Use of alkylformamide and acetamide in preparing .alpha.-acetyl-.alpha.'-methylsuccinate ester

A diester of .alpha.-acetyl-.alpha.'-methylsuccinic acid is prepared in improved yield under substantially anhydrous process conditions which minimizes decomposition of that diester by reacting an acetoacetate ester with an .alpha.-halopropionate ester in a solvent mixture containing a non-polar, aprotic liquid, e.g., toluene, and a dipolar aprotic liquid, e.g., DMF, at from about 50.degree. C. to reflux temperature in the presence of a phase transfer agent, a catalytic amount of iodide ion and solid form, substantially anhydrous alkali metal base or basic salt. Further improvement is obtained when the completed reaction mixture is diluted with water and adjusted to pH 8 to 9, and when the DMF/acetoacetate ester ratios are between about 1.7 and 3. The resulting diesters can be used under the conditions of this invention as intermediates in processes for making ibuprofen by combining and reacting the .alpha.-acetyl-.alpha.'-methylsuccinate diester with vinyl isobutyl ketone (or the corresponding Mannich base plus an alkylating agent) and an alkali metal base, e.g., potassium tert-butoxide, for a time sufficient to form a reaction mixture containing the .alpha.-methyl-.alpha.'-acetyl-.alpha.'-(5-methyl-3-oxohexyl)succinate ester, which can then be converted to ibuprofen by procedures now known.

DESCRIPTION 
Introduction 
This invention relates to processes for preparing derivatives of succinic 
acid esters, and to the use of those succinate ester derivatives in 
processes for making useful acid compounds. More particularly, this 
invention provides an improved process for preparing esters of 
.alpha.-acetyl-.alpha.'-methylsuccinic acid, which are useful as 
intermediates for preparing esters of 
.alpha.-methyl-.alpha.'-acetyl-.alpha.'-(5-methyl-3-oxohexyl)succinic acid 
and related compounds which are known to be useful in processes for 
preparing useful drug acids such as ibuprofen, and the like. This 
invention is most closely related to the invention described in U.S. 
application Ser. No. 938,972, filed Sept. 1, 1978, now U.S. Pat. No. 
4,194,053, issued Mar. 18, 1980, as a continuation-in-part of U.S. 
application Ser. No. 778,571, filed Mar. 17, 1977, now abandoned. 
BACKGROUND OF THE INVENTION 
It is known that diethyl .alpha.-acetyl-.alpha.'-methylsuccinate can be 
prepared in about sixty-three percent yield by reacting ethyl acetoacetate 
with ethyl .alpha.-bromopropionate in the presence of sodium hydroxide, 
potassium iodide and water. Chem. Abs. 62, 13037c abstracting (Zh. Pukl. 
Khim, 38(2), pp. 436-7 (1965). Also, J. Chem. Soc. (London), 4633-40 
(1970) reports that this same diester can be prepared in about forty-seven 
percent yield by reacting ethyl acetoacetate with ethyl 
.alpha.-bromopropionate in the presence of sodium in ethanol. Similar 
disclosures are found at Chem. Abs. 54, 10852h; Chem. Abs. 49, 1565c of J. 
Chem. Soc. (London) 3313 (1953); and Chem. Abs. 38, 2332 of J. Ind. Chem. 
Soc., 20, 173-7 (1943). 
David R. White, in the above-referenced application Ser. No. 938,972 and 
its predecessor application, described his findings that neither the 
aqueous basic system nor the ethanolic basic systems allowed the same 
alkylation to occur with the less expensive ethyl 2-chloropropionate in 
place of the ethyl 2-bromopropionate. He found that by using the 
2-chloropropionate ester at moderate temperatures (40.degree.-50.degree. 
C.), no significant alkylation reaction was seen; under more vigorous 
(higher) temperature conditions, using these base systems, 
2-chloropropionate and acetoacetate ester starting materials were consumed 
but little diethyl .alpha.-acetyl-.alpha.'-methylsuccinate ester 
accumulated in the product, evidencing that this valuable succinate ester 
intermediate is somewhat unstable and is further converted to undesired, 
useless by-products in those reaction mixtures. 
The White application claims a process for preparing the diester of 
.alpha.-acetyl-.alpha.'-methylsuccinic acid comprising reacting an ester 
of acetoacetic acid with an ester of .alpha.-halopropionic acid wherein 
halo is chloro or bromo in a substantially anhydrous mixture of a nonpolar 
aprotic organic liquid having a dielectric constant below about 11 at 
25.degree. C., e.g., toluene, at a temperature of from about 50.degree. C. 
to the reflux temperature of the mixture in the presence of a phase 
transfer agent, a catalytic amount of an iodide ion and a deprotonating 
base, e.g., potassium carbonate, having a surface area equivalent to a 
size below at least about 60 mesh, for a time sufficient to form the 
diester of the .alpha.-acetyl-.alpha.'-methylsuccinic acid. The above 
White applications are incorporated herein by reference for background and 
as an aid in describing elements used in this invention and distinctions 
therefrom. 
Research on this and related chemical process steps to prepare ibuprofen 
from aliphatic starting materials continues. Somewhat surprisingly, it has 
been found according to this invention that the use of nonpolar, aprotic 
organic liquid of low dielectric constant, e.g., toluene, and the use of a 
deprotonating base of a particular particle size by Dr. White, is not 
necessarily the best way to obtain the highest practical yields of the 
necessary intermediate, the .alpha.-acetyl-.alpha.'-methylsuccinic acid 
ester. In my research I have raised the dielectric constant of the 
reaction mixture by adding a dipolar, aprotic liquid solvent and used 
larger particle size potassium carbonate than described by the White 
applications and come up with process improvements which not only raise 
the yields of the above succinate ester intermediate but have defined a 
process improvement which is more compatible with the chemical steps which 
follow toward the synthesis of the end product, ibuprofen. 
For additional background to the use of 
.alpha.-acetyl-.alpha.-methylsuccinate esters in processes for preparing 
useful drug acid compounds, see British Pat. No. 1,265,800 and Belgian 
Pat. No. 820,267. 
OBJECTS OF THE INVENTION 
It is an object of this invention to provide an improved and more 
economical process for preparing esters of 
.alpha.-acetyl-.alpha.'-methylsuccinic acid. 
It is a more specific object of this invention to provide an improvement on 
the above-described White process for preparing 
.alpha.-acetyl-.alpha.-methylsuccinate diesters which improves the yields 
of such diesters. 
It is a further object of this invention to provide an improvement in the 
process for preparing .alpha.-acetyl-.alpha.'-methylsuccinate diesters 
from acetoacetic acid esters and 2-halopropionate esters, which is more 
compatible with subsequent steps in the overall process of preparing 
ibuprofen as an end product. 
Other objects, aspects and advantages of this invention will become 
apparent from the description and claims which follow. 
SUMMARY OF THE INVENTION 
Briefly, by this invention I have discovered that by adding a specific type 
of a dipolar, aprotic solvent, e.g., DMF, to the toluene mixture of the 
acetoacetate and 2-halopropionate esters that the yields of the 
.alpha.-acetyl-.alpha.'-acetyl-methylsuccinate ester intermediate product 
can be increased and that this dipolar, aprotic solvent addition obviates 
the need to mill and pre-dry the potassium carbonate or other 
deprotonating base to smaller particle size than is readily available from 
suppliers before being added to this reaction mixture. Moreover, I have 
also discovered that specific ratios of the dipolar, aprotic solvent in 
the reaction mixture and the use of an aqueous acid dilution of the 
reaction mixture after completion of the reaction to bring the pH of the 
mixture to about pH 8 to 9, to separate base and the dipolar, aprotic 
solvent prior to work-up of the mixture to recover the 
.alpha.-acetyl-.alpha.-methylsuccinate ester in usable form, also enhance 
the yields of the .alpha.-acetyl-.alpha.'-methylsuccinate ester. 
Optionally, and perhaps preferably for larger scale operations of the 
process, the succinate ester product reaction mixture can be filtered, and 
the resulting liquid phase treated with an aqueous medium to extract the 
dipolar, aprotic solvent from the organic liquid phase containing the 
succinate ester, for reuse in the process. This use of DMF as the added 
dipolar, aprotic solvent in the reaction mixture also makes preparation of 
the crude succinate ester product more compatible with process steps which 
follow. 
DETAILED DESCRIPTION OF THE INVENTION 
More specifically, this invention provides a process for preparing an 
.alpha.-acetyl-.alpha.'-methylsuccinate diester which comprises reacting 
an ester of acetoacetic acid with an ester of 2-halopropionic acid wherein 
halo is chlorine or bromine in a substantially anhydrous liquid solvent 
mixture of (a) a nonpolar, aprotic organic liquid having a dielectric 
constant below about 11 at 25.degree. C., and (b) a dipolar, aprotic 
organic liquid solvent having a dielectric constant over 25 at 25.degree. 
C., e.g., a di-C.sub.1 to C.sub.4 -alkylformamide or di-C.sub.1 to C.sub.4 
-alkylacetamide at a temperature of from about 50.degree. C. to the reflux 
temperature of the mixture in the presence of a phase transfer agent, a 
catalytic amount of an iodide ion and a deprotonating base for a time 
sufficient to form the diester. 
Examples of nonpolar, aprotic organic liquids having a dielectric constant 
below about 11 at 25.degree. C. are benzene, chlorinated benzenes, 
toluene, xylene, ethyl benzene, and the like, with toluene being preferred 
over benzene for employee safety purposes and because it has an optimum 
boiling point range for azeotroping out water which might enter the 
reaction mixture with reactants, catalysts, base, etc. 
Examples of the di-C.sub.1 to C.sub.4 -alkylformamide and di-C.sub.1 to 
C.sub.4 -alkylacetamides which can be used to dilute the toluene or other 
nonpolar, aprotic solvents are dimethylformamide (DMF), diethylformamide, 
dipropylformamide, dibutylformamide, and the corresponding di-C.sub.1 to 
C.sub.4 -alkylacetamides, e.g., dimethylacetamide (DMAC), etc., with the 
DMF being preferred for reasons of economy, ready availability, and its 
efficiency. 
I have found that the better yields of the 
.alpha.-acetyl-.alpha.'-methylsuccinate esters are obtained when the mole 
ratios of DMF, or other dipolar, aprotic organic solvent in the reaction 
mixture (at the start of the reaction) is between about 1.7 to about 3.0, 
relative to the mole content of the acetoacetate ester in the mixture. 
Preferably, the molar content of the DMF is started at about 2.6 to 2.8, 
relative to the acetoacetate ester content, to obtain the best yields. An 
added benefit is that with DMF, or other equivalent dipolar, aprotic 
solvent in the reaction mixture, the optimum reaction time is shortened to 
about 1.5 hours at 100.degree. to 105.degree. C. With the same DMF ratios, 
the maximum yields of the succinate we have obtained have been about 73 
percent at 90.degree. C., 74 percent at 109.degree. C. and 62 percent at 
114.degree. C. The amount of deprotonating base, e.g., potassium 
carbonate, in the mixture can vary in the molar ratio range of from about 
1 to about 1.5 molar equivalent of the deprotonating base per molar 
equivalent of the acetoacetate ester in the mixture. I have found that a 
molar ratio of about 1.3 molar equivalent of base, preferably potassium 
carbonate, per molar equivalent of acetoacetate ester gives the best 
results. With 1.3 molar equivalents of potassium carbonate as 
deprotonating base, relative to acetoacetate ester, the yield of 
.alpha.-acetyl-.alpha.-methylsuccinate ester is about 77 percent. 
With the aid of this invention either "milled" or "granular" potassium 
carbonate can be used. Granular potassium carbonate is the form normally 
obtained from suppliers thereof. Milled (ground to smaller particle size) 
potassium carbonate still gives better yields than the use of the granular 
form, but the granular form can now be used with the new added DMF, or 
other dipolar, aprotic solvent addition process. Attempts to conduct the 
process using granular potassium carbonate in 100 percent toluene as the 
only solvent for the reactants (no DMF or other dipolar, aprotic solvent 
present) gave yields of 25-40 percent. The more important feature or 
advantage of this invention with respect to the potassium carbonate is 
that the potassium carbonate, whether milled or not, can now be used 
successfully, without predrying. That is, the potassium carbonate can be 
dried in situ in the solvent mixture before the reactants are added to the 
reaction vessel. 
Our best laboratory yields to date have been in the 82 to 85 percent yield 
range, using milled potassium carbonate and a ratio of about 2.6 molar 
equivalent of the DMF per mole of acetoacetate ester reactant, with a 
work-up of the reaction mixture including an aqueous extraction of the 
reaction mixture to remove the salts and DMF from the succinate 
ester/toluene phase at a pH of about 8.5. Without the use of DMF, or 
equivalent dipolar, aprotic solvent, the yield of succinate ester varies 
in the range of 50 to 74 percent and the potassium carbonate must be 
carefully predried. 
Our current best pilot plant scale manufacturing procedure for this new 
improved process gives about 70 percent yield of succinate ester when 
granular potassium carbonate is used and workup of the reaction mixture 
involves only filtration of the mixture to remove solid salts from the 
liquid reaction mixture, then aqueous extraction of the toluene liquid 
phase to remove DMF therefrom. The aqueous wash here need not be 
controlled to pH 8 to 9, if the salts have been removed from the reaction 
mixture, but such pH 8 to 9 wash procedure can be used. In the 
manufacturing procedure, this filtration/aqueous procedure has a 
significant economic and engineering advantage of separating DMF from the 
salts, thus allowing recovery and recycle of the DMF. More recently, we 
have obtained higher yields in the pilot plant manufacturing process 
approaching 85 percent yield of succinate ester by using milled potassium 
carbonate instead of granular potassium carbonate. 
Thus, even though better yields of succinate ester product might be 
obtained using the laboratory procedure (pH 8-9 wash), other economic and 
engineering factors dictate the use of the filtration/aqueous wash 
manufacturing procedure for best production yields of this 
.alpha.-acetyl-.alpha.-methylsuccinate diester product of this process. 
We consider this discovery to be somewhat surprising and unique because 
other dipolar, aprotic solvents having similar high dielectric constants 
such as N-methyl-2-pyrrolidone (dielectric constant 32.2) were tried since 
DMF (dielectric constant 36) was more effective than dimethylsulfoxide 
(DMSO; dielectric constant 45), but the yield of succinate ester with 
N-methyl-2-pyrrolidone was seven percent lower than with DMF under the 
same conditions. Formamide was tried and it gave poor results. 
Without intending to be bound to particular theory of how or why the 
invention works to improve the yields of the succinate ester intermediate 
product, we offer the following as a possible explanation of what might 
happen in the reaction mixtures according to this invention. 
Yields of the succinate ester in this process step probably depend upon my 
discovery of how to maximize the rate of succinate ester formation in the 
reaction mixture while minimizing the rates of undesired by-product 
formation. DMF was the most effective of the dipolar, aprotic solvents 
tried, particularly at about 100.degree. C., but the other named dipolar, 
aprotic solvents can be used. At lower than the desired reaction 
temperature range, succinate ester is not formed rapidly enough to keep up 
with by-product formation, while at higher temperatures than about 
105.degree. C., the succinate ester cyclizes to lactones nearly as fast as 
it forms, thus lowering the yields of the usable succinate ester. DMF, and 
equivalent dipolar, aprotic solvents, seem to selectively accelerate 
succinate ester formation, probably by selective complexation with the 
anion of ethylacetoacetate, as opposed to the anion of succinate. Another 
factor possibly contributing to the higher yields of succinate ester 
according to the process of the invention, is the enhanced 
dissolution/dispersion of the potassium carbonate or other deprotonating 
base in the mixture, which dissolution/dispersion could increase the rate 
of anion formation in the reaction mixture. The amount of DMF or other 
dipolar, aprotic solvent in the mixture apparently needs to be adjusted to 
account for both of these anion formation and dissolution/dispersion 
factors. Since the rate of reaction seems to depend upon the available 
surface area of deprotonating base in the mixture, lower amounts of DMF or 
other dipolar, aprotic solvent may complex with and perhaps agglomerate 
some of the solid base, e.g., potassium carbonate particles. If the low 
amount of DMF or other dipolar, aprotic solvent causes agglomeration of 
solid base particles, and thus perhaps reduces the amount of base 
available for reaction, the yield of succinate ester would be lowered, as 
observed when only 1.0 molar equivalent of deprotonating base, e.g., 
potassium carbonate, is used. With DMF molar ratios, relative to the 
acetoacetate ester reactant, much higher than the 3.0 ratio, the 
complexation of anions in the reaction mixture probably is no longer 
selective, so that there may be an acceleration of the cyclization of 
succinate ester product to by-product lactone, thus lowering the yield of 
the desired succinate ester product. It is interesting to note that the 
optimum amount of DMF, or other dipolar, aprotic solvent in the mixture, 
usually corresponds roughly to the sum of the molar equivalents of the 
potassium carbonate (or other deprotonating base) and the acetoacetate 
reactant in the mixture. Overall, in laboratory scale operation of the 
process, the yields of succinate ester according to the improved process 
of this invention are increased by using both DMF in the reaction mixture 
and a pH 8.5 work-up, the description of which follows: 
When the reaction between the .alpha.-acetyl-.alpha.-methylsuccinate and 
2-halopropionate ester is complete, the reaction mixture is diluted with 
water to extract from the organic reaction mixture the base, water soluble 
materials including the DMF or other dipolar, aprotic solvent and to 
separate the dipolar, aprotic solvent from further contact with the 
succinate ester intermediate product. Addition of an acid, preferably any 
economical, readily available mineral acid, such as 2 to 10 percent 
sulfuric acid, to adjust the pH of the aqueous phase to between 8 and 9, 
preferably to about 8.5, has been found to enhance the separation of the 
succinate ester organic solution from unwanted materials and DMF. The 
water added to the succinate ester containing reaction mixture can be the 
acid solution itself or the acid can be added later. One or more washes of 
the toluene or other organic liquid phase with water may be done to ensure 
cleaner succinate ester product. The organic phase containing the 
succinate ester can then be treated to purify and isolate the succinate 
ester by known procedures, or prepare it in usable form, particularly for 
use in the next step of the process. For this latter purpose, we obtain 
the succinate ester in usable, but crude form by evaporating off most of 
the organic solvent to leave as residue the crude succinate ester. We have 
found it sufficient to evaporate the organic solvent under a vacuum 
pressure of 40 mm. Hg. to 65.degree.-70.degree. C. Then this residue 
succinate ester can be used as a reactant in the next step of the overall 
process for preparing ibuprofen. 
As indicated above, when this invention is applied to use in pilot plant or 
manufacturing scale operation of the process, economic and engineering 
factors may dictate that the pH 8-9 aqueous wash of the reaction mixture 
step be avoided, in favor of a simple filtration or centrifuging of the 
reaction mixture to separate solids (salts, such as potassium carbonate, 
potassium iodide, etc.) from the organic liquid mixture, followed by 
extraction (washing) of the organic liquid reaction mixture with water (pH 
control optional) to extract the DMF, or other dipolar, aprotic liquid 
from the non-aqueous miscible phase (e.g., toluene phase) containing the 
succinate ester product, and then to separate the liquid phases, and 
evaporate the succinate ester liquid phase, preferably under vacuum 
pressure, to remove most if not all of the nonpolar organic liquid from 
the succinate ester product. 
The next step in such process is a Michael condensation reaction between 
this .alpha.-acetyl-.alpha.'-methylsuccinate ester and isobutyl vinyl 
ketone to form a mixture of products having the following general 
formulae: 
##STR1## 
where each R is a C.sub.1 to C.sub.4 -alkyl. 
The process improvement of this invention fits nicely with the process 
improvements described in U.S. application Ser. No. 047,391, filed June 
11, 1979. With DMF being the preferred dipolar, aprotic solvent to use in 
each of these two process steps, the burden of solvent recovery for reuse 
in the overall process becomes easier, thus requiring the recovery of only 
toluene, or other nonpolar, aprotic organic solvent and DMF, or other 
dipolar, aprotic organic solvent, instead of toluene and DMF (for my 
improvement) and DMSO, as originally contemplated in the Michael addition 
reaction step.

The invention is described and exemplified further by the detailed examples 
which follow: 
EXAMPLE 1 
First Use of DMF in Reaction Mixture 
A mixture of 20.7 g. of milled, calcined potassium carbonate, 1.5 g. each 
of 60 mesh potassium iodide and Aliquat 336 (believed to be 
tricaprylmethylammonium chloride), 15.0 ml. each of ethyl 
2-chloropropionate and ethyl acetoacetate and 1.0 ml. of docosane and 50 
ml. of toluene is stirred under nitrogen at about 100.degree. C. with 5.0 
ml. of DMF added. The reaction is monitored over 6.5 hours, during which 
the temperature ranged from 61.degree. to 102.degree. C. and is maintained 
mostly at 102.degree. C. The reaction mixture turns from white to light 
yellow to yellow. Samples are taken periodically to analyze and monitor 
the amount of succinate product in the reaction mixture. After 6.5 hours 
the oil bath heat is lowered and the reaction mixture is cooled to 
45.degree. C. in thirty minutes. Then 100 ml. of water is added. The 
reaction mixture is then analyzed by gas liquid chromatographic (glc) 
methods and found to contain 143.3 mg./ml. of diethyl 
.alpha.-acetyl-.alpha.'-methylsuccinate for a 55.7% chemical yield. 
EXAMPLE 2 
Use of DMF Together With pH 8.5 Work-up Procedure 
The procedure of Example 1 is followed, except that 25 ml. toluene and 25 
ml. DMF are used, and the heating of the reaction mixture is done for a 
shorter period of time (one hour, fifty minutes), during which the 
temperature is raised from 51.degree. C. to 104.degree. C. The reaction 
mixture is cooled to 35.degree. C. over thirty-five minutes and then 110 
ml. of water is added with stirring. Then 10 percent sulfuric acid in 
water solution is added until the pH of the aqueous phase is about 8.5, 
and then the reaction mixture is worked up to recover the diethyl 
.alpha.-acetyl-.alpha.'-methylsuccinate product. Analysis of the reaction 
mixture by glc procedures shows it to contain 262.6 mg. of the acetyl 
succinate product per ml. A yield of 82.8 percent chemical is obtained. 
This example illustrates that a shorter reaction time and a less basic 
work-up of the reaction mixture (pH about 8.5) seems to be effective to 
obtain higher yields. 
EXAMPLE 3 
Process Run Without Milling The Potassium Carbonate 
A mixture of 22.1 g. of regular, granular, non-milled or dried, technical 
potassium carbonate, 23.0 ml. of technical DMF, 1.5 g. of Aliquat 336 and 
27 ml. of toluene are stirred at reflux until no more water azeotropes out 
of the mixture to dry the potassium carbonate and the reaction mixture. A 
total of 0.6 ml. of water is collected. Then 14.5 ml. each of ethyl 
acetoacetate (114.3 mmoles) and 14.5 ml. of ethyl 2-chloropropionate and 
1.5 g. of potassium iodide and 1.0 g. of n-docosane are added at room 
temperature and the resulting mixture is stirred and heated for three 
hours and five minutes over which time the temperature rises from 
60.degree. C. to 104.degree. C. and then back down to 
100.5.degree.-101.5.degree. C. The mixture is treated with water and 
aqueous ten percent sulfuric acid solution to raise the pH to 8.5 and 
analyzed to determine the content of the diethyl 
.alpha.-acetyl-.alpha.'-methylsuccinate ester product. Glc analysis shows 
the mixture to contain 168.2 mg./ml. of product, so that 113 ml. of 
reaction mixture contains 19.01 g. for a 72.4 percent chemical yield. 
This experiment is believed to evidence a real breakthrough in this process 
research. Even without milled or dried potassium carbonate, and using a 
high dielectric constant solvent (DMF) the reaction went reasonably well, 
comparable to the previous standard, operating procedure using milled, 
dried potassium carbonate with no DMF. 
EXAMPLE 4 
Succinate Preparation--Larger Scale Optional Procedure 
A slurry of 267 kg. calcined, granular potassium carbonate, 19.3 kg. each 
of potassium iodide, and Aliquat 336, 311 kg. of DMF, and 276 l. of 
toluene was stirred at reflux (118.degree.-120.degree.) for two hours 
while water was azeotroped off and collected in a trap. The resulting 
dried slurry was cooled to below 80.degree. C. Then 189 kg. of ethyl 
acetoacetate and 198 kg. of ethyl 2-chloropropionate were added and the 
reaction mixture was stirred at 103.degree..+-.3.degree. C. for ninety 
minutes. 
120 kg. toluene was added and the reaction mixture was cooled to 20.degree. 
C. The salts were filtered off using a centrifuge and the filtrate 
(toluene plus product) was washed with water (once with 280 l. water, then 
twice with 140 l. water each wash). The combined aqueous washes were 
backwashed with 85 kg. toluene. The combined toluene phases were 
concentrated under vacuum at 65.degree. C. to leave 348 kg. (350 l.) of 
crude .alpha.-acetyl-.alpha.'-methylsuccinate diester, assay 663 mg./ml. 
for a yield of 69 percent chemical. 
The procedure as described above was repeated, except that the K.sub.2 
CO.sub.3 was milled to &lt;200 mesh before use. The yield with this 
modification was 85 percent chemical.