a C1-C6 alkyl, phenyl or phenyl substituted by (Z)pS;
I T IT
R represents a C1-C4 alkyl, and each R may be the same as or different
from each other when q 1, q2, q3 or q4 represents an integer of 2 or more, and
moreover represents that two Rl3s may form oxo together when the two R13s are
bonded to the same carbon atom;
R14 represents a Ci-C6 alkyl, Ci-C6 haloalkyl, C3-C6 cycioalkyl (C1-C4) alkyl,
C3-C6 cycioalkyl, C3-Ce alkenyl or C3-Ce alkynyl;
R15 represents a hydrogen atom or C1-C6 alkyl;
R16 represents a -OH, C1-C4 alkoxy or C1-C4 alkylthio;
R17 represents a hydrogen atom, C\-Cs alkyl, C3-C6 cycioalkyl, C3-C6 alkenyl,
C3-C6 haloalkenyl, C3-C6 alkynyl, -C(R5)=NOR19, -C(0)OR19, -C(0)NH2, -
C(0)N(R5)R19
5 -C(0)NHC(0)R19, -C(0)N(R5)C(0)OR19, -N(R2I)R2°, phenyl
substituted by (Z)pU D9 to Dll, D18 to D20, D42 to D47 or D48;
R18 represents a hydrogen atom, C,-C6 alkyl, C3-C6 alkynyl, -C(0)R19a
5 -
C(0)OR19a or Ci-C6 haloalkylthio;
R19 represents a Ci-Ce alkyl, Ci-Ce haloalkyl or C2-C6 alkenyl;
R19a represents a Ci-C6 alkyl, CrC6 haloalkyl, C1-C4 alkoxy (Ct-C4) alkyl, Ci-
C4 alkylthio (C1-C4) alkyl, C1-C4 alkylsulfinyl (CrC4) alkyl, CrC4 alkylsulfonyl (Cx-
C4) alkyl, C3-C6 cycioalkyl, C2-C6 alkenyl, Q -Q alkoxycarbonyl, phenyl, phenyl
substituted by (Z)p!, D42, D43 or D44;
13
R,22 0r epresents a Ci-Cg haloalkyl, C1-C6 alkoxy car bony 1, phenyl, phenyl
substituted by (Z)pl, D42 to D46 or D47;
R21 represents a hydrogen atom, C1-C6 alkyl, C3-C6 alkenyl or C3-C6 alkynyl;
L represents a single bond or C1-C6 alkylene chain;
5 Q2 represents a hydrogen atom, C1-C6 haloalkyl, C2-C6 alkynyl, -NCR^R22, -
C(0)N(R23)R22
J phenyl, phenyl substituted by (Z)p], D18 to D20, D42 to D46 or D47;
R22 represents a Ci-C6 alkyl, Ci-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 alkenyl,
C3-C6 alkynyl, phenyl or phenyl substituted by (Z)pi;
R represents a hydrogen atom or C1-C6 alkyl;
10 pi represents an integer of 1 to 5;
p2 represents an integer of 0 to 4;
p3 represents an integer of 0 to 3;
p4 represents an integer of 0 to 2;
p5 represents an integer of 0 or 1;
15 q2 represents an integer of 0 to 5;
q3 represents an integer of 0 to 7;
q4 represents an integer of 0 to 9;
r represents an integer of 0 to 2;
t represents an integer of 0 or 1) and hydroxylamine in an aliphatic or an
20 aromatic hydrocarbon solvent which may be substituted by a halogen atom by adding
an additive selected from a phase-transfer catalyst, a Cj-Cg alcohol and an aprotic
polar solvent in the presence of a base and water.
[0018]
[2] The method for producing according to [1], the additive is a phase-transfer
25 catalyst
[3] The method for producing according to [1], the additive is a C1-C6 alcohol.
[4] The method for producing according to [1], the additive is an aprotic polar solvent
[0019]
[5] The method for producing according to [1] to [4], the l,3-bis(substituted phenyl)-
30 3-substituted-2-propen-l-one compound represented by Formula (2) and produced by
reacting, in the presence of a dehydration agent and a base,l,3-bis(substituted
phenyl)-3-substituted-3-hydroxypropan-l-one compound represented by Formula (3):
KK KK> (3)
(where R1, R2, X, A1, A2, A3, A4, A5, A6 and A7 represent the same meaning as
described above) is used.
[6] A method for producing a l,3-bis(substituted phenyl)-3-substituted-2-propen-l-
5 one compound represented by Formula (2) includes reacting a l,3-bis(substituted
phenyl)-3-substituted-3-hydroxypropan-l-one compound represented by Formula (3)
in the presence of a dehydration agent and a base.
[0020]
[7] The method for producing according to [5] or [6], the l,3-bis(substitutedphenyl)-
10 3-substiruted-3-hydroxypropan-l-one compound is used that is represented by
Formula (3) and produced by reacting an aromatic ketone compound represented by
Formula (4):
X O
L ' ^ l w A' X
(where R1, X, A5, A and A7 represent the same meaning as described above) and a
15 substituted acetophenone compound represented by Formula (5):
A
A3 1 (5)
(where R2, A1, A2, A3 and A4 represent the same meaning as described above) in a
suspended state in the presence or absence of an additive and in the presence of a base
20 in a solvent.
[0021]
[8] A method for producing a l,3-bis(substituted phenyI)-3-substituted-3-
hydroxypropan-1-one compound represented by Formula (3) is characterized by
reacting an aromatic ketone compound represented by Formula (4) and a substituted >
25 acetophenone compound represented by Formula (5) in a suspended state in the
presence or absence of an additive and in the presence of a base in a solvent.
15
[9] The method for producing accordmg to [8] is characterized in that the solvent is an
organic solvent and the reaction is conducted in the absence of the additive,
[10] The method for producing according to [8] is characterized in that the solvent is
water and the reaction is conducted in the presence of a water-soluble organic solvent
5 as the additive.
[11] The method for producing according to [8] is characterized in that the solvent is
water and the reaction is conducted in the presence of a surfactant as the additive.
[12] A method for producing a l,3-bis(substituted phenyl)-3-substituted-2-propen-lone
compound represented by Formula (2) in one step includes reacting an aromatic
10 ketone compound represented by Formula (4) and a substituted acetophenone
compound represented by Formula (5) in an organic solvent, in the presence of a base,
at a temperature of over 80°C.
[13] A compound represented by Formula (2), wherein R1, X, A1, A2, A3, A4, A5, A6
and A represent the same meaning as described above, and R represents a
15 substituent selected from the -S(0)rL2-Q2 and D-1 to D-50.
[14] A compound represented by Formula (3), wherein R1, X, A1, A2, A3, A4, A5, A6
and A represent the same meaning as described above, and R represents a
substituent selected from the -S(0)r-L2-Q2 and D-1 to D-50.
[15] A compound represented by Formula (2), wherein R1, X, A5, A and A7 represent
20 the same meaning as described above, and at least one of A , A , A and A is N, and
R2 is a halogen atom.
[16] A compound represented by Formula (3), wherein R1, X, A5, A6 and A7 represent
the same meaning as described above, and at least one of A1, A2, A3 and A4 is N, and
R2 is a halogen atom.
25
[Effects of the Invention]
[0022]
By the method for production according to the present invention, a 1,3-
bis(substituted phenyl)-3-substituted-3-hydroxypropan-l-one compound and a 1,3-
30 bis(substituted phenyl)-3-substituted-2-propen-l-one compound which are useful for
synthesizing a production intermediate of functional materials of medical drugs,
agricultural chemicals, electronic materials or the like can be produced in high yield
and high selectivity, in a solvent such as water and toluene which is easy to use in
industry, by utilizing an aromatic ketone compound and a substituted acetophenone
16
compound as starting raw materials by adequately selecting a surfactant, a
dehydration agent and a base. Therefore the present invention can provide methods
useful for industrial production.
Moreover, the present invention can provide methods for producing
5 agricultural chemicals, particularly an isoxazoline compound described in WO
05/085216 pamphlet which has excellent insecticidal-miticidal activity to harmful
insects for agriculture, spider mites, external or internal parasitic insects of mammals
and birds and its production intermediate.
10 BEST MODES FOR CARRYING OUT THE INVENTION
[0023]
The compound described in the present specification has E-form and Z-form
geometric isomers depending on their substituents. However, the present invention
15 includes these E-form, Z-form or E-form, and Z-form in any ratio. Moreover, the
compound described in the present specification has an optically active substance
generated by the presence of one or more asymmetric carbon atom(s), and the
compound described in the present specification includes every optically active
substance or racemic substance.
20 [0024]
Among the compounds described in the present specification, examples of
compounds which can produce acid addition salts by common methods include salts
of hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid
and hydroiodic acid; salts of inorganic acids such as nitric acid, sulfuric acid,
25 phosphoric acid, chloric acid and perchloric acid; salts of sulfonic acids such as
methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid,
benzenesulfonic acid and p-toluenesulfonic acid; salts of carboxylic acids such as
formic acid, acetic acid, propionic acid, trifluoroacetic acid, fumaric acid, tartaric
acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid,
30 ascorbic acid, lactic acid, gluconic acid and citric acid; or salts of amino acids such as
glutamic acid and asparaginic acid.
[0025]
Among the compounds described in the present specification, examples of
compounds which can produce metal salts by common methods include salts of alkali
17
metals such as lithium, sodium and potassium; salts of alkaline earth metals such as
calcium, barium and magnesium; or salts of aluminum.
[0026]
Among the compounds described in the present specification, examples of
compounds which can produce amine salts by common methods include salts of
ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine,
benzylamine, aniline, dimethylamine, diethylamine, dipropylamine, dibutylamine,
dipentylamine, pyrrolidine, piperidine, piperazine, morpholine, dibenzylamine,
trimethylamine, triethylamine, tripropylamine, tributylamine, tripentylamine and
tribenzylamine.
[0027]
Next, specific examples of each substituent described in the present
specification will be described below. Here, n-, i-, s- and t- mean normal, iso,
secondary and tertiary, respectively, and ph means phenyl.
[0028]
Halogen atoms in the compounds described in the present specification
include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Here,
the expression "halo" in the present specification also represents these halogen atoms.
[0029]
The expression Ca-Cb alkyl in the present specification represents hydrocarbon
groups of linier chains or branched chains having a to b pieces of carbon atoms.
Specific examples include a methyl group, ethyl group, n-propyl group, i-propyl
group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group, 1-
methylbutyl group, 2 -methylbutyl group, 3-methylbutyl group, 1-ethylpropyl group,
1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, nhexyl
group, 1-methylpentyl group, 2-methylpentyl group, 1,1-dimethylbutyl group,
1,3-dimethylbutyl group, heptyl group, octyl group, nonyl group, decyl group,
undecyl group and dodecyl group. Each of the groups is selected within the range of
each specified number of carbon atoms.
[0030]
Specific examples of the expression of aromatic heterocyclic groups in the
present specification include a 2-thienyl group, 3-thienyl group, 2-furyl group, 3-firry 1
group, 2-pyranyl group, 3-pyranyl group, 4-pyranyl group, 2-benzofuranyl group, 3-
benzofuranyl group, 4-benzofuranyl group, 5-benzofuranyI group, 6-benzofuranyl
18
group, 7-benzofuranyl group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-
isobenzofuranyl group, 2-benzothienyl group, 3-benzothienyl group, 4-benzothienyl
group, 5-benzothienyl group, 6-benzothienyl group, 7-benzothienyl group, 1-
isobenzothienyl group, 4-isobenzothienyl group, 5-isobenzothienyl group, 2-
5 chromenyl group, 3-chromenyl group, 4-chromenyl group, 5-chromenyl group, 6-
chroinenyl group, 7-chromenyl group, 8-chromenyl group, 1-pyrrolyl group, 2-
pyrrolyl group, 3-pyrrolyl group, 1-imidazolyl group, 2-imidazolyl group, 4-
imidazolyl group, 1-pyrazolyl group, 3-pyrazolyl group, 4-pyrazolyl group, 2-
thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, 4-
10 isothiazolyl group, 5-isothiazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-
oxazolyl group, 3-isoxazoIyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-pyridyl
group, 3-pyridyl group, 4-pyridyl group, 2-pyrazinyl group, 2-pyrimidinyl group, 4-
pyrimidinyl group, 5-pyrimidinyl group, 3-pyridazinyl group, 4-pyridazinyl group, 1-
indolizinyl group, 2-indolizinyl group, 3-indolizinyl group, 5-indolizinyl group, 6-
15 indolizinyl group, 7-indolizinyl group, 8-indolizinyl group, 1-isoindolyl group, 4-
isoindolyl group, 5-isoindolyl group, 1-indolyl group, 2-indolyl group, 3-indolyl
group, 4-indolyl group, 5-indolyl group, 6-indolyl group, 7-indolyl group, 1-indazolyl
group, 2-indazolyl group, 3-indazolyl group, 4-indazolyl group, 5-indazolyl group, 6-
indazolyl group, 7-indazolyl group, 1-purinyl group, 2-purinyl group, 3-purinyl group,
20 6-purinyl group, 7-purinyl group, 8-purinyl group, 2-quinolyl group, 3-quinolyl
group, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group, 7-quinolyl group, 8-
quinolyl group, 1-isoquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, 5-
isoquinolyl group, 6-isoquinolyl group, 7-isoquinolyl group, 8-isoquinolyl group, 1-
phthalazinyl group, 5-phthalazinyl group, 6-phthalazinyl group, 2-naphthyridinyl
25 group, 3-naphthyridinyl group, 4-naphthyridinyl group, 2-quinoxalinyl group, 5-
quinoxalinyl group, 6-quinoxalinyl group, 2-quinazolinyl group, 4-quinazolinyl
group, 5-quinazolinyl group, 6-quinazolinyl group, 7-quinazolinyl group, 8-
quinazolinyl group, 3-cinnolinyl group, 4-cinnolinyl group, 5-cinnolinyl group, 6-
cinnolinyl group, 7-cinnolinyl group, 8-cinnolinyl group, 2-pteridinyl group, 4-
30 pteridinyl group, 6-pteridinyl group and 7-pteridinyl group and 3-furazanyl group.
[0031]
Specific examples of the expression of aryl groups in the present specification
include a phenyl group, naphthyl group, anthryl and the above-described aromatic
heterocyclic groups.
19
[0032]
Examples of heterocyclic groups in the present specification include a 2-
tetrahydrofuranyl group, 3-tetrahydrofuranyl group, 2-tetrahydropyranyl group, 3-
tetrahydropyranyl group, 4-tetrahydropyranyl group, 1-pyrrolidinyl group, 2-
5 pyrrolidinyl group, 3-pyrrolidinyl group, 1-pyrrolinyl group, 2-pyrrolinyl group, 3-
pyrrolinyl group, 4-pyrrolinyl group, 5-pyrrolinyl group, 1-imidazolidinyl group, 2-
imidazolidinyl group, 4-imidazolidinyl group, 1-imidazolinyl group, 2-imidazolinyl
group, 4-imida2olinyl group, 1-pyrazolidinyl group, 3-pyrazolidinyl group, 4-
pyrazolidinyl group, l-pyrazolinyl group, 2-pyrazolinyl group, 3-pyrazolinyl group,
10 4-pyrazolinyl group, 5-pyrazolinyl group, 1-piperidyl group, 2-piperidyl group, 3-
piperidyl group, 4-piperidyl group, 1-piperazinyl group, 2-piperazinyl group, 3-
piperazinyl group, 1-indolinyl group, 2-indolinyl group, 3-indolinyl group, 4-indolinyl
group, 5-indolinyl group, 6-indolinyl group, 7-indolinyl group, 1-isoindolinyl group,
2-isoindolinyl group, 4-isoindolinyl group, 5-isoindolinyl group, 2~quinuclidinyl
15 group, 3-quinuclidinyl group, 4-quinuclidinyl group, 2-morpholinyl group, 3-
morpholinyl group, 4-morpholinyl group, 1-azetidinyl group, 2-azetidinyl group, 3-
azetidinyl group, 1-azetidinonyl group, 3-azetidinony group and 4-azetidinonyl group,
other than the above-described aromatic heterocyclic groups.
[0033]
20 The expression Ca-Cb haloalkyl in the present specification represents
hydrocarbon groups of linier chains or branched chains having a to b pieces of carbon
atoms in which hydrogen atom(s) bonding to carbon atom(s) is optionally substituted
by halogen atom(s). In this case, these halogen atoms may be the same as or different
from each other, when the alkyl group is substituted by 2 or more halogen atoms.
25 Specific examples include a fluoromethyl group, chloromethyl group, bromomethyl
group, iodomethyl group, difluoromethyl group, chlorofluoromethyl, dichloromethyl
group, bromofluoromethyl group, trifluoromethyl group, chlorodifluoromethyl group,
dichlorofluoromethyl group, trichloromethyl group, bromodifluoromethyl group,
bromochlorofluoromethyl group, dibromofluoromethyl group, 2-fluoroethyl group, 2-
30 chloroethyl group, 2-bromoethyl group, 2,2-difluoroethyl group, 2-chloro~2-
fluoroethyl group, 2,2,-dichloroethyl group, 2-bromo-2-fluoroethyl group, 2,2,2-
trifluoroethyl group, 2-chloro-2,2-difluoroethyl group, 2,2-dichloro-2-fluoroethyl
group, 2,2,2-trichloroethyl group, 2-bromo-2,2-difluoro ethyl group, 2-bromo-2-
chloro-2-fluoroethyl group, 2-bromo-2,2;-dichloroethyl group, 1,1^,2-tetrailuoroethyl
20
group, pentafluoroethyl group, l-chloro-l,2,2,2-tetrafluoroethyl group, 2-chloro-
1,1,2,2-tetrafluoroethyl group, l,2-dichloro-l,2,2-1rifluoroethyl group, 2- bromo-
1,1,2,2-tetrafluoroethyl group, 2-fluoropropyl group, 2-chloropropyl group, 2-
bromopropyl group, 2-chloro-2-fluoropropyl group, 2,3-dichloropropyl group, 2-
5 bromo-3-fluoropropyl group, 3-bromo-2-chloropropyl group, 2,3-dibromopropyl
group, 3,3,3-trifluoropropyl group, 3-bromo-3,3-difluoropropyl group, 2,2,3,3-
tetrafluoropropyl group, 2-chloro-3,3,3-trifluoropropyl group, 2,2,3,3,3-
pentafluoropropyl group, 1,1,2,3,3,3-hexafluoropropyl group, heptafluoropropyl
group, 2,3-dichloro-l,l,2,3,3-pentafluoropropyl group, 2-fluoro-l-methylethyl group,
10 2-chloro-l-methylethyl group, 2-bromo-l-methylethyl group, 2,2,2-trifluoro-l-
(trifluoromethyl)ethyl group, l,252,2-tetrafluoro-l-(trifluoromethyl)ethyl group, 2-
fluorobutyl group, 2-chlorobutyl group, 2,2,3,3,4,4-hexafluorobutyl group,
2,2,3,4,4,4-hexafluorobutyl group, 2,2,3,3,4,4-hexafluorobutyl group, 2,2,3,3,4,4,4-
heptafluorobutyl group, 1,1,2,2,3,3,4,4-octafluorobutyl group, nonafluorobutyl group,
15 4-chloro-l,l,2,2,3,3,4,4-octafluorobutyl group, 2-fluoro-2-methylpropyl group,
1,2,2,3,3,3-hexafluoro-1 -(trifluoromethyl)propyl group, 2-chloro-1,1 -dimethylethyl
group, 2-bromo-l,l-dimethylethyl group, 5-chloro-2,2,3,4,4,5,5-heptafluoropentyl
group, and tridecafluorohexyl group. Each of the groups is selected within the range
of each specified number of carbon atoms.
20 [0034]
The expression cyano (Ca-Cb) alkyl in the present specification represents
alkyl groups of linier chains or branched chains having a to b pieces of carbon atoms
in which hydrogen atom(s) bonding to carbon atom(s) is optionally substituted by a
cyano group. Specific examples include, a cyanomethyl group, 1-cyanoethyl group,
25 2-cyanoethyl group, 2-cyanopropyl group, 3-cyanopropyl group and 2-cyanobutyl
group. Each of the groups is selected within the range of each specified number of
carbon atoms.
[0035]
The expression Ca-Cb cycloallcyl in the present specification represents cyclic
30 hydrocarbon groups having a to b pieces of carbon atoms, and can form a 3-
membered ring to a 6-membered ring of monocyclic or composite ring structures. In
addition, each ring may be optionally substituted by an alkyl group within a range of
each specified number of carbon atoms. Specific examples include a cyclopropyl
group, 1-methylcyclopropyl group, 2-methylcyclopropyl group, 2,2-
21
dimethylcyclopropyl group, 2,2,3,3-tetramethylcyclopropyl group, cyclobutyl group,
cyclopentyl group, 2-methylcyclopentyl group, 3-methylcyclopentyl group,
cyclohexyl group, 2-methylcyclohexyl group, 3-methylcyclohexyl group, 4-
methylcyclohexyl group and bicyclo(2.2.1)heptane-2-yl group. Each of the groups is
5 selected with the range of each specified number of carbon atoms.
[0036]
The expression Ca-Cb halocycloalkyl in the present specification represents
cyclic hydrocarbon groups having a to b pieces of carbon atoms in which hydrogen
atom(s) bonding to carbon atom(s) is optionally substituted by halogen atom(s), and
10 can form a 3-membered ring to a 6-membered ring of monocyclic or composite ring
structures. In addition, each ring may be optionally substituted by an alkyl group
within a range of each specified number of carbon atoms, and a ring structure part, a
side chain part or both of them may be substituted by halogen atom(s). Moreover,
these halogen atoms may be the same as or different from each other, when the
15 cycloalkyl group is substituted by 2 or more halogen atoms. Specific examples
include a 2,2-difluorocyclopropyl group, 2,2-dichlorocyclopropyl group, 2,2-
dibromocyclopropyl group, 2,2-difluoro-l-methylcyclopropyl group, 2,2-dichloro-lmethylcyclopropyl
group, 2,2-dibromo-l-methylcyclopropyl group, 2,2,3,3-
tetrafluorocyclobutyl group, 2-(trifluoromethyl)cyclohexyl group, 3-
20 (trifluoromethyl)cyclohexyl group and 4-(trifluoromethyl)cyclohexyl group. Each of
the groups is selected within the range of each specified number of carbon atoms.
[0037]
The expression Ca- Cb alkenyl in the present specification represents
unsaturated hydrocarbon groups of Hnier chains or branched chains having a to b
25 pieces of carbon atoms and having one or more double bond(s) in the molecule.
Specific examples include a vinyl group, 1-propenyl group, 2-propenyl group, 1-
methylethenyl group, 2-butenyl group, l-methyl-2-propenyl group, 2-methyl-2-
propenyl group, 2-pentenyl group, 2-methyl-2-butenyl group, 3-methyl-2-butenyl
group, 2-ethyi-2-propenyl group, l,l-dimethyl-2-propenyl group, 2-hexenyl group, 2-
30 methyl-2-pentenyl group, 2,4-dimethyl-2,6-heptadienyl group and 3,7-dimethyl-2,6-
octadienyl group. Each of the groups is selected within the range of each specified
number of carbon atoms.
[0038]
: ' * - '^~^^^'^^^i^^ii^ts^^^»^^^mimm!^im^S's»iti?>--- :•..•.•;•-VJ m-&: -• -.-. < .v-'ss^asssssSS^s
22
The expression Ca-Cb haloalkenyl in the present specification represents
unsaturated hydrocarbon groups of linier chains or branched chains having a to b
pieces of carbon atoms in which hydrogen atom(s) bonding to carbon atom(s) is
optionally substituted by halogen atom(s) and having one or more double bond(s) in
5 the morcculc. In this case, these halogen atoms may be the same as or different from
each other, when the alkenyl group is substituted by 2 or more halogen atoms.
Specific examples include a 2,2-dichlorovinyl group, 2-fluoro-2-propenyl group, 2-
chloro-2-propenyl group, 3-chloro-2-propenyl group, 2-bromo-2-propenyl group, 3-
bromo-2- propenyl group, 3,3-difluoro-2-propenyl group, 2,3-dichloro-2-propenyl
10 group, 3,3-dichloro-2-propenyl group, 2,3-dibromo-2-propenyl group, 2,3,3-trifluoro-
2-propenyl group, 2,3,3-trichloro-2-propenyl group, 1-(trifluoromethyl) ethenyl
group, 3-chloro-2-butenyl group, 3-bromo-2-butenyl group, 4,4-difluoro-3-butenyl
group, 3,4,4-trifluoro -3-butenyl group, 3-chloro-4,4,4-trifluoro-2-butenyl group and
3-bromo-2-methyl -2-propenyl group. Each of the groups is selected within the range
15 of each specified number of carbon atoms.
The expression Ca-Cb aikynyl in the present specification represents
unsaturated hydrocarbon groups of linier chains or branched chains having a to b
pieces of carbon atoms and having one or more triple bond(s) in the morecule.
Specific examples include an ethynyl group, 1-propynyl group, 2-propynyl group, 2-
20 butynyl group, l-methyl-2-propynyl group, 2-pentynyl group, l-methyl-2-butynyl
group, l,l-dimethyl-2-propynyl group and 2-hexynyl group. Each of the groups is
selected within the range of each specified number of carbon atoms.
[0039]
The expression Ca-Cb alkoxy in the present specification represents alkyl-O-
25 groups, in which the alkyl has a to b pieces of carbon atoms as defined above.
Specific examples include a methoxy group, ethoxy group, n-propyloxy group, ipropyloxy
group, n-butyloxy group, i-butyloxy group, s-butyloxy group, t-butyloxy
group, n-pentyloxy group and n-hexyloxy group. Each of the groups is selected
within the range of each specified number of carbon atoms.
30 [0040]
The expression Ca-Cb haloalkoxy in the present specification represents
haloalkyl-O-groups, in which the haloalkyl has a to b pieces of carbon atoms as
defined above. Specific examples include a difluoromethoxy group, tnfluoromethoxy
group, chlorodifluoromethoxy group, bromodifluoromethoxy group, 2-fluoroethoxy
23
group, 2-chloroethoxy group, 2,2,2-trifluoroethoxy group, 1,1,2,2-tetrafluoroethoxy
group, 2-chloro-l,lJ2-trifluoroethoxy group, 2-bromo-l,2,2-trifluoroethoxy group,
pentafluoroethoxy group, 2,2-dichloro-l,l,2-trifluoroethoxy group, 2,2,2-trichloro-
1,1-difluoroethoxy group, 2-bromo- 1,1,2,2-tetrafluoroethoxy group, 2,2,3,3-
5 tetrafluoropropyloxy group, 1,1,2,3,3,3-hexafluoropropyloxy group, 2,2,2-trifluoro-l-
(trifluoromethyl)ethoxy group, heptafluoropropyloxy group and 2-bromo-1,1,2,3,3,3-
hexafluoropropyloxy group. Each of the groups is selected within the range of each
specified number of carbon atoms.
[0041]
10 The expression Ca-Cb alkylthio in the present specification represents alkyl-Sgroups,
in which the alkyl has a to b pieces of carbon atoms as defined above.
Specific examples include a methylthio group, ethylthio group, n-propylthio group, i
propylthio group, n-butylthio group, i-butylthio group, s-butylthio group, t-butylthio
group, n-pentylthio group and n-hexylthio group. Each of the groups is selected
15 within the range of each specified number of carbon atoms.
[0042]
The expression Ca-Cb haloalkylthio in the present specification represents
haloalkyl-S-groups, in which the haloalkyl has a to b pieces of carbon atoms as
defined above. Specific examples include a difluoromethylthio group,
20 trifluoromethylthio group, chlorodifluoromethylthio group, bromodifluoromethylthio
group, 2,2,2-trifluoroethylthio group, 1,1,2,2-tetrafluoroethylthio group, 2-chloro-
1,1,2-trifluoroethylthio group, pentafluoroethylthio group, 2-bromo-1,1,2,2-
tetrafluoroethylthio group, 1,1,2,3,3,3-hexafluoropropylthio group,
heptafluoropropylthio group, l,2,2,2-tetrafluoro-l-(trifluoromethyl)ethylthio group
25 and nonafluorobutylthio group. Each of the groups is selected within the range of
each specified number of carbon atoms.
[0043]
The expression Ca-Cb alkylsulfinyl in the present specification represents
alkyl-S(0)-groups, in which the alkyl has a to b pieces of carbon atoms as defined
30 above. Specific examples include a methylsulfinyl group, etbylsulfinyl group, npropylsulfinyl
group, i-propylsulfmyl group, n-butylsulfinyl group, i-butylsulfinyl
group, s-butylsulfinyl group and t-butylsulfmyl group. Each of the groups is selected
within the range of each specified number of carbon atoms.
[0044]
24
The expression Ca-Cb haloalkylsulfinyl in the present specification represents
haloallcyl-S(0)-groups, in which the haloalkyl has a to b pieces of carbon atoms as
defined above. Specific examples include a difluoromethylsulfinyl group,
trifluoromethylsulfinyl group, chlorodifluoromethylsulfmyl group,
5 bromodifluoromethylsulfinyl group, 2,2,2-trifluoroethylsulfinyl group, 2-bromo-
1,1,2,2-tetrafluoroethylsulfinyl group, 1,2,2,2-tetrafluoro-1-
(trifluoromethyl)ethylsulfinyl group and nonafulorobutylsulfmyl group. Each of the
groups is selected within the range of each specified number of carbon atoms.
[0045]
10 The expression Ca-Cb alkylsulfonyl in the present specification represents
alkyl-S02-groups, in which the alkyl has a to b pieces of carbon atoms as defined
above. Specific examples include a methysulfonyl group, ethylsulfonyl group, npropylsulfonyl
group, i-propylsulfonyl group, n-butylsulfonyl group, i-butylsulfonyl
group, s-butylsulfonyl group, t-butylsulfonyl group, n-pentylsulfonyl group and n-
15 hexylsulfonyl group. Each of the groups is selected within the range of each specified
number of carbon atoms.
[0046]
The expression Ca-Q, haloalkylsulfonyl in the present specification represents
haloalkyl-SCVgroups, in which the haloalkyl has a to b pieces of carbon atoms as
20 defined above. Specific examples include a difluoromethylsulfonyl group,
trifluoromethylsulfonyl group, chlorodifluoromethylsulfonyl group,
bromo difluoromethylsulfonyl group, 2,2,2-trifluoroethylsulfonyl group, 1,1,2,2-
tetrafluoroethylsulfonyl group, 2-chloro-l)2,2-trijEluoroethylsulfonyl group and 2-
bromo-l^^^-tetrafluoroethylsulfonyl group. Each of the groups is selected within
25 the range of each specified number of carbon atoms.
[0047]
The expression Ca-Cb alkylcarbonyl in the present specification represents
alkyl-C(0)-groups, in which the alkyl has a to b pieces of carbon atoms as defined
above. Specific examples include an acetyl group, propionyl group, butyryl group,
30 isobutyryl group, valeryl group, isovaleryl group, 2-methylbutanoyl group, pivaloyl
group, hexanoyl group and heptanoyl group. Each of the groups is selected within the
range of each specified number of carbon atoms.
[0048]
25
The expression Ca-Cb haloalkylcarbonyl in the present specification represents
haloalkyl-C(0)-groups, in which the haloalkyl has a to b pieces of carbon atoms as
defined above. Specific examples include a fluoroacetyl group, chloroacetyl group,
difluoroacetyl group, dichloroacetyl group, trifluoroacetyl group, chlorodifluoroacetyl
5 group, bromo difluoroacetyl group, trichloro acetyl group, pentafluoropropionyl group,
heptafluorobutanoyl group and 3-chloro-2,2-dimethylpropanoyl group. Each of the
groups is selected within the range of each specified number of carbon atoms.
[0049]
The expression Ca-Cb alkoxycarbonyl in the present specification represents
10 alkyl-O-C(O)-groups, in which the alky 1 has a to b pieces of carbon atoms as defined
above. Specific examples include a methoxycarbonyl group, ethoxycarbonyl group,
n-propyloxycarbonyl group, i-propyloxycarbonyl group, n-butoxycarbonyl group, ibutoxycarbonyl
group and t-butoxycarbonyl group. Each of the groups is selected
within the range of each specified number of carbon atoms.
15 [0050]
The expression Ca-Cb alkylthiocarbonyl in the present specification represents
alkyl-S-C(0)-groups, in which the alkyl has a to b pieces of carbon atoms as defined
above. Specific examples include a methylthio-C-(O)- group, ethylthio-C-(O)- group,
n-propylthio-C-(O)- group, i-propylthio-C-(O)- group, n-butylthio-C-(O)- group, i-
20 butylthio-C-(O)- group and t-butylthio-C-(O)- group. Each of the groups is selected
within the range of each specified number of carbon atoms.
[0051]
The expression Ca-Cb alkoxythiocarbonyl in the present specification
represents alkyl-0-C(S)-groups, in which the alkyl has a to b pieces of carbon atoms
25 as defined above. Specific examples include a methoxy-C(S)- group, ethoxy-C(S)-
group, n-propyloxy-C(S)- group and i-propyloxy-C(S)- group. Each of the groups is
selected within the range of each specified number of carbon atoms.
[0052]
The expression Ca-Cb aUcyldithiocarbonyl in the present specification
30 represents alkyl-S-C(S)-groups, in which the alkyl has a to b pieces of carbon atoms
as defined above. Specific examples include a methylthio-C(S)- group, ethylthio-
C(S)- group, n-propylthio-C(S)- group and i-propylthio-C(S)- group. Each of the
groups is selected within the range of each specified number of carbon atoms.
[0053]
26
The expression Cfl-Cb alkylaminocarbonyl in the present specification
represents carbamoyl groups whose one hydrogen atom is substituted by an alkyl
group, in which the alkyl has a to b pieces of carbon atoms as defined above. Specific
examples include a methylcarbamoyl group, ethylcarbamoyl group, n-
5 propylcarbamoyl group, i-propylcarbamoyl group, n-butylcarbamoyl group, ibutylcarbamoyl
group, s-butylcarbamoyl group, and t-butylcarbamoyl group. Each of
the groups is selected within the range of each specified number of carbon atoms.
[0054]
The expression di(Ca-Cb alkyl) aminocarbonyl in the present specification
10 represents carbamoyl groups whose both hydrogen atoms are substituted by alkyl
groups which may be the same as or different from each other and have a to b pieces
of carbon atoms as defined above. Specific examples include an N,Ndimethylcarbamoyl
group, N-ethyl-N-methyl carbamoyl group, N,N-diethyl carbamoyl
group, N,N-di-n-propylcarbamoyl group and N3N-di~n-butylcarbamoyl group. Each
15 of the groups is selected within the range of each specified number of carbon atoms.
[0055]
The expression Ca-Cb alkylaminosulfonyl in the present specification
represents sulfamoyl group whose one hydrogen atom is substituted by an alkyl group
which has a to b pieces of carbon atoms as defined above. Specific examples include
20 a methylsulfamoyl group, ethyl sulfamoyl group, n-propylsulfamoyl group, ipropylsulfamoyl
group, n-butylsulfamoyl group, i-butylsulfamoyl group, sbutylsulfamoyl
group and t-butylsulfamoyl group. Each of the groups is selected
within the range of each specified number of carbon atoms.
[0056]
25 The expression di(Ca-Cb alkyl) aminosulfonyl in the present specification
represents sulfamoyl groups whose both hydrogen atoms are substituted by alkyl
groups which may be the same as or different from each other and have a to b pieces
of carbon atoms as defined above. Specific examples include an N,Ndimethylsulfamoyl
group, N-ethyl-N-methylsulfamoyl group, N,N-diethylsulfamoyl
30 group, N,N~di-n-propylsulfamoyl group and N,N-di-n-butylsulfamoyl group. Each of
the groups is selected within the range of each specified number of carbon atoms.
[0057]
The expression Ca-Cb cycloalkyl(Cd-Cc) alkyl, Cfl-Cb alkoxy(Cd-Cc) alkyl or
Ca-Cb alkylthio(Cd-Cc) alkyl in the present specification represents a hydrocarbon
27
group of liner chains or branched chains whose hydrogen atoms bonding to carbon
atoms are optionally substituted by a Ca-Cb cycloalkyl group, Ca-Cb alkoxy group or
Ca-Cb alkylthio group as defined above, and whose number of substituted carbon
atoms is d-e. Each of the groups is selected within the range of each specified number
of carbon atoms.
[0058]
The expression (Ca-Cb) alkyl optionally substituted by R in the present
specification represents hydrocarbon groups of linier chains or branched chains,
whose hydrogen atoms bonding to carbon atom(s) is optionally substituted by any R8,
and whose number of substituted carbon atoms is a-b. Each of the groups is selected
within the range of each specified number of carbon atoms. In this case, these R s
ft
may be the same as or different from each other, when the substituent R on each (Ca-
Cb) alkyl groups are 2 or more.
[0059]
The expression hydroxy (Cd-Ce) haloalkyl, Ca-Cb alkoxy (CQ-Ce) haloalkyl or
Ca-Cb haloalkoxy (Cd-Ce) haloalkyl in the present specification represents haloalkyl
groups whose hydrogen atoms or halogen atoms bonding to carbon atoms are
optionally substituted by any Ca-Cb alkoxy group, Ca-Cb haloalkoxy group or hydroxy
group as defined above, and whose number of substituted carbon atoms is d-e.
Specific examples include a 2,2,2-trifluoro-l-hydroxy-l-(trifluoromethy!l)ethyl group,
difluoro(methoxy)methyl group, 2,2,2-trifluoro- 1-methoxy-1 -(trifluoromethyl)ethyl
group, difluoro(2,2,2-trifluoroethoxy)methyl group, 2,2,2-trifluoro-1-(2,2,2-
trifluoroethoxy)-l-(trifluoromethyl)ethyl group, and 3-(l,2-dichloro-l,2,2-
trifluoroethoxy)-l,l,2,2,3)3-hexafluoropropyl group. Each of the groups is selected
within the range of each specified number of carbon atoms.
[0060]
In the compounds described in the present specification, examples of a
substituent represented by X preferably include a halogen atom and C1-C4 haloalkyl,
and more preferably include a chlorine atom, bromine atom, iodine atom and
trifluoromethyl. In this case, each X may be the same as or different from each other,
when m which represents the number of substituents represented by X represents an
integer of 2 or more.
In the compounds described in the present specification, m which represents
the number of substituents represented by X is preferably 1, 2, and 3.
28
In the compounds described in the present specification, a position of a
substituent represented by X is preferably the meta position or para position to the
bonding position of a carbon to which R1 is bonded.
[0061]
5 In the compounds described in the present specification, examples of a
substituent represented by Y preferably include a halogen atom, nitro, CVC4 alkyl and
C1-C4 haloalkyl, and more preferably include a fluorine atom, chlorine atom, bromine
atom, iodine atom, nitro, methyl, ethyl and trifluoromethyl. In this case, each Y may
be the same as or different from each other, when n represents an integer of 2.
10 In the compounds described in the present specification, n which represents
the number of substituents represented by Y is preferably 0 and 1.
In the compounds described in the present specification, a position of
substituent represented by Y is more preferably the ortho position to the bonding
position of R".
15 [0062]
In the compounds described in the present specification, examples of a
substituent represented by R preferably include a C1-C4 haloalkyl, more preferably
include a difluoromethyl, chlorodifluoromethyl, bromodifluoromethyl and
trifluoromethyl, and extremely preferably include a chlorodifluoromethyl and
20 trifluoromethyl.
[0063]
In the compounds described in the present specification, examples of a
substituent represented by R2 preferably include a methyl, a halogen atom, cyano,
nitro, -NH2, -NHR4, -OH, -OR3, benzyloxy, -OS02R3, phenylsulfonyloxy, p-
25 toluenesulfonyloxy, -C(O)0H, -C(0)OR3,- C(0)NH2, -C(0)N(Rlb)R,a, -L-Q, -LN(
Rlc)Rld, D-l to D-50 or -S(0)rL2-Q2, and more preferably include a methyl,
chlorine atom, bromine atom, iodine atom, cyano, nitro, amino, -NHR4, hydroxy,
methoxy, methoxymethyloxy, acetyloxy, benzyloxy, methanesulfonyloxy,
trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, -C(0)OH, methoxycarbonyl,
30 ethoxycarbonyl, - C(0)NH2, -C(0)N(Rlb)Rla, -L-Q, -L-N(Rlc)Rld, G or -S(0)r-L2-Q2,
[0064]
In the compounds described in the present specification, examples of a
substituent represented by R3 preferably include a C1-C4 alkyl, C1-C4 alkoxy (C1-C4)
29
alkyl and C1-C4 haloalkyl, and more preferably include a methyl, ethyl,
methoxymethyl, methoxyethyl, ethoxymethyl and trifluoromethyl.
[0065]
In the compounds described in the present specification, examples of a
5 substituent represented by R4 preferably include a -CHO, C1-C4 alkylcarbonyl and C[-
C4 alkoxycarbonyl, and more preferably include a formyl, acetyl, propionyl,
methoxycarbonyl and ethoxycarbonyl.
In the compounds described in the present specification, an example of a
substituent represented by R5 preferably includes a hydrogen atom.
10 [0066]
In the compounds described in the present specification, examples of a
substituent represented by Rla preferably include a C1-C4 alkyl optionally substituted
by R8, -N(Rn)R10, -C(0)OR9, -C(0)NH2, -C(Q)NHR9, -C(R7)=NOR6, phenyl, phenyl
substituted by (Z)pi, D-5, D-7, D-10, D-ll, D-12, D-14, D-15, D-18, D-31, D-32, D-
15 42, D-43, D-45, D-46, D-48, E-l or E-7.
[0067]
In the compounds described in the present specification, examples of a
substituent represented by Rlb preferably include a hydrogen atom, C1-C6 alkyl, C1-C4
alkoxy (C1-C4) alkyl, cyano (C,-C4) alkyl, C3-C6 alkynyl, -C(0)R9 and -C(0)OR9, and
20 more preferably include a hydrogen atom, methyl, ethyl, methoxymethyl,
cyanomethyl, propargyl, acetyl, propionyl, butyryl, pivaloyl, methoxycarbonyl and
ethoxycarbonyl.
[0068]
In the compounds described in the present specification, examples of a
25 substituent represented by R8 preferably include a halogen atom, cyano, C3-C6
cycloalkyl, Q-G, alkoxy, CrC4 haloalkoxy, -C(0)N(R15)R14, -C(R7)=NOR6, phenyl,
phenyl substituted by (Z)pi, D-ll to D-14, D-18, D-19, D-25, D-26, D-31, D-32, D-
36, D42, D-45, D-48, D-49, E-l, E-2 or E-5, and more preferably include a fluorine
atom, chlorine atom, bromine atom, cyano, cyclopropyl, methoxy, ethoxy, 2,2,2-
30 trifluoroethoxy, -C(0)N(R,5)R14, -CH=NOCH3s phenyl, phenyl substituted by (Z)pl,
D-14, D-19, D-31, D-32, D-36, D-42 and E-5.
[0069]
In the compounds described in the present specification, examples of a
substituent represented by Z preferably include a halogen atom, cyano, nitro, C^-Ci
30
alkyl, C1-C4 haloalkyl and C1-C4 haloalkoxy, and more preferably include a fluorine
atom, chlorine atom, bromine atom, cyano, nitro, methyl, rrifluoromethyl and
trifluoromethoxy. In this case, each Z may be the same as or different from each
other, when p i , p2, p3 or p4 which represents the number of substituents represented
5 by Z represents an integer of 2 or more.
[0070]
In the compounds described in the present specification, p 1 which represents
the number of substituents represented by Z preferably includes 1 and 2.
In the compounds described in the present specification, p2 which represents
10 the number of substituents represented by Z preferably includes 0 and 1.
In the compounds described in the present specification, p3 which represents
the number of substituents represented by Z preferably includes 0 and 1.
In the compounds described in the present specification, p4 which represents
the number of substituents represented by Z preferably includes 0 and 1.
15 In the compounds described in the present specification, p5 which represents
the number of substituents represented by Z preferably includes 0 and 1.
[0071]
In the compounds described in the present specification, examples of a
substituent represented by R6 preferably include a C1-C4 alkyl, and more preferably
20 include a methyl and ethyl.
In the compounds described in the present specification, examples of a
substituent represented by R7 preferably include a hydrogen atom and C1-C4 alkyl,
and more preferably include a hydrogen atom and methyl.
[0072]
25 In the compounds described in the present specification, examples of a
substituent represented by R9 preferably include a C1-C4 alkyl, Q-C4 haloalkyl, C1-C4
alkoxy (C1-C4) alkyl, CrC4 alkylthio (C1-C4) alkyl, C3-C8 cycloalkyl, C3-C6 alkenyl
and C3-C6 alkynyl, more preferably include a methyl, ethyl, n-propyl, i-propyl, nbutyl,
i-butyl, s-butyl, t-butyl, trifluoromethyl, chloroethyl, 2,2,2-trifluoro ethyl,
30 methoxymethyl, ethoxymethyl, methoxyethyl, methylthiomethyL, cyclopropyl, allyl
and propargyl.
[0073]
In the compounds described in the present specification, examples of a
substituent represented by R10 preferably include a C1-C4 haloalkyl, -C(0)R14, -
31
C(0)OR14, phenyl, phenyl substituted by (Z)pl, D-3, D-4, D18, D-42, D-45, D-46, D-
48 or D-49, and more preferably include a 2,2,2-trifluoroethyl, -C(0)R14> -C(0)OR14,
phenyl, phenyl substituted by (Z)pi, D-18, D-42 and D-45.
[0074]
In the compounds described in the present specification, examples of a
substituent represented by R preferably include a hydrogen atom, Q-C6 alkyl and
C3-C6 alkynyl, and more preferably include a hydrogen atom, methyl, ethyl and
propargyl.
In the compounds described in the present specification, examples of a
substituent represented by R preferably include a Q-C4 alkyl, and more preferably
include methyl and ethyl.
In the compounds described in the present specification, examples of a
substituent represented by R preferably include a C1-C4 alkyl, and more preferably
include a methyl. In this case, each R may be the same as or different from each
other, when p i , p2, p3 or p4 which represents the number of substituents represented
by R13 represents an integer of 2 or more. In addition, two R13s may together form
oxo, when the two R13s are substituted on the same carbon atom.
[0075]
In the compounds described in the present specification, q2 which represents
the number of substituents represented by R 3 preferably includes 1 and 2.
In the compounds described in the present specification, q3 which represents
the number of substituents represented by R preferably includes 0, 1 and 2.
In the compounds described in the present specification, q4 which represents
the number of substituents represented by R13 preferably includes 03 1 and 2.
[0076]
In the compounds described in the present specification, examples of a
substituent represented by R14 preferably include a C1-C4 alkyl, C1-C4 haloalkyl, C3-
Ce cycloalkyl (Ci-Q) alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl and C3-C6 alkynyl, and
more preferably include a methyl, ethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl,
2,2,2-trifluoroethyl, cyclopropylmethyl, cyclopropyl, allyl and propargyl,
[0077]
In the compounds described in the present specification, examples of a
substituent represented by R15 preferably include a hydrogen atom and C1-C4 alkyl,
and more preferably include a hydrogen, methyl and ethyl.
32
In the compounds described in the present specification, r which represents the
number of oxygen on a sulfur atom includes 0, 1 and 2.
In the compounds described in the present specification, t which represents the
number of oxygen on a nitrogen atom in a pyridine ring includes 0 and 1.
5 [0078]
In the compounds described in the present specification, examples of L
preferably include a -CH2-, -CH(CH3)-! -CH(CN)-, ~CH(R2a)CH2- (where R2a
represents a hydrogen atom, cyano or C,-C6 alkyl), -N(R2c)- and -CH(R2a)N(R2c)-
(where R2a represents a hydrogen atom, cyano orCj-Ce alkyl and R2c represents a
10 hydrogen atom, C[-C6 alkyl, C1-C6 alkylcarbonyl, Q-Ce haloalkylcarbonyl or C3-C6
cycloalkyl carbonyl), and particularly preferably include a -CH2-, -CH(CH3)- and -
CH(CN)-.
[0079]
In the compounds described in the present specification, examples of R c
15 include a hydrogen atom, -C(0)R3a, -C(0)OR3a, -C(0)SR3a, -C(0)N(R3b)R3a, -
C(S)N(R3b)R3a or -S(0)2R3a, and particularly preferably include a -C(0)R3a, -
C(0)OR3a and -C(0)N(R3b)R3a.
[0080]
In the compounds described in the present specification, examples of R
20 preferably include a hydrogen atom, C1-C6 alkyl, Ci-Ce haloalkyl, C1-C4 alkoxy (Ci-
C4) alkyl, CrC4haloalkoxy (C]-C4) alkyl, CrC, alkylthio (C,-C4) alkyl, Q-C,
alkylsulfonyl (Ci-C4) alkyls cyano (Cj-C6) alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl
(Ci-C4) alkyl, C3-C6 alkenyl, C3-C6 alkynyl, -C(0)R3c, -C(0)OR3c, -C(0)SR3c, CrC6
haloalkylthio or Ci-Ce alkylsulfonyl, and particularly preferably include a hydrogen
25 atom, Ci-C6 alkyl, Ci-C6 haloalkyl, CrC4 alkoxy (CrC4) alkyl, CrC4 haloalkoxy
(d-C4) alkyl, C3-C6 cycloalkyl (CrC4) alkyl and -C(0)R3c.
[0081]
Examples of R3a include a Ci-C6 alkyl, CrC6 haloalkyl, (Ci-C4) alkyl
optionally substituted by R4a, C3-C6 cycloalkyl, C3-C6 halocyclo alkyl, E-1, E-2, E-4,
30 C2-Ce alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, phenyl, phenyl substituted by (V)p!,
D-3, D-4, D-12 to D-14, D-42 orD-43, and particularly preferably include a CrC6
alkyl, Ci-C6 haloalkyl, (Ci-C4) alkyl optionally substituted by R4a, C3-C6 cycloalkyl,
C3-C6 halocycloalkyl, phenyl and phenyl substituted by (V)pi.
[0082]
33
Examples of R3b include a hydrogen atom and C1-C6 alkyl.
Examples of R3c include a hydrogen atom C1-C4 alkyl, C[-Gi haloalkyl, C3-C6
cycloaikyl (C1-C4) alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl or C3-C6 alkynyl, or include
the case that R3c forms a 5-7 membered ring with a nitrogen atom, carbon atom,
5 oxygen atom or sulfur atom to be bonded, by forming an ethylene chain or benzene
ring bonded at ortho-position together with R3a.
[0083]
Examples of R4a include a halogen atom, cyano, nitro, C3-C6 cycloalkyl, C1-C4
alkoxy, Ci-C6 alkoxycarbonyl, SCO^R5*, D-42 or D-43.
10 Examples of R5a include C-G, alkyl.
[0084]
Examples of V include a halogen atom, cyano, nitro, CpCe alkyl, C1-C6
haloalkyl, -OH, CrC6 alkoxy, Cj-C6 haloalkoxy, Q-C6 alkylsulfonyloxy, C1-C6
halo alky Isulfonyloxy, C1-C6 alkylthio, C]-C6 haloalkylthio, Q-C6 alkylsulfmyl, C1-C6
15 haloalkylsulfinyl, C]-C6 alkylsulfonyl, Ci-C6 haloalkylsulfonyl, -NH2, Ci-C6
alkylamino, di(Ci~C6 alkyl) amino, C1-C6 alkoxycarbonyl, -C(0)NH2, C1-C6
alkylaminocarbonyl, Ci-Ce haloalkylaminocarbonyl, di(CrC6 alkyl) aminocarbonyl, -
C(S)NH2, -S(0)2NH2, Ci-C6 alkylaminolsulfonyl or di(C!-C6 alkyl) aminosulfonyl,
and each V may be the same as or different from each other, when p 1 represents an
20 integer of 2 or more, and moreover, when two Vs are adjacent, the two adjacent Vs
may form a 5-membered ring or a 6-membered ring with carbon atoms bonding to
each of the two Vs by forming -OCH2O- or -0CH2CH2O, and hydrogen atoms
bonding to each carbon atom forming the ring may be optionally substituted by
halogen atoms in this case.
25 [0085]
Examples of Z include a halogen atom, cyano, nitro, amino, C1-C6 alkyl, (Ci-
C6) alkyl optionally substituted by R16, CrC6 haloalkyl, Ci-C6 alkoxy, Ci-C6
haloalkoxy, Ci-C6 alkylthio, Ci-Ce haloalkylthio, Ci-C6 alkylsulfinyl, Ci-C6
haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, Ci-C6
30 alkoxycarbonyl, -C(0)NH2, -C(S)NH2, -S(0)2NH2, -C(0)N(R18)R17, -C(S)N(R18)R17,
Ci-Ce alkyl aminos ulfonyl or di (C1-C6 alkyl) aminosulfonyl, and preferably include a
halogen atom, CrC6 alkyl, Ci-C6 alkylthio, CrC6 alkylsulfinyl, CrC6
haloalkylsulfinyl, Ci-C6 alkylsulfonyl and C(0)N(R18)R17.
[0086]
34
Examples of L2 preferably include a single bond, methylene, ethylidene,
propylidene, 1-methyl-ethyliden, butylidene, 1-methyl-propylidene, 2-methylpropylidene,
pentylidene, 1-methylbutylidene, 2-methylbutylidene, 3-
methylbutyiidene, hexylidene, ethylene, trimethylene, tetramethylene, pentamethylene
5 and hexamethylene.
[0087]
Examples of Q2 include a hydrogen atom, Q-C6 haloalkyl, C2-Cg alkynyl, -
N(R23)R22, -C(0)N(R23)R22, phenyl, phenyl substituted by (Z)p), D18 to D20 or D-42
to D47, and preferably include a hydrogen atom, Q-C6 haloalkyl, C2-C6 alkynyl, -
10 N(R23)R22, -C(0)N(R23)R22 and D42 to D47.
[0088]
Specific examples of the expression of
(Rlb may form a 3-7 membered ring with a nitrogen atom to be bonded, by forming a
C2-C6 alkylene chain together with R a, and this alkylene chain may include one
15 oxygen atom, sulfur atom or nitrogen atom in this case)
in the present specification include an aziridine, azetidine, pyrrolidine, oxazolidine,
thiazolidine, imidazolidine, piperidine, morpholine, thiomorpholine, piperazine,
homopiperizine, and heptamethyleneimine, each of which is selected within the range
of each specified number of atoms.
20 [0089]
Specific examples of the expression of
(Rlc may form a 5-7 membered ring with a nitrogen atom to be bonded, by forming a
C4-C6 alkylene chain together with Rld, and this alkylene chain may include one
oxygen atom, sulfur atom or nitrogen atom in this case, and may be optionally
25 substituted by an oxo group or thioxo group)
in the present specification include an aziridine, azetidine, azetidine-2-one,
pyrrolidine, pyrrolidine-2-one, oxazolidine, oxazolidine-2-one, oxazolidine-2-thione,
thiazolidine, thiazolidine-2-one, thiazolidine-2-thione, imidazolidine. imidazolidine-2-
one, imidazolidine-2-thione, piperidine, piperidine-2-one, piperidine-2-thione, 2H-
30 3,4,5,6-tetrahydro-l,3-oxazin-2-one, 2H-3,4,5,6-tetrahydro-l ,3-oxazin-2-thione,
morpholine, 2H-3,455,6-tetrahydro-l,3-thiazine-2-one, 2H-3,4,5,6-tetrahydro-l,3-
thiazine-2-thione, thiomorpholine, perhydropyrimidine-2-one, piperazine,
homopiperizine, homopiperizine-2-one and heptamethyleneimine, each of which is
selected within the range of each specified number of atoms.
35
[0090]
Specific examples of the expression of
(R2a may form a 3-6 membered ring with a nitrogen atom to be bonded, by forming a
C2-C5 alkylene chain together with R , and this alkylene chain may include one
5 oxygen atom, sulfur atom or nitrogen atom in this case)
in the present specification include a cyclopropane ring, cyclobutane ring,
cyclopentane ring, tetrahydrofuran ring, tetrahydrothiophene ring, pyrrolidine ring,
cyclohexane ring, tetrahydropyran ring, tetrahydrothiopyran ring, piperidine ring,
cycloheptane ring, oxepane ring, thiepane ring and azepane ring. Each of the rings is
10 selected within the range of each specified number of atoms.
Examples of solvents capable to be used for the reactions during the
production of (2) from (3), the production of (3) from (4) and (5) and the production
of (2) from (4) and (5) in one step according to the present invention include aromatic
hydrocarbons which may be substituted by halogen atoms such as benzene, toluene,
15 xylene, chlorobenzene, o-dichlorobenzene or mesitylene; or aliphatic hydrocarbons
which may be substituted by halogen atoms such as n-pentane, n-hexane, n-heptane,
n-octane, cyclopentane, cyclohexane, methylcyclohexane, methylene chloride or 1,2-
dichloroethane; ethers such as diethyl ether, diisopropyl ether, cyclopentyl methyl
ether, t-butyl methyl ether; nitriles such as acetonitrile and propionitrile; esters such as
20 ethyl acetate and butyl acetate; amines such as triemylamine, tributylamine and
pyridine; nitromethane; nitroethane; water and a supercritical fluid, and preferably
include toluene, n-hexane, n-heptane, cyclohexane, methylene chloride, 1,2-
dichloroethane, chlorobenzene, diisopropyl ether, cyclopentyl methyl ether, t-butyl
methyl ether, acetonitrile, propionitrile, ethyl acetate, butyl acetate, triethylamine,
25 tributylamine, pyridine, nitromethane, water or the supercritical carbon dioxide, and
particularly preferably include toluene for the production of (2) from (3); water,
chlorobenzene, toluene, n-heptane, tributylamine or ethyl acetate for the production of
(3) from (4) and (5); and toluene for the production of (2) from (4) and (5) in one step.
These solvents may be used singly or in combination.
30 [0091]
An amount used of such solvents is not particularly limited. However, the
amount is usually 0.01 to 100 parts by weight, preferably 0.05 to 50 parts by weight,
and particularly preferably 0.1 to 15 parts by weight per part by weight of the
36
aromatic ketone compound or the substituted acetophenone compound or the 1,3-
bis(substitutedphenyl)-3-substituted-3-hydroxypropan-l-one compound.
[0092]
Examples of bases capable to be used for the reaction according to the present
5 invention include sodium hydroxide, potassium hydroxide, barium hydroxide,
calcium hydroxide, potassium carbonate, sodium carbonate, barium carbonate,
calcium carbonate, potassium bicarbonate, sodium bicarbonate, sodium acetate,
potassium acetate, sodium methoxide, potassium-t-butoxide, ammonia, methylamine,
ethylamine, n-propylamine, i-propylamine, n-butylamine, i-butylamine, t-butylamine,
10 n-pentylamine, i-pentylamine,benzylamine, aniline, dimethyl amine, diethylamine, din-
propylamine, di-i-propyl amine, di-n-butyl amine, di-i-butylamine, di-n-pentylarnine,
di-i-pentylamine, pyrrolidine, piperidine, piperazine, morpholine, dibenzylamine,
trim ethylamine, triethylamine, tri-n-propylamine, tri-n-butylamine, tripentyl amine,
tribenzylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 2-methyl-5-
15 ethylpyridine, 4-dimemylarriinopyridine, 1,8-diazabicycio (5,4,0)-7-undecene,
triethylenediamine, N,N,N',NLtetramethylethylenedi amine or 1,1,3,3-
tetramethylguanidine, and preferably include pyridine, 2-methyl-5-ethylpyridine,
tributylarnine and 4-dimethyIaminopyridine, for the production of (2) from (3);
diethylamine, di-i-propylamine, di-n-propylamine, di-n-butylamine, pyrrolidine,
20 triethylamine, tri-n-butylamine for the production of (3) from (4) and (5) performed in
an organic solvent; potassium carbonate and sodium carbonate for the production of
(3) from (4) and (5) performed in water; potassium carbonate, sodium carbonate tri-nbutylamine,
4-dimethylammopyridine, 1,8-diazabicyclo (5,4,0)-7-undecene and
1,1,3,3-tetramethylguanidine for the production of (2) from (4) and (5) in one step.
25 These bases may be used singly or in combination.
[0093]
An amount used of such bases is not particularly limited. However, the
amount is usually 0.01 to 100 times by mole, preferably 0.05 to 50 times by mole,
particularly preferably 0.05 to 10 times by mole per mol of the l,3-bis(substituted
30 phenyl)-3-substituted-3-hydroxypropan-l-one compound for the production of (2)
firom (3), and usually 0.01 to 50 times by mole, preferably 0.05 to 25 times by mole,
particularly preferably 0.05 to 5 times by mole per mol of the aromatic ketone
compound or the substituted acetophenone compound for the production of (3) from
(4) and (5), and the production of (2) from (4) and (5) in one step.
37
[0094]
Examples of surfactants or the like capable to be used for the reaction
according to the present invention as additives include as follows:
(A) Nonionic surfactant:
5 (A-l) Polyethylene glycol type surfactants: Examples of polyethylene glycol
type surfactants include polyoxyethylenealkyl (C^-is) ether, an ethyleneoxide adduct
of alkylnaphthol, polyoxyethylene (mono or di) alkyl (Cg.n) phenyl ether,
formaldehyde condensation products of polyoxyethylene (mono or di) alkyl (Ca-u)
phenyl ether, polyoxyethylene (mono, di, or tri) phenyl phenyl ether, polyoxyethylene
10 (mono, di or tri) benzyl phenyl ether, polyoxypropylene (mono, di, or tri) benzyl
phenyl ether, polyoxyethylene (mono, di, or tri) styryl phenyl ether, polyoxypropylene
(mono, di or tri) styryl phenyl ether, a polymer of polyoxyethylene (mono, di or tri)
styryl phenyl ether, a polyoxyethylene polyoxypropylene block polymer, an alkyl
(Ci2-is) polyoxyethylene polyoxypropylene block polymer ether, an alkyl (Cg-u)
15 phenyl polyoxyethylene polyoxypropylene block polymer ether, polyoxyethylene
bisphenyl ether, polyoxyethylene resin acid ester, polyoxyethylene fatty acid (C^-js)
monoester, polyoxyethylene fatty acid (Cii-is) diester, polyoxyethylene sorbitan fatty
acid (C12-18) ester, ethyleneoxide adduct of glycerol fatty acid ester, ethyleneoxide
adduct of castor oil, ethyleneoxide adduct of hardened caster oil, ethyleneoxide
20 adduct of alkyl (Ct2-ts) amine and ethyleneoxide adduct of fatty acid (C12-18) amide.
(A-2) Polyvalent alcohol type surfactants: Examples of polyvalent alcohol
type surfactants include glycerol fatty acid ester, polyglycerin fatty acid ester,
pentaerythritol fatty acid ester, sorbitol fatty acid (C12-IB) ester, sorbitan fatty acid
(C12.18) ester, sucrose fatty acid ester, polyvalent alcohol alkyl ether and fatty acid
25 alkanol amide.
(A-3) Acetylene type surfactants: Examples of acetylene type surfactants
include acetylene glycol, acetylene alcohol, ethyleneoxide adduct of acetylene glycol
and ethyleneoxide adduct of acetylene alcohol.
(A-4) Other surfactants: Examples of other surfactants include alkylglucoside.
30 [0095]
(B) Anionic surfactants:
(B-l) Carboxylic acid type surfactants: Examples of carboxylic acid type
surfactants include polyacrylic acid, polymethacrylic acid, polymaleic acid, a
copolymer of maleic acid and olefin (for example, isobutylene and diisobutylene), a
38
copolymer of acrylic acid and itaconic acid, a copolymer of methacrylic acid and
itaconic acid, a copolymer of maleic acid and styrene, a copolymer of acrylic acid and
methacrylic acid, a copolymer of acrylic acid and methyl acrylate, a copolymer of
acrylic acid and vinyl acetate, a copolymer of acrylic acid and maleic acid, N-methyl-
5 fatty acid (C12-18) sarcosinate, carboxylic acids such as resin acid and fatty acid (C6-20)
and the like, and salts of these carboxylic acids.
(B-2) Sulfate ester type surfactants: Examples sulfate ester type surfactants
include alkyl (C]2-i8) sulfate ester, polyoxyethylene alkyl (Cn-ia) ether sulfate ester,
polyoxyethylene (mono or di) alkyl (Cg-u) phenyl ether sulfate ester, sulfate ester of a
10 polyoxyethylene (mono or di) alkyl (Cn-ig) phenyl ether polymer, polyoxyethylene
(mono, di, or tri) phenyl phenyl ether sulfate ester, polyoxyethylene (mono, di, or tri)
benzyl phenyl ether sulfate ester, polyoxyethylene (mono, di, or tri) styryl phenyl
ether sulfate ester, sulfate ester of a polyoxyethylene (mono, di, or tri) styryl phenyl
ether polymer, sulfate ester of a polyoxyethylene polyoxypropylene block polymer,
15 sulfated oil, sulfated fatty acid ester, sulfated fatty acid and sulfate ester of sulfated
olefin and the like, and salts of these sulfate esters.
(B-3) Sulfonic acid type surfactants: Examples of sulfonic acid type
surfactants include paraffin (C12-22) sulfonic acid, alkyl (Cg-E2) benzene sulfonic acid,
formaldehyde condensation products of alkyl (Cg.^) benzene sulfonic acid,
20 formaldehyde condensation products of cresol sulfonic acid, a- olefin (C14-16) sulfonic
acid, dialkyl (Cg.12) sulfosuccinic acid, lignin sulfonic acid, polyoxyethylene (mono or
di) alkyl (Cg-12) phenyl ether sulfonic acid, polyoxyethylenealkyl (Ci2-is) ether
sulfosuccinate half ester, naphthalene sulfonic acid, (mono, or di) alkyl (Ci-6)
naphthalene sulfonic acid, formaldehyde condensation products of naphthalene
25 sulfonic acid, formaldehyde condensation products of (mono, or di) alkyl (Ci-e)
naphthalene sulfonic acid, formaldehyde condensation products of creosote oil
sulfonic acid, alkyl (Cg-12) diphenyl ether disulfonic acid, Igepon T (trade name),
polystyrene sulfonic acid and sulfonic acids of a styrene sulfonic acid - methacrylic
acid copolymer and the like, and salts of these sulfonic acids
30 (B-4) Phosphate ester type surfactants: Examples of phosphate ester type
surfactants include alkyl (C^-is) phosphate ester, polyoxyethylene alkyl (C^-ig) ether
phosphate ester, polyoxyethylene (mono or di) alkyl (C%.n) phenyl ether phosphate
ester, phosphate ester of a polyoxyethylene (mono, di, or tri) alkyl (Cg-12) phenyl ether
polymer, polyoxyethylene (mono, di, or tri) phenyl phenyl ether phosphate ester,
39
polyoxyethylene (mono, di, or tri) benzyl phenyl ether phosphate ester,
polyoxyethylene (mono, di, or tri) styryl phenyl ether phosphate ester, phosphate ester
of a polyoxyethylene (mono, di, or tri) styryl phenyl ether polymer, phosphate ester of
a polyoxyethylene polyoxypropylene block polymer, phosphatidylcholine,
5 phosphatidyl ethanolimine and phosphate ester of condensed phosphoric acid (for
example, tripolyphosphoric acid) and the like, and salts of these phosphate esters.
Salts of above-mentioned (B-l) to (B-4) include alkaline metals (such as
lithium, sodium and potassium), alkaline earth metals (such as calcium and
magnesium), ammonium and various types of amines (such as alkyl amines,
10 cycloalkyl amines and alkanol amines).
[0096]
(C) Cationic surfactants:
Examples of cationic surfactants include alkyl amine salts and alkyl
quaternary ammonium salts.
15 (D) Amphoteric surfactants:
Examples of amphoteric surfactants include betaine type surfactants and
amino acid type surfactants.
(E) Other surfactants:
Examples of other surfacants include silicone type surfactant and fluorine type
20 surfactant. Preferable examples include Soprofol (anionic/ nonionic surfactant, trade
name of RhodiaNicca, Ltd.), Solpol 3353 (nonionic surfactant, trade name of Toho
Chemical Industry Co., Ltd.), Epan (polyoxyethylene polyoxypropylene glycol, trade
name of Dai-ichi Kogyo Seiyaku Co., Ltd.), tetrabutylammonium bromide,
cetylpyridinium chloride, dodecyltrimethylammonium chloride, dodecylamine
25 hydrochloride, sodium dodecyl sulfate, sodium dodecanesulfonate,
dodecylbenzenesulfonic acid or the salt thereof, p-toluenesulfonic acid or the salt
thereof, polyethylene glycol, hexanoic acid or the salt thereof octanoic acid or the salt
thereof, decanoic acid or the salt thereof, iauric acid or the salt thereof, myristic acid
or the salt thereof, palmitic acid or the salt thereof, stearic acid or the salt thereof,
3 0 oleic acid or the salt thereof, proline or the salt thereof and phenylalanine or the salt
thereof.
Examples of the salts include alkali metals (lithium, sodium and potassium),
alkaline earth metals (calcium and magnesium), ammonium and pyridinium.
[0097]
40
Such surfactants are usually 0.0001 to 1 times by mole, preferably 0.001 to 1
times by mole, particularly preferably 0.01 to 0.5 times by mole per mol of the
aromatic ketone compound (4) or the substituted acetophenone compound (5).
[0098]
5 Examples of water soluble organic solvents capable to be used for the reaction
according to the present invention as additives include dimethylsulfoxide, sulfolane,
N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N, N'-
dimethylethylene urea, hexamethylphosphoric triamide, acetonitrile, propionitrile,
methanol, ethanol or nitromethane, and preferably dimethyl sulfoxide, sulfolane, N,N-
10 dimethylformamide, hexamethylphosphoric triamide, acetonitrile, methanol or
nitromethane, and particularly preferably N,N-dimethylacetamide, acetonitrile or
methanol. These may be used singly or in combination.
[0099]
An amount used of such water organic soluble solvents is usually 0,01 to 10
15 parts by weight, preferably 0.05 to 5 parts by weight, and particularly preferably 0.05
to 3 parts by weight per part by weight of the aromatic ketone compound or the
substituted acetophenone compound.
[0100]
Examples of compounds capable to be used for the reaction according to the
20 present invention as dehydration agents include thionyl chloride, sulfuric chloride,
methanesulfonyl chloride, p-toluenesulfonyl chloride, benzoyl chloride, acetyl
chloride, acetic anhydride, propionic anhydride or benzoic anhydride, and preferably
thionyl chloride, sulfuric chloride, methanesulfonyl chloride, benzoyl chloride, acetyl
chloride, acetic anhydride or benzoic anhydride.
25 [0101]
An amount used of such dehydration agents is usually 0.1 to 100 times by
mole, preferably 0.5 to 50 times by mole, particularly preferably 1 to 15 times by
mole per mol of the l,3-bis(substituted phenyl)-3-substimted-3-hydrox}^ropan-l-one
compound.
30 [0102]
For perfonning the production of (2) from (3) according to the present
invention, for example, l,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-lone
compound represented by Formula (3) or the salt thereof, a solvent as represented
by toluene, a base as represented by triethylamine, tri-n-butylamine, pyridine and 4-
41
dimethylaminopyridine, a dehydration agent as represented by thionyl chloride and
acetic anhydride are fed into a reactor, and the mixture may be stirred for usually
about 10 minutes to 150 hours, and preferably about 1 to 96 hour(s) usually at 0 to
150QC and preferably at 20 to 120°C.
5 [0103]
For performing the production of (3) from (4) and (5) or the production of (2)
from (4) and (5) in one step according to the present invention, for example, a
predetermined amount of the aromatic ketone compound represented by Formula (4)
and the substituted acetophenone compound represented by Formula (5), a solvent as
10 represented by toluene, a base as represented by triethylamine and tri-n-butylamine
are fed into a reactor, and the mixture may be stirred for usually about 10 minutes to
150 hours, and preferably about 1 to 96 hour(s) usually at 0 to 150 °C and preferably
at20tol00°C,
[0104]
15 For example, a predetermined amount of the aromatic ketone compound
represented by Formula (4) and the substituted acetophenone compound represented
by Formula (5), water, a base as represented by potassium carbonate and a water
soluble organic solvent are fed into a reactor, and the mixture may be stirred for
usually about 10 minutes to 150 hours, and preferably about 1 to 96 hour(s) usually at
20 0 to 100°C and preferably at 20 to 100°C.
For example, a predetermined amount of the aromatic ketone compound
represented by Formula (4) and the substituted acetophenone compound represented
by Formula (5), water, a base as represented by potassium carbonate, a surfactant and
the like are fed into a reactor, and the mixture may be stirred for usually about 10
25 minutes to 150 hours, and preferably about 1 to 96 hour(s) usually at 0 to 100°C and
preferably at 20 to 100°C.
[0105]
For example, a predetermined amount of the aromatic ketone compound
represented by Formula (4) and the substituted acetophenone compound represented
30 by Formula (5), a solvent as represented by toluene and a base as represented by
potassium carbonate are fed into a reactor, and the mixture may be stirred for usually
about 10 minutes to 150 hours, and preferably about I to 120 hour(s) usually at 0 to
150°C and preferably at 20 to 120°C.
42
For example, a predetermined amount of the aromatic ketone compound
represented by Formula (4) and the substituted acetophenone compound represented
by Formula (5), a solvent as represented by toluene, a base as represented by tri-nbutylamine
and 4-dimethylarninopyridine, a dehydration agent as represented by
5 benzoic anhydride are fed into a reactor, and the mixture may be stirred for usually
about 10 minutes to 150 hours, and preferably about 1 to 120 hour(s) usually at 0 to
150 °C and preferably at 20 to 120°C.
[0106]
Among them, preferable embodiments include, for example, the case that the
10 solvent is an organic solvent and the reaction is performed without additives; the case
that the solvent is water and the reaction is performed with an water soluble organic
solvent as the additive; and the case that the solvent is water and the reaction is
performed with a surfactant as the additive.
Here, for producing (2) through (3) from (4) and (5) in one pot, it is preferable
15 that an organic solvent is used as the solvent, and the reaction temperature is set to a
temperature of over 80°C. In addition, (2) can also be produced in one step by adding
a dehydration agent as represented by benzoic anhydride to the reaction.solution
without isolating (3) produced from (4) and (5).