Ester derivatives of 1-halo-1,1,2,3-propane tetracarboxylic acid

Novel polyfunctional compounds and a novel process for their preparation are disclosed. These compounds may be converted into the acid or salt forms of cis and trans aconitic acids as well as into a racemic mixture of isocitric acid, alloisocitric acid and the lactones of isocitric acid and alloisocitric acid and their salts. All of the acid and salt forms produced are useful as metal sequestrants and/or detergent builders. The novel polyfunctional compounds can also be saponified to their corresponding alkali metal salts which, in turn, are also metal ion sequestering agents and detergent builders. The polyfunctional compounds are the reaction products obtained from the reaction of selected salts of monoalkyl esters of maleic acid with selected active hydrogen containing compounds.

This invention broadly relates to novel polyfunctional compounds and a 
process for their preparation. The novel compounds may be converted into 
cis and trans aconitic acid and into a racemic mixture of isocitric acid, 
alloisocitric acid and the lactones of isocitric acid and alloisocitric 
acid. These compounds may also be saponified to form alkali metal salts 
corresponding to the particular compound employed. These salts, in turn, 
are metal sequestering agents and/or detergent builders. In the preferred 
embodiments the polyfunctional compounds are converted into either cis and 
trans aconitic acid or into a racemic mixture of isocitric acid, 
alloisocitric acid and the lactones of isocitric acid and alloisocitric 
acid and cis and trans aconitic acid, are useful as food acidulants and 
metal ion sequestrants. The alkali metal, ammonium and substituted 
ammonium salts of isocitric acid, alloisocitric acid and cis and trans 
aconitic acid have utility both as metal ion sequestrants and detergent 
builders. 
The reaction of active hydrogen compounds with unsaturated esters such as 
esters of maleic acid is known and is generally accomplished by means of 
the well known Michael reaction. This reaction is considered thoroughly in 
Chapter 3 of Volume 10 of the publication entitled "Organic Reactions" 
edited by Roger Adams et al and published in 1959 by John Wiley & Sons 
Inc. In its original sense, as described in the publication, this reaction 
involves the addition of a donor moiety containing an alpha-hydrogen atom 
in a system 
##STR1## 
to a carbon-carbon double bond which forms part of a conjugated acceptor 
system of general formula 
##STR2## 
The addition proceeds under the influence of alkaline or basic catalysis. 
Inherently in the Michael reaction, the donor moiety, under the influence 
of the basic catalysis (sodium metal is a catalyst of choice) forms an 
anion which in turn reacts with the beta carbon of the acceptor system. 
Through the use of this reaction a series of compounds have been prepared. 
A listing of a large number of these reactions and reaction products 
appears on pages 271-544 of the above-mentioned publication. The reaction 
in certain selected instances does not require an added catalyst because 
one of the reactants contains its own basic function. The Michael 
reaction, thus, is extremely useful for the synthesis of selected 
compounds. However, disadvantages arise in attempting to prepare certain 
mixed esters by this route because of transesterification which can take 
place under the conditions of the Michael reaction thereby producing 
mixtures of mixed esters in correspondingly diminished yield rather than a 
single mixed ester in relatively high yield. Further, reverse Michael 
reactions can occur to produce rearranged starting reactants. The 
resulting mixtures are normally extremely difficult to separate. These 
difficulties, thus, militate strongly against the use of the Michael 
reaction and indeed the applicability of this reaction for desired mixed 
ester products. In particular, with reference to the preferred 
preparations of aconitic acid and the mixture of isocitric acid, 
alloisocitric acid and their lactones in this invention, prior art 
processes were practically limited to natural fermentation. Although some 
synthetic methods have been proposed in the literature such as in the 
articles by Michael, J. pr. Chem. 49 (ii), 21 (1894), Pucher and Vickery, 
J. Biol. Chem. 163 169-184 (1946) and Gawron et al., J.A.C.S. 80 5856-5860 
(1958), none of these methods appear to have been commercialized. 
Accordingly, an object of the present invention is to provide a process for 
producing novel mixed ester compounds by adding an active methylene or an 
active methine compound across the double bond of selected salts of maleic 
acid esters, wherein the reverse Michael reaction is substantially 
inhibited and wherein the reaction takes place in the absence of added 
alkaline catalyst. 
A further object is to produce a novel polyfunctional compound which may be 
converted into cis and trans aconitic acid or into a mixture of isocitric 
acid, alloisocitric acid and the lactones of isocitric acid and 
alloisocitric acid as well as salts of these acids. 
Yet another object is to provide a novel method for preparing novel 
polyfunctional compounds which can be converted into metal ion 
sequestrants and detergent builders. 
Other objects and advantages will appear as the description proceeds. 
The attainment of the above objects is made possible by this invention 
which includes novel polyfunctional compounds as well as a process for 
their preparation. These novel compounds have the general formula (I) as 
follows: 
##STR3## 
wherein R is a primary alkyl group of one to four carbon atoms and 
preferably a methyl or ethyl group, 
wherein M.sub.1 is hydrogen, calcium, magnesium, strontium, barium, sodium, 
potassium or lithium, 
wherein x is 1 or 2 and is equivalent to the valency of M.sub.1, 
wherein Q is preferably H but in alternative embodiments may also represent 
a primary alkyl group of 1 to 4 carbon atoms 
wherein Z is phenyl; substituted phenyl having electron withdrawing 
substituents on the ring such as, for example, chlorine, bromine and 
nitro; cyano (--CN); 
##STR4## 
nitro (--NO.sub.2) or a carboxylic ester (--COOR.sub.2) wherein R.sub.2 is 
a primary alkyl group containing 1 to 4 carbon atoms, preferably a methyl 
or ethyl group, and 
wherein Y is dependent on Z and when Z is a carboxylic ester (COOR.sub.2), 
Y represents a carboxylic moiety (COOR.sub.1) wherein R.sub.1 is a 
lithium, sodium or potassium cation or a primary alkyl group containing 
from 1 to 4 carbon atoms and preferably a methyl or ethyl group, cyano 
(--CN) and 
##STR5## 
when Z is a cyano, phenyl or substituted phenyl group, Y represents cyano 
(--CN); and when Z is nitro (--NO.sub.2), Y is hydrogen or methyl. 
Additionally, the above objects are attained by the novel process of this 
invention to prepare the polyfunctional compounds of formula (I). 
PROCESS FOR PREING THE NOVEL POLYFUNCTIONAL COMPOUNDS 
This process is preferably substantially anhydrous and includes reacting by 
heating a salt of a monoalkyl ester of maleic acid with an active 
methylene or methine containing compound which is also referred to herein 
as the active hydrogen containing compound. The monoalkyl ester salt of 
maleic acid is of the general formula (II): 
##STR6## 
in which R and x are as previously defined and M represents calcium, 
magnesium, strontium, barium, sodium, potassium or lithium. In this 
process in the compound of formula (II) M cannot represent hydrogen 
whereas in formula (I) M.sub.1 can represent hydrogen as well as the 
cations represented by M and thus the two separate designations of M and 
M.sub.1 are utilized. The active hydrogen containing compound is of the 
general formula (III): 
##STR7## 
in which Y, Q and Z are as previously defined. 
The salts of the monoalkyl ester of maleic acid [formula (II)] employed in 
the process of this invention are prepared by treating a monoalkyl ester 
of maleic acid with a base. The monoalkyl ester of maleic acid is in turn 
readily available by reacting maleic anhydride with a lower alkyl alcohol 
having 1 to 4 carbon atoms, for example, methanol, ethanol, propanol and 
butanol. More specifically, maleic anhydride may be dissolved in the 
alcohol either at room temperature or by heating at an elevated 
temperature, e.g. about 50.degree. C. to 60.degree. C. Addition of the 
appropriate base, i.e. alkali metal or alkaline earth metal hydroxide such 
as sodium or potassium hydroxide or magnesium, barium, strontium or 
calcium hydroxide to a pH of about 7 to 9, neutralizes the acid portion of 
the molecule to produce the desired salt of formula (II). The monoalkyl 
maleate salt thus prepared is separated from the reaction mixture by 
conventional techniques, e.g. distilling off the alcohol under reduced 
pressure, or crystallization from the appropriate alcohol. 
The active hydrogen containing compounds of formula (III) are known 
compounds. Malonate esters such as, for example, diethyl malonate and 
dimethyl malonate and cyanoacetate esters such as, for example, methyl 
cyanoacetate and ethyl cyanoacetate are preferred. 
The subject invention, encompassing novel compounds and a novel process for 
their preparation, overcomes one or more of the disadvantages of the prior 
art heretofore described. This is accomplished with the advantage that 
such compounds may be easily prepared in good yields suitable for 
subsequent conversion into metal sequestering agents and, preferably, into 
either cis and trans aconitic acid or a mixture of isocitric acid, 
alloisocitric acid and the lactones of isocitric acid and alloisocitric 
acid. 
The invention is hereinafter set forth in more details, specific features 
thereof being particularly delineated in the appended claims. 
In the practice of the present invention a compound of formula (II) above 
is reacted preferably under substantially anhydrous conditions with a 
compound of formula (III) at an elevated temperature to form a reaction 
product which is the polyfunctional compound of formula (I) except for the 
cases wherein M.sub.1 =H. The latter compounds are obtained with an 
additional step involving acidification as will be more fully described 
hereinafter. 
Since the ester group of the mono maleic ester salt (formula II) can 
hydrolyze in the presence of moisture to produce a non-reactive species 
(i.e. a mono salt of maleic acid), the reaction is preferably run under 
substantially anhydrous conditions. This can be accomplished by pre-drying 
the reactants and any reaction solvent by conventional means before 
carrying out the reaction. 
Generally, the reaction of the compounds of formulae (II) and (III) to 
produce the novel compounds of formula (I) proceeds at temperatures of 
about 25.degree. C. to 200.degree. C. and more preferably between about 
100.degree. C. and 160.degree. C. The actual reaction temperature will 
depend on whether a solvent is employed and the mutual solubilities of the 
reactants. Thus, if dimethyl formamide is utilized as the reaction solvent 
or co-solvent, a temperature as low as room temperature (about 25.degree. 
C.) to about 100.degree. C. can be utilized whereas if the active hydrogen 
containing compound of formula (III) is utilized in excess as both solvent 
and reactant, higher temperatures up to about 200.degree. C. may be 
employed. Generally while reflux temperatures are normally operable, it is 
desirable to keep the temperature in the range of about 100.degree. C. to 
160.degree. C. to maintain reasonable reaction rates and to avoid the 
reverse Michael reaction and other decomposition reactions which tend to 
take place at the higher temperatures. 
The time necessary to complete the reaction is not critical. It will depend 
on temperatures, on the nature of the reactants, the solvent used, if any, 
concentration of the reactants and the homogeneity of the system. 
Generally about one to three hours is sufficient to obtain the maximum 
yield. 
The reaction takes place preferably in the liquid phase. Generally, the 
active hydrogen containing compound of formula (III) is a liquid and will 
dissolve the ester salt compound of formula (II). Since an excess of the 
reactant of formula (III) is beneficial to the reaction, such as excess is 
preferred as side reactions are minimized and eventual separation of the 
components is easier. Suitable active hydrogen compounds of formula (III), 
e.g. dimethyl malonate, methyl sodium malonate, diethyl malonate, dipropyl 
malonate, dibutyl malonate, phenyl acetonitrile, methyl cyanoacetate, 
ethyl cyanoacetate, nitroethane and the like may be utilized. 
Additionally, a co-solvent for both reactants may be used instead of an 
excess of the formula (III) compound provided the co-solvent does not 
contain an active hydrogen which will compete with the formula (III) 
compound under the reaction conditions and provided the co-solvent 
dissolves the reactants sufficiently to facilitate the reaction. Suitable 
solvents are, for example, dimethylformamide, dimethylacetamide and 
dimethyl sulfoxide. 
The desired reaction product (i.e. a compound of formula I) can be readily 
recovered from the reaction mixture by conventional methods such as for 
example by adding an insolubilizing liquid, e.g. ethyl ether. Upon the 
addition of a sufficient amount of such an insolubilizing liquid, the 
product precipitates out of solution and is readily separated from the 
reaction media by conventional means. The recovered product is 
sufficiently pure for conversion into the corresponding metal sequestrant 
salt. Upon filtration or vacuum distillation, washing, recrystallization 
if desired and drying, the desired product may be obtained in purer form. 
Alternatively, the acid form of the reaction product may be isolated by 
treating the reaction product with an aqueous solution of a mineral acid 
to liberate the carboxylic acid (M.sub.1 =H in formula I) which is readily 
separated from the aqueous layer by extraction with a suitable solvent 
such as ethyl ether or by filtration in those cases where the carboxylic 
acid is a solid. 
The present invention thus permits the synthesis of the desired 
polyfunctional compound of formula (I); further, in certain cases such 
compounds are produced in good yields. An additional advantage of this 
invention is that the novel products are obtained in readily recoverable 
form and that the novel synthesis or process permits the formation of the 
product without the use of added catalyst. 
HYDROLYSIS OF SELECTED POLYFUNCTIONAL COMPOUNDS TO PRODUCE METAL ION 
SEQUESTRANTS AND DETERGENT BUILDERS 
The compounds of formula (I), with the exception of those cases wherein Z 
is a nitro group, may be hydrolyzed under basic conditions to obtain the 
salt forms of the compounds represented by formula (IV) below. The acid 
forms of the compounds of formula (IV) are obtained by conventional 
acidification of the salt forms produced by the basic hydrolysis. Formula 
(IV) is as follows: 
##STR8## 
wherein Z, Q and Y are as previously defined and wherein M.sub.1 
represents hydrogen, sodium, potassium, lithium, calcium, magnesium, 
barium or strontium and x is 1 when M.sub.1 is hydrogen or alkali metal 
and 2 when M.sub.1 is alkaline earth metal. In those cases wherein Y and Z 
are carboxylic functions, i.e. --COOR.sub.1 and --COOR.sub.2 or a cyano 
group, alkaline hydrolysis converts each of the groups to a 
--COOM.sub.1.sup.+x function wherein M.sub.1 is an alkali metal or 
alkaline earth metal cation and x is as previously defined. 
The alkaline hydrolysis is accomplished by heating the compounds of formula 
(I) with a stoichiometric amount or a slight excess of an alkali metal 
hydroxide, an alkaline earth metal hydroxide or an alkali metal carbonate 
in aqueous or aqueous alcoholic media. The hydrolysis is carried out at a 
pH of about 9-12, preferably about 10-11 and at a temperature of about 
25.degree. C. to about 100.degree. C., preferably about 40.degree. C. to 
about 60.degree. C. The preferred temperature and pH ranges in the 
hydrolysis procedure are used to maintain reasonable reaction rates and to 
minimize reverse Michael reactions. 
Isolation of the salt forms of formula (IV) obtained by the above alkaline 
hydrolysis is carried out by conventional techniques such as solvent 
precipitation, evaporation, drying and recrystallization from suitable 
solvents such as alcohol-water. 
In the cases where the alkaline earth metal salts of formula (IV) are 
produced, these may be converted into the alkali metal salt form by 
treatment with an aqueous solution of an alkali metal carbonate which 
precipitates the alkaline earth metal cations as the insoluble carbonate. 
The latter is then removed by filtration and the alkali metal salt of 
formula (IV) is isolated from the filtrate by conventional methods as 
previously described above. 
Both the alkali metal and alkaline earth metal salt forms of formula (IV) 
may also be conventionally treated with a cation exchange resin to produce 
the acid forms of formula (IV) which may then be isolated by conventional 
methods such as extraction with a suitable solvent followed by evaporation 
of the solvent from the extract. 
The acid forms of formula (IV) may be utilized as such (e.g. as metal ion 
sequestrants) or converted in the desired salt forms or mixture of acid 
and salt forms by neutralization with the required amount of the desired 
alkali metal hydroxide, ammonium hydroxide, an organic amine such as 
mono-, di- and tri-ethanolamine, morpholine and mixtures thereof. As 
previously indicated the alkali metal, ammonium and substituted ammonium 
salt forms of formula (IV) have utility as metal ion sequestrants and 
detergent builders. 
CONVERSION OF SELECTED HYDROLYZED POLYFUNCTIONAL COMPOUNDS INTO 
TRICARBALLYLIC AND SUPSTITUTED TRICARBALLYLIC ACIDS AND THEIR SALTS 
In the cases where the compounds of formula (IV) have the structure 
##STR9## 
wherein Q is as previously defined, these compounds may be decarboxylated 
by heating alone at atmospheric pressure or under vacuum at temperatures 
greater than about 75.degree. C., preferably about 75.degree. C. to 
175.degree. C., depending on the decomposition point of the particular 
compound. Alternatively, decarboxylation of these compounds may be 
accomplished by heating the compounds with a dilute mineral acid solution, 
e.g. hydrochloric acid, at a pH of less than about 2 and under atmospheric 
pressure. These decarboxylation procedures produce tricarballylic acid and 
substituted tricarballylic acids having the formula 
##STR10## 
These acids may be neutralized with bases such as alkali metal hydroxides, 
ammonium hydroxide and alkylolamines to produce metal ion sequestrants and 
detergent builders. 
ESTERIFICATION OF THE POLYFUNCTIONAL COMPOUNDS TO PRODUCE MIXED POLYESTER 
COMPOUNDS 
In the case of the compounds of formula (I) wherein M.sub.1 is H, these 
compounds may be completely esterified to produce mixed polyester 
compounds. This is accomplished by conventional reactions such as 
1. reaction with diazomethane or 
2. reaction with thionyl chloride followed by reaction with a normal 
alkanol of 1 to 12 carbons. 
The products produced have the formula: 
##STR11## 
wherein R.sub.3 is a normal alkyl group of 1 to 12 carbon atoms and 
wherein R, Z, Q and Y are as previously defined except that in the case 
where a cyano group is initially present it also becomes converted in the 
process scheme of 2 above to COOR.sub.3. Similarly in those cases where Y 
is COOR.sub.1 and R.sub.1 is H, sodium, potassium or lithium, Y is 
converted to COOR.sub.3. 
HALOGENATION OF SELECTED POLYFUNCTIONAL COMPOUNDS 
The compounds of formula (I) having the structure 
##STR12## 
wherein R, R.sub.1 and R.sub.2 are as previously defined, can be 
halogenated with hypochlorous acid, hypobromous acid, sodium hypochlorite, 
sodium hypobromite, chlorine or bromine in aqueous or mixed 
aqueous/methanolic solution at pH's from about 2 to 8 to produce novel 
compounds having the following formula: 
##STR13## 
or salts thereof and wherein R, R.sub.1 and R.sub.2 are as previously 
defined and are preferably methyl or ethyl and Q.sub.1 is Br or Cl and 
preferably chlorine. 
The halogenation process is preferably carried out in an aqueous reaction 
medium. The compound of formula (IA) is introduced into a reaction vessel 
with water and, while stirring the mixture, a solution of a compound 
capable of generating HOX (wherein X=Cl or Br) is slowly added. The amount 
of reaction medium (i.e. water) used is not critical and is generally from 
about 50 to about 95% by weight of the total initial reaction mixture 
(i.e. compound IA plus water). The HOX required is conveniently generated 
from an alkali metal or alkaline earth metal hypohalite by acidification 
with a mineral acid solution such as hydrochloric or hydrobromic acid. 
Sodium hypochlorite or sodium hypobromite solutions are readily available 
as 5-15% solutions and are readily employed in this process. When the 
latter are used, the pH of the halogenation reaction mixture is controlled 
below about pH 8 and preferably between about 5 and about 7 by the 
simultaneous addition of a mineral acid. If bromine or chlorine is used in 
the halogenation reaction either directly or as bromine or chlorine water, 
the pH of the halogenation reaction mixture is maintained in the above 
range by the addition of alkali metal carbonates or hydroxides. The 
preferred pH range is utilized to maintain reasonable reaction rates. 
The amount of HOX required in the halogenation process is about 1 to about 
1.1 moles per mole of the compound of formula (IA). If a substantially 
greater ratio of HOX than 1.1 moles per mole of the compound of formula 
(IA) is utilized, it will not affect formation of the product but is 
uneconomical. If substantially less than one mole is employed, the 
reaction will not proceed to completion. 
The temperature of the halogenation process is usually in the range from 
about 0.degree. to 50.degree. C. to avoid premature decarboxylation prior 
to halogenation of the compound and to avoid excessive loss of halogen 
which is in equilibrium with the hypohalous acid. Ambient temperatures are 
preferred as a matter of practicality and to keep side reactions to a 
minimum. After addition of the HOX reactant is complete, the reaction is 
monitored by periodic sampling and analysis by NMR. The characteristic NMR 
frequency of the methylene protons will shift from high field in the case 
of the compound of formula (IA) to a lower field as the halogenated 
compound of formula (V) is formed in the reaction mixture. When the 
desired degree of halogenation is obtained, the compound of formula (V) 
which is water soluble is isolated in its acid form by conventional 
methods involving acidification of the reaction mixture and extraction of 
the compound with a suitable organic solvent such as ethyl ether. 
CONVERSION OF SELECTED HALOGENATED POLYFUNCTIONAL COMPOUNDS INTO A MIXTURE 
OF CIS AND TRANS ACONITIC ACID 
The compounds of formula (V) may be "dehydrohalogenated" without isolation 
either under strongly alkaline conditions to produce a 
propene-1,1,2,3-tetracarboxylate which upon acidification decarboxylates 
to form aconitic acid (i.e. cis and trans aconitic acids) or under acidic 
aqueous conditions to produce directly a mixture of isocitric acid and 
alloisocitric acids and the lactones thereof. In both cases the 
"dehydrohalogenation" appears to proceed through an initial substitution 
of OH for the halogen followed by elimination of water under the alkaline 
conditions or decarboxylation under the acidic conditions. 
In the case of "dehydrohalogenation" of the compound of formula (V), an 
aqueous solution of the formula (V) compound is neutralized and made 
alkaline to a pH of about 10 to about 12.6, preferably from about 11 to 
about 12, by the slow addition of an alkaline earth metal hydroxide 
selected from the group Ca(OH).sub.2, Sr(OH).sub.2 and Pa(OH).sub.2, 
preferably Ca(OH).sub.2. The alkaline solution is heated at about 
25.degree. C. to about 100.degree. C. preferably about 50.degree. C. to 
about 70.degree. C. until "dehydrohalogenation" is complete, i.e. about 
1/2 hour to 2 hours. The "dehydrohalogenation" is prereferably monitored 
by NMR. This is done by sampling the solution, treating with excess 
Na.sub.2 CO.sub.3, filtering the insoluble calcium carbonate that forms, 
evaporating the filtrate and examining the residue by NMR. The reaction is 
stopped at maximum formation of the propene 1,1,2,3 tetracarboxylate salt 
(VI) by observing the intensity of the chemical shift for the methylene 
protons on carbon 3 at about 3.34.delta.. The tetracarboxylate calcium 
salt in the reaction mixture is then treated with dilute mineral acid to 
liberate the free acid which then undergoes decarboxylation to produce a 
mixture of cis and trans aconitic acids. The reaction scheme for the above 
described preparation of cis/trans aconitic acids is thus as follows: 
##STR14## 
CONVERSION OF SELECTED HALOGENATED POLYFUNCTIONAL COMPOUNDS INTO A MIXTURE 
OF CIS AND TRANS ACONITIC ACID, ISOCITRIC ACID, ALLOISOCITRIC ACID AND THE 
LACTONES OF ISOCITRIC ACID AND ALLOISOCITRIC ACID 
In the case where Sr(OH).sub.2 is used to "dehydrohalogenate" the compounds 
of structure V described above, it is possible to obtain a mixture of 
strontium salts of propene-1,1,2,3-tetracarboxylic acid and the 
1-hydroxypropane-1,1,2,3-tetracarboxylic acid intermediate by following 
the reaction by NMR and stopping the reaction at the maximum formation of 
the propene-1,1,2,3-tetracarboxylate species (i.e. maximum intensity of 
the chemical shift for the methylene protons on carbon 3). On 
acidification with an aqueous solution of a mineral acid, e.g. 
hydrochloric acid, or treatment with a cation exchange resin in its acid 
cycle, decarboxylation occurs to give a mixture of cis and trans aconitic 
acid, isocitric acid, alloisocitric acid and the lactones of isocitric 
acid and alloisocitric acid. The mixture of products may be isolated by 
conventional techniques such as solvent extraction or by evaporation of 
the water followed by extraction with a suitable solvent such as acetone 
and subsequent evaporation of the acetone extract. 
In the case where Ba(OH).sub.2 is used to "dehydrohalogenate" the compounds 
of structure V described above in the pH range 11-12, the reaction forms 
predominantly the 1-hydroxypropane-1,1,2,3-tetracarboxylate species as the 
barium salt. On acidification with an aqueous solution of a mineral acid, 
e.g. hydrochloric acid, or treatment with a cation exchange resin in the 
acid cycle, decarboxylation occurs to give a mixture of isocitric acid, 
alloisocitric acid and the lactones of isocitric acid and alloisocitric 
acid together with some cis and trans aconitic acid. 
CONVERSION OF SELECTED HALOGENATED POLYFUNCTIONAL COMPOUNDS INTO A MIXTURE 
OF ISOCITRIC ACID, ALLOISOCITRIC ACID AND THE LACTONES THEREOF 
In the special case where the compounds of structure V are reacted with 
Mg(OH).sub.2 in aqueous medium, a pH of only about 8-9 is achievable. 
Under these conditions and between temperatures of about 25.degree. C. and 
about 105.degree. C., preferably from 90.degree.-105.degree. C., the 
halogen atom is substituted by a hydroxyl group with simultaneous 
decarboxylation as well as saponification (with sufficient Mg(OH).sub.2) 
to give a mixture of the magnesium salts of isocitric acid and 
alloisocitric acid. The latter salts may then be converted into the acid 
and lactone forms by either treatment with a suitable cation exchange 
resin or acidification with mineral acid and isolation by conventional 
techniques such as solvent extraction or evaporation of the water present 
followed by extraction of the residue with a solvent such as acetone and 
subsequent evaporation of the acetone extract. 
Alternatively, the compounds of structure V may be treated under weakly 
alkaline conditions of about pH 8-9 utilizing an aqueous solution 
containing the stoichiometric amount (one equivalent per mole of V) of 
alkali metal hydroxide or alkaline earth metal hydroxide at temperatures 
between 25.degree. C. and 75.degree. C. Under these conditions a novel 
.beta.-lactone ester of the following structure is obtained: 
##STR15## 
wherein R, R.sub.1 and R.sub.2 are as previously defined. In place of the 
alkali metal or alkaline earth metal hydroxides, a weak organic base such 
as pyridine or triethylamine may also be reacted with compounds of 
structure V under anhydrous conditions to produce the same product (i.e. 
compound VII). 
In another embodiment, an aqueous solution of an alkali metal carbonate 
with or without an auxiliary organic base such as pyridine is reacted with 
a compound of formula V to produce a compound of formula VIII: 
##STR16## 
wherein R, R.sub.1 and R.sub.2 as previously defined and M is an alkali 
metal cation selected from the group lithium, sodium and potassium. 
The compound of structures (VII) and (VIII) may be readily hydrolyzed by 
heating with the appropriate amount of aqueous solution of an alkali metal 
hydroxide, alkali metal carbonate or an alkaline earth metal hydroxide at 
a pH of about 9-11 and preferably between about 9 and 10 to produce 
tetracarboxylate salts having the following structure: 
##STR17## 
wherein M.sub.2 is Li, Na or K or an alkaline earth metal cation selected 
from the group Ca, Sr and Ba and x is 1 or 2 and corresponds to the 
valence of the cation M.sub.2. 
The compounds of formula (IX) wherein M.sub.2 is Ca, Sr or Ba may also be 
treated with a solution of an alkali metal carbonate to produce the 
corresponding alkali metal salts (i.e. formula (IX) wherein M.sub.2 is Li, 
Na or K and x=1. The alkali metal salts of formula (IX) are useful as 
detergent builders and metal ion sequestrants. 
The compounds of formula (IX) may each be converted into a mixture of 
isocitric acid, alloisocitric acid and the lactones of isocitric acid and 
alloisocitric acid by acidification with a dilute solution of a mineral 
acid such as hydrochloric acid, whereby decarboxylation occurs to produce 
the said mixture of products. 
In another preferred embodiment the halogenated species of formula (V) may 
be heated with an aqueous solution of mineral acid, e.g. refluxing with 
10% hydrochloric acid for about 1 to about 16 hours to simultaneously 
hydrolyze the ester groups, dehydrohalogenate and decarboxylate the 
compound to produce a mixture of isocitric acid, alloisocitric acid and 
the lactones thereof. The temperature of reaction is about 25.degree. C. 
to about 110.degree. C., preferably about 90.degree. C. to 100.degree. C. 
The reaction is run for a sufficient amount of time to result in the 
desired end product, usually about 6 hours to about 10 hours. 
The reaction scheme thus is the same as that for aconitic acid up to the 
product of formula (V). The remaining sequences is as follows: 
##STR18## 
Representative compounds of formula (I) prepared according to the process 
of the invention include 
1--Calcium Bis[Methyl .alpha.-(dimethyl malonyl)succinate] 
##STR19## 
2--Ethyl sodium .alpha.-(diethyl malonyl)succinate 
##STR20## 
3--Methyl hydrogen .alpha.-(diethyl malonyl)succinate 
##STR21## 
4--Ethyl hydrogen .alpha.-(dimethyl malonyl)succinate 
##STR22## 
5--Methyl hydrogen .alpha.-(1-nitroethyl)succinate 
##STR23## 
6--Methyl hydrogen .alpha.-(acetyl carboethyl methinyl)succinate 
##STR24## 
7--Methyl hydrogen .alpha.-(cyanobenzyl)succinate 
##STR25## 
8--Methyl hydrogen .alpha.-(cyano carboethoxy methinyl)succinate 
##STR26## 
9--Methyl sodium .alpha.-(methyl sodium malonyl)succinate 
##STR27## 
10--Potassium butane-1,2,2,4-tetracarboxylic methyl ester-3-carboxylate 
##STR28## 
Representative compounds of formula V are as follows: 
1--Methyl hydrogen .alpha.-(dimethyl chloromalonyl)succinate 
##STR29## 
2--Ethyl hydrogen .alpha.-(diethyl chloromalonyl)succinate 
##STR30## 
3--Methyl hydrogen .alpha.-(diethyl-2-chloromalonyl)succinate 
##STR31## 
4--Ethyl hydrogen .alpha.-(dimethyl chloromalonyl)succinate 
##STR32## 
5--Methyl hydrogen .alpha.-(dimethyl bromomalonyl)succinate 
##STR33## 
Representative compounds of formulas (VI), (VII), (VIII) and (IX) obtained 
from the halogenated compounds of formula (V) are as follows: 
1--Tetrasodium propene-1,1,2,3-tetracarboxylate 
##STR34## 
2--Methyl hydrogen .alpha.-(dimethyl hydroxymalonyl)succinate 
.beta.-lactone 
##STR35## 
3--Ethyl hydrogen .alpha.-(diethyl hydroxymalonyl)succinate .beta.-lactone 
##STR36## 
4--Ethyl hydrogen .alpha.-(diethyl hydroxymalonyl)succinate 
##STR37## 
5--Dicalcium 1-hydroxy propane-1,1,2,3-tetracarboxylate 
##STR38## 
6--Tetrasodium propane-1-hydroxy-1,1,2,3-tetracarboxylate

The following examples will more fully illustrate the embodiments of this 
invention. All parts and proportions referred to herein and in the 
appended claims are by weight unless otherwise indicated. 
EXAMPLE I 
A. PREATION OF SODIUM METHYL MALEATE 
One mole of maleic anhydride is dissolved in 1000 ml methanol and 0.5 mole 
of sodium carbonate is added. The solution is filtered and the methanol is 
distilled off under pressure. After drying the product in a vacuum oven, 
152 g of sodium methyl maleate is obtained. 
B. PREATION OF CALCIUM BIS(METHYL MALEATE) 
##STR40## 
One mole of maleic anhydride is dissolved with stirring in 1000 ml methanol 
at 50.degree.-60.degree. C. The mixture is cooled to 25.degree. C. and 
with the aid of a pH meter, the pH is adjusted to 8.6 with calcium 
hydroxide while maintaining the temperature below 25.degree. C. with an 
ice bath. 149 g of calcium bis(methyl maleate) is recovered by 
crystallizing out of methanol followed by drying in a vacuum oven. 
C. PREATION OF LITHIUM METHYL MALEATE 
Twenty grams of maleic anhydride is dissolved in 200 mls methanol, 4.8 
grams (0.2 moles) lithium hydroxide is added. The mixture is stirred until 
all the lithium hydroxide dissolves (at this point the pH reads 7.0). To 
the solution is added acetone and the solid is filtered and dried. 23 
grams product is obtained. 
D. PREATION OF POTASSIUM METHYL MALEATE 
46.5 grams (0.46 mole) maleic anhydride is dissolved in 500 mls methanol. 
36 g K.sub.2 CO.sub.3 is added to a pH of 8.5-8.6, the solution is 
filtered and evaporated to dryness. 77.6 grams of product is obtained. 
Purity=96.4% by NMR analysis. 
E. PREATION OF SODIUM ETHYL MALEATE 
Fifty-seven grams (0.57 moles) maleic anhydride is dissolved in 500 mls 
ethanol. With the aid of a pH meter the pH is adjusted to 8.5-8.6 with 
sodium carbonate. The solution is evaporated on the roto evaporator and 
dried in a vacuum oven. Ninety-four grams (0.57 moles) of product having a 
purity of 99.4% (NMR analysis) is obtained. 
EXAMPLE II 
PREATION OF METHYL HYDROGEN .alpha.-(DIMETHYL MALONYL)SUCCINATE 
##STR41## 
Method A 
Into a 500 ml, one neck flask equipped with magnetic stirrer is placed 100 
grams sodium methyl maleate and 350 grams dimethyl malonate. The reaction 
temperature is maintained at 100.degree.-105.degree. C. for 5 hours. The 
excess malonate is distilled off under vacuum and the residue is extracted 
with ether:acetone (5:1) to remove unreacted malonate and thereby leaving 
a gummy residue of the sodium salt of the title compound. The latter is 
then dissolved in water, acidified with 1:1 sulfuric acid and the 
resulting liquid organic layer is separated from the water layer. On 
standing this liquid crystallizes. The total solid, 180 grams, is 
extracted with hexane to remove any malonate and the solid is dried. 
Yield: 153 grams. The water soluble fraction from above is evaporated to 
dryness and extracted with hexane. Ten grams of additional product is 
obtained in this manner. Total yield: 163 grams (94% of theoretical). 
Method B 
Fifty grams sodium methyl maleate is mixed with 200 grams dimethyl malonate 
in a 500 ml one neck flask equipped with a magnetic stirrer. The 
temperature is maintained at 100.degree.-105.degree. C. for 4 hours, then 
the excess malonate is distilled off under vacuum. The viscous liquid 
obtained is dissolved in water and 0.33 moles sulfuric acid in 25 mls 
water is added. The liquid separates and crystallizes on standing. The 
entire solution including the crystals is filtered and the product is 
washed with water leaving a white solid (23 grams). The water layer is 
extracted with ether and the ether distilled off. On standing the residue 
crystallizes; yield: 12.5 grams, m.p. 101.5.degree. C. Total yield of 
product: 35.5 grams. 
Method C 
24.3 grams (0.145 mole) potassium methyl maleate is added to 100 g of 
dimethyl malonate. The mixture is heated to 110.degree.-115.degree. C. for 
4-5 hours. Complete solution is attained in 3-4 hours. The reaction 
solution is then distilled under pressure to remove excess dimethyl 
malonate. The distillation residue is dissolved in 200 mls water and 
acidified with 15 g conc. HCl in 25 mls water. The resulting organic layer 
is extracted with ethyl ether and the ethereal extract evaporated to give 
a residue of 42 g (theoretical: 39 grams). The product crystallizes on 
standing. 
The structure of the products obtained by the three methods is confirmed by 
NMR analysis (CDCl.sub.3) to correspond to the title compound: 
##STR42## 
CH.sub.2 (a) ABX multiplet, two peaks, one at 2.76.delta., one at 
2.86.delta. 
Ch(b) multiplet, 3.44-3.70.delta. 
Ch.sub.3 (c) singlet at 3.70.delta. 
Ch.sub.3 (d) singlet at 3.76.delta. 
Ch(e) doublet centered at 3.99.delta.. 
EXAMPLE III 
PREATION OF METHYL HYDROGEN .alpha.-(DIETHYL MALONYL)SUCCINATE 
##STR43## 
Ninety grams of sodium methyl maleate is reacted with 200 grams of diethyl 
malonate at 100.degree.-110.degree. C. for four hours. After the reaction 
mixture is cooled to 25.degree. C., 1000 mls of water is added and the 
unreacted diethyl malonate layer is separated. The aqueous layer is 
acidified with a mixture of 61 g of conc. hydrochloric acid and 50 mls 
water and the organic layer is separated. The organic layer is dissolved 
in ether and washed with water to remove dissolved methyl hydrogen 
maleate. The ether is then distilled off, obtaining 95 grams (55% yield) 
of product. The structure is confirmed by NMR analysis (CDCl.sub.3): 
##STR44## 
CH.sub.3 (a) triplet centered at 1.25.delta. CH.sub.2 (b) doublet (ABX) 
one peak at 2.75.delta., one at 2.83.delta. 
Ch(c) multiplet, 3.43-3.78.delta. 
Ch.sub.3 (d) singlet, 3.67.delta. 
Ch(e) doublet centered at 3.92.delta. 
Ch.sub.2 (f) quartet centered at 4.19.delta.. 
EXAMPLE IV 
PREATION OF ETHYL HYDROGEN .alpha.-(DIETHYL MALONYL)SUCCINATE 
##STR45## 
One hundred grams of sodium ethyl maleate is reacted with 500 grams of 
diethyl malonate at 100.degree.-110.degree. C. for 5 hours. The solution 
is cooled and is mixed with 1000 mls water. The aqueous layer is separated 
and acidified with 110 grams of 6.5 N hydrochloric acid. The liquid 
organic layer which separates is dissolved in ether and extracted twice 
with water to remove ethyl hydrogen maleate. After evaporation of the 
ether, a residue of 140 g (46% yield) of the title compound is obtained. 
The structure is confirmed by NMR analysis (CDCl.sub.3): 
##STR46## 
CH.sub.3 (a) triplet, 1.1-1.45.delta. CH.sub.2 (b) doublet centered at 
2.67.delta. 
Ch(c) multiplet centered at 3.60.delta. 
Ch(d) doublet centered at 3.92.delta. 
Ch.sub.2 (e) quartet centered at 4.15.delta. 
Ch.sub.2 (f) quartet centered at 4.20.delta.. 
EXAMPLE V 
PREATION OF ETHYL HYDROGEN .alpha.-(DIMETHYL MALONYL)SUCCINATE 
##STR47## 
Twenty five grams (0.15 mole) of sodium ethyl maleate (of 99.4% purity) is 
mixed with 100 grams of dimethyl malonate and the solution heated at 
100.degree.-107.degree. C. for 6 hours. The solution is then evaporated 
under reduced pressure to remove excess dimethyl malonate. The 
distillation residue is dissolved in 200 mls water and acidified with 40 g 
of 4.5 N hydrochloric acid. The product which separates as a liquid, is 
extracted with 100 mls chloroform and the chloroform extract is distilled 
under reduced pressure. Forty five grams of a liquid product is obtained 
as a residue. NMR analysis (CDCl.sub.3) is consistent with the title 
compound containing traces of dimethyl malonate: 
##STR48## 
CH.sub.3 (a) triplet centered at 1.22.delta. CH.sub.2 (b) ABX doublet, 
2.55-2.87.delta. 
Ch(c) ABX multiplet, 3.15-3.57.delta. 
Ch.sub.3 (d) singlet, 3.75.delta. 
Ch(e) doublet centered at 3.93.delta. 
Ch.sub.2 (f) quartet centered at 4.12.delta.. 
EXAMPLE VI 
PREATION OF METHYL HYDROGEN .alpha.-(ACETYL CARBOETHOXY 
METHINYL)SUCCINATE 
##STR49## 
Into a 100 ml, one neck flask equipped with a magnetic stirrer is placed 10 
grams sodium methyl maleate and 40 grams ethyl acetoacetate. The mixture 
is heated to 110.degree. C. for 45 minutes. Water, 200 mls, is then added 
to the reaction mixture and the upper layer, consisting of ethyl 
acetoacetate, is removed. The water layer is acidified with a mixture of 7 
grams conc. H.sub.2 SO.sub.4 and 10 mls water. The liquid that separates 
is extracted with ether and the ether extract is distilled in vacuo to 
leave a viscous residue. The residue is extracted 4-5 times with hot 
hexane to remove ethyl acetoacetate and leaving behind 14 grams (77.8% of 
theoretical) of the title compound (neutralization equivalent found, 264). 
NMR analysis (CDCl.sub.3) of the product confirms the structure and shows 
the product to consist of a 58:42 weight ratio of keto:enol forms: 
##STR50## 
CH.sub.3 (a) triplet centered at 1.27.delta. CH.sub.3 (b) singlet, 
2.28.delta. 
Ch.sub.2 (c) ABX multiplet, 2.57-2.88.delta. broad 
Ch(d) multiplet, 3.46-3.81.delta. 
Cooch.sub.3 (e) singlet, 3.60.delta. 
Ch(f) doublet, 3.90-4.09.delta. 
Cooch.sub.2 (g) quartet centered at 4.16.delta.. 
##STR51## 
CH.sub.3 (a') triplet centered at 1.25.delta. CH.sub.3 (b') singlet at 
1.82.delta.. 
All other spectral assignments are the same as for the keto form. 
EXAMPLE VII 
A. PREATION OF LITHIUM METHYL .alpha.-(CYANO CARBOETHOXY 
METHINYL)SUCCINATE 
##STR52## 
Fifty grams (0.38 mole) of lithium methyl maleate is dissolved in a mixture 
of 150 grams ethyl cyanoacetate and 100 grams DMF (dimethyl formamide) at 
80.degree.-90.degree. C. The temperature is then raised to 
100.degree.-105.degree. C. for 45 minutes. The solution is evaporated in 
vacuo to remove excess solvents and the residue is extracted twice with 
500 mls ether to leave 96 grams of the title compound as a gummy residue. 
The structure is confirmed by NMR analysis (D.sub.2 O): 
##STR53## 
CH.sub.3 (a) triplet centered at 1.15.delta. CH.sub.2 (b) multiplet, 
2.69-3.05.delta. 
Ch(c) multiplet, 3.25-3.48.delta. 
Ch.sub.3 (d) singlet, 3.68.delta. 
Ch(e) hidden under CH.sub.2 (f) group 
Ch.sub.2 (f) quartet centered at 4.24.delta.. 
B. PREATION OF METHYL HYDROGEN .alpha.-(CYANOCARBOETHOXY 
METHINYL)SUCCINATE 
##STR54## 
Ninety six grams of the product obtained above in VII(A) is dissolved in 
water and a mixture of 38 grams conc. hydrochloric acid in 50 mls water is 
added to the solution. The product which separates is extracted with 
ether. Evaporation of the ether extract yields 74 grams of product 
containing traces of ethyl cyanoacetate and DMF. NMR analysis (CDCl.sub.3) 
confirms the structure: 
##STR55## 
CH.sub.3 (a) triplet centered at 1.33.delta. CH.sub.2 (b) multiplet at 
2.98-3.08.delta. 
Ch(c) multiplet at 3.35-3.70.delta. 
Ch.sub.3 (d) singlet, 3.72.delta. 
Ch(e) doublet centered at 4.25.delta. 
Ch.sub.2 (f) quartet centered at 4.30.delta.. 
EXAMPLE VIII 
PREATION OF METHYL HYDROGEN .alpha.-(CYANOBENZYL)SUCCINATE 
##STR56## 
Into a 200 ml, one-neck flask is placed 35 grams of sodium methyl maleate 
(0.23 moles), 85 grams (0.73 moles) of phenyl acetonitrile and 80 g(1.1 
moles) dimethyl formamide. The reaction mixture is heated to 
125.degree.-140.degree. C. for five hours and then distilled in vacuo. The 
residue is extracted three times with 300 ml ether. The solid (56 grams) 
is then dissolved in water and acidified with 23 grams conc. HCl in 50 
mls water. The liquid that separates out is dissolved in ether and washed 
with water to remove unreacted starting materials. The ether is distilled 
off to give a residue of 50 grams of product (yield: 88.degree.). The 
structure is verified by NMR (in CDCl.sub.3): 
##STR57## 
CH.sub.2 (a) ABX multiplet at 2.50-3.00.delta. CH(b) multiplet, 
3.30-3.56.delta. 
Ch.sub.3 (c) singlet, 3.67.delta. 
Ch(d) multiplet, 4.20-4.60.delta. 
Ch(e) (phenyl) at 7.35.delta.. 
EXAMPLE IX 
PREATION OF METHYL HYDROGEN .delta.(1 NITROETHYL)SUCCINATE 
##STR58## 
Into a 100 ml, one neck flask is placed 10 grams of sodium methyl maleate, 
60 mls N,N-dimethyl formamide (DMF) and 40 grams nitroethane. The solution 
is heated at 60.degree. C. for two hours and then partially distilled in 
vacuo to remove the DMF and nitroethane. The residue, by NMR analysis 
(D.sub.2 O), has the following structure: 
##STR59## 
CH.sub.3 (a) doublet of doublets [ one centered at 1.44.delta.; one 
centered at 1.57.delta. 
Ch.sub.2 (b) multiplet, 2.5-2.72.delta. 
Ch(c) multiplet centered at 3.25.delta. 
Ch.sub.3 (d) singlet, 3.65.delta. 
Ch(e) multiplet, 4.77-5.1.delta.. 
The residue from above is dissolved in water and acidified with 7 mls conc. 
hydrochloric acid. The water is distilled off and the residue is extracted 
with acetone. The acetone is evaporated and the liquid residue is 
extracted with hexane to remove dissolved DMF. The residue is then 
triturated with ether, filtered and the ether is removed under vacuum. 
Five grams (14% yield) of product is obtained. The structure is confirmed 
by NMR analysis (CDCl.sub.3): 
##STR60## 
CH.sub.3 (a) doublet of doublets [ one centered at 1.56.delta.; one 
centered at 1.78.delta. 
Ch.sub.2 (b) multiplet, 2.6-2.9.delta. 
Ch(c) multiplet, 3.32-3.64.delta. 
Ch.sub.3 (d) singlet, 3.65.delta. 
Ch(e) multiplet centered at 5.0.delta.. 
EXAMPLE X 
PREATION OF SODIUM METHYL .alpha.-(METHYL SODIUM MALONYL)SUCCINATE 
##STR61## 
as follows: 
One mole of dimethyl malonate is dissolved in 100 mls methanol and 1/2 mole 
of NaOH dissolved in 100 mls of methanol is added. The solution is stirred 
for 6 hours, the methanol is evaporated off and the solid filtered and 
washed with ether. One mole of sodium methyl malonate is recovered. 
Twenty grams of the sodium methyl malonate (0.14 mole) and 15 grams (0.1 
mole) sodium methyl maleate are mixed with 100 grams of dimethyl formamide 
(DMF) and the mixture heated at 115.degree.-118.degree. C. for 1/2 hour 
while stirring the mixture. The reaction mixture is then cooled and 100 
mls of acetone is added to extract out DMF. The solid is triturated first 
with 400 mls of ether and then with 400 mls of 1:1 acetone:ether. Twenty 
six grams (73% yield) of product is obtained. NMR analysis of the product 
is D.sub.2 O confirms the structure and in addition shows the presence of 
some fumarate and malonate: 
##STR62## 
H(a) 3.55-3.80.delta. H(b+c) 3.10-3.6.delta. 
Ch.sub.3 (d+e) 3.7.delta.. 
EXAMPLE XI 
PREATION OF METHYL HYDROGEN TETRAMETHYL 
BUTANE-1,2,2,4-TETRACARBOXYLATE-3-CARBOXYLIC ACID 
##STR63## 
A mixture of 16.8 g (0.1 mole) of potassium methyl maleate and 50 g of 
trimethyl ethane-1,1,3-tricarboxylate is heated at 140.degree. C. for 5 
hours. The reaction mixture is cooled and mixed with 200 ml of water and 
200 ml of ethyl ether. After shaking the mixture, the water layer, which 
contains the potassium salt of the title compound, is separated and 
acidified with 10 g of concentrated hydrochloric acid. The acidified 
mixture is extracted with ethyl ether and the ether layer is evaporated to 
give 16 g of the title compound. The structure of the compound is 
confirmed by NMR (CDCl.sub.3): 
##STR64## 
CH.sub.2 (a+a') multiplet at 2.6-2.9 CH(b) multiplet at 2.9-3.14 
Ch.sub.3 (c) three singlets at 3.65-3.9. 
EXAMPLE XII 
PREATION OF METHYL HYDROGEN .alpha.-(DIMETHYL CHLOROMALONYL)SUCCINATE 
##STR65## 
Thirteen grams (0.05 moles) of the product prepared in Example II, i.e. 
methyl hydrogen .alpha.-(dimethyl malonyl)succinate, is dissolved in 150 
mls of water. Sodium hypochlorite, 70 grams of a 5.25% by weight solution, 
is added slowly while stirring the solution during a 15 minute period 
until the pH rises to 7.0. The solution is then acidified is then 
acidified to pH 1.9 and is extracted with ether. The ether extract is 
evaporated to give fifteen grams of the title compound as a liquid. NMR 
analysis (CDCl.sub.3) confirms the structure: 
##STR66## 
CH.sub.2 (a) multiplet consisting of a doublet and singlet 
2.83-3.04.delta. 
Ch(b) doublet of doublets, 4.04-4.30.delta. 
Cooch.sub.3 (c) singlet at 3.74.delta. 
Cooch.sub.3 (d) singlet at 3.87.delta.: 
EXAMPLE XIII 
PREATION OF METHYL HYDROGEN .alpha.-(DIETHYL CHLOROMALONYL)SUCCINATE 
##STR67## 
Into a beaker is placed 90 grams of the product prepared in Example III, 
i.e. methyl hydrogen .alpha.-(diethyl malonyl)succinate, and 200 mls 
water. 500 mls of NaOCl solution (5.25% by weight) is added slowly during 
a 1/2 hour period to a pH of 7.0. The solution is then acidified with 
dilute hydrochloric acid (10%), to a pH of 1.0 and extracted with ether. 
The ether extract is evaporated to give 95 g (95% yield) of the title 
compound as a syrupy residue. The structure is confirmed by NMR analysis 
(CDCl.sub.3): 
##STR68## 
CH.sub.3 (a) triplet centered at 1.28.delta.CH.sub.2 (b) ABX multiplet [ 
doublet centered at 2.91.delta.; singlet at 2.82.delta. 
Ch.sub.3 (c) singlet at 3.70.delta. 
Ch(d) multiplet, 3.95-4.23.delta. 
Ch.sub.2 (e) quartet centered at 4.28.delta.. 
EXAMPLE XIV 
PREATION OF ETHYL HYDROGEN .alpha.-(DIETHYL CHLOROMALONYL)SUCCINATE 
##STR69## 
One hundred grams of the compound prepared in Example IV, i.e. ethyl 
hydrogen .alpha.-(diethyl malonyl)succinate, is mixed with 300 mls water. 
Five hundred mls of (5.25% by weight) sodium hypochlorite is added during 
45 minute period to a pH of 7.0. The solution is then acidified to a pH of 
1 with dilute (10%) hydrochloric acid and the product which separates is 
extracted with ether. The ether extracts are evaporated to give 92 g (82% 
yield) of the title product as a syrupy residue. The structure is 
confirmed by NMR analysis (CDCl.sub.3): 
##STR70## 
CH.sub.3 (a) triplet centered at 1.26.delta. CH.sub.3 (b) triplet centered 
at 1.29.delta. 
Ch.sub.2 (c) ABX multiplet one peak at 2.81.delta., a doublet centered at 
2.93.delta. 
Ch(d) mutliplet, 4.0-4.3.delta. 
Ch.sub.2 (e) superimposable quartets (2 pairs 4.05-4.5.delta.). 
EXAMPLE XV 
PREATION OF ETHYL HYDROGEN .alpha.-(DIMETHYL CHLOROMALONYL)SUCCINATE 
##STR71## 
Seventy grams of the compound prepared in Example V, i.e. ethyl hydrogen 
.alpha.-(dimethylmalonyl)succinate is dissolved in 200 mls water. Five 
hundred grams of 5.2% sodium hypochlorite is then added slowly over a 30 
minute period while maintaining the pH of the reaction mixture in the 
range 6-7 by the simultaneous addition of dilute hydrochloric acid. The 
reaction mixture is then acidified to a pH of 2 with concentrated 
hydrochloric acid and extracted with ethyl ether. After separation and 
evaporation of the ethyl ether layer, there is obtained 73 g (96.6% yield) 
of the title compound as a residue. The structure is confirmed by NMR 
analysis (CDCl.sub.3): 
##STR72## 
CH.sub.3 (a) triplet centered at 1.22.delta. CH.sub.2 (b) ABX multiplet at 
2.72-2.97.delta. 
Ch.sub.3 (c) singlet at 3.80.delta. 
Ch(d) ABX multiplet at 3.80-4.00.delta. 
Ch.sub.2 (e) quartet centered at 4.15.delta.. 
EXAMPLE XVI 
PREATION OF METHYL HYDROGEN .alpha.-(DIMETHYL BROMOMALONYL)SUCCINATE 
##STR73## 
To 3.3 grams (0.0125 mol) of the compound of Example II, i.e. methyl 
hydrogen .alpha.-(dimethyl malonyl)succinate, dissolved in 100 mls water, 
is slowly added over a 15 minute period 27 mls of sodium hypobromite 
solution (4.2% by weight) to a pH of 7.0. After 20 minutes, the solution 
is acidified to a pH of 1.0 with dilute (5%) hydrochloric acid and 
extracted with ether. The ether extract is evaporated to give 3 g (75% 
yield) of the title compound as a syrupy residue. The structure is 
confirmed by NMR analysis (CDCl.sub.3): 
##STR74## 
CH.sub.2 (a) doublet [ one peak at 2.93.delta.; one peak at 
3.03.delta.CH(b) triplet centered at 4.10.delta. 
Ch.sub.3 (c) split into 2 doublets centered at 3.17.delta. 
Ch.sub.3 (d) single, 3.85.delta. 
EXAMPLE XVII 
PREATION OF METHYL HYDROGEN .alpha.-(DIMETHYL HYDROXYMALONYL)SUCCINATE 
.beta.-LACTONE 
##STR75## 
Twenty six grams of the compound prepared in Example II, i.e. methyl 
hydrogen .alpha.-(dimethyl malonyl)succinate, is dissolved in 150 mls 
water. A solution of 5.25% sodium hypochlorite is then added slowly until 
the pH of the reaction mixture increases to 7.0. The water medium is then 
removed in vacuo at 40.degree. C. to leave a yellow residue which is taken 
up in chloroform and filtered. The chloroform filtrate is evaporated to 
give a purified residue which is then redissolved in water and passed 
through a cation exchange resin in the acid form. The water layer in the 
eluate is separated and evaporated to give 25 grams of 
##STR76## 
as a residue. The organic layer (2 g) from the eluate corresponds to the 
lactone product (confirmed by infrared and NMR analysis). Infrared 
analysis shows a peak for a four membered lactone at 5.4.mu.. The NMR 
analysis (CDCl.sub.3) is as follows: 
##STR77## 
CH.sub.2 (a) ABX multiplet, one peak at 3.07.delta. one doublet centered 
at 2.94.delta. 
Ch(b) multiplet centered at 4.66.delta. 
Cooch.sub.3 (c) singlet at 3.82.delta. 
Cooch.sub.3 (d) singlet at 3.96.delta. 
Cooch.sub.3 (e) singlet at 4.00.delta.. 
EXAMPLE XVIII 
PREATION OF ETHYL HYDROGEN .alpha.-(DIETHYL HYDROXYMALONYL)SUCCINATE 
.beta.-LACTONE 
Procedure A 
##STR78## 
Ten grams (0.032 mole) of the compound prepared in Example XIV, i.e. ethyl 
hydrogen .alpha.-(diethyl chloromalonyl)succinate is dissolved in 100 mls 
of ethanol and Ca(OH).sub.2 is added until the pH reaches 8.6. The ethanol 
is removed under vacuum at 45.degree. C., 100 mls of pyridine is added and 
the resulting solution is heated at 90.degree. C. for one hour. The 
pyridine is removed in vacuo and the residue is extracted with ethyl 
ether. Evaporation of the ether extracts gives 8 g (84% yield) of the 
title compound. The structure is confirmed by NMR analysis (CDCl.sub.3): 
##STR79## 
CH.sub.3 (a) superimposed triplets, 1.0-1.5.delta. CH.sub.2 (b) ABX 
multiplet, 2.75-3.00.delta. 
Ch.sub.2 (c) superimposed quartets, 3.92-4.50.delta. 
Ch(d) ABX multiplet, 4.50-4.73.delta.. 
Procedure B 
Six grams of the compound prepared in Example XIV, i.e. ethyl hydrogen 
.alpha.-(diethyl chloromalonyl)succinate, is dissolved in 50 mls of 
chloroform and 100 grams of triethyl amine is added. The solution is 
stirred at 40.degree.-50.degree. C. for 45 minutes. The excess amine and 
chloroform are removed in vacuo and the residue is extracted with ether. 
The ether extracts are then evaporated to dryness to give 5 grams of the 
title compound. The structure is confirmed by NMR analysis (CDCl.sub.3). 
EXAMPLE XIX 
PREATION OF ETHYL HYDROGEN .alpha.-(DIETHYL HYDROXYMALONYL)SUCCINATE 
##STR80## 
Five grams (0.016 mole) of the compound prepared in Example XIV, i.e. ethyl 
hydrogen .alpha.-(diethyl chloromalonyl)succinate, is dissolved in 100 mls 
of water and Na.sub.2 CO.sub.3 is added to a pH of 8.6. Sixty mls of 
pyridine is added and the solution is heated at 80.degree. C. for one hour 
(at this point the pH is 7.0). The solvents (H.sub.2 O+pyridine) are 
removed under vacuum and the residue is extracted with acetone. The 
acetone extract is evaporated to leave a residue of the sodium salt of the 
title compound. The structure is confirmed by NMR analysis (D.sub.2 O): 
##STR81## 
CH.sub.3 (a) superimposed triplets at 1.1-1.47.delta. CH.sub.2 (b) ABX 
multiplet at 2.5-2.8.delta. 
Ch(c) ABX multiplet at 3.7-4.1.delta. 
Ch.sub.2 (d) superimposed quartets at 4.0-4.5.delta.. 
The above salt is dissolved in 100 mls of water and the pH is adjusted to 
1.0 with dilute hydrochloric acid (10%). The acidified solution is then 
extracted with ethyl ether and the ether extract is evaporated to yield 
3.5 g (70% yield) of the title compound. The structure is confirmed by NMR 
analysis (CDCl.sub.3): 
##STR82## 
CH.sub.3 (a) superimposed triplets at 1.12-1.50.delta. CH.sub.2 (b) ABX 
multiplet at 2.56-2.94.delta. 
Ch(c) ABX multiplet at 3.74-4.02.delta. 
Ch.sub.2 (d) superimposed quartets at 3.98-4.52.delta.. 
EXAMPLE XX 
PREATION OF METHYL HYDROGEN .alpha.-(DIMETHYL HYDROXYMALONYL)SUCCINATE 
##STR83## 
A mixture of 15 g (0.05 mole) of the compound prepared as in Example XII, 
i.e. methyl hydrogen .alpha.-(dimethyl chloromalonyl)succinate, and 200 ml 
of water is neutralized to a pH of 9.0 by the addition of 2.8 g (0.026 
mole) of sodium carbonate. The resulting solution is refluxed for 30 
minutes whereby the pH drops to about 2. The solution is evaporated and 
the residue extracted with acetone. The acetone solution is filtered and 
evaporated to yield 9 g of a syrupy product corresponding to the title 
compound. The structure is confirmed by NMR analysis (CDCl.sub.3): 
##STR84## 
CH.sub.2 (a) ABX multiplet at 2.60-3.00.delta. CH(b) hidden 
Ch.sub.3 (c) singlet at 3.76.delta. 
Ch.sub.3 (d) singlet at 3.90.delta.. 
EXAMPLE XXI 
PREATION OF .alpha.-(2-HYDROXY DISODIUM MALONYL)DISODIUM SUCCINATE 
##STR85## 
Ten grams (0.03 mole) of the compound prepared in Example XIV, i.e. ethyl 
hydrogen .alpha.-(diethyl chloromalonyl)succinate is mixed with 75 ml 
water and 4.4 g (0.06 mole) of Ca(OH).sub.2. After 15 minutes an 
additional 3 grams of Ca(OH).sub.2 is added to maintain the pH at 
9.5-10.0. The resulting mixture is heated at 60.degree.-70.degree. C. for 
4 hours while stirring and maintaining the pH at 9.5-10.0 by further 
addition of Ca(OH).sub.2 as required. Sodium carbonate, 0.1 mole, is then 
added and the reaction mixture is stirred at 60.degree.-70.degree. C. for 
15 minutes. The solution is filtered to remove CaCO.sub.3 and the pH of 
the filtrate is adjusted to 9.0 with dilute hydrochloric acid. After 
evaporation of the water, a residue of 9 g of the title compound 
containing traces of sodium chloride is obtained. The structure of the 
product is confirmed by NMR analysis (D.sub.2 O): 
##STR86## 
H(a) 2.25-2.7 H(b) 3.0-3.9 
EXAMPLE XXII 
PREATION OF ISOCITRIC AND ALLOISOCITRIC ACID LACTONES 
Procedure A 
##STR87## 
One gram of the product prepared in Example XXI above is acidified with 
dilute HCl (10% (with liberation of CO.sub.2) and evaporated to dryness in 
vacuo. The product consists of a mixture of isocitric and alloisocitric 
acid lactones by NMR analysis (D.sub.2 O): 
##STR88## 
H(a) ABX multiplet at 2.94-3.28.delta. H(b) ABX multiplet at 
3.78-4.19.delta. 
H(c) doublet at 5.38-5.58.delta. 
H(c') doublet at 4.3-4.5.delta. (traces of isocitric acid and alloisocitric 
acid). 
Procedure B 
Fifty grams of the compound prepared in Example XIV, i.e. ethyl hydrogen 
.alpha.-(diethyl chloromalonyl)succinate is dissolved in 100 ml of water 
to which 10 ml of concentrated hydrochloric acid has been added. The 
solution is refluxed for 16 hours and then evaporated in vacuo to leave 28 
g of a solid residue consisting of a 1:1 mixture of the lactones of 
isocitric acid and alloisocitric acid (structure determined by NMR 
analysis--D.sub.2 O). 
EXAMPLE XXIII 
PREATION OF TETRASODIUM PROPENE 1,1,2,3 TETRACARBOXYLATE 
##STR89## 
Twelve grams (0.036 mole) of the product prepared in Example XII, i.e. 
methyl hydrogen .alpha.-(dimethyl chloromalonyl)succinate, is mixed with 
200 mls water. Ca(OH).sub.2 is then slowly added at first maintaining the 
pH at 10.0 and then heating to 60.degree.-70.degree. C. until all the 
ester groups are saponified. A total of 10 grams of Ca(OH).sub.2 is added 
(pH 11.6) and the slurry is stirred for 2-3 hours at 60.degree.-70.degree. 
C. Thirteen grams of Na.sub.2 CO.sub.3 is then added and the mixture is 
stirred for 15 minutes at 50.degree. C. The precipitated CaCO.sub.3 is 
filtered and the filtrate is evaporated to give 10 g of the title 
compound. The structure is confirmed by NMR analysis (D.sub.2 O): 
--CH.sub.2 -- singlet at 3.34.delta.. 
EXAMPLE XXIV 
PREATION OF 1:1 CIS:TRANS ACONITIC ACID 
##STR90## 
Nine grams of the product as prepared in Example XXIII, i.e. tetrasodium 
propane-1,1,2,3-tetracarboxylate, is dissolved in 100 mls water and 
acidified with dilute HCl (10%). Liberation of CO.sub.2 is instantaneous. 
The residue, after evaporation of water, is extracted with acetone. The 
acetone is evaporated to leave a residue consisting of a 1:1 by weight 
mixture of cis:trans aconitic acid. The structure of the product is 
confirmed by NMR analysis (D.sub.2 O): 
##STR91## 
EXAMPLE XXV 
PREATION OF A MIXTURE OF ISOCITRIC ACID, ALLOISOCITRIC ACID AND THE 
LACTONES THEREOF 
Thirty grams (0.1 mole) of the compound prepared in Example XII, i.e. 
methyl hydrogen .alpha.-(dimethyl chloromalonyl)succinate, is mixed with 
200 ml water. Sodium hydroxide, 20 g (0.5 mole), is added slowly while 
maintaining the temperature at 60.degree. C. and the pH between 9 and 10. 
After heating for 3-4 hours at 60.degree. C., the solution is cooled and 
acidified to a pH of 1.2 with dilute hydrochloric acid. The solution is 
then evaporated in vacuo and the residue remaining is extracted with 
acetone. The acetone extract is then filtered and the filtrate, evaporated 
to give a residue of 17 grams of a mixture of 1:1 isocitric acid: 
alloisocitric acid and the lactones thereof (identified by NMR). 
EXAMPLE XXVII 
PREATION OF A MIXTURE OF ISOCITRIC ACID, ALLOISOCITRIC ACID AND THE 
LACTONES THEREOF 
Fifteen grams (0.05 mole) of the product prepared in Example XV, i.e. ethyl 
hydrogen .alpha.-(dimethyl chloromalonyl)succinate is mixed with 200 mls 
of water. Magnesium hydroxide, 25 g (0.43 mole), is added slowly while 
maintaining the reaction mixture at 80.degree.-90.degree. C. and the pH at 
9.0. After refluxing the reaction mixture for 2 hours, the solution is 
cooled and then acidified with 86.2 g of 50% sulfuric acid. The acidified 
solution is evaporated to yield a residue which is then extracted with 
acetone. The acetone extract is filtered and the filtrate evaporated to 
give 10.4 g of residue consisting of a mixture of isocitric acid and 
alloisocitric acid and the lactones thereof (identified by NMR). 
EXAMPLE XXVIII 
PREATION OF A MIXTURE OF ISOCITRIC ACID, ALLOISOCITRIC ACID AND THE 
LACTONES THEREOF 
Fifteen grams (0.05 mole) of the compound prepared in Example XV, i.e. 
ethyl hydrogen .alpha.-(dimethyl chloromalonyl)succinate, is mixed with 
200 ml water. Strontium hydroxide, 24 g (0.2 mole), is then added while 
heating the mixture at 70.degree.-75.degree. C. and while maintaining the 
pH at 10.0. The solution is then cooled and acidified with 120 g of 15% 
hydrochloric acid. The acidified solution is then evaporated in vacuo to a 
residue which, in turn, is extracted with acetone. The acetone extract is 
filtered and the filtrate is evaporated in vacuo to give 7.7 grams of 
syrup consisting of a mixture of isocitric acid, alloisocitric acid and 
the lactones thereof (identified by NMR analysis). 
This invention has been described with respect to certain preferred 
embodiments and various modifications and variations in the light thereof 
will be suggested to persons skilled in the art and are to be included 
within the spirit and preview of this application and the scope of the 
appended claims.