STEREO-ISOMERES SPECIFIQUES DE DERIVES D'ACIDE PHENOXYALCANOIQUE

STEREOSPECIFIC ISOMERS OF PHENOXYALKANOIC ACID DERIVATIVES

Abrégé anglais

A B S T R A C T
Stereo-specific isomers of phenoxy-alkanoic acid derivatives,
especially phenoxy-propionic acid derivatives, can be prepared by re-
acting a substituted phenol, e.g., 4-chloro-2-methyl phenol or 2,4-
dichlorophenol with a lactic acid derivative of formula:
<IMG>
wherein X-O- is a leaving group, e.g., methane sulphonyl; R2 = 1-4
C alkyl; and R1 = H, metal ion, alkyl or (substituted) ammonium and
x denotes the absolute configuration of the lactic acid derivative
concerned, at elevated temperature with a base. The R-(+)-isomers
exhibit selective activity against broad-leaved weeds.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of phenoxy-alkanoic acid
derivatives having the following general formula and possessing
the R- or S- configuration at the carbon atom marked x:
<IMG> (I)
wherein R represents an alkyl group of up to 4 carbon atoms; n
is 0 or an integer up to 4; Hal represents a halogen atom; m is
0 or an integer up to 5; the total of n and m is 0 or an integer
up to 5, R1 represents a hydrogen atom, a metal-salt forming or
an optionally alkyl substituted ammonium ion, or an optionally
substituted alkyl, cycloalkyl, alkenyl, aryl or aralkyl group;
and R2 represents an alkyl group of up to 4 carbon atoms, which
comprises reacting a derivative of lactic acid of formula II
possessing the S- or R- configuration at the carbon atom marked
x:
<IMG> (II)
with a phenol of formula III:
<IMG> (III)
14

(wherein the group X-O- is a group which will leave the molecule and be re-
placed by a deprotonated phenol of formula III, and Hal, R, m and n have the
meanings hereinbefore specified) in the presence of a base and under condi-
tions of elevated temperature to produce a compound of formula I with the
required configuration.
2. A process as claimed in claim 1, wherein a compound of formula II is
used, wherein R represents a methyl group and the leaving group X-O- is an
-O.SO2.Q, -O.CO.Q or -O.CH(OH).CV3 group, wherein Q represents a hydrocarbyl
group and V represents a halogen atom.
3. A process as claimed in claim 2, wherein the leaving group X-O- is
an alkylsulphonyl or arylsulphonyl group containing up to 10 carbon atoms.
4. A process as claimed in claim 3, wherein the leaving group is a
methano sulphonyl group or a para-toluene sulphonyl group.
5. A process as claimed in claim 1, 2 or 3, wherein the reaction be-
tween the lactic acid derivative of formula II and the phenol of formula III
is carried out at a temperature between 50°C and 200°C.
6. A process as claimed in claim 1, 2 or 3, wherein the reaction be-
tween the lactic acid derivative of formula II and the phenol of formula III
is carried out at a temperature between 130°C and 170°C.
7. A process as claimed in claim 1, wherein the reaction between the
lactic acid derivative of formula II and the phenol of formula III is carried
out in the presence of a base.
8. A process as claimed in claim 7, wherein the base applied is an
alkali metal carbonate or bicarbonate.
9. A process as claimed in claim 7, wherein the base applied is anhy-
drous sodium carbonate.

10. A process as claimed in claim 1, wherein a lactic acid derivative of
formula II is used which has keen prepared by reacting an acid halide of for-
mula X-halide or the corresponding acid anhydride or a halogenated aldehyde
with a derivative of lactic acid of formula IV possessing the S- or R- con-
figuration at the carbon atom marked x:
<IMG>
wherein X and R1 have the meanings hereinbefore specified.
11. A process as claimed in claim 10, wherein the reaction is carried
out at a temperature in the range -5°C to +80°C.
12. A process as claimed in claim 10 or 11, wherein the process is carr-
ied out in the presence of an organic base.
13. A process as claimed in claim 10 or 11, wherein the lactic acid
derivative of formula IV is reacted with a compound V.SO2.Q, V.CO.Q, O(CO.Q)2
or H.CO.CV3, wherein Q and V are as defined in claim 2.
14. A process as claimed in claim 10 or 11, wherein the lactic acid
derivative of formula IV is reacted with an alkyl sulphonyl halide or with an
arylsulphonyl halide.
15. A process as claimed in claim 10 or 11, wherein the lactic acid
derivative of formula IV is reacted with methane sulphonyl chloride or para-
toluene sulphonyl chloride.
16. A process as claimed in claim 1, 2 or 3, wherein a compound accord-
ing to formula I is prepared, wherein the alkyl, alkenyl and alkylene groups
contain up to 6 carbon atoms, the aryl, aralkyl and alkaryl groups up to 10
carbon atoms, the halogen atoms are fluorine or chlorine and the hetero atoms
are oxygen or nitrogen.
16

17. Phenoxy-propionic acid derivatives of the general formula:
<IMG>
possessing the R- or S-configuration at the carbon atom marked x, wherein R
represents an alkyl group of up to 4 carbon atoms; n is 0 or an integer up to
4; Hal represents a halogen atom; m is 0 or an integer up to 5; the total of n
and m is 0 or an integer up to 5 and R1 represents an optionally alkyl substi-
tuted ammonium ion or an optionally substituted alkyl, cycloalkyl, alkenyl,
aryl or aralkyl group; and R2 represents a methyl group.
18. Phenoxy-propionic acid derivatives as claimed in claim 17, possessing
the R-configuration at the carbon atom marked x in formula I wherein R repre-
sents a methyl group; n is 0 or 1; Hal represents a chlorine atom; m is 1, 2
or 3; R1 represents an ammonium ion substituted by one or two alkyl groups of
up to 20 carbon atoms or an alkyl group of up to 12 carbon atoms; and R2
represents a methyl group.
19. A method of eradicating or controlling broad-leaved weeds which com-
prises applying to a locus a herbicidally active amount of a compound of for-
mula I as claimed in claim 17 or 18.
17

Description

~L~S~4~8
The present invention relates to a process for the preparation of
herbicidally active compounds. Some of the compounds are believed to
be novel and the present invention therefore also relates to those
compounds per se as well as to compositions containing them. The in-
vention relates further to a method of eradicating or controlling weedsby applying the compounds according to the present invention or the
compositions containing them to a crop or a locus infested with weeds.
It is known that phenoxy-propionic acids and derivatives thereof,
such as 2-(4-chloro-2-methylphenoxy)propionic acid and 2-~2,4-dichloro-
phenoxy)propionic acid and their respective alkali- and dimethylamine
salts can be successfully applied to combat broad-leaved weeds. It is
also known that one of the optical isomers of substituted phenoxy
propionic acids exerts a higher physiological activity than the other
isomer. The most active isomer is normally obtained by applying optical
resolution techniques on the corresponding racemate but these techniques
are laborious and have also the drawback of producing the less active
isomer which is of considerable less use and has to be converted into
the more active isomer in a subsequent process step.
The Applicants have now found a stereospecific route towards
specific isomers of the phenoxy-alkanoic acid derivatives which avoids
the need to employ lengthy resolution techniques. The process according
to the invention is in particular suitable for the preparation of
esters of phenoxy-propionic acid derivatives which apparently cannot
be selectively prepared via the stereospecific route towards dextra-
rotatory 2-(2,4-dichlorophenoxy)propionic acid described in British
Patent Specification No. 1,114,040.
--2--
~r,
q~

5~4b8
Thus, the present invention provides a process for the
preparation of phenoxy-alkanoic acid derivatives having the following
general formula and possessing the R- or S-configuration at the carbon
atom marked x:
(Hal)
nr~ 2
R O
~ - O - C C 0 R (I)
(R)n
wherein R represents an alkyl group of up to 4 carbon atoms; n is 0 or
an integer up to 4; Hal represents a halogen atom; m is O or an integer
up to 5; the total of n and m being zero or an integer from 1 to 5; Rl
represents a hydrogen atom, a metal-salt forming or an optionally alkyl
substituted ammonium ion, or an optionally substituted alkyl, cycloalkyl,
alkenyl, aryl or aralkyl group; and R represents an alkyl group of up
to 4 carbon atom, which comprises reacting a derivative of lactic acid of
formula II possessing the S-or R-configuration at the carbon atom marked
x:
COOR
X _ O Xc -H (II)
R2
with a phenol of formula III:
(Hal) m
HO ~ (III)
(R)n
., ,.~
-- 3 --

~5~4i,8
(wherein the group X-O- is a eroup which will leave the molecule and
be replaced by a deprotonated phenol of formula III, and Hal, R, m
and n have their meaning hereinbefore specified) in the presence of
a base and under conditions of elevated temperature to produce a
compound of for~ula I with the required configuration.
The process according to the present invention is particularly
suitable ~or the preparation of phenoxy-propionic acid derivatives
of the general formula I, i.e., compounds wherein R represents a
methyl group.
The leaving group X-O- in formula II must, as stated above, be
capable of being replaced by a deprotonated phenol of formula III
and suitable examples of such groups are the following: -O.S02.Q,
-O.CO.Q and -O.CH(OH).CV3, wherein Q represents a hydrocarbyl group,
suitably an alkyl or aryl group containing up to 10 carbon atoms,
and V represents a halogen atom, e.g., chlorine, fluorine or bromine.
Preferably, the leaving group X-O- is an alkylsulphonyl or aryl-
sulphonyl group, e.g. methane-sulphonyl or para-toluenesulphonyl.
It has been found that the presence of one of~these leaving groups
in the lactic acid derivative II enables the desired optically-
active isomer of formula I to be obtained during the reaction of II
with the phenol III. Not only is the desired optically-active isomer
produced by this process but the yields are in excess of 70% and
often as high as 80% or more.
Reaction between the lactic acid derivative II and the phenol III
may be carried out at temperatures between 50C and 200C, preferably
between 130 C and 170C.
--4--

~5S~ 8
As with all st~reospecific processes the reaction conditions
must be carefully selected and tested for each particular case to
ensure that the optical integrity of the required product is un-
affected by these conditions. One such condition is the nature of the
base present in the reaction between the lactic acid derivative II
and the phenol III; the base may be organic or inorganic and particular
examples are N-ethyl-morpholine or an alkali metal carbonate or bi-
carbonate. Especially good results have been obtained with anhydrous
sodium carbonate.
The phenol III may be employed as the solvent for the reaction but
an (additional) solvent such as tetrahydrofuran or a higher ether may
be employed.
The lactic acid derivative II used as starting materi~l in the
process for the preparation of R-(+)-phenoxy propionic acid derivatives
according to the invention may be readily prepared by reaction of an
acid halide of formula X-halide or the corresponding acid anhydride or
halogenated aldehyde with a derivative of lactic acid of formula IV
possessing the S- or R-configuration at the carbon atom marked ~:
COOR
HO ~ H (IV)
CH3
wherein X and R1 have the meanings hereinbefore specified. Preferably,
the reaction is carried out in the presence of a base, for example an
organic nitrogenous base, e.g. pyridine or a trialkylamine, such as
triethylamine. Generally, reaction takes

94~8
place at room temperature but, if desired, cemperatures in the range
-5 C to +80 C may be employed. The acid halide or corresponding acid
anhydride or halogenated aldehyde may be selected from one of the
following: V.S02.Q, V.CO.Q, (C.Q)2 and H.CO.CV3, wherein Q and V
have the meaning hereinbefore specified. Preferably an alkylsulphonyl
or arylsulphonyl halide is employed, for example, methanesulphonyl
chloride or para-toluenesulphonyl chloride.
Compound IV is a cheap readily available material where R
represents a hydrogen atom, i.e., it is S-(+)-lactic acid. The
remsining compounds embraced by formula IV, the esters, may con-
veniently be prepared from S-(+)-lactic acid by an esterification
reaction with the appropriate alcohol. Alternatively, since
S-(-)-ethyl lactate is also a readily available compound this can
be converted into the desired lactic acid derivative IV by a trans-
esterification procedure.
It will be appreciated that in the production of compounds ofgeneral formula I, wherein R is other than hydrogen, it may ac-
cording to the circumstances be convenient to introduce the R
substituent into the starting material IV or, alternatively, it may
be desirable to start wibh the acid (II; R1=H) and introduce the
R substituent at a later stage or at the final stage in the process.
For instance, in the preparation of long-chain esters of the
phenoxy-propionic acids, it is very convenient to start with
S-(+)-lactic acid, or preferably with S-(-)-ethyl lactate (II; R=H
or ethyl) and then to transesterify the R-(+)-phenoxy propionic acid
ethyl ester obtained under normal transesterification conditions.

~ 1 59~
It was foulld that good yields could also be obtained starting from
S~ linevyl lac-tate by reacting that compound (which can be prepared
from S-~)-lactic acid and linevol) with methane sulphonyl chloride
followed by reaction of the product with 4-chloro-2-methyl phenol.
Equally it may be convenient in the production of compounds of
formula I, wherein R is hydrogen, to start with an ester and re-
move the ester grouping at an intermediate or during the last stage
in the process and to convert the acid obtained into the corre-
sponding salt by reacting it with an appropriate base.
Preferably, in the general formula I the alkyl, alkenyl and
alkylene groups contain up to 6 carbon atoms, the aryl, aralkyl, and
alkaryl groups up to 10 carbon atoms, the halogen atom unless other-
wise specified is a chlorine or fluorine atom and the hetero atoms
are oxygen and nitrogen.
The phenoxy propionic acid derivatives of formula I (in
particular the R-(+)-isomers), wherein R, n, Hal, m and R are as
defined hereinabove and R represents an optionPlly alkyl sub-
stituted a~monium ion, or an optionally substituted alkyl, cyclo-
alkyl, alkenyl, aryl or aralkyl group are believed to be novel
compounds.
The process according to the invention produces selective
herbicides for cereal crops, which are active against broad-leaved
weeds. It is advantageous to use long-chain esters of phenoxy propionic acids
since these compounds appear to be oil-soluble which facilitate
their handling, in that they can easily be mixed with commercial

wild oat herbicides.
In order to denote the absolute configuration of the products,
starting materials and intermediates used in the process according
to the invention and R- and S-notation has been employed as stated
in Experientia, Volume 12, pages 81-94, 1956.
The process according to the invention will now be illustrated
by the following Examples.
EXAMPLE I - Preparation of R-(+)-2-(4-chloro-2-methylphenoxy)-
propionic acid potassium salt
(a) S-(-)-ethyl lactate mesylate (C ~ ]D5= -64.89 ) was prepared in
79% yield from S-(-)-ethyl lactate, methanesulphonyl chloride and
pyridine using a molar ratio of 1:1:1.05.
The mesylate (6.o mol.) was stirred with 6.o moles of 4-chloro-
2-methylphenol and anhydrous sodium carbonate (3.3 mol.) at 100-114 C
for 17 hours. The mixture was then cooled, filtered, and the filter
cake washed several times with toluene, water, 2N NaOH and then with
diluted sulphuric acid and neutral with water. The mixture was dried
azeotropically and the toluene removed in vacuo to yield 866 g (59%)
of R-(+)-2-(4-chloro-2-methylphenoxy)propionic acid ethyl ester,
possessing an ra ]D5 f +22.9 (C3; methanol).
(b) A portion of the R-(+)-(4-chloro-2-methylphenoxy)propionic acid
ethyl ester was hydrolysed by refluxing with formic acid and 2 molar
HCl for 7 hours. The solution was then added to ice/water and the

3L~L594~8
resulting solid fi:ltered, washed with water, taken up in diethyl
ether and extracted with sodium hydrogen carbonate in water. The
aqueous solution was neutralized with concentrated hydrochloric
acid to precipitate the acid which was filte:red, washed and dried.
The yield of R-(+)-2-(4-chloro-2-methylphenoxy)propionic acid was
83%, m.p. 83-85 C and optical rotation [ a ~D3= +14.62 (C2,
ethanol).
(c) An aqueous solution of the potassium salt of R-(+)-2-(4-chloro-
2-methylphenoxy)propionic acid was prepared by addition of 0.395 mol.
of the acid to a stirred solution of potassium hydroxide (0.395 mol.)
in water ~30 ml), with ice-cooling. The resulting solution was
diluted to 121 ml with water to make a 70% w/v acid equivalent solution.
The salt possessed an ~ ~D f +3.6 (C3, water).
EXAMPLE II
Using R-(+)-2-(4-chloro-2-methylphenoxy)propionic acid, prepared
as described in Example I(b) a number of derivatives was obtained
using conventionPl techniques. The compounds obtained as well as
their optical rotation data are given in Table I.
EXAMPLE III - Preparation of R-(+)-2-(2,4-dichlorophenoxy)propionic
acid linevol ester via S-(-)-ethyl lactate
(a) S-(-)-ethyl lactate mesylate ( C ~ ~ 25= -65.14 ) was prepared
in 81% yield from S-(-)-ethyl lactate, methane sulphonyl chloride and
pyridine in a molar ratio of 1:1:1.05.
12 mol. of the mesylate obtained were stirred with 12 mol.
2,4-dichlorophenol at 90-122 C for 8 hours. Over the first 5 hours
anhydrous sodium carbonate (6.6 moles) was added in 5 equal portions.
The mixture was filtered and washed with hot toluene (total volume

~L594~8
6 litres). The combined oreanic layers were concentrated and then
washed with 2 x 1200 ml water, 2 x 1800 ml 1 M NaOH and then
diluted sulphuric acid and water to neutrality (4 x 1200 ml). The
solution was dried azeotropically and evaporated to yield 9.6 moles
(80%) of R-(+)-2-(2,4-dichlorophenoxy)propionic acid ethyl ester,
possessing an Ca ~ D5 f +29.5 (C3, ethanol).
(b) 5 moles of the ester prepared according to III(a) were treated
with 5.25 moles of linevol 79, in 1300 ml toluene in the presence of
0.15 mol. concentrated H2S04. The mixture was refluxed with removal
of the ethanol-toluene azeotrope, for 8 hours. The solution was
cooled, washed with water (3 x 500 ml) and dried azeotropically and
the solvent removed in vacuo. A quantitative yield of the linevol
ester(s) of R-(+)-2-(2,4-dichlorophenoxy)propionic acid was obtained:
~ ~ 25= +19 1 (C3, ethanol)-
--10--

~1594~8
. . . .
O O ~ O
,,+,
~U ~ ~ ~ C~
h o o_ ~ o, o
~1C~
~ ~D U~
.~ ~ + + + +
0~11 1111 11 ~1
~ U~
C\.l Q c~l Q c~l Q C\l Q ~ Q
~I r~ ~, r~ ,~
.
_ ~rl
~0 h
~1 h + ~ a ~ ~ ~~
~ 1 C~
_ + + + + + ~1
rd td
rl~1 rl rl c~ O
~ l
~1~
~ ~ .~
,_ ~ ~
r~ ~1
~C ~ I O
_ ~ N IN ,~_~ ~N
r ~ ~ _ u~
$
O --c~ y 1~ o
~/ ~ ~ .
~ ll ll ll ll ll ll
C) X ~ X X X ~C

~S~4~8
EXAMPLE IV
According to ~he procedure described in Example I(b)
R-(+) 2-(2,4-dichlorophenoxy)propionic acid was obtained by re-
acting R-(+)-2-(2,4-dichlorophenoxy)propionic acid ethyl ester
with formic acid under reflux conditions in the presence of 2N
HCl. The free acid was obtained in 95.5% yield, m.p. 121-122C and
had an ~ ] D5 5 f +28 (C1.4, ethanol).
The R-(+)-acid obtained was used to prepare some deriva-tives by
conventional techniques such as the potassium salt, the dimethyl-
ammonium salt, the tert.-octylammonium salt as well as the salts
obtained by reacting R-(+)-2-(2,4-dichlorophenoxy)propionic acid
2 ( 3)2 (CH2)6-C(CH3)3 and NH2-cH2-(cH2)7-cH=cH-(cH2) -CH
( Ca ~25-5 = +3.74 , C3,ethanol).
EXAMPLE V
According to the method described in Example I(a)
R-(+)-2-(2,4,5-trichlorophenoxy)propionic acid ethyl ester was prepared
by stirring S-(-)-ethyl lactate mesylate with 2,4,5-trichlorophenol
and sodium carbonate for 2.5 hours at 120C. After filtration, washing
with water, NaOH and again water R-(+)-2-(2,4,5-trichlorophenoxy)propionic
acid ethyl ester was obtained in 80~ yield, m.p. 39-42C and
¦ ~ ~D5-5 = +51-3 (C3, ethanol).
Part of the compound obtained was used to prepare the corre-
sponding linevol ester by a transesterification process. After heating
R-(+)-2-(2,4,5-trichlorophenoxy)propionic acid ethyl ester with
linevol in the presence of concentrated sulphuric acid for 10 hours
at reflux temperature (119 C), the solution was washed with water
-12-

and stripped off solvent. The linevol ester was obtained as an oil
in qUantitQtiVe yield. C ~ ]D5 5 =+40.2 (C3, ethanol).
EXAMPLE VI - Preparation of R-(+)-2-(4-chloro-2-methylphenoxy)propionic
linevol ester via S-(-)-linevyl lactate
(a) S-(+)-lactic acid (1.5 m), linevol 79 (1 m), benzene (250 ml)
and concentrated sulphuric acid (0.05 m) were refluxed, removing water
azeotropically for 2 hours. The benzene solution was then washed with
water (3 x 500 ml) to neutrality and azeotropically dried and solvent
was removed in vacuo to eive S-(-)-linevyl lactate in 76% yield
( r a ~ 23 = -12.62 ).
(b) S-(-)-linevyl lactate (0.5 m), triethylamine (0.54 m) and toluene
(200 ml) were stirred together while methane sulphonyl chloride (0.54 m)
was added, keeping the temperature in the range 20-30 C. The toluene
solution was washed with water (3 x 250 ml), 2N HCl (100 ml) and with
water to neutrality, then azeotropically dried and toluene removed in
vacuo to yield S-(-)-linevyl lactate mesylate in 97% yield ( r a ~D3=
-40.34 (C2, ethanol).
(c) S-(-)-linevyl lactate mesylate (0~4 m), 4-chloro-2-methylphenol
(0.4 m), anhydrous sodium carbonate (0.4 m) and toluene (40 ml) were
stirred together at 130-135 C for 8 hours. The organic solution was
then washed with water (2 x 300 ml), 2~ sodium hydroxide (2 x 100 ml)
and with water to neutrality. The solution was dried azeotropically and
evaporated in vacuo to give R-(+)-2-(4-chloro-2-methylphenoxy)propionic
acid linevol ester in 68% yield ( r ~D5 = +17.17 (C3, ethanol)).