Process for preparing arylalkanoic acid derivatives

2-Aryl-C.sub.3 to C.sub.6 -alkanoate esters are prepared economically by reacting an enol ether of an aryl alkyl ketone with a trivalent thallium salt in an organic solvent. The trivalent thallium ions can be regenerated by adding a peracid and a reactive form of manganese, ruthenium, cobalt, iridium, hafnium, osmium or neobium to oxidize monovalent thallium ions to the trivalent state, in a sequential, continuous or stoichiometric procedure. A continuous process using a Scheibel column is disclosed. The ester intermediate product is then converted to the corresponding 2-aryl-C.sub.3 - to C.sub.6 -alkanoic acid or salt thereof. The aryl group is selected so the resulting acid product will be a useful compound such as an anti-inflammatory, analgesic and anti-pyretic drug or agriculturally useful product. Examples of drug acids which can be made by this process include ibuprofen, flurbiprofen, fenoprofen and naproxen and the like.

INTRODUCTION 
This invention relates to chemical processes for preparing 2-arylalkanoic 
acid ester compounds. More particularly, this invention provides a 
continuous process for preparing useful 2-aryl C.sub.3 to C.sub.6 
-alkanoate, and preferably 2-arylpropionate esters, and the resulting 
acids and salts thereof using trivalent thallium ions while providing for 
the continuous regeneration the trivalent thallium ions used in the 
process. 
BACKGROUND OF THE INVENTION 
(a) 2-Arylalkanoic acids 
A variety of 2-arylalkanoic acids are now known to be useful as active 
anti-inflammatory, analgesic and anti-pyretic pharmaceutical drug 
products. A few of the better known include the 2-arylpropionic acid 
derivatives such as fenoprofen which is 2-(3-phenoxyphenyl)propionic acid 
and related compounds which are described in Marshall U.S. Pat. No. 
3,600,437, ibuprofen which is 2-(4-isobutylphenyl)propionic acid which is 
described with other related compounds in Nicholson et al. U.S. Pat. No. 
3,385,886, naproxen which is 2-(6-methoxy-2-naphthyl)propionic acid which 
is described with other related compounds in Belgian Pat. No. 747,812 
(Derwent Index No. 71729R-B). In addition a large variety of other 
2-aryl-C.sub.3 to C.sub.6 -alkanoic acid compounds are described in the 
medical, pharmaceutical and patent literature including the above patent 
references as well as Shen U.S. Pat. No. 3,624,142, and Adams et al. U.S. 
Pat. No. 3,793,457 which patents describe some fluoro-substituted 
biphenylalkanoic acids. Another compound of interest of this latter type 
is flurbiprofen which is 2-(2-fluoro-4-biphenylyl)propionic acid. Thus, a 
large variety of 2-aryl-C.sub.3 to C.sub.6 -alkanoic acids, and 
particularly the 2-arylpropionic acid drug compounds are known and more of 
such compounds will undoubtedly be discovered and described in the future 
patent and other technical literature. 
(b) Prior Processes 
The above patent references also describe a variety of process routes for 
preparing useful 2-aryl-C.sub.2 to C.sub.6 -alkanoic acids. However, some 
of the prior processes suffer a variety of disadvantages including 
expensive starting materials, dangerous by-products, and gross quantities 
of by-products necessitating substantial expense in destroying or getting 
rid of such by-products. As a result chemists skilled in chemical process 
research continue to study and search for improved processes for making 
the more economically significant 2-aryl-C.sub.3 to C.sub.6 -alkanoic 
acids, and particularly the 2-arylpropionic acids. 
Among the possible process routes being explored to prepare the useful 
ester compounds are processes involving the use of trivalent thallium 
salts as reactants. A. McKillop et al. in the Journal of the American 
Chemical Society (JACS), 95 (1973) pp. 3340-3343 describe a process for 
preparing methyl arylacetates by the oxidative rearrangement of 
acetophenones with thallium (III) nitrate (TTN). Treatment of acetophenone 
at room temperature with 1 equivalent of TTN in a mixture of methanol and 
70% aqueous perchloric acid (5 to 1) resulted in smooth reduction of the 
TTN to thallium (I) nitrate; precipitation of the inorganic salt was 
complete after 5 hours. Filtration and evaporation of the filtrate gave an 
oil which by glpc analysis, consisted of two components in the ratio of 
16:1. They were identified as methyl phenylacetate (94%) and 
.omega.-methoxyacetophenone (6%). Distillation of the mixture gave pure 
methyl phenylacetate in 84% yield. When this process was applied to the 
oxidation of propiophenone with TTN in acidic methanol a mixture of 
products was obtained, which consisted of methyl .alpha.-methylphenyl 
acetate (45%) and .alpha.-methoxypropiophenone (32%). 
See also Chemical Abstracts, 82, (1975) page 501, item 16821x (abstracting 
Japan Kokai 74 48661) which refers to the production of 2-substituted 
benzothiazolacetic acid esters using perchloric acid-methanol mixtures. 
However, chemists and engineers concerned with designing large scale 
chemical processes would prefer to avoid process conditions which would 
involve the use of perchloric acid-methanol mixtures which are potentially 
hazardous or explosive. 
E. C. Taylor and A. McKillop also disclosed a process for preparing methyl 
2-phenylpropionate as the only substantial product by reacting 
propiophenone with anhydrous trivalent thallium trinitrate on a solid 
support at the April, 1974 American Chemical Society (ACS) meeting in Los 
Angeles and the IU meeting in Belgium in August, 1974, respectively, 
and now in J. Amer. Chem. Soc., 98, 6752 (1976). However, as is apparent 
from the above reports, working directly with the ketone reactant (here 
the propiophenone) and trivalent thallium salt in an aqueous organic 
medium results in a yield-lowering mixture of products which chemical 
process chemists and engineers would prefer to avoid. Also, when the 
ketone is reacted directly with the anhydrous trivalent thallium salt on a 
solid support (TTN: support 1:2 w/w) a large quantity of the inert support 
is required because the trivalent thallium salt supported thereon reacts 
mole for mole (stoichiometric proportions) with the ketone reactant. The 
reaction in commercial scale operation would thus produce huge quantities 
of monovalent thallium salt on solid support which must be handled or 
otherwise disposed of, thus inherently increasing the total cost of the 
process. Those skilled in the chemical process art continue to search for 
improved, technically practical, economical processes for preparing these 
valuable drug compounds, which would avoid the above problems. 
Also, prior to this invention, one of the co-inventors herein, has 
described and claimed in U.S. application Ser. No. 696,720, filed June 16, 
1976, a process for preparing a 2-aryl-C.sub.2 to C.sub.6 -alkanoate ester 
by reacting an enol ether with trivalent thallium ions in an organic 
liquid containing at least a minor amount of an alcohol, water or other 
nucleophile at a temperature of from about -25.degree. C. to about reflux 
temperature of the mixture for a time sufficient to form the 
2-aryl-C.sub.2 to C.sub.6 -alkanoate ester. However, as that process 
proceeds, the trivalent thallium ion content of the mixture is consumed as 
it reacts stoichiometrically with the enol ether content of the mixture 
and is converted to its reduced and oxidatively inactive monovalent 
thallium ion state. The availability of a practical and economic method 
for regenerating the reactivity of the thallium ion content in these 
mixtures to obtain the desired quantities of the ester product would 
greatly extend the utility of this chemistry. 
OBJECTS OF THE INVENTION 
It is an object of this invention to provide an improved process for 
preparing 2-aryl-substituted C.sub.3 to C.sub.6 -alkanoate esters, and the 
acids therefrom, based upon the use of trivalent thallium salts, which 
process minimizes the production of undesired yield-lowering by-products 
and potential hazards and eliminates the necessity for using inert, solid 
support materials for the thallium salt reactant to obtain substantially 
only the desired 2-arylalkanoate ester intermediate product. 
It is a further object of this invention to provide an improved process for 
preparing 2-aryl-substituted C.sub.3 to C.sub.6 -alkanoate esters which 
are useful as intermediates for preparing the corresponding 2-aryl-C.sub.3 
to C.sub.6 -alkanoic acids which are useful as the active ingredient in 
anti-inflammatory, analgesic and anti-pyretic pharmaceutical formulations, 
either per se or as a pharmaceutically acceptable salt thereof. 
Another object of this invention is to provide an improved process for 
preparing 2-aryl-C.sub.3 to C.sub.6 -alkanoate esters using trivalent 
thallium ions in a mild chemical continuous manner involving the 
regeneration of trivalent thallium ions from monovalent thallium ions in a 
continuous manner, using a per acid and various metallic compounds as 
oxidation promoters in a cyclic process. 
Other objects, aspects and advantages of this invention will be apparent to 
one skilled in this art from the description and claims which follow.

SUMMARY OF THE INVENTION 
Briefly, according to this invention it has been found that the 
2-aryl-substituted-C.sub.3 -C.sub.6 -alkanoate esters can be prepared with 
more efficient, minimum use of thallium salts and in improved yields by 
conducting the reaction of the enol ether with the trivalent thallium ions 
to form the ester product in a continuous, two liquid phase manner wherein 
the enol ether containing liquid phase is contacted with the trivalent 
thallium and non-thallium reactive metal containing liquid phase to form 
the ester product which remains essentially in the same liquid phase as 
the enol ether reactant, and the thallium ions remain in the original 
liquid phase containing thallium ions, the ester product is separately 
recovered from the organic liquid enol ether/ester phase, the liquid phase 
containing the bulk of the monovalent thallium ions and the non-thallium 
oxidation promoter metal compounds is contacted with a percarboxylic acid 
having a pKa above about 2 in an amount and for a time sufficient to 
effect oxidation of the monovalent thallium ions to the trivalent thallium 
valence state therein and the liquid phase containing the trivalent 
thallium ions is recycled back to the continuous enol ether reaction 
vessel for contact with additional enol ether liquid phase for production 
of more ester product. The enol ether containing liquid phase can be less 
dense (lighter) or more dense (heavier) than the trivalent thallium ion 
liquid phase. The enol ether liquid phase is preferably a C.sub.5 to 
C.sub.10 -hydrocarbon liquid phase and the thallium ion liquid phase is 
preferably a mixture of water with a C.sub.1 to C.sub.10 -alkanoic acid. A 
particularly preferred C.sub.5 to C.sub.10 -hydrocarbon liquid to contain 
and carry the enol ether reactant in hexane or a commercial mixture 
thereof, when the thallium ion liquid phase is an aqueous acetic acid 
mixture. 
DETAILED DESCRIPTION OF THE INVENTION 
More specifically, this invention provides an improved process for 
preparing 2-aryl-C.sub.3 to C.sub.6 -alkanoate esters which involves the 
reaction of an enol ether of the formula 
##STR1## 
with trivalent thallium ions in an organic liquid medium containing at 
least one equivalent of an alcohol or water at a temperature of from about 
-25.degree. C. to about reflux temperature of the mixture of a time 
sufficient to form the 2-aryl-C.sub.3 to C.sub.6 -alkanoate ester product 
##STR2## 
wherein Ar is the aromatic moiety of a useful acid product, containing 
from 6 to 13 carbon atoms, in which the aryl ring portion of the aromatic 
moiety is a phenyl, phenoxyphenyl, naphthyl or biphenylyl group bonded to 
the carbon atom adjacent to the carbonyl carbon atom (of the carboxylate 
ester product) at an aryl ring carbon; R in III above is C.sub.1 to 
C.sub.4 -alkyl, benzyl, phenyl, tris (C.sub.1 to C.sub.3 -alkyl)silyl or 
the like; R' is equal to R or is C.sub.1 to C.sub.4 -alkyl, preferably 
methyl or ethyl, phenyl, or benzyl group derived from the solvent medium; 
and Y and Z denote the residue of the C.sub.3 to C.sub.6 -alkyl moiety and 
each of Y and Z can be hydrogen or C.sub.1 to C.sub.4 -alkyl, with Y and Z 
having a total of from one to 4 carbon atoms. 
We prefer to prepare the enol ether reactant from a readily available 
ketone of the formula 
##STR3## 
wherein Ar is as defined above and R.sup.1 is (CH.sub.2).sub.n H where n 
is 2 to 5 or --CH(Y)Z wherein Y and Z are as defined above, through a 
ketal intermediate of the formula 
##STR4## 
wherein Ar, R and R.sup.1 are as defined above, under substantially 
anhydrous, acidic conditions. 
The reaction of the enol ether and the trivalent thallium ions to form the 
ester products of the process will proceed in a variety of solvents and 
solvent mixtures, e.g., in lower aliphatic C.sub.2 to C.sub.6 alkanols, 
liquid alkanoic acids or alcohol/alkanoic acid mixtures. This reaction can 
also be carried out in a two-phase system comprising the above types of 
alcoholic and acids combined with organic liquid solvents such as 
hydrocarbons, e.g., hexane, heptane, and commercially available 
hydrocarbon solvent mixtures such as Skellysolve.RTM. B, and the like, or 
with chlorohydrocarbons, e.g., methylene chloride, chloroform, carbon 
tetrachloride, ethylene dichloride, and the like, or with liquid aromatic 
hydrocarbons, e.g., benzene, toluene, xylene. 
This process can be used as part of an overall process to prepare a wide 
variety of useful aryl-C.sub.3 to C.sub.6 -alkanoic acids. Acid products 
of immediate concern to us are those which have medicinal uses when 
compounded into appropriate pharmaceutical formulations and dosage forms. 
Examples of such compounds which can be made from this process include 
those wherein Ar is 3-phenoxyphenyl, C.sub.3 to C.sub.5 -alkylphenyl, 
4-biphenylyl substituted with up to 3 fluorine atoms on ring carbons 
thereof and 2-naphthyl substituted in the 6-position thereof with methoxy. 
Also, 2-phenyl C.sub.3 to C.sub.6 -alkanoic acids such as 
2-phenylpropionic acid, and 2-methyl-2-phenylpropionic acid and the like 
which have plant growth regulatory properties can also be prepared by the 
process of this invention. 
Enol ether compounds (III) are sometimes formed as a mixture of 
stereoisomers, but the success of the process does not depend upon the 
isomer configuration or isomer ratio of enol ether, so the 
stereoconfigurations are not shown here, and such mixtures of enol ethers 
can be used in this process. 
For use in this invention, the trivalent thallium ions are provided in the 
form of salts thereof with an organic carboxylic acid having a pKa above 
about 2 which will ionize under the reactant mole ratio, solvent and 
temperature reaction conditions to create an electrophilic thallium ion 
species in the mixture. It has been found that these salts are the best 
thallium ion sources in a process wherein the trivalent thallium ions are 
to be regenerated in a separate vessel for recycling back to the enol 
ether to ester reaction mixture for re-use in the process. Examples of 
organic acid salts of thallium for this purpose include those of the 
C.sub.1 to C.sub.6 -alkanoic acids and the C.sub.1 to C.sub.6 
-haloalkanoic acids such as the acetate, propionate, isobutyrate, 
hexanoate, .alpha.-chloroacetate, .alpha.-bromoacetate, 
.alpha.-chloropripionate, .alpha.-bromopropionate, .alpha.-chlorobutyrate, 
as well as thallium benzoate, and the like. Thallium acetate salts are 
preferred for reasons of cost and availability. 
Although the enol ether to ester reaction of this process will proceed to 
at least some extent at low temperatures, as low as about -25.degree. C., 
and the reactants and products are stable enough to withstand reflux 
temperatures of the reaction mixtures at atmospheric pressure, temperature 
ranges of from about -10.degree. to about 100.degree. C. are sufficient 
and preferred. With some combination of reactants and solvents it may be 
desirable to conduct the reaction at elevated pressures to push the 
reactions to completion in shorter periods of time, but for most 
combinations of reactants atmospheric pressure is sufficient to complete 
the reaction less than 10 hours. The aryl group on the enol ether starting 
material is selected to provide the resulting 2-aryl-C.sub.3 to C.sub.6 
-alkanoic acid product with useful properties, such as anti-inflammatory, 
analgesic and anti-pyretic drug properties or herbicidal, plant growth 
regulatory or other practically useful properties. The substituent on 
oxygen of the enol ether can be any group which will form a 2-aryl-C.sub.3 
to C.sub.6 -alkanoate ester and which ester group is easily removed by 
known procedures to form the corresponding 2-aryl-C.sub.3 to C.sub.6 
-alkanoic acid products. In its preferred forms the process of this 
invention produces substantially only the 2-aryl-C.sub.3 to C.sub.6 
-alkanoate ester, thus bringing the practical yields closer to the 
theoretical yields, while avoiding the necessity for including any bulky, 
inert support materials for the thallium compound in the reaction mixture 
and also the necessity of acid catalysis. 
The preferred enol ether starting materials are those having an aryl (Ar) 
group, which is common to useful drug acids and include, for example, 
3-phenoxyphenyl, C.sub.3 to C.sub.5 -alkylphenyl, 4-biphenylyl, 
4-biphenylyl substituted with a total of up to about 3 fluorine atoms in 
the phenyl ring thereof, and 2-naphthyl substituted in the 6-position with 
methoxy and R is C.sub.1 to C.sub.4 -alkyl, and R.sup.1 is C.sub.2 to 
C.sub.4 -alkyl. Useful compounds can also be made by the process of this 
invention where the aryl group is a simple unsubstituted phenyl, naphthyl 
or biphenylyl. 
Ketones which can be used to prepare the enol ether starting materials for 
use in the process of this invention are known compounds or can be 
prepared by procedures known in the art. Examples include those of the 
formula 
##STR5## 
wherein Ar denotes the aryl moiety in known arylalkanoic acid compounds, 
and includes those Ar groups described, for example, in Marshall U.S. Pat. 
No. 3,745,223, Marshall U.S. Pat. No. 3,600,437, the biphenylyl and 
substituted biphenylyl groups described in Shen U.S. Pat. No. 3,624,142, 
the fluoro-4-biphenylyl groups described in Adams et al. U.S. Pat. Nos. 
3,793,457 and 3,755,427, 2-fluoro-4-biphenylyl, the 3,4-(disubstituted 
phenyl) groups described in Krausz et al. U.S. Pat. No. 3,876,800, and the 
4-substituted phenyl groups described, for example, in Nicholson et al. 
U.S. Pat. No. 3,228,831 and the 6-substituted 2-naphthyl groups in Belgian 
Pat. No. 747,812, and R.sup.1 is 
EQU -(CH.sub.2).sub.n -H or 
##STR6## 
wherein n is 2 to 5, Y and Z are C.sub.1 to C.sub.4 -alkyl or hydrogen 
with at least one of Y and Z being C.sub.1 to C.sub.4 -alkyl. A preferred 
subgroup of ketones for use in preparing the ketals and enol ethers for 
use in the process of this invention are the aryl ethyl ketones, wherein 
the Ar group is as exemplified above. The most preferred ketones would be 
those which possess the Ar moieties which are of established economic 
interest for use in preparing the most useful and commercialized acid 
compounds, e.g., useful drug acid compounds. Examples of these ketones 
would be those ketones wherein Ar in the above formula IV is 
4-isobutylphenyl, 4-phenoxyphenyl, 3-phenoxyphenyl, 2-fluoro-4-biphenylyl, 
6-methoxynaphthyl, and R.sup.1 is -(CH.sub.2).sub.n H wherein n is 2 to 4. 
Procedures for making the enol ether starting materials from the ketones 
for the process of this invention are known in the art. Examples of such 
procedures include: 
(A) reaction of the selected ketone with a trialkyl orthoester such as 
trimethyl orthoformate in the presence of an acid catalyst such as 
sulfuric acid, methanolic hydrogen chloride, p-toluenesulfonic acid, 
ferric chloride or ammonium nitrate, styrene-divinylbenzene copolymer 
sulfonic acid resin materials such as those sold under tradenames or 
trademarks such as Amberlyst-15 (see "Amberlyst-15, Superior Catalyst for 
the Preparation of Enol Ethers and Acetals" by S. A. Patwardhan et al. in 
SYNTHESIS, May, 1974, pp. 348-349). 
(B) reaction of the ketone with simple alcohols, preferably C.sub.1 to 
C.sub.4 -alkanols, in the presence of an acid catalyst, including the use 
of sulfonic acid exchange resins such as the styrene/divinylbenzene 
copolymer sulfonic acid resins exemplified by Amberlyst-15 (Rohm & Haas 
Company, Philadelphia) and Dowex 50 (Dow Chemical Company, Midland, 
Michigan) at low temperature, e.g., -28.degree. C., favors the formation 
of the ketone acetal (see J. of Organic Chemistry, Vol. 24, November, 
1959, pp. 1731-1733, an article by N. B. Lorette et al., entitled 
"Preparation of Ketone Acetals from Linear Ketones and Alcohols"). 
(C) reaction of the selected ketone with acetone dimethyl acetal 
(2,2-dimethoxypropane) to effect transketalization, as described in an 
article entitled "Preparation of Ketals from 2,2-Dimethoxypropane" by N. 
B. Lorette et al. in J. Org. Chem., Vol. 25, April, 1960, pp. 521-525. 
(D) conversion of the corresponding ketal (acetal) to the enol ether by 
distillation over catalysts such as p-toluenesulfonic acid (see SYNTHESIS, 
supra). 
For the preparation of the preferred aryl alkyl ketones a Friedel-Crafts 
reaction can be used, e.g., to effect reaction according to the following 
general format 
##STR7## 
wherein R" is the residue of the desired aryl (Ar) group and R.sup.1 is 
the residue of the carboylic acyl halide. For example, the 
6-methoxy-2-naphthyl propiophenone can be prepared by reacting 
6-methoxynaphthalene with propionyl chloride in the presence of aluminum 
chloride in methylene chloride. The resulting 6-methoxy-2-naphthyl ethyl 
ketone is converted to the methyl eno ether starting material for this 
process by reacting it with trimethyl orthoformate in the presence of acid 
and heating in vacuo. The 3-phenoxyphenyl ethyl ketone methyl enol ether 
can be prepared by reacting 3-hydroxyphenyl ethyl ketone with phenyl 
bromide in the presence of potassium carbonate to form 3-phenoxyphenyl 
ether ketone and then reacting this ketone with trimethylorthoformate to 
form the ketal followed by heating with acid. The enol ether of 
2-fluoro-4-biphenylyl ethyl ketone is formed by reacting 
2-fluoro-4-biphenylyl ethyl ketone with trimethylorthoformate to form the 
ketal, then heating with p-toluenesulfonic acid in vacuo. The 
2-fluoro-4-biphenylyl ethyl ketone can be prepared from 
4-bromopropiophenone via 4'-bromo-3'-nitropropiophenone (see Chemical 
Abstracts, 61, p. 8232g), 4-propionyl- 2-nitrobiphenyl (Ullman reaction, 
4-propionyl-2-aminobiphenyl (reduction) and finally the Schiemann 
Reaction. See U.S. Pat. No. 3,793,457, Example 1, for a similar synthesis 
of 2-fluoro-4-biphenyl methyl ketone. The difluorobiphenyl ketone can be 
prepared by reacting 4-cyano-2,2'-difluorobiphenyl with ethyl magnesium 
bromide to form the difluoro biphenylyl ethyl ketone. See U.S. Pat. No. 
3,755,427. This ketone can be converted to the enol ether by the procedure 
described above. A preferred method for preparing the enol ether for 
preparing ibuprofen esters according to this invention is set forth in the 
detailed examples below. 
The rate of reaction between the enol ether and the trivalent thallium ion 
source is affected by the solvent in which the reaction is run and the 
concentration of thallium ion in the reaction mixture. For example, the 
reaction of stoichiometric quantities of trivalent thallium acetate and 
the p-isobutylpropiophenone methyl enol ether in absolute methanol 
requires extended reaction times for good conversion to methyl 
2-(p-isobutylphenyl)propionate. Reaction occurs rapidly in such mixtures 
to about 50%, and then the reaction rate slows dramatically. However, with 
the use of excess trivalent thallium acetate relative to the molar content 
of enol ether in the methanol mixture, this reaction was found to proceed 
rapidly at or slightly above room temperature. The rate of enol ether to 
ester product reaction is enhanced as the concentration of a C.sub.1 to 
C.sub.6 -alkanoic acid, e.g., acetic acid (as co-solvent with methanol) 
increases. However, as the amount of alkanoic acid co-solvent increases, 
the rate of the competing enol ether hydrolyses reaction to form ketone or 
methoxy ketone by-products is increased. To minimize undesired competing 
reactions, the use of 80/20 v/v mixture of methanol/acetic acid or acetic 
acid/water solutions as solvent mixtures gave adequate enol ether to ester 
product reaction rates with only minor hydrolysis. 
When the enol ether plus trivalent thallium ion reaction to form the ester 
product plus monovalent thallium ions reaction subsides or stops, that 
reaction mixture is treated according to the process of this invention to 
regenerate trivalent thallium ions which have become depleted in the 
reaction mixture. The monovalent thallium ions are oxidized back to the 
trivalent state, in a separate vessel, by providing (a) a perorganic acid 
preferably a percarboxylic acid having a pKa above about 2 in an amount 
which is at least about stoichiometrically equivalent to the monovalent 
thallium content in the mixture in the presence of (b) a reactive form of 
a non-thallium metal selected from the group consisting of at least one of 
manganese, ruthenium, cobalt, iridium, hafnium, osmium and neobium, said 
non-thallium reactive metal form being provided in a sufficiently soluble 
form to promote oxidation of monovalent thallium ions to the trivalent 
thallium valence state. Generally these promoter metals are placed in the 
thallium ion solution phase. The amount of manganese, ruthenium, cobalt, 
iridium, hafnium, osmium and neobium metal or compound thereof needed to 
catalyze the thallium oxidation is quite small. While less than 1% by 
weight of the non-thallium reactive metal compound, based on the weight of 
the thallium salt being treated, promotes the oxidation by the 
percarboxylic acid, it is preferred that from about 1% to about 10%, by 
weight relative to the weight of the thallium salt present of the selected 
non-thallium metal compound catalyst be used. 
Examples of useful forms of these manganese, ruthenium, cobalt, iridium, 
hafnium, osmium and neobium oxidation promoter elements include reactive 
salt forms thereof including the sulfate, halides, the organic acid salts, 
such as the salts thereof with C.sub.1 to C.sub.6 -alkanoic acids, benzoic 
acid and the like, the oxides and hydroxides of such metals such as 
manganous oxide, manganese hydroxide, alkali metal, such as sodium, 
potassium lithium and other forms of the permanganate ion, as well as 
organic/inorganic reactive forms of such metals such as 
tris(triphenylphosphine) ruthenium dichloride or dibromide and the like. 
The preferred metal promoters for this reaction for reasons of reactivity 
and cost are the reactive forms of manganese, ruthenium and cobalt. Those 
which are less preferred are the reactive forms of iridium, hafnium, 
osmium and neobium, but they can be used under the proper conditions, 
including time, solvent choice, peracid choice, and the like. 
Of these metal promoter compounds, all of them work well in a C.sub.1 to 
C.sub.10 -alkanoic acid, e.g., acetic acid or aqueous alkanoic acid, e.g., 
aqueous acetic acid, which contains enough alkanoic acid to prevent 
hydroylsis of thallium (III) alkanoate in the mixture to thallium (III) 
oxide, Tl.sub.2 O.sub.3. Manganese compounds can also be used in organic 
liquid/aqueous systems such as C.sub.5 to C.sub.10 -hydrocarbon solvents 
free of aliphatic unsaturation, methanol or other liquid alcoholic 
solvents or alcohol/water solvent mixtures including primary, secondary or 
tertiary alcohols and mixtures of these alcoholic solvents with water. Of 
the organic liquid media ruthenium works in tert-alkanols but not so well 
in primary or secondary alcohol systems. Ruthenium and cobalt work best in 
C.sub.1 to C.sub.10 -alkanoic acids or aqueous C.sub.1 to C.sub.10 
-alkanoic acids. The remaining metal promoter compounds work best in 
aqueous C.sub.1 to C.sub.10 -alkanoic acid. 
Manganese is the preferred thallium oxidation promoter catalyst. A 
preferred form of the manganese catalyst is divalent manganese diacetate, 
which is usually available as its tetrahydrate, although other forms of 
manganese may be used including manganese C.sub.1 to C.sub.5 -alkanoate 
salts other than the manganese diacetate referred to above, manganese 
sulfate, manganese chloride or bromide, manganese dioxide, alkali metal 
permanganates, principally sodium, potassium and lithium permanganates, 
and the like. 
The amount of peracid, e.g., a percarboxylic acid such as peracetic acid, 
used to oxidize monovalent thallium ions to the trivalent thallium ion 
state in the presence of the non-thallium oxidation promoter metal, e.g., 
manganese diacetate, is not critical since any excess peracid is rapidly 
decomposed to give a peracid-free solution of trivalent thallium alkanoate 
salt. The oxidation of the enol ether reactant by these trivalent thallium 
ion solutions was found to give the same product mixtures as obtained with 
commercially available trivalent thallium salts under similar conditions. 
However, the use of percarboxylic acids, such as, peracetic acid, for 
regeneration of trivalent thallium ions offers additional advantages. The 
methyl 2-(p-isobutylphenyl)proionate ester (ibuprofen ester) product was 
found to be relatively stable toward peracid. In fact, as indicated above, 
the oxidation of monovalent thallium acetate to trivalent thallium acetate 
with peracid could be carried out in the presence of the ibuprofen ester 
product with no apparent effect on the ester of the Tl.sup.+ to Tl.sup.+++ 
reaction. Peracetic acid solutions prepared using a sulfonic acid resin 
catalyst (as opposed to a soluble acid catalyst such as p-toluenesulfonic 
acid) are preferred if a large number of cycles of the process is to be 
carried out. The gradual buildup of strong acid, such as sulfuric acid 
which is present in some commercial grades of 40% peracetic acid solutions 
of p-toluenesulfonic acid if it is used as a catalyst in peracid 
formation, was found to inhibit the Tl.sup.+ to Tl.sup.+++ oxidation 
reaction after a number of cycles. With sulfuric or sulfonic acid free 
peracid solutions, the enol ether plus trivalent thallium ion .fwdarw. 
ester product and Tl.sup.+ to Tl.sup.+++ oxidation reactions proceed 
readily even after a large number of cycles. In the process of this 
invention the liquid phase containing all or most of the thallium ion 
content is separated from the liquid phase containing all or most of the 
enol ether and ester materials, and the aqueous thallium ion phase is 
treated with an effective amount of a perorganic acid as described above 
in the presence of one or more of the oxidation promoter metals to oxidize 
the monovalent thallium ions to the trivalent thallium valence state and 
then the resulting liquid phase containing the trivalent thallium ion rich 
phase is returned for admixture with the liquid phase containing the enol 
ether for conversion thereof to the respective ester product. 
To produce larger quantities of the 2-aryl-C.sub.3 to C.sub.6 -alkanoate 
esters in a continuous manner when thallium salts derived from organic 
acids having a pKa of 2 or higher are used, after essential exhaustion of 
the first or prior quantities of enol ether in the mixture of the 
trivalent thallium ions needed for further reaction with enol ether can be 
generated from monovalent thallium ions in a separate vessel by providing 
or otherwise mixing with the monovalent thallium ion containing mixture at 
least about a stoichiometric amount, preferably a slight excess, of a 
peracid derived from an organic carboxylic acid having a pKa of about 2 or 
above in the presence of a reactive form of, preferably salt, oxide or 
base form of a metal selected from the group consisting of at least one of 
manganese, ruthenium, cobalt, iridium, hafnium, osmium and neobium, said 
non-thallium metal, salt, oxide or base being provided in a form and 
concentration, in the separate reaction vessel to promote oxidation of 
monovalent thallium ions to the trivalent thallium valence state. 
Thereafter the regenerated trivalent thallium ion can be recombined with 
enol ether, by moving and adding the regenerated trivalent thallium ion 
mixture to the reaction vessel which contains more enol ether with which 
to react to form the additional 2-aryl-C.sub.3 to C.sub.6 -alkanoate 
ester. This regeneration of thallium (III) ions from thallium (I) ions 
allows thallium (III) organic acid salts to be used in an essentially 
catalytic manner. The utility of these highly toxic thallium compounds is, 
thus, greatly extended and the hazards of working with them are greatly 
reduced. Peracetic acid which is free of strong acids such as sulfuric 
acid is preferred for use in this process. Commercial 40% peracetic acid 
contains about 1% sulfuric acid. We prefer preparing the peracid with a 
commercially available sulfonic acid ion-exchange resin which can be 
removed by filtration before use of the resulting peracid solution in this 
process. Alternatively, p-toluenesulfonic acid can be used to generate the 
peracid for use in this process. 
In the embodiment of the process represented by the drawing, the continuous 
reactor 3 can be a Scheibel-type extractor column for mixing the lighter 
and heavier liquid phases. In a typical example (see the drawing), the 
lighter liquid phase in tank 1 can be, e.g., a solution of the enol ether 
reactant in hexane or Skellysolve.RTM. B. The heavier liquid phase in feed 
tank B, 11, can be an aqueous acetic acid solution containing trivalent 
thallium ions (thallium acetate) and an oxidation promoting amount of 
manganese acetate. The lighter organic phase is introduced into the 
reactor 3 via line 2. The heavier aqueous phase is introduced into the 
reactor 3 via line 12. The lighter organic liquid phase is taken from the 
reactor 3 via line 4 to stripper vessel 5 where the lighter organic liquid 
phase containing the ester product is washed with aqueous acetic acid from 
line 7 to remove (strip) adhering aqueous thallium ions therefrom, and 
then the ester product phase is removed from the continuous process system 
via line 6. The aqueous acid wash liquid containing any thallium ions 
removed from the ester product is transferred from the stripper 5 via line 
8 for combination with any makeup acid or water introduced via line 9 and 
the resulting aqueous liquid mixture is transferred via line 10 to mixture 
with the oxidized thallium ion rich liquid phase from line 26 in line 27 
and the resulting mixture is fed back into the feed tank B, 11, for reuse 
in the process. 
The heavier liquid phase from the reactor 3 is drained or removed via line 
13 and transferred to stripper vessel 14 where the heavy liquid thallium 
ion phase is washed with organic liquid from line 15, e.g., hexane, to 
remove organic liquid soluble materials such as by-products produced 
during the enol ether+trivalent thallium ion reaction in reactor 3. The 
heavier aqueous thallium ion/non-thallium oxidation promoter metal 
compound liquid phase from stripper 14 is transferred via line 19 to the 
concentrator 20. Water and acid are removed via line 21, if necessary. The 
water/acid mixture can be separated, e.g., by distillation, the acid 
reoxidized with hydrogen peroxide and the resulting peracid recycled back 
to the system. The concentrated aqueous thallium ion/non-thallium 
oxidiation promoter metal compound phase is transferred from the 
concentrator 20 via line 22 to the reactor 23 where the monovalent 
thallium ions in the aqueous phase are reacted with peracetic acid (or 
other equivalent peracid) from line 24 and oxidized to the trivalent 
thallium ion valence state in the presence of the oxidation promoter metal 
compound, e.g., manganese acetate. By-product oxygen can be removed from 
the oxidation vessel 23 via line 25. The aqueous trivalent thallium ion 
rich phase is transferred from oxidation reactor 23 via line 26 for mixing 
with aqueous acid, if needed, from line 10, and the resulting mixture is 
transferred to the liquid phase feed tank B, 11, for reuse in the process. 
The organic liquid washed phase from stripper 14 is transferred via line 16 
to concentrator 17 and the organic liquids therefrom can be recirculated 
via line 15 to again wash more aqueous phase. By-products can be removed 
from the continuous reaction system via the concentrator 17 and line 18. 
Make up organic wash liquid can be added via line 30. 
The continuous reactor 3 can be maintained at the desired temperature by 
the use of a heating/cooling jacket around the reactor. The heat transfer 
assembly is represented by the heat exchange lines 28 and 29. 
The ester intermediate product can be hydrolyzed or otherwise converted to 
the corresponding acid by conventional means. For example, the ester can 
be heated with reflux with a mixed aqueous/alcoholic solution of alkali 
metal hydroxide until the acid is formed, say for 0.5 to 3 hours. On 
cooling, the reaction mixture can be treated to recover the acid product, 
e.g., by washing the hydrolyzed reaction mixture with water, extracting 
with hexane or commercial mixtures of hexanes (e.g., Skellysolve.RTM. B), 
to remove organic solubles, and the aqueous phase acidified and extracted 
with hexane. The extracts containing the acid product can be washed with 
aqueous salt solutions and dried. Thereafter, removal of the solvent by 
vacuum distillation leaves a crystalline acid product or an oil which 
crystallizes upon standing. 
Preferred embodiments of the process of this invention include the 
preparation of any of the included ester products using thallium salts of 
a C.sub.1 to C.sub.10 -alkanoic acid, preferably of acetic acid, in an 
organic liquid mixture containing aqueous alkanoic acid to effect enol 
ether conversion to the ester products. When these thallium alkanoate 
salts are used in such a common ion alkanoic acid solvent, the 
non-thallium reactive metal compounds, particularly manganese and 
ruthenium, readily promote the re-oxidation of monovalent thallium ions to 
the trivalent thallium state. The manganese and ruthenium can also be 
provided as the acetate or other alkanoate salt thereof. Peracetic acid is 
the preferred oxidizing acid for use with the acetate salts of the metals 
in aqueous acetic acid solutions thereof. The process can preferably 
include the use of a two phase liquid system comprising aqueous C.sub.1 to 
C.sub.10 -alkanoic acid as one phase to contain the bulk of the thallium 
and non-thallium oxidation promoter metal compounds, e.g., manganese or 
ruthenium acetates, and a C.sub.5 to C.sub.10 -hydrocarbon free of 
aliphatic unsaturation as the other liquid phase to contain the bulk of 
the enol ether reactant and ester product. Examples of such C.sub.5 to 
C.sub.10 -hydrocarbon solvents include pentane, hexane, heptane, octane, 
decane, benzene, toluene, xylene, norcarane, norpinane, norbornane, and 
mixtures thereof, including commercial mixtures such as Skellysolve.RTM. 
B, and the like. This continuous two liquid phase process is particularly 
well adapted for preparing C.sub.1 to C.sub.6 -alkyl esters of ibuprofen 
by reacting a 4-isobutylpropiophenone C.sub.1 to C.sub.6 -alkyl enol ether 
with trivalent thallium ions in a water immiscible organic liquid mixture 
containing an aqueous C.sub.1 to C.sub.10 -alkanoic acid, preferably 
aqueous acetic acid, in which the trivalent thallium ions consumed in the 
enol ether conversion reaction are regenerated in a separated aqueous acid 
phase by reacting monovalent thallium ions resulting from that reaction 
with a percarboxylic acid having a pKa above about 2 in an amount at least 
stoichiometrically equivalent to the monovalent thallium ion content of 
the mixture in the presence of a reactive form of manganese, ruthenium 
cobalt, iridium, hafnium, osmium and/or neobium, preferably manganese or 
ruthenium, said non-thallium reactive metal being provided in a 
sufficiently aqueous acid soluble form, preferably as their acetate salts, 
and in amount to promote or catalyze the oxidation of monovalent thallium 
ions to the trivalent thallium valence state, for reuse of the trivalent 
thallium ions to react with additional enol ether reactant. 
The enol ether to 2-aryl-C.sub.3 -C.sub.6 -alkanoate and thallium (I) to 
thallium (III) ion regeneration process can be conducted in a continuous 
manner using a known-type of liquid-liquid extraction column reaction 
apparatus. Thus, for example, such a column can be operated in a 
counter-current or cocurrent mode with a solution of thallium (III) 
acetate in aqueous acetic acid being charged as one stream. A second 
stream of a solution of 4-isobutylpropiophenone methyl enol ether in a 
water immiscible hydrocarbon such as hexane or heptane is pumped into the 
column to mix and react with the thallium (III) ion content of the aqueous 
mixture. The flow of the aqueous acetic acid solution and the hydrocarbon 
phases are controlled so that phase separation and reaction can take place 
in the counter-current or cocurrent column. The temperature of the 
reaction mixture can be controlled to the desired range, say, 0.degree. to 
100.degree. C., by the use of heating jackets around the counter-current 
column or by other equivalent means. The time needed for the conversion of 
the enol ether to the ester product is quite short, within 10 minutes in 
most cases, so that the reaction contact time or residence time of the 
liquids in the column can be readily controlled by controlling the flow of 
the reactant fluids into and out of the column. 
The aqueous acetic acid phase rich in thallium (I) ions can be withdrawn 
from the bottom of the column and piped to a separate vessel where it is 
contacted with peracetic acid solution in the presence of one of the above 
mentioned metal promoter compounds, e.g., manganese acetate, to oxidize 
the thallium (I) ions in the mixture to the thallium (III) valence state, 
and this resulting thallium (III) rich solution in aqueous acetic acid can 
be pumped back to the primary counter-current or co-current column or 
backmixed reactor/settler system for further reaction with enol ether to 
form additional quantities of the 2-aryl-C.sub.3 to C.sub.6 -alkanoate 
ester product. 
The hydrocarbon phase containing the 2-aryl-C.sub.3 to C.sub.6 -alkanoate 
ester product in a counter-current column can be drawn off the top of the 
column and piped to an appropriate vessel for separation of the ester 
purification and conversion to the corresponding 2-aryl-C.sub.3 to C.sub.6 
-alkanoic acid, as described above. The hydrocarbon solvent can be 
recycled to dissolve more enol ether reactant for reaction in the 
counter-current column with thallium (III) ions therein. 
Literature descriptions of suitable liquid-liquid counter-current/cocurrent 
column extractors can be found, e.g., in E. G. Scheibel, AlChEJ, Vol. 
2(1), March, 1956; Coulson and Richardson, "Chemical Engineering", pp. 
748-774, Pergamon Press Ltd., London (1967). 
The invention is further described and exemplified by the detailed examples 
which follow but they are not intended to limit the scope of the 
invention. 
EXAMPLE 1: 
Preparation of Ibuprofen via isobutylpropiophenonene methyl enol ether 
starting from p-isobutylbenzene 
(A) Preparation of p-isobutylpropiophenone. 
In a 500 ml. 3-necked, round bottomed flask there was placed 25.50 ml. 
(40.14 g., 0.29 mmole) of phosphorus trichloride and 43.65 ml. (43.34 g., 
0.58 mmole) of propionic acid. This mixture was stirred for 2.25 hours 
under nitrogen atmosphere at room temperature to prepare the propionyl 
chloride. By NMR propionyl chloride formation was complete in about 1.5 
hours. Then 80 ml. of anhydrous methylene chloride was added and the 
resulting solution was cooled to about -5.degree. C. (an ice-methanol 
bath). While stirring the cooled mixture 87.50 g. (0.66 mmole) of aluminum 
chloride (technical grade) was added. After 10 minutes of stirring 67.11 
g. (0.50 mmole) of isobutylbenzene was added dropwise from an additional 
funnel over 55 minutes while maintaining the temperature of the mixture at 
about 0.degree. to 5.degree. C. The mixture was stirred for an additional 
1.25 hours to insure as complete a reaction as possible and then poured 
into a solution of 250 ml. of ice water and 150 ml. of concentrated 
hydrochloric acid with vigorous stirring. The Friedal-Crafts reaction was 
complete in about 45 minutes under these conditions (by GLC analyses). The 
resulting mixture was extracted three times with 300 ml. portions of 
methylene chloride. The combined methylene chloride extracts were washed 
with 250 ml. of water and three times with 250 ml. of molar concentration 
aqueous sodium carbonate solution. The aqueous sodium carbonate extracts 
were back extracted with 100 ml. of methylene chloride and the combined 
methylene chloride layers were dried over sodium sulfate. The dried 
methylene chloride solution was concentrated under vacuum to give crude 
p-isobutylpropiophenone as a pale yellow oil weighing 97.85 g. By GLC 
analyses 3% methylene chloride was present. The chemical yield was about 
95 g. or about 100% of theory. 
(B) Preparation of p-isobutylpropiophenone dimethyl ketal. 
To 11.33 g. (0.10 mole) of methyl acetimidate hydrochloride, prepared by 
known methods, in a 100 ml. 3-necked, round bottom flask there was added a 
solution of 9.71 g. (actual 9.42 g.; 49.6 mmole) of crude 
p-isobutylpropiophenone, prepared as described in part A above, in 23 ml. 
of absolute methanol. The resulting solution was stirred for 12 hours at 
room temperature to insure complete reaction. Gas liquid chromatographic 
analysis (GLC analysis) of an aliquot of the reaction mixture indicated 
greater than 99% ketal formation. The resulting mixture was filtered to 
remove the precipitated ammonium chloride and concentrated under vacuum. 
Hexane (50 ml.) was added to the residue and the resulting solution was 
again filtered to remove any acetamide which might be present. Removal of 
the hexane solvent under vacuum gave p-isobutylpropiophenone dimethyl 
ketal as a pale yellow oil which was used without further purification. 
The NMR was in accord. 
(C) Preparation of 1-(p-isobutylphenyl)-1-methoxy propene (also named 
p-isobutylpropiophenone methyl enol ether). 
In a 100 ml. round bottomed flask there was placed the crude 
p-isobutylpropiophenone dimethyl ketal, prepared from 49.6 mmole of crude 
p-isobutylpropiophenone by the procedure described in part C hereinabove, 
and 3.0 g. (56.1 mole) of anhydrous, finely ground ammonium chloride which 
had been dried under vacuum. Under vacuum (60 mm. Hg.) the mixture was 
heated with vigorous stirring to 130.degree.-135.degree. C. The pressure 
was then reduced to 6 to 8 mm. and the mixture was maintained at 
130.degree.-135.degree. C. for 3 hours. On cooling, the ammonium chloride 
was removed by filtration under nitrogen and the solids were washed with 
10 ml. of hexane. Concentration of the filtrate under vacuum gave 10.6 g. 
of a pale yellow oil. By NMR analyses (internal standard nitromethane) the 
oil consisted of 89.5% of the p-isobutylpropiophenone methyl enol ether 
and 5% of the p-isobutylpropiophenone dimethyl ketal. It was used without 
further purification. The overall chemical yield was 9.57 g. (94.6% of 
theory). 
(D) Preparation of ibuprofen via methyl 2-(p-isobutylphenyl)propionate from 
the p-isobutylpropiophenone methyl enol ether. 
In a 500 ml. 3-necked round bottomed flask (Morton type) fitted with a 
mechanical stirrer, a reflux condenser and a thermometer there was placed 
39.45 g. (150 mmole) of thallium acetate, 2.8 g. (4.1 mmole) of manganese 
diacetate.tetrahydrate, 40 ml. of distilled water and 160 ml. of glacial 
acetic acid. While stirring the resulting mixture there was added about 6 
ml. of 41% peracetic acid solution. (The peracetic acid solution was 
prepared from 60 ml. of glacial acetic acid, 19 ml. of 90% hydrogen 
peroxide solution and 2.5 g. of a sulfonated polymer resin (Dowex 
MSC-1-H)). Once the resulting solution turned dark brown about 30 to 40 
minutes at room temperature, an additional 33 ml. of 41% peracetic acid 
solution (for a total of about 39 ml., 300 mmole of peracetic acid) was 
added over about 5 minutes with ice bath cooling. This monovalent thallium 
oxidation reaction is quite exothermic. The temperature was maintained 
below 50.degree. C. at all times. The resulting trivalent thallium ion 
containing solution was placed in an oil bath and the temperature was 
adjusted to 40.degree. C. With vigorous stirring, a solution of 10.5 g. of 
crude p-isobutylpropiophenone methyl enol ether, prepared as described 
above, from 49.7 mmole of crude p-isobutylpropiophenone in 50 ml. of 
hexane was added via the addition funnel as rapidly as possible. The 
oxidative rearrangement of the enol ether reaction is exothermic. A 
5.degree. C. temperature rise was noted. A GLC analyses of an aliquot 
sample of the reaction mixture after 3 minutes indicated reaction was 
complete. In other similar runs the reaction time was found to be less 
than 30 seconds under these conditions. After 17 minutes stirring was 
discontinued and the mixture was rapidly cooled to 10.degree. C. Upon 
transfer to a separatory funnel, the hexane layer was removed and the 
aqueous acetic acid layer was extracted three times with 100 ml. portions 
of hexane. Hexane extracted essentially all of the desired products (enol 
ether reactant and ibuprofen ester) from the 80% acetic acid in water acid 
layer. Dilution of the aqueous acid layer followed by extraction with 
hexane gave only 160 mg. of additional material which consisted of polar 
oxidation products such as .alpha.-hydroxy-p-isobutylpropiophenone. The 
combined hexane extracts were washed with three 100 ml. portions of 
distilled water, 50 ml. of saturated sodium sulfate solution. After drying 
the hexane fraction over sodium sulfate, the dried hexane fraction was 
concentrated under vacuum to 10.28 g. of crude methyl ibuprofen ester 
product as a pale yellow oil. By NMR (internal standard nitromethane) this 
pale yellow oil contained 90.2% of methyl ibuprofen ester and about 8% 
p-isobutylpropiophenone, for an overall yield of 9.27 g. (86.6% of 
theory). 
(E) Preparation of ibuprofen from the ester. 
A 5.11 g. portion of the crude ibuprofen methyl ester prepared as described 
in part D above was dissolved in 20 ml. of hexane and 12 ml. of methanol 
and cooled to 0.degree. to 5.degree. C. Then 6.0 g. (75 mmole) of a 50% 
sodium hydroxide solution was added and the resulting mixture was heated 
under reflux for 2 hours. On cooling the mixture was transferred to a 
separatory funnel with about 50 ml. of 1N sodium hydroxide solution and 
hexane. The hexane layer was extracted with about 10 ml. of 1N aqueous 
sodium hydroxide and the combined aqueous layer was extracted with 50 ml. 
of fresh hexane. The neutral fraction isolated from the combined hexane 
extracts consisted primarily of p-isobutylpropiophenone. The aqueous layer 
was acidified with 50% aqueous sulfuric acid and extracted 3 times of 50 
ml. portions of hexane. The combined hexane extracts were washed 3 times 
with 50 ml. portions of water and dried over sodium sulfate. Removal of 
solvent by vacuum evaporation gave crude ibuprofen as a pale yellow solid, 
weighing 4.20 g., having a purity of 96.7% by GLC analysis, again the 
impurities being about 1.4% p-isobutylbenzoic acid and 1.1% of the meta 
isomer of ibuprofen. The crude yield was 80.8% of theory. 
Recrystallization of the crude ibuprofen from hexane (2 ml./g.) gave 3.44 
of ibuprofen (70.3% yield). 
EXAMPLE 2 
Conducting Process in Continuous Manner Using a Scheibel Column 
This example demonstrates a series of continuous runs of the process 
involving reaction between the enol ether (1) (4-isobutylpropiophenone 
methyl ether), in hexane and trivalent thallium acetate and manganese 
acetate in an acetic acid-water phase in a continuous apparatus system 
including a Schiebel column with auxiliary equipment, e.g., pumps, 
containers, purge tanks, and the like. Scheibel columns are well known in 
the chemical engineering field. See, e.g., Bulltein No. 33 (1963) of the 
York Process Equipment Company, 42 Intervale Road, Parsippany, N.J., 
07054; and "Semicommercial Multistage Extraction Column, Performance 
Characteristics" by Edward G. Scheibel et al in Industrial and Engineering 
Chemistry, Vol. 42, No. 6, pp. 1048 et seq. 
The two input liquid phase feed composition were: (1) an 80% acetic acid in 
water solution containing 20% w/v trivalent thallium acetate and about 
2.7% of divalent manganese diacetate based on the thallium salt content, 
introduced near the top of the Scheibel column, and (2) hexane containing 
20% enol ether reactant introduced near the bottom of the column. The flow 
rates of the aqueous and hexane phases are adjusted to provide contact in 
the Scheibel column reactor between the enol ether and thallium ions in a 
ratio of about 2 molar equivalents of trivalent thallium ions per molar 
equivalent of enol ether. 
The output compositions of the enol ether reactant stream (light phase) are 
set forth in the table below. A preliminary study of the hydrodynamics 
(hold up and flood rates) of the system including the Scheibel column was 
made with pure solvents (blanks) before experimenting with the thallium 
and enol ether solutions. The experimental conditions were varied from run 
to run to learn how to maximize the conversion of enol ether to ester 
product by (1) altering the residence of time of the enol ether solution 
in the column (decreasing or increasing the light phase flow), and/or (2) 
providing increased mixing efficiency or by simultaneously increasing the 
total throughput in the column and agitator speed (Scheibel, 1956). From 
the table below it can be seen that the amount of hydrolysis (or 
by-product ketone formation from the enol ether) is not significant 
compared to a sequential or batch operation of the process, where usually 
5% to 10% of the enol ether reactant is converted to the ketone by-product 
per batch or sequence. This reduced by-product production in the 
continuous process is due to faster reaction between the enol ether and 
the trivalent thallium ions, the low residence time of the enol ether in 
the Scheibel column reactor part of the system and the relatively slow 
hydrolysis rate of the enol ether reactant to the undesired ketone 
by-products. 
Since the oxidation of the thallium acetate by peracetic acid is done 
outside of the main Scheibel column reaction chamber, there are no 
significant amounts of oxidized by-products, e.g., p-isobutylbenzoic acid. 
Furthermore, since much smaller volumes of thallium ion solutions are being 
oxidized with the percarboxylic acid in the continuous process at any one 
time, the safety hazards of this process are significantly reduced 
compared to the sequential or stoichiometric procedure for the enol ether 
to ester process. 
When the heavier thallium ion/manganese ion acetic acid solution phase 
drains from the Scheibel column, it contains monovalent thallium acetate, 
trivalent thallium acetate and manganese salt passes through the Scheibel 
column without reaction. This heavier solution is transferred to a mixing 
tank where it is reacted with a 40% to 42% peracetic acid solution, 
prepared using p-toluenesulfonic acid or a sulfonated resin bead catalyst, 
for a few minutes (5 to 10 minutes) to effect oxidation of the monovalent 
thallium ions in the solution mixture in the presence of the manganese 
acetate catalyst to the trivalent thallium ion state, while by-product 
oxygen gas is removed from the mixing tank. Thereafter the heavy phase 
containing the trivalent thallium ions, manganese diacetate in acetic 
acid/water solution can be concentrated or diluted with acetic acid and 
water to adjust the concentration of the thallium ions to the desired 
level before re-introduction of the heavy phase into the Scheibel column 
reactor for further reaction with enol ether in the lighter hexane phase. 
A rough calculation shows that for a 100 kg./day of ibuprofen production a 
Scheibel column reactor being 0.75 m. long .times. 0.15 m. internal 
diameter can handle about 100 liters/hour total liquid flow. In this 
process the degree of mixing in the Scheibel column reactor has been found 
to be influential in experimental runs to shorten or lengthen residence 
times. 
In these runs (see Table below) the holdup of the thallium ion phase (heavy 
phase) in the column is about 75% of the column volume. Applied to the 
production scale of 100 kg./day of ibuprofen, using the same proportional 
amount of thallium acetate as indicated above in Example 1 for circulation 
the remaining parts of the continuous loop of the apparatus system, the 
total thallium acetate in the continuous system would be about 5 kg. of 
thallium acetate, an order of magnitude lower than the amount of thallium 
ions needed for the sequential operation and about two orders of magnitude 
lower than that needed for the batch operation. 
A sample of the reaction mixture from run number 8 in the table below was 
worked up to convert the methyl 2-(4-isobutylphenyl)propionate ester 
product in the mixture to its acid, 2-(4-isobutylphenyl)propionic acid, 
(generic name) ibuprofen). The sample was first washed with 80% acetic 
acid in water solution and hydrolyzed with sodium hydroxide and then 
crystallized out of hexane. The total conversion was found to be 63%. 
However, if correction is made for the unreacted enol ether (since the 
reaction conditions are not yet optimized and the reaction can be made to 
go to completion by changing the various parameters available in this 
system, e.g., flow rate and temperature) the overall conversion of the 
reacted enol ether is about 92%. This is quite consistent if one scans the 
column in the Table below showing weight percent of the products in the 
light liquid phase. The sum of the enol ether (unreacted) and the 
ibuprofen ester product is in the range of 92% to 97%. This means that 
with better optimization, it would be possible to achieve about 95.+-.3% 
conversion of the enol ether to isolated ibuprofen acid as compared to 
about 80.+-.5% conversion in the sequential or batch operation. 
TABLE (A) 
__________________________________________________________________________ 
SUMMARY OF DATA FROM CONTINUOUS REACTION BETWEEN ENOL ETHER AND THALLIUM 
(III) 
ACETATE IN A SCHEIBEL COLUMN TO PRODUCT IBUPROFEN 
Light Heavy 
Phase Phase % Conversion Isolated Product 
Flow Flow Wt. % Product (GLC) 
of Enol Ether 
% Enol 
Ibuprofen 
(Chemical) 
Rate Rate Stir- 
(Light Phase Output) 
to Ibuprofen 
Ether 
Based on Based on 
(ml./min.) 
(ml./min.) 
ring Ibuprofen 
Methyl Ester 
Con- Reacted Total Enol 
Expt. 
(Enol Ether 
(T1 in Rate 
Enol 
Ke- 
Methyl 
(Chemical) 
verted to 
Enol Ether 
Ether Into 
No. in Hexane) 
80% HOAc) 
(RPM) 
Ether 
tone 
Ester Yield Ketone 
Only Column 
__________________________________________________________________________ 
1 8 5.5 80 78 8 14 13 &lt;1% -- -- 
2 8 3.4 80 84 6 10 7 &lt;1% -- -- 
3 5.8 7.8 325 80 7 13 11 &lt;1% -- -- 
4 5.8 13 325 77 8 15 14 &lt;1% -- -- 
5 3.7 18 425 68 8 24 24 &lt;1% -- -- 
6 3.7 24 425 52 9 39 42 &lt;1% -- -- 
7 3.7 24 590 39 8 53 57 &lt;1% -- -- 
8 3.7 36 590 29 7 64 68 &lt;1% 92% 63% 
9 2.2 50 590 18 5 77 80 &lt;1% -- -- 
__________________________________________________________________________ 
Additional Data: 
(a) No emulsion problems; extremely good separation. 
(b) Feed composition: 
% EE 90 
% Ketone 8 
% Ketal 1.5 
% EE in Hexane phase = 20 
% T1(OAc) in 80% HOAc phase = 20 
(c) Hold up in column at end of expt. #9: 
Light Phase 85 ml. 
Heavy Phase 540 ml. 
(d) Temperature in Scheibel column 20.degree. - 
(3) HOAc is acetic acid 
EE is p-isobutylpropiophenone methyl ether 
Ketone is p-isobutylprophenone 
Ketal is p-isobutylpropiophenone dimethyl ketal 
In the same manner, the methyl enol ethers of (a) 6-methoxy-2-naphthyl 
ethyl ketone, (b) 3-phenoxypropiophenone and (c) p-chloropropiophenone are 
converted respectively to their corresponding 2-arylpropionate esters, 
namely to (a) methyl 2-(6-methoxy-2-naphthyl)propionate (which can be 
hydrolyzed to the acid 2-(6-methoxy-2-naphthyl)propionic acid, known 
generally as naproxen); (b) methyl 2-(3-phenoxyphenyl)propionate (which 
can be hydrolyzed to the acid 2-(3-phenoxyphenyl)propionic acid, known 
generically as fenoprofen); and (c) methyl 2-(4-chlorophenyl)propionate, 
which can be hydrolyzed to the acid, 2-(4-chlorophenyl)propionic acid, a 
known acid. 
In a similar manner, the methyl enol ether of 3,4-dichloropropiophenone is 
converted to methyl 2-(3,4-dichlorophenyl)propionate. This ester is 
hydrolyzed to the acid, 2-(3,4-dichlorophenyl)propionic acid, which is a 
known acid having agriculturally significant, weed killing properties.