Note: Descriptions are shown in the official language in which they were submitted.
~ 71529-53D
1338512
Background o~ the Invention
This application is a divisional application of
application No. 593,713 filed on March 15th, 1989. It relates
to the compound 2- (4-acetoxyphenoxy~propanoic acid.
The invention of the paren~ application relates
to a method ~or the synthesis of 2- (4-hydroxyphenoxy) alkanoic
acids. Such compounds are useful in the production of
herbicides and dyes.
It is known in the art to produce herbicidal agents
which are of the 2- (aryloxyphenoxy) alkanoic acid class . Within
this context, ~ryl includes phenyl, pyridyl, benzoxazolyl, etc.
These and other compounds are more fully described in U. S.
Patents 4,589,908; 4,130,413; 4,391,995; 4,301,295; 4,238,626;
3,784,697; 3,721,703; 3,954,442; 4,657,577; 4,629,493;
4,046,553; and 4,368,068.
The production of these herbicides requires the use of
an intf~ te which is a 2- (4-hydroxyphenoxy) alkanoic acid or
ester (I) of the formula: 1
O COO (R or H)
~C (I)
1l
B ~/ D
OE~
wherein the variables are hereLnafter defined.
1 33 85 1 2
However, prior processes for producing these intermediate
compounds have employed hydroquinone and other compounds as
starting materials. Mono-o-alkylation of hydroquinone is
achieved hy using a large excess of hydroquinone, ~ut this method
warrants low conversicm. Alternatively, one can make mono-o-
protected hydroquinone, alkylate, and remove the protecting
group. However, the cost of such a manufacturing procedure is
very large. Mono-o-alkylated hydroquinone derivatives, such as
2-(4-hydroxyphenoxy)propionic acid are difficult to obtain
because ~oth of the hydroxyl groups of hydroquinone tend to react
with the alkylating agent. Such processes are discussed at
length in U.S. Patbnts 3,600,437; 4,532,346; 4,547,583;
4,613,677; 4,489,207; 4,368,068 and 5ritish Patent 1,591,063.
U . s . Patent 4, 665, 212 teaches the condensation of hydroquinone or
hydroquinone salts with certain aromatic sulfonyl containing
acids, esters and salts. U.S. Patent 4,511,731 teaches the
preparation of propanoate monoethers of hydroquinone via
sequential oxidation of hydroxystyrene. While such processes are
effective for producing her3~icide precursors, they are
economically disadvantageous since the rate of conversion and
-
1 33 ~5 1 2
selectivity, and hence the yield, is relatively low; on the order
of about lo9c. U.S. Patent 4,528,394 describes a method which
improves upon this yield by using a benzaldehyde precursor, such
that the yield is increased to about 50~. However, this system
is disadvantageous because of the vigorous reaction conditions
required and undesired side reactions which occur such as the
self-condensation of the benzaldehyde. These may also undergo
undesired oxidation to carboxylic acids under Baeyer-Villiger
conditions. The present invention improves on these methods by
preparing intermediates derived from certain ketones and
conducting a E~aeyer-Villiger oxidation thereon. The
intermediates are prepared in a stepwise fashion and several
advantages are thereby noted. These include a higher yield,
perhaps in the 80-95~ range, easier purific~tion of the
intermedi tes ~nd less vigorous reaction con ~itions.
71529-53D
1 33 85 1 ~
Summary of the Invention
The invention of the parent application provides a
method for synthesizing 2- (4-hydroxyphenoxy) alkanoic acids
which comprises reacting a hydroxyaromatic ketone derivative
(II) of the formula
OH
~D ( I I )
O R
or a salt thereof; with a substituted acid of the formula
;~1
X/\COOH
1 338~ 1 ~
under basic conditions to thereby ~onn a 2-(acylphenoxy~alkanoic
acid ~III) of the fornul~
~,
COOH
)'~ ~ C
, ~,
B ~ D
O R
( III) -
and then oxidizing the thusly formed 2- (acylphenoxy~ alkanoic acid
(ITI) with a peracid or peroxide to obtain a
2-(acyloxyphenoxy)alkanoic acid (IV) of the ~ormula
Rl
~\ COOH
A~s
C
o
( IV)
and then hydrolyzing or alcoholizing said
2- (acyloxyphenoxy) alkanoic acid with R20H/H+ to obtain a
A
-53D
1 3385 1 2 71529
2- (4-hydroxyphenoxy)alkanoic acid (V) of the formula
COOE
A~ (V)
OH
wherein R is C1 to CI8 alkyl or C6 to C10 aryl, preferably C
to C4 alkyl, and most preferably methyl; and
wherein Rl is H, phenyl or Cl to C18 alkyl, preferably Cl to C4
alkyl and most preferably H or methyl; and
wherein R2 is Cl to C18 alkyl, preferably Cl to C4 alkyl or
aryl such as phenyl or naphthyl which may be substituted or
unsubstituted; and
wherein A, B, C and D are independently H, S, O, N, X, CN, Cl to
C18 alkyl, or C6 to~C10 aryl, protected using methods well-known
to those skilled in the art to avoid reaction of said
substituents under the conditions of the process, i . e ., alkyla-
tion, oxidation, solvolysis; and X is F, Cl, Br, I or a sulfonic
ester. It must however be noted that the invention of the parent
application is
I 3385 1 2
not limited to 4-substituted isomers o~ 2- (acylphenoxy) alkanoic
acid esters but also contemplates 2- and 3-substituted
2-~acylphenoxy)alkanoic acid esters. In the alternative,
instead of the aforesaid substituted acid, one could use a
substituted ester of the formula:
.
Rl
~~ ~~ COOR
X
wherein R3 is Cl to C18 alkyl, preferably Cl to C4 alkyl or aryl
such as phenyl or naphthyl which may be substituted or
unsubstituted. If this alternative is chosen, then an a~lditional
hydrolysis st~ is co duct~d prlor to the ~xid~tion step.
~ 71529-53D
1 33851 2
Detailed Description of the Pref erred Embodiment
In the production of the 2- (hydroxyphenoxy) alkanoic
acids (V), the one begins with a hydroxyaromatic ketone and
reacts it with one of the aforesaid substituted acids under basic
conditions. This reaction product is then subjected to a Baeyer-
Villiger oxidation with peracetic acid being the preferred
reagent. The resulting product is then hYdrolYzed or alcoholized
to the desired 2- (4-hydroxyphenoxy) alkanoic acids (V) . The
reaction sequence may be ~en~ralized as:
OH
A~C C 2
B/~\D
O~\R
Rl Rl
10 0/1\C02H C02H
~/1\/ Baeyer- A~C
B~D Oxidation B/\~\D
oAR Rl OC-R
II O co2~ IV
A~ ~C
R OH/H > ~l ,1~
B ~ D
OH
1 3 3 8 5 ~ 2
The compounds of the formulae III, IV and V possess an
asymmetric carbon center and can therefore occur as pure
enantiomers (optically active) or racemic as mlxtures of
enantiomers . An important f eature of this reaction is to begin
the synthesis with a hydroxyaromatic ket~one which is specif ically
a 4-hydroxyphenyl ketone compound (II). The most preferred
ketone being 4-hydroxyacetophenone, as well as its sodium or
potassillm salts. These hydroxyaromatic ketones are then reacted
with one of the aforesaid X-substituted acids which may be
either racemic or- optically active. preferred acids are halogen
substituted propanoic acids such as 2-chloropropanoic acid, and
2-bL~ ~L~L~anoiC acid. This reaction proceeds by the
Williamson ' s ether synthesis which is well-known to the skilled
artisan . The reaction may take place by ref luxing the hydroxy-
aromatic ketone with the ~A~ lkAnoiC acid in a solvent such as
dimethylformamide under basic corditions. The basic conditions
may be provided either by direct use of a base such as an alkali
metal or alkaline earth metal hydroxide or carbonate, amines or
a hydride. Alternatively, within the meaning of the invention
of the parent application, the basic media may be provided by
using one of the aforesaid salt forms of the hydroxyaromatic
ketone, such as 4-hydroxyacetophenone sodium or potassium salt.
Alternative solvents for the refluxing reaction non-exclusively
include polar protic solvents , e . g ., water or alcohol ; or polar
aprotic solverts, e.g., ketones, ethers, nitriles, and
sulfoxides. The reaction may take place at from about O.l to
about 72 hours, or more preferably from about 1 to about 48 hours
71529-53D
. --
1338512
at a temperature of from about 0C to about 300C or more
pref erably f rom about 2 5 C to about 2 0 0 C .
In another embodiment, one may employ one of the af ore-
said substituted esters for the substituted acids. Hydrolysis
is then performed prior to the oxidation step. Suitable esters
non-exclusively include halogen substituted propanoates such as
methyl 2-chloropropanoate, methyl 2-bromopropanoate and ethyl
2-chloropropanoate and ethyl 2- [ (methylsulfonyl)oxy]propanoate
and ethyl 2-[ (toluylsulfonyl)oxy]propanoate. Preferred
hydrolysis agents are bases, and non-e~cluisvely include sodium
hydroxide, potassium hydroxide, and potassium carbonate.
1338512
The reaction product of this juncture is a
2-(acylphenoxy)alkanoic acid (III) . In one preferred embodiment
the foregoing reactants are 4-hydroxyacetophenone potassium salt
and 2-bromopropanoic acid with refluxing in dimethylformamide.
Altern~tively, the reactants are 4-hydroxyacetophenone, potassium
hydroxide and 2-bromopropanoic acid with refluxing in
dimethylformamide. Therefore the preferred
2-(acylphenoxy)alkanoic acid produced is
2- (4-acetylphenoxy) propanoic acid. This is then oxidized by the
Baeyer-Villiger oxidation process which is also well known to the
skilled artisan per se. The oxidation is conducted by refluxing
the 2- (acylphenoxy) alkanoic acid with a peracid or peroxide in a
suitable solvent. The most preferred oxidizing agent is
peracetic acid. Others non-exclusively include hydrogen
peroxide, alkyl peroxides, chloroperacetic acid, peroxybenzoic
acid, meta-chloroperoxybenzoic acid and trifluoroperoxyacetic
acid. One preferred solvent for the refluxing is acetic acid.
Alternative solvents for the refluxing reaction non-exclusively
include water, alcohols, esters, ethers, halogenated hydrocarbons
and carboxylic acids. The reaction may take place at from about
- 13385l2 `
0.01 to about 24 hours, or more preferably from about 0.1 to
about lo hours at a temper~ture of from about o c to ~bout 100C
or more preferably from about 25C to about 75C. The reaction
may be performed at either elevated or reduced pressures.
~lowever, the reaction is preferably performed at reduced
pressures to remove heat generated during the reaction.
The reaction product of this juncture is a
2-(acyloxyphenoxy)alkanoic acid (IV) which in the most preferred
embodiment is 2-(4-acetoxyphenoxy)propanoic acid. This latter
component is then hydrolyzed or alcoholized. The alcoholysis
may be conducted by contacting with alcohols under acidic
conditions and elevated temperatures for a period of time
sufficient to permit the reaction to approach completion. The
amount of alcohol used may be, for example, about 0.5 to about
1, 000 mol equivalents, preferably about 1 to about 100 mol
equivalents based on the ester being alcoholized. The acids
which may be employed for this purpose are organic acids such as
methanesulfonic acid, para-toluenesulfonic acid, mineral acids
such as sulfuric, hydrochloric and phosphoric acids, and acidic
ion exchange resins. In some instances, it may be desirable to
71529-53D
1 3385 1 2
employ a combination of alcohol and water to achieve a measure
of solvolysis. The alcoholysis process may also esterify the
product 2-(4-hydro~yphenoxy)alkanoic acid, which in the
preferred embodiment is 2-(4-hydroxyphenoxy)propanoic acid. The
product of such an esterification is alkyl 2- (4-hydroxyphenoxy) -
propanoate .
Alcoholysis may take place at from about 0.1 to about 10
hours, or more preferably from about 0.5 to about 4 hours at a
temperature of from about 20C to about 200C or more preferably
from about 60C to about 140C. The reaction is collducted with
an anticipated conversion of from about 90% to about 99g with
a selectivity of from about 90% to about 98~. The solvolysis
product is a 2- (4-hydroxyphenoxy) alkanoic acid which in the
preferred embodiment is 2-(4-hydroxyphenyl)propanoic acid. The
alcoholysis process provides for the recovery of the phenolic
product in relatively higher yields. The product may be
recovered by conventional purification methods usually involving
a combination of crystallization, filtration, washing and
distillation in any order deemed advantageous for the system at
2 0 hand .
The following non-limiting examples serve to illustrate
the inventions of the parent application and this divisional
application .
Example 1
Potassium hydroxide (17.0 g, 0.3 mol) is added to
water (50 mL) and allowed to dissolve. The solution is added to
4-hydroxyacetophenone (13.6 g, 0.1 mol) to produce the
14
~ 71529-53D
.
1 33~5 1 2
potassium salt of 4-hydroxyacetophenone. 2-Bromopropanoic
acid (17.0 g, 0.11 mol) is added to the potassium salt of
4-hydroxyacetophenone to give a yellow suspension. The solution
is heated to reflux (102C) during which a yellow solution results.
The solution ls refluxed for 24 hours and cooled to room
temperature. The pH is ad]usted to 6-7 and extracted with ethyl
acetate (3xlO0 m~) and the solution is concentrated under reduced
pressure . The aqueous layer is acidif ied to pH 2 and extracted
with ethyl acetate (3x150 m1) . The solution is concentrated to give
7 . 0 g of a brown li~uid which is 2- (4-acetylphenoxy) propanoic
acid at a yield of 34%.
1 3385 ~ 2
Exam~le 2
qO a solution of the potassium salt of 4-hydroxyacetophenone (8 . 8
g, o. 05 mol) in dimethylformamide (25 mL) is added methyl
2-bromopropanoate ~10.2 g, 0.06 mol) over 30 minutes and stirred
at 80-90C for 4 hour5 under nitrogen. The reaction is cooled to
room temperature and methylene chloride (75 mL) and water (75 mL)
are added. The organic phase is separzted, washed with water
( 100 mL), dried and concentrated to give methyl
2-(4-acetylphenoxy)prop~noate (8.5 g) (yield 76%) .
Methyl 2-~4-acetylphenoxy)propanoate (7.0 g, 31.S mmol) is
combined with 2N NaOH (20 mL) and refluxed overnight. Water (30
mL) is added to the reaction which is then washed with methylene
chloride (50 mL). It is then acidi~ied to pH=l with concentrated
hydrochloric acid and extracted with ethyl acetate (3x100 mL) .
The organic phase is dried and concentrated to provide
2-(4-acetylphenoxy)propanoic acid (5.0 g) (yield 92%): m.p.
104.3C, IR (KBr) 3000 (~r, vs), 2940 (~r,s), 1754 (vs), 1650
(vs); lH NM3~ (CDC13) delta 1.69 (d, J=6.8 Hz, 3H), 2.55 (s,3H),
4.~3 (q, J=6.8 HZ, lH); 6.92 and 7.93 (dd, J= 9.0 Hz, 4H).
16
1 3385 1 2
. .
Exam~ l e 3
To a solution of 2-(4-acetylphenoxy)propanoic acid (5.08 g, 24.4
mmol) in acetic acid (20 mL) i5 added purified peracetic acid
(16%, 15.80 g, 33.3 mnlol) over 30 minutes. The reaction mixture
is stirred under reflux at 55C to 60C and 60-64 mm Hg for 9
hours. The solution is rotovapped and vacuumed to remove the
acetic acid. The product obtained is 5 . 0 g of
2-(4-acetoxyphenoxy)propanoic acid (yield 919~): m.p. 102C, lH
NMR ~CDCl3) delta 1.63 (d, J=7.0 Hz, 3H), 2.26 (s, 3H), 4.85 (q,
Js7 . 0 Hz , lH), 7 .10 (m, 4H) .
FY~Tnnle 4
2-(4-Acetoxyphenoxy)propanoic acid (1.2 g, 5.3 mmol) is
hydrolyzed by refluxing ethanol (15 mL) and 2 drops of
concentr~ted hydrochloric acid (36S) for 2 hours. Ethanol is
removed under reduced pressure to give
2- ( 4 -hydroxyphenoxy) propanoic acid ( 0 . 9 g yield 93 % ): m . p . 13 6-
13~.5 C, IR (KE~r) 3265 (vs), 1707 (vs); lH NMR (acetone-d6)
dclta 1.52 (d, J=6.8 HZ, 3H), 4.67 (o" J=6.8 Hz, 1H), 6.75 (M,
4H) . 17
