Preparation of 2-(4-hydroxyphenoxy) propionates

A multi-stage catalytic process for preparing a 2-(4-hydroxyphenoxy)-propionate, especially methyl 2-(4-hydroxyphenoxy)-propionate, with a purity greater than 99% by esterifying the corresponding 2-(4-hydroxyphenoxy)-propionic acid with an excess amount of alcohol, e.g. methyl alcohol, in a series of at least 2 up to 10 sequential stages at temperatures of 20.degree. to 150.degree. C. and pressures of 0.05 to 5 bar in the presence of a distillable acid catalyst such as hydrochloric acid or hydrogen chloride. In a first esterification stage, unreacted alcohol is removed from the ester product in vacuo at temperatures of 30.degree. to 100.degree. C. together with other volatile components, including the acid catalyst. Without a separate purification of the resulting ester as the bottoms product of the first stage, the esterification step is repeated in at least one additional stage. The final ester product of this multi-stage process is characterized by a water content of less than 0.1%, a halide content of less than 100 ppm, an organic halogen content of less than 50 ppm and a content of all other contaminating compounds of less than 0.1%.

The present invention relates to a process for the preparation of a 
2-(4-hydroxyphenoxy)propionates, in particular methyl 
2-(4-hydroxyphenoxy)propionate of high purity by the multi-stage reaction 
of the esterification mixture of the corresponding 
2-(4-hydroxyphenoxy)propionic acids with an alcohol in the presence of 
distillable acid without the use of any additional purifying operation. 
The preparation of carboxylates by the reaction of a carboxylic acid with 
an alcohol in the presence of catalytic amounts of an acid is described, 
eg, in Houben-Weyl, Methoden der Organischen Chemie, Vol. 5E, 1985, pp 
658-663. Typical yields are in the range of 72-96%. In order to obtain 
esters of high purity it is therefore imperative to carry out additional 
purifying operations such as distillation. 
Journal of Organic Chemistry 24, 261-262 (1959) and Journal of Organic 
Chemistry 28, 2898 (1963) reveal the preparation of methyl esters using 
stoichiometric amounts of acetone dimethyl acetate acting as water-binding 
agent. A drawback of this process is the non-quantitative conversion, the 
formation of stoichiometric amounts of acetone, and the elaborate 
preparation of acetone dimethyl acetate. 
Chem. Ind. pp 1 568-1569 (1968) recommends the use of sulfuric acid as 
catalyst for the preparation of methyl carboxylates in Soxleth equipment. 
In this case either the catalyst remains in the product formed or 
alternatively the product must be isolated from the sulfuric acid, e.g. by 
distillation of the ester. 
For separation of the water of reaction formed the use of a cosolvent, e.g. 
toluene, is recommended (Journal of Organic Chemistry 23, 108-110 (1958)). 
In this case the toluene is used as solvent for the phase separation of 
the remaining sulfuric acid. A drawback of this method is the use of large 
amounts of sulfuric acid and an additional solvent, which must either be 
purified and recycled or disposed of. 
Furthermore considerable problems arise due to the presence, in the 
product, of traces of the acid catalyst or reaction products of carboxylic 
acid with the product. When large amounts of hydrochloric acid (or 
hydrogen chloride) are used as acid catalyst undesirable chlorinated 
reaction products of the alcohols and carboxylic acids used may be formed 
even under standard reaction conditions (Houben-Weyl, Methoden der 
Organischen Chemie, Vol. 5/3, pp 831-837 (1962)). 
It is thus an object of the present invention to overcome the above 
drawbacks, in particular to provide a process for the production of 
hydroxyphenoxypropionates of high purity without further purification and 
thus with a reduction of purification losses. 
Accordingly, we have found a novel and improved process for the preparation 
of 2-(4-hydroxyphenoxy)propionates of the general formula I 
##STR1## 
in which R.sup.1 denotes C.sub.1 -C.sub.18 alkyl, C.sub.2 -C.sub.8 
alkynyl, tetrahydrofurfuryl, or C.sub.3 -C.sub.18 alkoxyalkyl and 
R.sup.2, R.sup.3, R.sup.4, and R.sup.5 denote hydrogen, C.sub.1 -C.sub.4 
alkyl, fluorine, chlorine, or bromine by the reaction of 
2-(4-hydroxyphenoxy)propionic acids of the general formula II 
##STR2## 
in which R.sup.2, R.sup.3, R.sup.4, and R.sup.5 have the meanings stated 
above, with alcohols of the general formula III R.sup.1 --OH (III) in 
which R.sup.1 has the meanings stated above, wherein the esterification of 
2-(hydroxyphenoxy)propionic acid II is carried out two to ten times at 
temperatures ranging from 20.degree. to 150.degree. C. and a pressure of 
from 0.05 to 5 bar with an alcohol III in the presence of distillable 
acid. 
The process of the invention may be carried out as follows: 
The reaction of the invention may be carried out either continuously or 
batchwise at temperatures ranging from 20.degree. to 150.degree. C., 
preferably from 40.degree. to 130.degree. C. and more preferably from 
50.degree. to 120.degree. C. and a pressure of from 0.05 to 5 bar, 
preferably from 0.5 to 2 bar and more preferably standard pressure 
(atmospheric pressure) usually by admixing a distillable acid to a mixture 
of 2-(hydroxyphenoxy)-propionic acid II and an alcohol III (a fresh 
alcohol or one recovered from one of the reaction sequences) followed by 
removal of alcohol and optionally other volatile components in vacuo at 
temperatures ranging from 30.degree. to 100.degree. C. and preferably from 
50.degree. to 90.degree. C. and a pressure of 15-720 mbar, preferably 
20-700 mbar and more preferably 30-650 mbar, without purification of the 
bottoms. The bottoms are caused to react in accordance with the present 
invention without purification for another one to nine times (i.e. in all 
two to ten times), preferably one to four times (i.e. in all two to five 
times) and more preferably once or twice (i.e. in all two to three times) 
at temperatures ranging from 20.degree. to 150.degree. C., preferably from 
40.degree. to 130.degree. C. and more preferably from 50.degree. to 
120.degree. C. and a pressure of from 0.05 to 5 bar, preferably from 0.5 
to 2 bar and more preferably standard pressure (atmospheric pressure) 
usually by admixing a distillable acid to a mixture of 
2-(hydroxyphenoxy)propionic acid II and an alcohol III followed by removal 
of alcohol and optionally other volatile components in vacuo at 
temperatures ranging from 30.degree. to 100.degree. C. and preferably from 
50.degree. to 90.degree. C. and a pressure of 15-720 mbar, preferably 
20-700 mbar and more preferably 30-650 mbar, without purification of the 
bottoms. 
The molar ratio of the alcohol III to 2-(hydroxyphenoxy)propionic acid II 
is usually 1:1 to 30:1, preferably 1.5:1 to 20:1 and more preferably 2:1 
to 15:1. 
The molar ratio of distillable acid to alcohol III is usually 0.0001:1 to 
0.1:1, preferably 0.001:1 to 0.05:1 and more preferably 0.005:1 to 0.03:1. 
Suitable distillable acids are hydrochloric acid, hydrobromic acid, 
hydrogen chloride, hydrogen bromide, and halogenated acetic acid 
derivatives such as trichloroacetic acid, trifluoroacetic acid, 
trifluoromethanesulfonic acid, and boron trifluoride, and also compounds 
which liberate such distillable acids in aqueous medium (e.g., methyl 
chloroformate-H.sub.2 O, methanol, CO.sub.2, hydrogen chloride), 
preferably hydrochloric acid, hydrogen chloride, and boron trifluoride and 
more preferably hydrochloric acid and hydrogen chloride. 
The process of the invention is suitable for the esterification of racemic 
2-(4-hydroxyphenoxy)propionic acids, and for the chiralic enantiomers, 
preferably those having an enantiomer ratio of R:S of smaller than 5:95 
and more preferably smaller than 2:98, or greater than 95:5 and more 
preferably greater than 98:2. 
During esterification of the chiralic carboxylic acid the chirality in the 
resulting ester remains substantially intact (preferably .+-.5 and more 
preferably .+-.5). 
In a particular embodiment the 2-(4-hydroxyphenoxy)propionic acid is 
dissolved in the corresponding alcohol and, for the first esterification 
stage, mixed with catalytic amounts of an acid and heated. There then 
commences the removal of the solvent in vacuo from the first 
esterification stage. The excess alcohol and the resulting water of 
reaction, or any water already present in the acid, are distilled off as 
quickly as possible and, when methanol is used as alcohol component, 
preferably under reduced pressure, in order to increase the water content 
of the distillate. At the same time, a large part of the previously added 
acid is also removed. The temperature of the molten product is adjusted 
such that the product is just still liquid and readily stirrable. 
The second esterification stage then commences with the addition of fresh 
alcohol and a preferably reduced amount of acid. If two esterification 
stages suffice to attain the desired conversion, it is preferred to use an 
amount of alcohol comparable to that employed in the first stage. If three 
or more esterification stages are necessary to attain the desired degree 
of conversion, amount of alcohol used in the second and all of the 
following esterification stages except the last stage are advantageously 
distinctly reduced (e.g., by a third). The second and all of the following 
distillation phases are carried out in a manner analogous to that employed 
in the first stage. Following the last of the alcohol distillations 
required (in which case the alcohol distillate is kept for the first 
esterification stage of the following batch), the temperature of the 
reaction mixture lowered to such an extent that the melt remains just 
stirrable (preferably from 60.degree. to 90.degree. C.) and a reduced 
pressure is applied to the reaction vessel for the removal of traces of 
the acid used. To accelerate the removal of readily volatile impurities it 
is recommended to simultaneously pass in a stream of nitrogen into the 
reaction medium. 
The 2-(4-hydroxyphenoxy)propionate prepared by the process of the invention 
is characterized, without any necessity for a purification stage, by a 
purity of &gt;99%, a water content of &lt;0.1%, a halide content of &lt;100 ppm, an 
organic halogen content of &lt;50 ppm and a content of other individual 
contaminating compounds, in particular hydroxyphenoxypropionic acid 
oligomers, of &lt;0.1%. 
The product can then be used directly, without further purification, for 
subsequent reactions, or be subjected to ancillary processing (eg flaked) 
for storage and transport. 
The substituents R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 in the 
compounds I, II, and III have the following meanings: 
R.sup.1 
C.sub.1 -C.sub.18 alkyl, preferably C.sub.1 -C.sub.12 alkyl and more 
preferably C.sub.1 -C.sub.8 alkyl, such as methyl, ethyl, n-propyl, 
isopropyl, n-butyl, isobutyl, tert-butyl, ethylhexyl, 
C.sub.3 -C.sub.18 alkoxyalkyl, preferably C.sub.3 -C.sub.12 alkoxyalkyl and 
more preferably C.sub.3 -C.sub.8 alkoxyalkyl such as methoxyethyl and 
ethoxyethyl, 
C.sub.2 -C.sub.8 alkynyl, preferably propargyl, 
tetrahydrofurfuryl, 
R.sup.2, R.sup.3, R.sup.4, and R.sup.5 
hydrogen, 
C.sub.1 -C.sub.4 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 
isobutyl, and tert- butyl, preferably methyl and ethyl and more preferably 
methyl, 
fluorine, chlorine or bromine. 
In particular those compound I, II and III are preferred in which R.sup.1 
stands for methyl and R.sup.2, R.sup.3, R.sup.4, and R.sup.5 all stand for 
hydrogen. 
The 2-(4-hydroxyphenoxy)propionate I are suitable for use as intermediates 
in the synthesis of plant protectants and medicines.

EXAMPLES 
Example 1 
To 191 g (1 mol) of 2-(4-hydroxyphenoxy)propionic acid, moist (5% H.sub.2 O 
content) and 160 g (5 mol) of methanol there were added 2 g (0.02 mol) of 
36% strength hydrochloric acid and the mixture was refluxed for 2 h. 
Following removal of the solvent in vacuo (600-30 mbar/80.degree. C. base 
temperature) there were obtained 194 g of methyl hydroxyphenoxypropionate 
(ester content: 95,9%, chloride value: 2100 ppm ). 
The product thus obtained (chloride value: 2100 ppm) was again refluxed 
with 160 g (5 mol) of methanol and 2 g (0.02 mol) of 36% strength 
hydrochloric acid over a period of 1.5 h. The product was worked up in a 
manner similar to that described above to give 196 g of methyl 
hydroxyphenoxypropionate (ester content: 99,4%, chloride value: 190 ppm ). 
The product thus obtained (chloride value: 190 ppm) was again refluxed with 
160 g (5 mol) of methanol and 2 g (0.02 mol) of 36% strength hydrochloric 
acid over a period of 1 h. The product was worked up in a manner similar 
to that described above to give 196 g (100% ) content: 99,7%! of methyl 
hydroxyphenoxypropionate (chloride value: 29 ppm; organic chlorine: &lt;10 
ppm, other impurities: &lt;0,1%, hydroxyphenoxypropionic acid not 
detectable!). 
EXAMPLE 2 
In a manner similar to that described in Example 1 191 g (1 mol) of 
R-2-(4-hydroxyphenoxy)propionic acid, moist (5% H.sub.2 O content) and 
having an R:S-ratio of 99.3:0.7 was caused to react. Following three 
esterification stages there were obtained 196 g (100% ) content: 99,7% of 
methyl R-2-(4-hydroxyphenoxy)propionate having an enantiomer ratio R:S of 
99.4:0.6 (chloride value: 29 ppm; organic chlorine: &lt;10 ppm, other 
impurities: &lt;0,1%, R-hydroxyphenoxypropionic acid impurities not 
detectable!). 
EXAMPLE 3 
Into a mixture of 191 g (1 mol) of 2-(4-hydroxyphenoxy)propionic acid, 
moist (5% of H.sub.2 O content), and 160 g (5 mol) of methanol there was 
blown in 0.73 g (0.02 mol) of hydrogen chloride and the mixture was caused 
to react and purified in a manner similar to that described in example 1. 
There were obtained 196 g (100%) content: 99,7%! of methyl 
2-(4-hydroxyphenoxy)propionate (chloride value: 34 ppm; organic chlorine: 
&lt;10 ppm, other impurities: &lt;0,1%, hydroxyphenoxypropionic acid not 
detectable!). 
EXAMPLE 4 
In a manner similar to that described in example 10.5 g (0.013 mol) of 
hydrogen chloride were blown into a mixture of 182 g (1 mol) of 
R-2-(4-hydroxyphenoxy)propionic acid (enantiomer ratio R:S of 99.2:0.8) 
and 160 g (5 mol) of methanol and the mixture was refluxed over a period 
of 4 h. Following removal of the solvent in vacuo another 160 g of 
methanol without further hydrogen chloride were added and the mixture was 
refluxed over a period of 4 h and the solvent removed in vacuo. 
Subsequently nitrogen was passed through the reaction mixture under a 
reduced pressure of 15 mbar over a period of 5 h. There were obtained 196 
g (100%) content: 99,6%! of methyl R-2-(4-hydroxyphenoxy)propionate 
having an enantiomer ratio R:S of 99.2:0.8 (chloride value: 33 ppm; 
organic chlorine not detectable, other impurities: &lt;0,1%, 
R-hydroxyphenoxypropionic acid impurities not detectable!). 
EXAMPLE 5 
Example 4 was repeated except that 1 g (0.012 mol) of hydrogen bromide was 
blown in the first esterification stage. There were obtained 196 g (100% ) 
content: 99,4%! of methyl 2-(4-hydroxyphenoxy)propionate (0.3% of 
hydroxyphenoxypropionic acid). 
EXAMPLE 6 
Operating in a manner similar to that described in Example 1 149 g of 
methanol coming from a distillate of the third esterification stage of 
Example 1 were used in the first esterification stage. There were obtained 
1 96 g (100%) content: 99,7%! of methyl 2-(4-hydroxyphenoxy)propionate 
(0.1% of hydroxyphenoxypropionic acid). 
EXAMPLE 7 
193 g (1 mol) of R-2-(4-hydroxyphenoxy)propionic acid, moist (6% H.sub.2 O 
content), and 160 g of recycled methanol were refluxed with 1,5 g of a 36% 
strength hydrochloric acid over a period of 2 h. Following removal of the 
solvent in vacuo (700-20 mbar/90.degree. C. base temperature) 130 g of 
fresh methanol metered were metered in at 70.degree. C. and 0.3 g (0.008 
mol) of hydrogen chloride was blown in, the mixture then being refluxed 
over a period of 2 h and the solvent removed in vacuo as above. 
Subsequently 160 g of fresh methanol were metered in at 70.degree. C. and 
the mixture was refluxed over a period of 4 h and the solvent removed in 
vacuo as above. Nitrogen was then passed through the reaction mixture 
under reduced pressure (ca 500 mbar). There were obtained 196 g (100% ) 
content: 99,7%! of methyl R-2-(4-hydroxyphenoxy)propionate having an 
enantiomer ratio R:S of 99.5:0.5 (chloride value: 37 ppm; organic chlorine 
not detectable, 0.1% of R-hydroxyphenoxypropionic acid chlorine). 
EXAMPLE 8-12 
Methyl R-2-(4-hydroxyphenoxy)propionate was prepared in all five batches 
(Examples 8-12) in a manner similar to that described in Example 6 and in 
each case the distillate recovered from the third distillation stage of 
the previous batch was used for the first esterification stage of the 
following batch. The results are in Table 1. 
TABLE 1 
__________________________________________________________________________ 
Example 
Methyl Hydroxyphenoxypropionate 
Hydroxyphenoxypropionic acid 
Chloride 
No. content in %! content in %! 
content in ppm! 
__________________________________________________________________________ 
8 99.6 0.1 27 
9 99.7 0.1 41 
10 99.7 0.1 36 
11 99.6 0.1 33 
12 99.7 0.1 35 
__________________________________________________________________________ 
in no case could organic chlorine be detected (&lt;10 ppm). Other impurities, 
in particular oligomers of hydroxyphenoxypropionic acid were under 0.1% 
(for each individual component and &lt;0,3% in all). 
EXAMPLES 13-16 
To 365 g (2 mol) of R-2-(4-hydroxyphenoxy)propionic acid and 300 g of an 
alcohol specified in Table 2 below there were added 3 g of hydrochloric 
acid and the mixture was refluxed over a period of 1 h and the excess 
alcohol was removed by distillation under standard pressure conditions. 
Subsequently, 300 g of the same alcohol were added and 0.7 g of hydrogen 
chloride was blown in and the mixture refluxed over a period of 2 h. The 
solvent was then removed in vacuo (65.degree. C./20 mbar) and nitrogen was 
passed through the bottom of the distilling apparatus over a period of 2 
h. The results are listed in Table 2. 
TABLE 2 
______________________________________ 
Example Content 
No. Alcohol . . . R-hydroxyphenoxypropionate 
%! 
______________________________________ 
13 ethanol ethyl 99.4 
14 n-butanol n-butyl 99.5 
15 isobutanol isobutyl 99.5 
16 ethoxyethanol 
ethoxyethyl 99.4 
______________________________________