PROCEDE D'OBTENTION DE DERIVES D'ACIDE HALOGENOPHENOXYGRAS PAR HALOGENATION SELECTIVE, ET DERIVES D'ACIDE HALOGENOPHENOXYGRAS

PROCESS FOR PRODUCING HALOGENOPHENOXYFATTY ACID DERIVATIVES BY SELECTIVE HALOGENATION AND HALOGENOPHENOXYFATTY ACID DERIVATIVES

Abrégé anglais

Disclosed are a process for producing a
halogenophenoxyfatty acid derivative represented by the
formula (I):
(see fig. I)
[wherein R is CN, -CONR3R4 (in which R3 and R4 are H, alkyl,
phenyl, benzyl or the like or together form alkylene) or
-COAR5 (in which R5 is H, alkyl, phenyl, benzyl or the like
and A is O or S), R1 and R2 are H or alkyl, X is halogen or
alkyl and Y is halogen] which comprises selectively
halogenating a phenoxyfatty acid represented by the following
formula:
(see fig. II)
with a halogenating agent; and a novel halogenophenoxyfatty
acid derivative represented by the formula:
(see fig. III)

[wherein R', R1', R2', X' and Y' have the meanings similar to
R, R1, R2, X and Y]. The halogenophenoxyfatty acid derivative
is useful as intermediate for producing herbicide or the
like.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing a halogenophenoxyfatty acid
derivative represented by the formula (I):
<IMG>
[wherein R represents a cyano group, -CON(R3)R4 (wherein R3
and R4 which may be identical or different each represent a
hydrogen atom, a C1-C6 alkyl group, a phenyl group, a phenyl
group having 1 to 5 substituents which may be identical or
different and are selected from halogen atom, nitro group,
cyano group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6
alkoxy group, C1-C6 haloalkoxy group, C1-C6 alkylthio group
and C1-C6 haloalkylthio group, a benzyl group or a benzyl
group having 1 to 5 substituents which may be identical or
different and are selected from C1-C6 alkyl group, C1-C6
haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group,
C1-C6 alkylthio group and C1-C6 haloalkylthio group or R3 and
R4 together represent a C4-C5 alkylene group) or -COAR5
(wherein R5 represents a hydrogen atom, a C1-C6 alkyl group,
a phenyl group, a phenyl group having 1 to 5 substituents
which may be identical or different and are selected from
halogen atom, nitro group, cyano group, C1-C6 alkyl group,
C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy
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group, C1-C6 alkylthio group and C1-C6 haloalkylthio group, a
benzyl group or a benzyl group having 1 to 5 substituents
which may be identical or different and are selected from
C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group,
C1-C6 haloalkoxy group, C1-C6 alkylthio group and C1-C6
haloalkylthio group and A represents an oxygen atom or a
sulfur atom), R1 and R2 which may be identical or different
each represent a hydrogen atom or a C1-C6 alkyl group, and X
represents a halogen atom or a C1-C6 alkyl group and Y
represents a halogen atom], which comprises:
selectively halogenating a phenoxyfatty acid represented
by the following formula:
<IMG>
(wherein R, R1, R2 and X are as defined above) with a
halogenating agent in an inert solvent.
2. A process according to claim 1 wherein the
halogenating agent is a chlorinating agent.
3. A halogenophenoxyfatty acid derivative represent by
the formula (I'):
-17-

<IMG>
wherein R' represents a cyano group or -CON(R3')R4' (wherein
R3' and R4' which may be identical or different each
represent a hydrogen atom, a C1-C6 alkyl group, a phenyl
group, a phenyl group having 1 to 5 substituents which may be
identical or different and are selected from halogen atom,
nitro group, cyano group, C1-C6 alkyl group, C1-C6 haloalkyl
group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C1-C6
alkylthio group and C1-C6 haloalkylthio group, a benzyl group
or a benzyl group having 1 to 5 substituents which may be
identical or different and are selected from C1-C6 alkyl
group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6
haloalkoxy group, C1-C6 alkylthio group and C1-C6
haloalkylthio group or R3' and R4' together represent a C4-C5
alkylene group), R1' and R2' which may be identical or
different each represent a hydrogen atom or a C1-C6 alkyl
group, X' represents a fluorine atom, an iodine atom, a
bromine atom or a C1-C6 alkyl group and Y' represents a
halogen atom, with the proviso [1] that R' does not represent
a cyano group) when R1' and R2' each represent a hydrogen
atom, X' represents a fluorine atom and Y' represents a
chlorine atom, [2] that R' does not represent a cyano group,
when R1' and R2' each represent a hydrogen atom and X' and Y'
each represent a bromine atom, and [3] that R' does not
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represent -CONH2, when R1' and R2' each represent a hydrogen
atom and X' and Y' each represent a fluorine atom].
4. A halogenophenoxyfatty acid derivative according to
claim 3 wherein in the formula (I'), R' represents a cyano
group or -CON(R3')R4' (wherein R3' and R4' which may be
identical or different each represent a hydrogen atom, a
C1-C6 alkyl group, a phenyl group or a phenyl group
substituted with 1 to 5 halogen atoms which may be identical
or different and R3' and R4' together represent a C4-C5
alkylene group), R1' represents a hydrogen atom or a C1-C6
alkyl group, R2' represents a hydrogen atom, X' represents a
fluorine atom or a C1-C6 alkyl group and Y' represents a
chlorine atom.
5. A process according to claim 2, wherein the
chlorination is conducted using chlorine gas as the
chlorinating agent in an inert solvent at a temperature of
from -20°C to the boiling temperature of the solvent.
6. A process according to claim 2 or 5, wherein X is a
chlorine or fluorine atom.
7. A halogenophenoxyfatty acid derivative according to
claim 3, wherein in the formula (I'):
-19-

R' represents CONH 2, CONHCH3, CONHC2H5, CONHC3H.gamma.-i, CON(CH3)2, CN,
<IMG>
<IMG>
R1' represents H or CH3;
R2' represents H;
X' represents F or CH3; and
Y' represents Cl.
-20-

Description

2091864
1 BACKGROUND OF THE INVENTION
Field o,f the Invention
The present invention relates to a process for
producing halogenophenoxyfatty acid derivatives
represented by the formula (I):
Y
R1
X O O-C-R (I)
R2
[wherein R represents a cyano group, -CON(R3)R4 (wherein
R3 and R4 which may be identic<31 or different each
represents a hydrogen atom, a lower alkyl group, a
phenyl group, a phenyl group having 1 to 5 substituents
which may be identical or different and are selected
from halogen atom, nitro group, cyano group, lower alkyl
group, lower haloalkyl group, lower alkoxy group, lower
haloalkoxy group, lower alkylthio group and lower
haloalkylthio group, a benzyl group or a benzyl group
having 1 to 5 substituents which may be identical or
different and are selected from lower alkyl group, lower
haloalkyl group, lower alkoxy group, lower haloalkoxy
group, lower alkylthio group and lower haloalkylthio
group and R3 and R4 may together represent an alkylene
group) or -COAR5 (wherein R5 represents a hydrogen atom,
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2091864
a lower alkyl group, a phenyl'group, a phenyl group having 1
to 5 substituents which may be identical or different and are
selected from halogen atom, nitro group, cyano group, lower
alkyl group, lower haloalkyl group) lower alkoxy group) lower
haloalkoxy group, lower alkylthio group and lower
haloalkylthio group, a benzyl group or a benzyl group having
1 to 5 subst ituents which may be ide~nt ical or different and
are selected from lower alkyl group, lower haloalkyl group,
lower alkoxy group, lower haloalkoxy group, lower alkylthio
group and lower haloalkylthio group and A represents an
oxygen atom or a sulfur atom), R1 and R2 which may be
identical or different each represents a hydrogen atom or a
lower alkyl group, X represents a halogen atom or a lower
alkyl group and Y represents a halogen atom] and further
relates to a part of halogenophenoxyfatty acid derivatives
obtained by the process.
The term "lower" alkyl group or the like in the
present specification denotes a grouip having one to six
carbon atoms. The "alkylene" group in the present
specification denotes such a group having 4 or 5 carbon
atoms.
In general, halogenophenox:yfatty acid derivatives
are produced by halogenating monohalogenophenols to obtain
dihalogenophenols and then preparing' halogenophenoxyfatty
acid derivatives from the resulting dihalogenophenols. The
dihalogenophenols are prepared by th.e processes disclosed in
Japanese Patent Kokai (Laid-Open) Nos. 60-193939, 62-223140
and 3-99033 and Japanese Patent Kokoku (Post Exam. Publ.) No.
3-22377.
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25711-655

2091864
1 However, these processes involve the possibil-
ity of producing the toxic dioxines as by-products.
Besides, it is necessary to use hydrogen peroxide in the
process of Japanese Patent Kokai (Laid-Open) No. 62-
223140, nitrogen-containing bases in the process of
Japanese Patent Kokoku (Post Exam. Publ.) No. 3-22377
and water and two phase system in the process of
Japanese Patent Kokai (Laid-Open) No. 3-99033 in
addition to the chlorinating agents .
Furthermore, as a process for producing
halogenophenoxyfatty acid derivatives by halogenating
monohalogenophenoxyfatty acid derivatives, it was
reported to carry out the halo~genation using halogenat-
ing agents and catalysts such ,as iodine and iron
[J.O.C., 426 (1946)]. However, this process has the
problem in after-treatment of the used catalysts.
SUMMARY OF THE INVENTION
The inventors have made intensive research in
order to develop a novel process for producing halogeno-
phenoxyfatty acid derivatives :in a high yield without
using catalysts. As a result, the present invention has
been accomplished.
The halogenophenoxyfatty acid derivatives
represented by the formula (I) which are produced by the
process of the present invention are useful as
intermediates for pharmaceuticals, agricultural
chemicals and chemical products and some of them which
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2091864
are novel compounds which have not yet been mentioned in
literature.
The novel compounds are represented by the
following formula (I'):
Y,
1'
R
X' O O-C-R'
2~
R
[wherein R' represents a cyano group or -CON(R3~)R4~ (wherein
R3~ and R4~ which may be identical or different each
represent a hydrogen atom, a lower alkyl group, a phenyl
group, a phenyl group having 1 to 5 substituents which may be
identical or different and are selected from halogen atom,
nitro group, cyano group, lower alkyl group) lower haloalkyl
group, lower alkoxy group, lower haloalkoxy group, lower
alkylthio group and lower haloalkylthio group, a benzyl group
or a benzyl group having 1 to 5 substituents which may be
identical or different and are sele~~ted from lower alkyl
group, lower haloalkyl group, lower alkoxy group, lower
haloalkoxy group, lower alkylthio group and lower
haloalkylthio group or R3~ and R4~ 'together represent an
alkylene group), R1~ and R2~ which may be identical or
different each represent a hydrogen atom or a lower alkyl
group, X' represents a fluorine atom, an iodine atom, a
bromine atom or a lower alkyl group and Y' represents a
halogen atom, with the proviso [1] 'that R' does not represent
a cyano group) when R1~ and R2~ each represent a hydrogen
- 4 -
25711-655

209864
atom, X' represents a fluorine atom and Y' represents a
chlorine atom, (2] that R' does not represent a cyano group,
when R1~ and R2~ each represent a hydrogen atom and X' and Y'
each represent a bromine atom and [~i] that R' does not
represent -CONH2, when R1~ and R2~ each represent a hydrogen
atom and X' and Y' each represent a fluorine atom.
DETAILED DESCRIPTION OF PREFERRED EbsBODIMENTS
The halogenophenoxyfatty acid derivatives of the
present invention can be produced, f:or example, by the
process as illustrated below.
R 1 haloge~ating R 1
X I -R - -~s X O O-C-R
R2 Rz
(wherein R, R1, R2, X and Y are as defined above).
The objective halogenophenoxyfatty acid derivatives
can be produced by selectively haloc~enating the phenoxyfatty
acids represented by the formula (II:) with halogenating
agents in the presence of inert solvents.
The inert solvents used in the present invention
may be any of those which do not considerably hinder the
progress of the above reaction. Examples of the solvents are
halogenated hydrocarbons such as methylene chloride,
chloroform, carbon tetrachloride and. perchloroethylene,
carboxylic acids such as formic acid., acetic acid and
- 5 -
25711-655

20 918 8 ~
propionic acid, aromatic hydrocarbons such as nitrobenzene)
chlorobenzene, dichlorobenzene and t:richlorobenzene, esters
such as ethyl acetate, nitriles
- 5a -
25711-655

2091864
1 such as acetonitrile and benzonitrile, amides such as
dimethylformamide and dimethylacetamide, sulfolane,
dimethyl sulfone, dimethyl sulfoxide, 1,3-dimethyl-2-
imidazolidinone, and water. These inert solvents may be
used each alone or in combination.
As the halogenating agents, there may be used,
for example, chlorine, bromine, iodine, hydrochloric
acid-hydrogen peroxide, sulfuryl chloride, phosphorus
pentachloride, N,N-dichlorourea, N-chlorosuccinimide, N-
bromosuccinimide, hypohalogenous acid t-butyl esters,
trichloroisocyanuric acid and trichloromethanesulfonyl-
halogenides. The amount of the halogenating agent can
be optionally selected from th.e range of from 0.1 mol to
an excess mol per mol of the p~henoxyfatty acids
represented by the formula (II).
If necessary, organic bases, inorganic bases
or organic salts can be used in the process of the
present invention. Examples of the organic bases are
amines such as triethylamine a.nd pyridine, examples of
the inorganic bases are alkali metal or alkaline earth
metal hydroxides such as sodium hydroxide, potassium
hydroxide, calcium hydroxide a.nd barium hydroxide and
alkali metal or alkaline earth metal carbonates such as
sodium carbonate, potassium carbonate and calcium
carbonate, and examples of they organic salts are alkali
metal or alkaline earth metal salts of organic acids
such as sodium acetate, potassium acetate, calcium
acetate and sodium benzoate ar,~d ammonium acetate.
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20 918 6 4
1 The amount of them can be optionally selected from the
range of from 0.1 mol to an excess mol per mol of the
phenoxyfatty acids represented by the formula (II).
The reaction temperature can be optionally
selected from the range of from -20°C to the boiling
point of the inert solvents used.
The reaction time depends on the reaction
temperature and the reaction scale, but can be selected
from the range of several minutes to 48 hours.
After completion of the reaction, the reaction
mixture containing the objective products is isolated by
usual methods such as extraction with solvents and, if
necessary, is purified by column chromatography,
recrystallization, distillation or the like whereby the
halogenophenoxyfatty acid derivatives represented by the
formula (I) or (I') can be produced.
Representative examples of the
halogenophenoxyfatty acid derivatives represented by the
formula (I') which are novel compounds are shown in
Table 1.

2091864
Y'
Rl
X' O O-C-R~
R2'
Table 1
No. X Y R1 RZ R
Yield Property
(%) (mP/C)
1 F C1 H H CONHZ 90.4 148.3
2 F C1 H H CONHCH3 92.0 87.9-88.1
3 F C1 H H CONHCZH5 75.6 66.8-67.0
4 F C1 H H CONHC3H7-i 81.5 117.1
F C1 H H CON(CHg)2 74.7 79.8-81.7
Cl
6 F C1 H H 81.6 151.6-152.5
O ~' C1
CONH
7 F C1 H H CON 84.7 103.6
8 F C1 CH3 H CN 80.6 Oil
9 CHg C1 C1 H CONHZ 70.2 Oil
NMR data of the compounds in the above Table 1
which are shown to be oil in tlhe column of "property"
are shown in Table 2.
_ g __

2091864
Table 2
No. 1H-NHR(CDClg, ppm)
8 1.63(3H, d), 4.97 (1H, m), 6.99 (1H,
m), 7.08 (1H, d. d), 7.17 (1H, d).
d.
9 2.27(3H, s), 4.49 (2H, s), 5.64 (1H,
br),6.79 (1H, br), 6.80 (1H, d), 7.02
(1H,d. d), 7.20 (1H, d).
1 The present invention is illustrated by the
following nonlimiting typical examples.
Example 1 Preparation of 2-chloro-4-fluorophenoxyaceto-
nitrile (compound No. 25)
C1
C12
F O O-CHZCN -j- F O O-CHZCN
1.51 g (0.01 mol) of 4-fluorophenoxyaceto-
nitrile and 0.82 g (0.01 mol) of sodium acetate were
dissolved in a mixed solvent comprising 7 ml of acetic
acid and 3 ml of water and chlorine gas was introduced
into the solution at a rate of 12.3 ml/min for 60
minutes at 50°C with stirring.
After termination of the reaction, to the
reaction mixture was added 3 m:l of a 10% aqueous sodium
thiosulfate solution and the solvent was distilled off
under reduced pressure. To the resulting residue was
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2091864
1 added 20 ml of a 10% aqueous sodium hydrogencarbonate
solution and the objective product was extracted with
ethyl acetate (30 ml x 2).
The organic layer was dried over anhydrous
sodium sulfate and concentrated under reduced pressure.
The resulting concentrate was distilled to obtain 1.54 g
of 2-chloro-4-fluorophenoxyacetonitrile.
This compound was known compound and had the
same melting point and NMR as those mentioned in
literature.
Yield: 83.0%
Example 2 Preparation of 2,4-dichlorophenoxyacetamide
(compound No. 10)
C1
O 0
C1 O O-CH2CINH2 C12 -~ C1 O 0-CH2CNH2
1.86 g (0.01 mol) of 4-chlorophenoxyacetamide
was dissolved in 11 ml of acetic acid with heating at
50°C and chlorine gas was introduced thereinto at that
temperature for 50 minutes at a rate of 12.3 ml/min.
After termination of the reaction, to the
reaction mixture was added 3 ml of a 10% aqueous sodium
thiosulfate solution and the solvent was distilled off
under reduced pressure. To tree residue was added 20 ml
of a 10% aqueous sodium hydrogencarbonate solution and
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u. t X091864
1 the objective product was extracted with ethyl acetate
(30 ml x 2).
The organic layer was dried over anhydrous
sodium sulfate and concentrated under reduced pressure.
The resulting crystal was washed with n-hexane to obtain
2.02 g of the objective 2,4-dichlorophenoxyacetamide.
Yield: 92.0$
This compound was known compound and had the
same melting point and NMR as those mentioned in
literature.
Example 3 Preparation of 2,4-dichlorophenoxyacetic acid
(compound No. 17)
C1
0 O
Cl;~
C1 O O-CH2COH -~ Cl O O-CHZCOH
1.87 g (0.01 mol) o~f 4-chlorophenoxyacetic
acid was added to 10 ml of di.methylformamide and
chlorine gas was introduced t,hereinto at 50°C for 45
minutes at a rate of 12.3 ml/'min with stirring.
After termination of the reaction, to the
reaction mixture was added 3 ml of a 10% aqueous sodium
thiosulfate solution and the solvent was distilled off
under reduced pressure. To t:he residue was added 20 ml
of a 10% aqueous sodium hydrc>gencarbonate solution and
- l:l -

~0 918 6 4
1 the objective product was extracted with ethyl acetate
(30 ml x 2).
The organic layer was dried over anhydrous
sodium sulfate and concentrated under reduced pressure.
The resulting crystal was washed with n-hexane to obtain
2.07 g of the objective 2,4-dichlorophenoxyacetic acid.
Yield: 93.6%
This compound was known compound and had the
same melting point and NMR as those mentioned in
literature.
Table 3 shows typical examples of the
halogenophenoxyfatty acid derivatives represented by the
formula (I) which were prepared in the same manner as in
Examples 1-3.
Since the compounds shown in Table 3 are known
compounds, they were identified by the identity of their
melting point, NMR and IR witla those mentioned in
literature.
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2091864
Y R1
X O - O-C-R ( I )
R2
Tables 3
No. X' Y' Rl' RZ' R' Yield (%)
C1 C1 H H CONH2 92.0
11 C1 C1 H H CONHCH3 94.4
12 C1 C1 H H CONHC2H5 93.3
13 C1 C1 H H CONHC3H~-i 87.5
14 C1 Cl H H CON(CH3)2 77.4
C1
C1 C1 H H CiJNH ~ C1 81 7
C1
16 C1 C1 H H CON, I 96.2
V
17 Cl C1 H H CC~OH 93.6
18 C1 C1 H H C00CH3 81.5
19 C1 C1 H H COOC2H5 83.6
C1 C1 H H COOC3H~-i 87.1
21 F Cl H H COON 80.6
22 F C1 H H COOCH3 84.2
23 F C1 H H COOCZH5 76.3
24 F C1 H H COOC3H~-i 80.9
F C1 H H CN 83.0
26 Cl C1 CH3 H CO()H 82.0
27 C1 C1 CHg H CO1JH2 88.9
28 C1 C1 CH3 H CON 74.5
29 C1 C1 CHg H COOCH3 81.5
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._ X091864
1 The halogenophenoxyi°atty acid derivatives
represented by the formula (I) are important especially
as intermediates in preparation of the herbicides
disclosed in Japanese Patent lCokai (Laid-open) No. 3-
163063. The typical herbicides which are final products
can be prepared, for example, by the process as
illustrated below.
Y
Y R1 Bromina- R1 CH2=CHOC4H9-n
tion I
X O O-C-R --~ X ~ O 0-C-R
Catalyst
R2 Br R2
0
Y R1 II Y R1
R3"O-C._OR3 ~~
X O O-C-R ~ X O 0-C-R
I Base
CHgC RZ R3"-C-CH2C R2
II II II
O O O
Cyclyzation alkylation
R1
I
R-C-O OH
R2 Rq ~~
X X
Halogena-
y O tion y O Hal
~ R1 NI \
N~ORS" N~OR5"
R-C-O I R-C-O
R2 R4,. R2 Rq ~~
- 14 -

~0 918 fi 4
1 (wherein R, R1, R2, X and Y are as defined above, R3"
denotes a lower alkoxyl group, R4" denotes a lower alkyl
group or a lower haloalkyl group, R5" denotes a lower
alkyl group or a lower haloalltyl group and Hal denotes a
halogen atom.)
- 15 -

Dessin représentatif