CA1115287A - Ether polycarboxylate compounds and the production thereof - Google Patents
Ether polycarboxylate compounds and the production thereofInfo
- Publication number
- CA1115287A CA1115287A CA268,030A CA268030A CA1115287A CA 1115287 A CA1115287 A CA 1115287A CA 268030 A CA268030 A CA 268030A CA 1115287 A CA1115287 A CA 1115287A
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- CA
- Canada
- Prior art keywords
- compound
- formula
- ethyl
- methyl
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/305—Saturated compounds containing more than one carboxyl group containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
Abstract
ABSTRACT OF THE DISCLOSURE
Novel polyfunctional compounds which may be hydrolyzed to the corresponding salts, which in turn are metal sequestering agents and/or detergent builders, are disclosed, as well as a novel method for their preparation. The compounds are the reaction product obtained from the reaction of selected salts of monoalkyl esters of maleic acid with selected active hydrogen containing compounds. The products are of the formula x M1 +x wherein R is a primary alkyl group of one to six carbon atoms, wherein M1 is H, Ca, Mg, Ba, Sr, Na, K or Li, wherein x is 1 or 2 and is equivalent to the valency of M1, wherein Y is oxygen, and wherein Z is 1) an ester moiety of the general formula:
Novel polyfunctional compounds which may be hydrolyzed to the corresponding salts, which in turn are metal sequestering agents and/or detergent builders, are disclosed, as well as a novel method for their preparation. The compounds are the reaction product obtained from the reaction of selected salts of monoalkyl esters of maleic acid with selected active hydrogen containing compounds. The products are of the formula x M1 +x wherein R is a primary alkyl group of one to six carbon atoms, wherein M1 is H, Ca, Mg, Ba, Sr, Na, K or Li, wherein x is 1 or 2 and is equivalent to the valency of M1, wherein Y is oxygen, and wherein Z is 1) an ester moiety of the general formula:
Description
~ .S~37 This invention broadly relates to novel polyfunctional compounds and a process for their preparation. The compounds may be hydrolyzed to form the corresponding salts. These salts in turn are metal sequestering agents and/or detergent builders and in the preferred embodiment are salts of substituted as well as unsubstituted carboxymethyloxysuccinic acid (CMOS).
Additional compounds and processes are disclosed as alternative embodiments such as, for examplej the sulfur and imino analogs of CMOS as well as selected phenoxy and hydroxyalkoxy derivatives of succinic acid.
Salts of carboxymethyloxysuccinic acid as well as other ether polycarboxylic acid salts, e.g. tri-alkali metal salts, are known detergent builders and have been considered in U.S. Patent No. 3,692,685 and Belgian Patent No. 782,696 granted October 26, 1972.
~'~
, ~
, .
C.667 Canada ~52~37 Generally, these compounds have been prepared by the reaction of the mixed calcium salt of glycolic acid and maleic acid in a~ueous alkaline medium with a subsequent exchange of the calcium cations with the desired metal cation.
The reaction is believed to proceed according to a novel form of the Michael reaction involving a mixed polyvalent metal salt of glycolic and maleic acid as the reacting species.
This reaction takes place in aqueous solution in a critical alkaline pH range and, in addition, requires the presence of polyvalent metal cations in the reaction mixture and thus cannot be carried out with alkali metal salts to the exclu-sion of these polyvalent metal cations.
The Michael reaction referred to above is considered thoroughly in Chapter 3 of Volume lO of a 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 atoms in a system 0 = C-CH- to a carbon-carbon double bond 20 which forms part of a conjugated acceptor system of general ;
I I I
formula -C = C-C = 0. The addition proceeds under the influence of alkaline or basic catalysis.
:,.
. ' .
. ~, ' ~ ,.
C.G~7 Canada .
Inherently in this 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 sys~em. Through the 5 ~ use of this reaction a series of compounds have been pre-pared. 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 an extremely useful organic tool ~or synthesis of selected compounds. Xowever~ disadvantages arise in attempting to prepare certain mixed esters ~y th~s route because of transesterlfication which can take place under the conditions of the Michael reaction thereby produc-ing mixtures of mixed esters in correspondingly diminished yield rather than a single mixed ester in relatively high yleld. Such mixtures, are normally extremely difficult to separate. These difficulties, thus, militate stron~ly Z against the use of the Michael reaction and indeed the appli-cability of this reaction for desired mixed ester products.
Further, when the donor moiety descrlbed above is an alpha hy-droxy ester, the preparation o addition compounds via the Michael . ~ , . .
reaction hecomes impractical because of the -dominance of the ~25 reverse Michael reaction which leads back to either the start-.
ing materials or rearranged starting materials. This is ~ar-; -ticularly true when attempting to add alpha hydroxy ester ' , : , .
.-~ . - ' .
~ ' . .
C.~67 Canada S2~37 compounds across the double bond of maleic esters in the pre-sence of alkaline catalyst.
Accoxdingly, an object of the present invention is to provide a process for producing novel mixed ester compounds by adding alpha hydroxy ester compounds 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 cata-lyst.
;10A further object is to produce compounds which by hydrolysis may be converted to substituted as well as unsub-stituted carboxymethyloxysuccinic acid and salts thereo.
Yet anothèr object of the invention is to provide ;a process for preparing nitrogen and sulfur analogs of sub-L5 stituted and unsubstituted carboxymethyloxysuccinic acid, acid esters and salts thereof.
Other objects and advantages will appear as the description proceeds.
,The attainment of the above ob~ects is made possible by this invention which includes novel compounds as well as a process for their preparation. ~hese novel compounds have the general foxmula (I) as follows:
CH~ - CH Y-Z' ~ Ml x (Ij - ~ COOR COO ~ ) x in which Y represents oxygen but in alternative embodiments may also represent sulfur or imino (NH)~ In ormula (I), Z
preferably represents the ollowing estex moiety:
:
.
, . . .
l~lS2~7 c. 667 Canada ¦-- ¦ 2 -C C--O - R
. _ H _ in which P~l represents isopropyl or secondary butyl, i.e. a propyl or butyl group lin~ed to the oxygen atom by a second-ary carbon atom of the group, such secondary substitution is .
. essential ~o facilitate the formation of the compound of formula (I) without allowing undue transesterification; and in which R2 represents hydrogen as well as a methyl ! ethyl or phenyl group when Y is oxygen or sulfur; and when Y is , :~ imino (NH), ~2 repre~ents hydrogen~ methyl, ethyl, isopropyl, ~::
. isobutyl, secondary butyl, benzyl, p-hydroxybenzyl o~r 2-(meth~lthio)ethyl~ ~lternative embodiments of Z in formula ~ . . .
(I) are the 2-hydroxyethyl or 3-hydroxypropyl groups. R, in formula (I), represents a primary alkyl group of one to six : carbon atoms such as methyl, ethyl~ propyl, butyl, pentyl or hexyl. Ml in for~ula (I) represents hydrogen, calcium, magne- -sium, strontium, barium, sodium, potassium or lithium and x is equivalent to the valency of Ml.
` 20 . A~ditionally, the above objects are attained by the novel process of this invention to prepare the polyfunctional : compounds of formula ~I). This process is preferably sub-.
: stantially anhydrous and includes reacting by heating a salt ,~
of a monoalkyl ester of maleic acid with an active hydrogen 25~ containing compound. The monoalkyl ester salt of maleic acid is of the general formula (II): ~-~ ' '~ ' ~ ' , ' '.
~ -6~
.
.. . . .
.
.
5Z~7 C.6~7 Canada CH ;,ÇH
COOR COOM
in which R is 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 re-present hydrogen whereas in formula (I) ML can represent hydroyen as well as the cations represented by M and thus the two separate designations of M and Ml are utilized. The active hydrogen containing compound is of the' general formula (III) -10 H - Y - Z (III) in which Y and Z are as previously defined.
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 de- ' sc'ribed. This is accomplished with the advantage that such compounds may be easily prepared in good yields suitable for ,:
subsequent conversion into metal sequestering agents, prefer- ~
ably into salts of car~oxymethyloxysucclnic acid. ~ ;
' The invention is hereinafter set forth in more de-tails, 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 substan*i-ally anhydrous conditions with a compound o'f formula (III) at , 25 an elevated temperature to form a reaction product which is .. . ..
the polyfunctional cbmpound of formula (I).
' The desired reaction product is soluble in the reac- ' .
tion mixture. It can be readily recovered from the reaction mixture by conventional methods such as for example insolu-' 30 bilizing liquld, for example, ethyl ether. Upon the addition ., , ' ' ' .
C.667 C~nad~
~5iZ~37 of a sufficient amount of such an insolubilizing liquid, the product crystallizes out of solution and is readily separated from the reaction media by conventional means. Upon filtra-tion or vacuum distillation, washing, recrystallization if desired and drying, the desired product may be obtained in purer form. The recovered product is sufficiently pure for conversion to the corresponding metal sequestrant salt.
The present invention permits the synthesis of the desired polyfunctional compound of formula (I), furthex, i,n certain cases such compounds are produced in good yield. An additional advantage of this invention is that ~he novel prod- ' ucts are obtained in readily recoverable form and that 'the novel synthesis or process'permits the formation of the prod-uct without the use of added catalyst. ' ' , ' lS The reaction of the salt of a monoalkyl ester of maleic'acid of formula (II) with the active hydrogen contain-ing compound-of formula (III) proceeds preferably under sub-, stantially anhydrous conditions. The' est~r portion o-f the r ' maleic acid salt will hydrolyze, depending on the amount 'of w,ater present and for this reason water deleteriously affects the y,ie,ld and is therefore best kept at a minimum. This can , ~ be done by drying the reactants and th,e medium before hand by , conventional means.
,' ' ~ Generally, the reaction of the above described com-25 pounds of ormulae (II) and ~III) to produce the novel com-pounds of formula (I) proceeds at elevated temperatures in the ranye of about 25C to 200C and more preferably about : .
.
, , 8 ~
, C.667 C~nada ~5~37 :
100C to 160C. The actual reaction temperature will depend on whether a solvent is employed and the mutuai solubilities of the reactants. Thus, if dimethyl formamide is utilized as the solvent or co-solvent, a temperature as low as room temperature (about 25C) to about 100C can be utilized whereas if the active hydrogen containing compound o formula '(II) is utilized in excess as both solvent and reactant - higher temperatures up to about 200C may be employed. Gen- ' erally while re~lux ~emperatures are normally opera~le, it is desirable to keep the temperature in the range of about ; 100C oo 160C to maintain reasonable reaction rates and to avoid the reverse Michael reaction and other decomposition reactions which tend to take place at higher temperatures.
The time necessary to complete the reaction is not critical. It will depen'd on temperature, on the nature of the reactants, the sblvent used, if any, concentration of the Eeactants and the homogeneity of the system. Generally about one to three hours is'sufficient to obtain maximum yield. In some'cases such as the reaction involving isopropyl glycolate, a'substantial yield results in about one half hour.
The reaction takes place preferably in the li~uid ' pha'se. Generally, the active hydrogen containing compound of'formula (III) is a liquid and wi11 dissolve the mono-' este~ compound of ~ormula ~II). Since an excess of the reac-tant of formula tIII) is beneficial to the reaction it is a , preferred mode as side reactions are minimized and eventual separation o the components is easier. Suitable esters of 'formula ~III), e.g. isopropyl glycolate, isopropyl lactate, isopropyl mandelate, secondary butyl glycolate, secondary ' 30 ~ butyl mandelate, isopropyl alpha hydroxy butyratè and the ' - like may be utilized. Additionally, a cosolvent for both .
_9_ ~52~7 c. 66~ Canada 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) compoùnd and provided the co-solve~t dissolves the reactants sufficiently to facilitate the reaction. Suit- ~
able solvents are,.for example, dimethylformamide, dimethyl- . .
acetamide and dimethyl sulfoxide.
The reaction product obtained by the above proce-: due is the compound of formula (I~, which as.previously stated can be separated from the reaction mixture by con-ventional means.
' The compound of formula (I) ~ay be hydrolyzed under either acidic or basic conditions to obtain either the free acid form or the salt form as represented by formula (IV) as ~ollows:
fH2 - CH - Y- Z (IV) xl X 1 wherein Y represents oxygen but in alternative embodiments' may also represent sulfur or imino ~NH); Z prefexably 20 ... represents . l. the following moiety
Additional compounds and processes are disclosed as alternative embodiments such as, for examplej the sulfur and imino analogs of CMOS as well as selected phenoxy and hydroxyalkoxy derivatives of succinic acid.
Salts of carboxymethyloxysuccinic acid as well as other ether polycarboxylic acid salts, e.g. tri-alkali metal salts, are known detergent builders and have been considered in U.S. Patent No. 3,692,685 and Belgian Patent No. 782,696 granted October 26, 1972.
~'~
, ~
, .
C.667 Canada ~52~37 Generally, these compounds have been prepared by the reaction of the mixed calcium salt of glycolic acid and maleic acid in a~ueous alkaline medium with a subsequent exchange of the calcium cations with the desired metal cation.
The reaction is believed to proceed according to a novel form of the Michael reaction involving a mixed polyvalent metal salt of glycolic and maleic acid as the reacting species.
This reaction takes place in aqueous solution in a critical alkaline pH range and, in addition, requires the presence of polyvalent metal cations in the reaction mixture and thus cannot be carried out with alkali metal salts to the exclu-sion of these polyvalent metal cations.
The Michael reaction referred to above is considered thoroughly in Chapter 3 of Volume lO of a 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 atoms in a system 0 = C-CH- to a carbon-carbon double bond 20 which forms part of a conjugated acceptor system of general ;
I I I
formula -C = C-C = 0. The addition proceeds under the influence of alkaline or basic catalysis.
:,.
. ' .
. ~, ' ~ ,.
C.G~7 Canada .
Inherently in this 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 sys~em. Through the 5 ~ use of this reaction a series of compounds have been pre-pared. 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 an extremely useful organic tool ~or synthesis of selected compounds. Xowever~ disadvantages arise in attempting to prepare certain mixed esters ~y th~s route because of transesterlfication which can take place under the conditions of the Michael reaction thereby produc-ing mixtures of mixed esters in correspondingly diminished yield rather than a single mixed ester in relatively high yleld. Such mixtures, are normally extremely difficult to separate. These difficulties, thus, militate stron~ly Z against the use of the Michael reaction and indeed the appli-cability of this reaction for desired mixed ester products.
Further, when the donor moiety descrlbed above is an alpha hy-droxy ester, the preparation o addition compounds via the Michael . ~ , . .
reaction hecomes impractical because of the -dominance of the ~25 reverse Michael reaction which leads back to either the start-.
ing materials or rearranged starting materials. This is ~ar-; -ticularly true when attempting to add alpha hydroxy ester ' , : , .
.-~ . - ' .
~ ' . .
C.~67 Canada S2~37 compounds across the double bond of maleic esters in the pre-sence of alkaline catalyst.
Accoxdingly, an object of the present invention is to provide a process for producing novel mixed ester compounds by adding alpha hydroxy ester compounds 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 cata-lyst.
;10A further object is to produce compounds which by hydrolysis may be converted to substituted as well as unsub-stituted carboxymethyloxysuccinic acid and salts thereo.
Yet anothèr object of the invention is to provide ;a process for preparing nitrogen and sulfur analogs of sub-L5 stituted and unsubstituted carboxymethyloxysuccinic acid, acid esters and salts thereof.
Other objects and advantages will appear as the description proceeds.
,The attainment of the above ob~ects is made possible by this invention which includes novel compounds as well as a process for their preparation. ~hese novel compounds have the general foxmula (I) as follows:
CH~ - CH Y-Z' ~ Ml x (Ij - ~ COOR COO ~ ) x in which Y represents oxygen but in alternative embodiments may also represent sulfur or imino (NH)~ In ormula (I), Z
preferably represents the ollowing estex moiety:
:
.
, . . .
l~lS2~7 c. 667 Canada ¦-- ¦ 2 -C C--O - R
. _ H _ in which P~l represents isopropyl or secondary butyl, i.e. a propyl or butyl group lin~ed to the oxygen atom by a second-ary carbon atom of the group, such secondary substitution is .
. essential ~o facilitate the formation of the compound of formula (I) without allowing undue transesterification; and in which R2 represents hydrogen as well as a methyl ! ethyl or phenyl group when Y is oxygen or sulfur; and when Y is , :~ imino (NH), ~2 repre~ents hydrogen~ methyl, ethyl, isopropyl, ~::
. isobutyl, secondary butyl, benzyl, p-hydroxybenzyl o~r 2-(meth~lthio)ethyl~ ~lternative embodiments of Z in formula ~ . . .
(I) are the 2-hydroxyethyl or 3-hydroxypropyl groups. R, in formula (I), represents a primary alkyl group of one to six : carbon atoms such as methyl, ethyl~ propyl, butyl, pentyl or hexyl. Ml in for~ula (I) represents hydrogen, calcium, magne- -sium, strontium, barium, sodium, potassium or lithium and x is equivalent to the valency of Ml.
` 20 . A~ditionally, the above objects are attained by the novel process of this invention to prepare the polyfunctional : compounds of formula ~I). This process is preferably sub-.
: stantially anhydrous and includes reacting by heating a salt ,~
of a monoalkyl ester of maleic acid with an active hydrogen 25~ containing compound. The monoalkyl ester salt of maleic acid is of the general formula (II): ~-~ ' '~ ' ~ ' , ' '.
~ -6~
.
.. . . .
.
.
5Z~7 C.6~7 Canada CH ;,ÇH
COOR COOM
in which R is 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 re-present hydrogen whereas in formula (I) ML can represent hydroyen as well as the cations represented by M and thus the two separate designations of M and Ml are utilized. The active hydrogen containing compound is of the' general formula (III) -10 H - Y - Z (III) in which Y and Z are as previously defined.
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 de- ' sc'ribed. This is accomplished with the advantage that such compounds may be easily prepared in good yields suitable for ,:
subsequent conversion into metal sequestering agents, prefer- ~
ably into salts of car~oxymethyloxysucclnic acid. ~ ;
' The invention is hereinafter set forth in more de-tails, 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 substan*i-ally anhydrous conditions with a compound o'f formula (III) at , 25 an elevated temperature to form a reaction product which is .. . ..
the polyfunctional cbmpound of formula (I).
' The desired reaction product is soluble in the reac- ' .
tion mixture. It can be readily recovered from the reaction mixture by conventional methods such as for example insolu-' 30 bilizing liquld, for example, ethyl ether. Upon the addition ., , ' ' ' .
C.667 C~nad~
~5iZ~37 of a sufficient amount of such an insolubilizing liquid, the product crystallizes out of solution and is readily separated from the reaction media by conventional means. Upon filtra-tion or vacuum distillation, washing, recrystallization if desired and drying, the desired product may be obtained in purer form. The recovered product is sufficiently pure for conversion to the corresponding metal sequestrant salt.
The present invention permits the synthesis of the desired polyfunctional compound of formula (I), furthex, i,n certain cases such compounds are produced in good yield. An additional advantage of this invention is that ~he novel prod- ' ucts are obtained in readily recoverable form and that 'the novel synthesis or process'permits the formation of the prod-uct without the use of added catalyst. ' ' , ' lS The reaction of the salt of a monoalkyl ester of maleic'acid of formula (II) with the active hydrogen contain-ing compound-of formula (III) proceeds preferably under sub-, stantially anhydrous conditions. The' est~r portion o-f the r ' maleic acid salt will hydrolyze, depending on the amount 'of w,ater present and for this reason water deleteriously affects the y,ie,ld and is therefore best kept at a minimum. This can , ~ be done by drying the reactants and th,e medium before hand by , conventional means.
,' ' ~ Generally, the reaction of the above described com-25 pounds of ormulae (II) and ~III) to produce the novel com-pounds of formula (I) proceeds at elevated temperatures in the ranye of about 25C to 200C and more preferably about : .
.
, , 8 ~
, C.667 C~nada ~5~37 :
100C to 160C. The actual reaction temperature will depend on whether a solvent is employed and the mutuai solubilities of the reactants. Thus, if dimethyl formamide is utilized as the solvent or co-solvent, a temperature as low as room temperature (about 25C) to about 100C can be utilized whereas if the active hydrogen containing compound o formula '(II) is utilized in excess as both solvent and reactant - higher temperatures up to about 200C may be employed. Gen- ' erally while re~lux ~emperatures are normally opera~le, it is desirable to keep the temperature in the range of about ; 100C oo 160C to maintain reasonable reaction rates and to avoid the reverse Michael reaction and other decomposition reactions which tend to take place at higher temperatures.
The time necessary to complete the reaction is not critical. It will depen'd on temperature, on the nature of the reactants, the sblvent used, if any, concentration of the Eeactants and the homogeneity of the system. Generally about one to three hours is'sufficient to obtain maximum yield. In some'cases such as the reaction involving isopropyl glycolate, a'substantial yield results in about one half hour.
The reaction takes place preferably in the li~uid ' pha'se. Generally, the active hydrogen containing compound of'formula (III) is a liquid and wi11 dissolve the mono-' este~ compound of ~ormula ~II). Since an excess of the reac-tant of formula tIII) is beneficial to the reaction it is a , preferred mode as side reactions are minimized and eventual separation o the components is easier. Suitable esters of 'formula ~III), e.g. isopropyl glycolate, isopropyl lactate, isopropyl mandelate, secondary butyl glycolate, secondary ' 30 ~ butyl mandelate, isopropyl alpha hydroxy butyratè and the ' - like may be utilized. Additionally, a cosolvent for both .
_9_ ~52~7 c. 66~ Canada 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) compoùnd and provided the co-solve~t dissolves the reactants sufficiently to facilitate the reaction. Suit- ~
able solvents are,.for example, dimethylformamide, dimethyl- . .
acetamide and dimethyl sulfoxide.
The reaction product obtained by the above proce-: due is the compound of formula (I~, which as.previously stated can be separated from the reaction mixture by con-ventional means.
' The compound of formula (I) ~ay be hydrolyzed under either acidic or basic conditions to obtain either the free acid form or the salt form as represented by formula (IV) as ~ollows:
fH2 - CH - Y- Z (IV) xl X 1 wherein Y represents oxygen but in alternative embodiments' may also represent sulfur or imino ~NH); Z prefexably 20 ... represents . l. the following moiety
2 11 . . _ -C--C- M 1 , ' .
25 which may b'e either a carboxylic moiety when Mlis H or a. .~
carboxylate moiety when Mlrepresents sodium, potassium, .
'' ' . ' . ' ' :''':
.
'' ' ' ' ~
-10- , .
', ' ' ' ~152~7 C.~67 Canada lithium, calcium, magnesium, barium or strontium wherein R2 - ;
is hydrogen, methyl, ethyl or phenyl and x is 1 when Ml is hydrogen or alkali metal and 2 when ~lis alkaline earth metal, or -5 2. 2-hydroxyethyl or 3-hydroxypropyl.
Desirably alkaline hydrolysis may be carried out by different methods depending on the cation desired in the final hydrolyzed product~ When ~he cation Mlassociated ...
with the compound of formula (I) is alkaline earth it is . : :
first desirable to replace this cation wlth hydrogen by ~ ;
conventional treatment with an ion exchange resin or with .~ :
an alkali metal by treatment with an aqueou~ soIution of an alkali metal carbonate which exchanges the cation and preci- i pitates the alkaline earth metal as the carbonate which can then be removed by filtration. If sufficient alkali metal carbonate is used, then upon heating the aqueous mixture all of the ester groups are hydrolyzed while at the same - ~ time the alkaline earth metal carbonate is precipitated. ~ :
Alternatively, the compound of formula (I) whereln M1 is H, obtained by treatment with ion exchange resin as descri~ed above, may be further treated with an alkal.i metal hydroxide .
to neutralize the free carboxyl.group and to hydrolyze the remaining ester groups.
In another embodiment when M is alkaline earth , ' - . 1 : :
.metal cation in the compound of formula (I) the ester groups may be hydrolyzed directly with an alkaline earth metal hydroxide to produce the corresponding alkaline earth metal -. salts of formula (IV) which in turn may be conventionally -11- ' .
. . . - .
~ . . : .
'. , . ' :':
, . ~.
.
- i , . ~, . , : .: ' :
~15Z87 c. ~7 Canada treated with ion exchange resins to achieve the free acid form of formula (IV). In the special case ~lhere ~Il o formula (I) is Ba, Ca or Sr the compound may be acidified : with a stoichiometric amount o sulfuric acid to precipi-tate the alkaline earth metal sulfate which may then be filtered off to leave behind the compound of formula (I) here Ml is H. This formula (I) compound may then be txeated as described above to produce the acid and salt .forms of formula (IV).
. Alkaline hydrolysis is accomplished ~y heating the ; compounds'of formula (I) with an alkali or alkaline earth metal, hydroxide or alkali metal carbonate. ~he basic hy-drolys.is is carried out at a temperature of ahout.25C to about 100C, preferably ~0C to 60C.
The pH of this hydrolysis is 9 to 12 and prefer- .
ahly 10 to 11.
The compounds of formula (IV) wherein Mlis H may he obtained in bolutions having.a concentration of about 1 : to 50% by weight,preferably about 10 to 30% by weight, directly by aoid hydrolysis of the compounds'of formula (I). ..
This hydrolysis is accomplished by using about a O.S to 2~ .
by weight solution of a mineral acid such as, for example, hydrochloric, sulfuric, phosphoric and the like, preferably : -; ' sulfuric to facilitate separation. The temperatures utilized are generally.about 25C to 100C preferably 50C to 100C. ..
The amount of acid required must be enough to neutralize the a1kali metal or alkaline earth metal of formula (I) and tô
: ' , . . , ' -12- .
.~ ' , ' ' ' ' . ' .
' ' , . ' ' ' .
~15Z~7 c. 667 Canada provide an excess to catalyze the hydrolysis. This excess ; calculated on an anhydrous basis is generally about 10% by . weight of the compound of formula ~I) used. Isolation of the formula (IV~ compound wherein M1is H ls carried out after neutrali2ation of the excess mineral acid utilized by conventional techniques such as solvent precipitation, - evaporation of the solution to dryness followed by extrac-tion by a suitable solvent such as acetone, ethyl ether and the like. The preferred temperature and pH ranges are used lQ to obtain reasonable reaction rates and to avoid revexse Michael reactions. Isolation of the salts of formula (I~) obtained as described above is carried out by conventional techniques such as solvent precipitation, drying and re-crystallization from suitable solvents such as alcohol-water.
The salts of the monoalkyl ester of maleic acid [formula (II)] employed in the process of this invention are pre.pared 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 6 carbon atoms, for example, methanol, ethanol, propanol, butanol, pentanol or hexanol.
More specifically, maleic anhydride may be dissolved in the alcohol either at room temperature or by heating at an ele-~; ~ vated temperature, e.g. 50C to 60C. Addition of the appro-- 25 priate base, i.e. alkali metal or alkaline earth metal hy-. .
droxide such as sodium or potassium hydroxide or magnesium .
.
; , ' .................................................... ~:
' ~$~5~7 c. 66~ Canada harium, strontium or calcium hydroxide to a p~I 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 technlques, e.g. distilling off the alcohol under reduced pressure, or crystallization from the appro-~ prlate alcohol.
: . The active hydrogen containing compounds of formula ~III) are known compounds~ Glycolate esters are particularly preferred wherein the substituents of formula tIII) are as . follows: .
Y is oxygen, R1 is isopropyl or secondary butyl and R2 is hydrogen, methyl, ethyl or phenyl.
In addition, according to another embodim~nt of the -lS invention, analogs of carboxymethyloxysuccinic ac.id can also : .:
- be prepared with the instant process by utilizing other ac-tive hydrogen conta.ining compounds such as alpha-hydroxy car-: boxylic esters, alpha-amino carboxylic esters and alpha-thiol carboxylic esters in place of the glycolate esters described above-~ Examples of other alpha-hydroxy carboxylic esters ; which can be employed in the practice of this invention are .
esters derived from lactic acid, alpha-hydroxy butyric acid ~.
. and mandelic acid~
: ~ . . . .
The rlitrogen analogs of the compound of. formula (I~
that can be prepared by the process.of this invention are prepared from esters of alpha-amino carboxylLc acids, for example, esters derived from ~lycine, alanine, valinej leucine, .' . ~
~ -14- . :
~.:
.
C.6G7 Canada ~ leucine, phenylalanine, tyrosine, methionine and the like.
It will be readily understood that when the esters of alpha amino acids (i.e., for example, the above series glycine through methionine inclusive) are used, ~2 in formula (I) 5- will represent, respectively, hydrogen, methyl, isopropyl, isobutyl, secondary butyl, benzyl, p hydroxybenæyl or 2-(methylthio)ethyl groups~
- The sulfur analogs can be prepared by substituting alpha-thiol carboxylic esters, for example, esters of thio-glycolic acid also referred ~o as mercapto acetic acid, in place of the glycolate esters described above.
Representative compounds of ~ormula (I) prepared according to the process of the invention lnclude 1. Sodium [(l-carboisopropoxy-3-carboxylate-4-carbomethoxy)-2-oxabutane] ;
CH2--ICl:I -O--CH2--COOCH(CH3)2 COOCH 3 COONa 2. Potassium [(l-carboisopropoxy-3-caxboxylate-4-carbomethoxy~-2-oxabutanel ~ -CIH2 CH CH2 COOCH(CH3)
25 which may b'e either a carboxylic moiety when Mlis H or a. .~
carboxylate moiety when Mlrepresents sodium, potassium, .
'' ' . ' . ' ' :''':
.
'' ' ' ' ~
-10- , .
', ' ' ' ~152~7 C.~67 Canada lithium, calcium, magnesium, barium or strontium wherein R2 - ;
is hydrogen, methyl, ethyl or phenyl and x is 1 when Ml is hydrogen or alkali metal and 2 when ~lis alkaline earth metal, or -5 2. 2-hydroxyethyl or 3-hydroxypropyl.
Desirably alkaline hydrolysis may be carried out by different methods depending on the cation desired in the final hydrolyzed product~ When ~he cation Mlassociated ...
with the compound of formula (I) is alkaline earth it is . : :
first desirable to replace this cation wlth hydrogen by ~ ;
conventional treatment with an ion exchange resin or with .~ :
an alkali metal by treatment with an aqueou~ soIution of an alkali metal carbonate which exchanges the cation and preci- i pitates the alkaline earth metal as the carbonate which can then be removed by filtration. If sufficient alkali metal carbonate is used, then upon heating the aqueous mixture all of the ester groups are hydrolyzed while at the same - ~ time the alkaline earth metal carbonate is precipitated. ~ :
Alternatively, the compound of formula (I) whereln M1 is H, obtained by treatment with ion exchange resin as descri~ed above, may be further treated with an alkal.i metal hydroxide .
to neutralize the free carboxyl.group and to hydrolyze the remaining ester groups.
In another embodiment when M is alkaline earth , ' - . 1 : :
.metal cation in the compound of formula (I) the ester groups may be hydrolyzed directly with an alkaline earth metal hydroxide to produce the corresponding alkaline earth metal -. salts of formula (IV) which in turn may be conventionally -11- ' .
. . . - .
~ . . : .
'. , . ' :':
, . ~.
.
- i , . ~, . , : .: ' :
~15Z87 c. ~7 Canada treated with ion exchange resins to achieve the free acid form of formula (IV). In the special case ~lhere ~Il o formula (I) is Ba, Ca or Sr the compound may be acidified : with a stoichiometric amount o sulfuric acid to precipi-tate the alkaline earth metal sulfate which may then be filtered off to leave behind the compound of formula (I) here Ml is H. This formula (I) compound may then be txeated as described above to produce the acid and salt .forms of formula (IV).
. Alkaline hydrolysis is accomplished ~y heating the ; compounds'of formula (I) with an alkali or alkaline earth metal, hydroxide or alkali metal carbonate. ~he basic hy-drolys.is is carried out at a temperature of ahout.25C to about 100C, preferably ~0C to 60C.
The pH of this hydrolysis is 9 to 12 and prefer- .
ahly 10 to 11.
The compounds of formula (IV) wherein Mlis H may he obtained in bolutions having.a concentration of about 1 : to 50% by weight,preferably about 10 to 30% by weight, directly by aoid hydrolysis of the compounds'of formula (I). ..
This hydrolysis is accomplished by using about a O.S to 2~ .
by weight solution of a mineral acid such as, for example, hydrochloric, sulfuric, phosphoric and the like, preferably : -; ' sulfuric to facilitate separation. The temperatures utilized are generally.about 25C to 100C preferably 50C to 100C. ..
The amount of acid required must be enough to neutralize the a1kali metal or alkaline earth metal of formula (I) and tô
: ' , . . , ' -12- .
.~ ' , ' ' ' ' . ' .
' ' , . ' ' ' .
~15Z~7 c. 667 Canada provide an excess to catalyze the hydrolysis. This excess ; calculated on an anhydrous basis is generally about 10% by . weight of the compound of formula ~I) used. Isolation of the formula (IV~ compound wherein M1is H ls carried out after neutrali2ation of the excess mineral acid utilized by conventional techniques such as solvent precipitation, - evaporation of the solution to dryness followed by extrac-tion by a suitable solvent such as acetone, ethyl ether and the like. The preferred temperature and pH ranges are used lQ to obtain reasonable reaction rates and to avoid revexse Michael reactions. Isolation of the salts of formula (I~) obtained as described above is carried out by conventional techniques such as solvent precipitation, drying and re-crystallization from suitable solvents such as alcohol-water.
The salts of the monoalkyl ester of maleic acid [formula (II)] employed in the process of this invention are pre.pared 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 6 carbon atoms, for example, methanol, ethanol, propanol, butanol, pentanol or hexanol.
More specifically, maleic anhydride may be dissolved in the alcohol either at room temperature or by heating at an ele-~; ~ vated temperature, e.g. 50C to 60C. Addition of the appro-- 25 priate base, i.e. alkali metal or alkaline earth metal hy-. .
droxide such as sodium or potassium hydroxide or magnesium .
.
; , ' .................................................... ~:
' ~$~5~7 c. 66~ Canada harium, strontium or calcium hydroxide to a p~I 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 technlques, e.g. distilling off the alcohol under reduced pressure, or crystallization from the appro-~ prlate alcohol.
: . The active hydrogen containing compounds of formula ~III) are known compounds~ Glycolate esters are particularly preferred wherein the substituents of formula tIII) are as . follows: .
Y is oxygen, R1 is isopropyl or secondary butyl and R2 is hydrogen, methyl, ethyl or phenyl.
In addition, according to another embodim~nt of the -lS invention, analogs of carboxymethyloxysuccinic ac.id can also : .:
- be prepared with the instant process by utilizing other ac-tive hydrogen conta.ining compounds such as alpha-hydroxy car-: boxylic esters, alpha-amino carboxylic esters and alpha-thiol carboxylic esters in place of the glycolate esters described above-~ Examples of other alpha-hydroxy carboxylic esters ; which can be employed in the practice of this invention are .
esters derived from lactic acid, alpha-hydroxy butyric acid ~.
. and mandelic acid~
: ~ . . . .
The rlitrogen analogs of the compound of. formula (I~
that can be prepared by the process.of this invention are prepared from esters of alpha-amino carboxylLc acids, for example, esters derived from ~lycine, alanine, valinej leucine, .' . ~
~ -14- . :
~.:
.
C.6G7 Canada ~ leucine, phenylalanine, tyrosine, methionine and the like.
It will be readily understood that when the esters of alpha amino acids (i.e., for example, the above series glycine through methionine inclusive) are used, ~2 in formula (I) 5- will represent, respectively, hydrogen, methyl, isopropyl, isobutyl, secondary butyl, benzyl, p hydroxybenæyl or 2-(methylthio)ethyl groups~
- The sulfur analogs can be prepared by substituting alpha-thiol carboxylic esters, for example, esters of thio-glycolic acid also referred ~o as mercapto acetic acid, in place of the glycolate esters described above.
Representative compounds of ~ormula (I) prepared according to the process of the invention lnclude 1. Sodium [(l-carboisopropoxy-3-carboxylate-4-carbomethoxy)-2-oxabutane] ;
CH2--ICl:I -O--CH2--COOCH(CH3)2 COOCH 3 COONa 2. Potassium [(l-carboisopropoxy-3-caxboxylate-4-carbomethoxy~-2-oxabutanel ~ -CIH2 CH CH2 COOCH(CH3)
3. Calclum bisl(l-carboisopropoxy-3-carboxylate-
4-carbomethoxy)-2-oxabutane~
r7~2 fH - O - CEI2 - COOCH tCH3) 2~ ~+
. LCOOCH3 COO- 2 .
4. Magnesium bis~ carboisopropoxy-3-carboxylate- `~
4-carbomethoxy)-2-oxabutane]
r IH2 7H O CH2 - COOCH(CH3)2]
3Q 5. Sodium [(2-carboisopropoxy-4-carboxyldte-5-carbomethoxy)-3-oxapentane]
CH2 - CH - O - IH - COOCH(CH3)2 COOCU3 COONa C~3 .
' C,6G7 Canad~
.
6. Potassium [(2~carboisopropoxy-4-carboxylate~5-.~ carbomethoxy)-3-oxapentane]
.~ CH~ CH - O fH COOCH(CH3)2 . 5 7. Calcium bis[(2-carboisopropoxy-~-carboxylate-~ 5-carbomethoxy)-3-oxapentane]
i: rfH2 - fH - O - f~_ COOCH(CH3)21 ++
~COOCH3 COO CH3 ~ 2 8. Magnesium bis[(2-carboisopropoxy-4-carboxylate-I0 5-carbometho~y)-3-oxapentane]
' ~H2 - fH - O - fH - COOCH(CH3)2 ~ ~+
LCOOCH3 COO~ CH3 2 . 9. Sodium E (3~carboisopropoxy-5-c.arboxylate-6-carbo-i': ' met~oxy)-4-oxahexane]
.5 CH2 --- CH--O--CH--COOCH (CH3) 2 . ~OOCH3 COONa 1 2 . H3 . . 10. Potassium ~(3-carboisopropoxy-5-carboxylate-6- .
~: carbomethoxy)-4-oxahexane]
;, . . . ~. .
~ 20 ~ CH2 - fH_o~_ ICH_ COOCH(CH3)2 ~; COOCH3 COOK I 2 ~
: ~H3 .. 11. Calcium bis[(3-carboisopropoxy-~-carboxylate~-6-carbomethoxy)-4-oxahexane~
:~ 25 [fH2 - fH - O - fH COOCH(CH3)2 ] ++
: 12. Magnesium bis~(3-carboisopropoxy-5-carboxylate- :
6-carbomethoxy)-4-oxahexane]
., , ~ : -16-:; : ' ~: " ' ` ' ' : "
,~.' ' ' ' " ', ':
~1152~7 C . ~67 Cana~a _ _ fH2 F~l ~ H --COOCH(CH3)2 Mg 13. Sodium [(l-phenyl-l-carboisopropoxy-3-carboxyl-ate-4-carbomethoxy)-2-oxabutane]
~ 5 fH2 - CH - O fH COOCH(CH3)2 ; COOCH3 COONa.
14. Calcium bis~ phenyl-l-carboisopropoxy-3-carboxylate-4-carbomethoxy-2-oxabutane] -. CH2 - fH - O - fH - COOCH(CH3)2 Ca COOCH3 COO 0 _ 2 . 15. Sodium ~ carboisopropoxy-3-carboxylate-4-; carbomethoxy)-2-azabutane~
fH2 fH NH - CH2COOCH(CH3)2 COOCH3 COONa 16. Sodium [(2-carboisopropoxy-4-carboxylate-5~ .
carbomethoxy)-3-azapentane].
: fH .
ICH2 CH - MH - CHCOOCH(CH3)2 COOCH3 COONa .
17. Calcium bis[(l-carboisopropoxy-3-carboxylate 4-carbomethoxy)-2-azabutane]
rfH2 - CIH - NH CH2COOCHtCH3)~
. LCOOCH3 COO 2 18. Calcium bis~ carboisopropoxy-3-carboxylate-4-carbomethoxy~-2-thiabutane3 [fH2 - fH - S - CH2 CoocH(c~I3?2~ Ca~
: OOCH~ COO . 2 . ' ~, - ' ' ' .
- ' ' ' .' . ;:
~5~7 C.~67 Canada 19. Calcium bis[methyl (l-phenaza)succinate3 ~H2 - jH - NE~ - 0 ] C ~~
20. Calcium bis[~l-hydroxy-4-carboxylate-5-carbo-methoxy)-3-oxapentane _ CH~ - CH -O -CH2CH2OH Ca ; 21. Calcium bis[(l~carboisopropoxy-3-carboxylate-4-carbomethoxy)-2-oxabutane]
lQ rf CH - O CH2 - COOCH(CH3)2] Ca~
~COOCH2CH3COO 2 The following examples will more fully illustrate the embodiments of this inventLon. All parts and proportions referred to herein and in the appended claims are by weight - unless otherwise indicated.
, ' , '~ .. ~ ' . ' ' EXAMPLE I
.
A. PREPAR~TION OF ISOPROPYL_G YCOLAl~ `
100 grams of glycolic acid is dissolved in 250 ml -~ 20 o~ isopropanol containing 15 ml of~concentrated sulfuric acid.
The solution is refluxed for 10 hours, neutralized with cal-c~um carbonate to pH 6 and then filtered to remove the pre-; ~ cipitated ca1cium sulfate. The filtrate is then evapoxated i on the hot water bath at reduced pressure to remove excess 25 ; isopropanol and the residue dis~illed in ~acuo to give the product, isopropyl glycolate, b.p. 75-80C (30 mm3.
' .' ~
, ~15~7 C.667 Canada , Sec-butyl glycolate is prepared in the same manner as above but using sec-butanol in place of the isopropanol.
B. PREPARATION OF CA~CIUM BIS~METHYL M~ATE) CH CH
COOCH3 COO Ca One mole of maleic anhydride is dissolved with stir-- ring in 1000 ml methanol at 50~60C. The mixture is cooled to 25C and with the aid of a pH meter, the p~l is adjusted to 8.6 with calcium hydroxide while maintairling the temperature below 25C 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. PR~PA~ATION OF CA~CIUM BIS[(l-CARBOISOPROPOXY-3-CARBOXYLATE
-4-CARBOMETHOXY)-2-OXABUTANE]
, 200 grams (1.7 moles) of isopropyl glycolate and 50 grams ~0.33 moles) of calcium bis(methyl maleate) are first heated to 100C to dissolve the salt. The reaction mixture is ;
then heated to reflux (150~C) for 2 hours. After cooling the reaction to room temperature, ether is added to the solution to precipitate a solid material which is filtered and washed with ether; 47 g of solid (Product A~ is obtained. The ether layer also contains additional product in the form of the acid.
.
The ether solution is evaporated on a roto evaporator and the resulting viscous liquid is dissolved in water and neukralized to a pH of 7.0 with calcium hydroxi-de to form the saltO The wa~er is removed on the roto evaporator, the residue taken up in ether and the precipitated soIid filtered; -19 g of product (Product B~ is obtained. NMR analysis o Products A and B
, - . .
.
. ' ' . ~
,.
' .
~152~7 C.667 Canada using potassium acid phthalate as an internal standard con-firmed that Product A contained 92.5% of the aesired product and Product B contained 80.7% of the desired product. The total yield of the desired product, i.e. calcium bis[(l-car-boisopropoxy-3-carboxyla~e-4-carbomethoxy)-2-oxabutane] is 66 .
g total o~ Products A and B, which is 66.7% actual yield.
D. PREPARATION OF THE TRISODIUM SALT OF CARBOX~METHYLOXY-SUCCINIC ACID BY SAPONIFICATION OF CALCIUM BIS~ CAR-BOISOPROPOXY-3-CARBOXYLATE-4-CARBOMETHOXY)-OXABUTANE-2]
_ _ _ .................................. .
Three grams (0.011 mole) of calcium bis[(l-carbo-isopropoxy-3-carboxylate-4-carbomethoxy)-2-oxabutane~ (Product A from step B above~ is saponified using 0.048 mole sodium hy-droxide. ~fter heating to 50C for 2-3 hours, the solution is neutralized to pH 7 with H2SO~ to precipitate calcium as CaSO~.
Sodium carbonate (0.5 g) is then added to raise the pH to 8.6 and to precipitate out any remaining calcium as calcium car- -bonate. The solution is filtered and the fitrate is evaporated to dryness. The trisodium salt of carboxymethyloxysuccinic .. . . .
acid is obtained in a yield of 2.7 g; the NMR of this product is identical to that of the trisodium salt obtained by the preparative method disclosed in U.S. 3,692,685.
-..
E. PREPARATION OF CALCIUM BIS~(l-CARBOISOPROPOXY-3-CARBOXYLATE
-4-CARBOMETHOXY)-2-OXABUTANE]
- The product of B above is prepared in the same manner excep~ that certain parameters are changed. The mole ratio of ` ~ maleate to glycolate is 0.17:1, calcium hydroxide solution is -added to the reaction mixture to a pH of 8.6 and the reaction .:
.
- ' ' ~
~5z~7 C.~,~;7 Canada r.
is run for 2-3 hours. The solid product which precipitates ,- out on addition of ether contains 87.7~ of calcium bisE(1-.. carboisopropoxy-3-car~oxylate-4-car~omethoxy)-2-oxabutane~
and the viscous liquid product contains 71~8% o the mono-S acid product. The total yield of product calculated as the , . . .
calcium salt is 69.2% of the theoreticalr ~:~
~ .
, ',, ' : .
. . . .
, ' .
', , '.
~ . ' I
r , : .
.~, ~, . ,' ' .
~' ~ . '' . ' , ' , ' ' ' , .
' ' . ' ' .
~' " ' ' ' ' .
~, ' ', '' '. ~'.
'' ~
~' i .' , . . .
.' , , " . '.
.
' ' ,,, ' ' ~' ' , ' ' ~ ' ' ' ' ,.
- , ~
, .
,: . . ... . :
` ~115~87 c. GG7 Canada .
EXAMPLE II
_ .
A. PREPARATION OF M~GNESIUM BIS(~THYL MALE~TE) Fif-ty grams of maleic anhydride is dissolved in 200 .
ml methanol and magnesium hydroxide is added to a pH of 7.3.
The solution is filtered, the methanol is distilled of~ and the product is dried under vacuum. An NMR analysis of the product taken using potassium acid phthalate as the standard indicates that the product contains 78.7% magnesium bis- .
(methyl maleate).
B. MAGNESIUM BIS[(l-CARBOISOPROPOXY-3-CARBOXYLAT~-4-CARBO- .
METHOXY)-2-OXABUTANE]
Five grams (0.03 moles) of dried magnesium bis-~methyl maleate), the dired product from A above ha~ing an . .
.85.3% purity is placed into 11 grams of isopropyl glycolate :
15and the solution is heated to 85-90C for 2 hours and then to 100-105C for one hour. The excess glycolate is removed under.vacuum.and the r.~sidue is extracted twice with ether ~.~
leaving the èther insoluble solid product. Seven grams of ...
.
.this solid, magnesium bis~ carboisopropoxy-3-carboxylate-4-carbomethoxy)-2-oxabutane], is obtained; evaporation of . the combined ether extracts affords 2.1 grams of a liquid :: .
.. . .
5Z.5% product as the acid. .This acid can in turn be con- . ... ~:::
verted to the desired magnesium salt product by neutraliza-` tion with Mg(OH)2. The total yield of product is 80~ of .theory based on the dry s:olid salt and the acid ass~ming 100% conversion of the acid to the saitupon neutralization.
. . ...
-.'~ :
.
!
' ' .
~'"' , ' ' . , ~:' ~:
C.6~J7 Canada S~
~ .
EXAMPLE III
PREPARATION 0~ MAGNESIUM BIS~(2-CARBOISOPROPOXY-4-CARBOXYLATE-
r7~2 fH - O - CEI2 - COOCH tCH3) 2~ ~+
. LCOOCH3 COO- 2 .
4. Magnesium bis~ carboisopropoxy-3-carboxylate- `~
4-carbomethoxy)-2-oxabutane]
r IH2 7H O CH2 - COOCH(CH3)2]
3Q 5. Sodium [(2-carboisopropoxy-4-carboxyldte-5-carbomethoxy)-3-oxapentane]
CH2 - CH - O - IH - COOCH(CH3)2 COOCU3 COONa C~3 .
' C,6G7 Canad~
.
6. Potassium [(2~carboisopropoxy-4-carboxylate~5-.~ carbomethoxy)-3-oxapentane]
.~ CH~ CH - O fH COOCH(CH3)2 . 5 7. Calcium bis[(2-carboisopropoxy-~-carboxylate-~ 5-carbomethoxy)-3-oxapentane]
i: rfH2 - fH - O - f~_ COOCH(CH3)21 ++
~COOCH3 COO CH3 ~ 2 8. Magnesium bis[(2-carboisopropoxy-4-carboxylate-I0 5-carbometho~y)-3-oxapentane]
' ~H2 - fH - O - fH - COOCH(CH3)2 ~ ~+
LCOOCH3 COO~ CH3 2 . 9. Sodium E (3~carboisopropoxy-5-c.arboxylate-6-carbo-i': ' met~oxy)-4-oxahexane]
.5 CH2 --- CH--O--CH--COOCH (CH3) 2 . ~OOCH3 COONa 1 2 . H3 . . 10. Potassium ~(3-carboisopropoxy-5-carboxylate-6- .
~: carbomethoxy)-4-oxahexane]
;, . . . ~. .
~ 20 ~ CH2 - fH_o~_ ICH_ COOCH(CH3)2 ~; COOCH3 COOK I 2 ~
: ~H3 .. 11. Calcium bis[(3-carboisopropoxy-~-carboxylate~-6-carbomethoxy)-4-oxahexane~
:~ 25 [fH2 - fH - O - fH COOCH(CH3)2 ] ++
: 12. Magnesium bis~(3-carboisopropoxy-5-carboxylate- :
6-carbomethoxy)-4-oxahexane]
., , ~ : -16-:; : ' ~: " ' ` ' ' : "
,~.' ' ' ' " ', ':
~1152~7 C . ~67 Cana~a _ _ fH2 F~l ~ H --COOCH(CH3)2 Mg 13. Sodium [(l-phenyl-l-carboisopropoxy-3-carboxyl-ate-4-carbomethoxy)-2-oxabutane]
~ 5 fH2 - CH - O fH COOCH(CH3)2 ; COOCH3 COONa.
14. Calcium bis~ phenyl-l-carboisopropoxy-3-carboxylate-4-carbomethoxy-2-oxabutane] -. CH2 - fH - O - fH - COOCH(CH3)2 Ca COOCH3 COO 0 _ 2 . 15. Sodium ~ carboisopropoxy-3-carboxylate-4-; carbomethoxy)-2-azabutane~
fH2 fH NH - CH2COOCH(CH3)2 COOCH3 COONa 16. Sodium [(2-carboisopropoxy-4-carboxylate-5~ .
carbomethoxy)-3-azapentane].
: fH .
ICH2 CH - MH - CHCOOCH(CH3)2 COOCH3 COONa .
17. Calcium bis[(l-carboisopropoxy-3-carboxylate 4-carbomethoxy)-2-azabutane]
rfH2 - CIH - NH CH2COOCHtCH3)~
. LCOOCH3 COO 2 18. Calcium bis~ carboisopropoxy-3-carboxylate-4-carbomethoxy~-2-thiabutane3 [fH2 - fH - S - CH2 CoocH(c~I3?2~ Ca~
: OOCH~ COO . 2 . ' ~, - ' ' ' .
- ' ' ' .' . ;:
~5~7 C.~67 Canada 19. Calcium bis[methyl (l-phenaza)succinate3 ~H2 - jH - NE~ - 0 ] C ~~
20. Calcium bis[~l-hydroxy-4-carboxylate-5-carbo-methoxy)-3-oxapentane _ CH~ - CH -O -CH2CH2OH Ca ; 21. Calcium bis[(l~carboisopropoxy-3-carboxylate-4-carbomethoxy)-2-oxabutane]
lQ rf CH - O CH2 - COOCH(CH3)2] Ca~
~COOCH2CH3COO 2 The following examples will more fully illustrate the embodiments of this inventLon. All parts and proportions referred to herein and in the appended claims are by weight - unless otherwise indicated.
, ' , '~ .. ~ ' . ' ' EXAMPLE I
.
A. PREPAR~TION OF ISOPROPYL_G YCOLAl~ `
100 grams of glycolic acid is dissolved in 250 ml -~ 20 o~ isopropanol containing 15 ml of~concentrated sulfuric acid.
The solution is refluxed for 10 hours, neutralized with cal-c~um carbonate to pH 6 and then filtered to remove the pre-; ~ cipitated ca1cium sulfate. The filtrate is then evapoxated i on the hot water bath at reduced pressure to remove excess 25 ; isopropanol and the residue dis~illed in ~acuo to give the product, isopropyl glycolate, b.p. 75-80C (30 mm3.
' .' ~
, ~15~7 C.667 Canada , Sec-butyl glycolate is prepared in the same manner as above but using sec-butanol in place of the isopropanol.
B. PREPARATION OF CA~CIUM BIS~METHYL M~ATE) CH CH
COOCH3 COO Ca One mole of maleic anhydride is dissolved with stir-- ring in 1000 ml methanol at 50~60C. The mixture is cooled to 25C and with the aid of a pH meter, the p~l is adjusted to 8.6 with calcium hydroxide while maintairling the temperature below 25C 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. PR~PA~ATION OF CA~CIUM BIS[(l-CARBOISOPROPOXY-3-CARBOXYLATE
-4-CARBOMETHOXY)-2-OXABUTANE]
, 200 grams (1.7 moles) of isopropyl glycolate and 50 grams ~0.33 moles) of calcium bis(methyl maleate) are first heated to 100C to dissolve the salt. The reaction mixture is ;
then heated to reflux (150~C) for 2 hours. After cooling the reaction to room temperature, ether is added to the solution to precipitate a solid material which is filtered and washed with ether; 47 g of solid (Product A~ is obtained. The ether layer also contains additional product in the form of the acid.
.
The ether solution is evaporated on a roto evaporator and the resulting viscous liquid is dissolved in water and neukralized to a pH of 7.0 with calcium hydroxi-de to form the saltO The wa~er is removed on the roto evaporator, the residue taken up in ether and the precipitated soIid filtered; -19 g of product (Product B~ is obtained. NMR analysis o Products A and B
, - . .
.
. ' ' . ~
,.
' .
~152~7 C.667 Canada using potassium acid phthalate as an internal standard con-firmed that Product A contained 92.5% of the aesired product and Product B contained 80.7% of the desired product. The total yield of the desired product, i.e. calcium bis[(l-car-boisopropoxy-3-carboxyla~e-4-carbomethoxy)-2-oxabutane] is 66 .
g total o~ Products A and B, which is 66.7% actual yield.
D. PREPARATION OF THE TRISODIUM SALT OF CARBOX~METHYLOXY-SUCCINIC ACID BY SAPONIFICATION OF CALCIUM BIS~ CAR-BOISOPROPOXY-3-CARBOXYLATE-4-CARBOMETHOXY)-OXABUTANE-2]
_ _ _ .................................. .
Three grams (0.011 mole) of calcium bis[(l-carbo-isopropoxy-3-carboxylate-4-carbomethoxy)-2-oxabutane~ (Product A from step B above~ is saponified using 0.048 mole sodium hy-droxide. ~fter heating to 50C for 2-3 hours, the solution is neutralized to pH 7 with H2SO~ to precipitate calcium as CaSO~.
Sodium carbonate (0.5 g) is then added to raise the pH to 8.6 and to precipitate out any remaining calcium as calcium car- -bonate. The solution is filtered and the fitrate is evaporated to dryness. The trisodium salt of carboxymethyloxysuccinic .. . . .
acid is obtained in a yield of 2.7 g; the NMR of this product is identical to that of the trisodium salt obtained by the preparative method disclosed in U.S. 3,692,685.
-..
E. PREPARATION OF CALCIUM BIS~(l-CARBOISOPROPOXY-3-CARBOXYLATE
-4-CARBOMETHOXY)-2-OXABUTANE]
- The product of B above is prepared in the same manner excep~ that certain parameters are changed. The mole ratio of ` ~ maleate to glycolate is 0.17:1, calcium hydroxide solution is -added to the reaction mixture to a pH of 8.6 and the reaction .:
.
- ' ' ~
~5z~7 C.~,~;7 Canada r.
is run for 2-3 hours. The solid product which precipitates ,- out on addition of ether contains 87.7~ of calcium bisE(1-.. carboisopropoxy-3-car~oxylate-4-car~omethoxy)-2-oxabutane~
and the viscous liquid product contains 71~8% o the mono-S acid product. The total yield of product calculated as the , . . .
calcium salt is 69.2% of the theoreticalr ~:~
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EXAMPLE II
_ .
A. PREPARATION OF M~GNESIUM BIS(~THYL MALE~TE) Fif-ty grams of maleic anhydride is dissolved in 200 .
ml methanol and magnesium hydroxide is added to a pH of 7.3.
The solution is filtered, the methanol is distilled of~ and the product is dried under vacuum. An NMR analysis of the product taken using potassium acid phthalate as the standard indicates that the product contains 78.7% magnesium bis- .
(methyl maleate).
B. MAGNESIUM BIS[(l-CARBOISOPROPOXY-3-CARBOXYLAT~-4-CARBO- .
METHOXY)-2-OXABUTANE]
Five grams (0.03 moles) of dried magnesium bis-~methyl maleate), the dired product from A above ha~ing an . .
.85.3% purity is placed into 11 grams of isopropyl glycolate :
15and the solution is heated to 85-90C for 2 hours and then to 100-105C for one hour. The excess glycolate is removed under.vacuum.and the r.~sidue is extracted twice with ether ~.~
leaving the èther insoluble solid product. Seven grams of ...
.
.this solid, magnesium bis~ carboisopropoxy-3-carboxylate-4-carbomethoxy)-2-oxabutane], is obtained; evaporation of . the combined ether extracts affords 2.1 grams of a liquid :: .
.. . .
5Z.5% product as the acid. .This acid can in turn be con- . ... ~:::
verted to the desired magnesium salt product by neutraliza-` tion with Mg(OH)2. The total yield of product is 80~ of .theory based on the dry s:olid salt and the acid ass~ming 100% conversion of the acid to the saitupon neutralization.
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C.6~J7 Canada S~
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EXAMPLE III
PREPARATION 0~ MAGNESIUM BIS~(2-CARBOISOPROPOXY-4-CARBOXYLATE-
5-CARBoMETHoxY)-3~oxAPENTANE]
C~2 - CH - O-CHCOOCH(CH3)2 Mg Five grams (0.028 moles) of magnesium bis(methyl .maleate) prepared as in Example II(Al is pl'aced into 32 grams (0.27 moles) 1sopropyl lactate. The solution is heated to 110-115C for two hours and the isopropyl lactate distilled off under reduced pressure. The residue is extract.ed twice with ether. Seven grams of ether insoluble solid magnesium bisE(2-carboisopropoxy-4-carboxylate-5-carbomethoxy)-3-oxa-pentane].is obtained. The NMR analysis of this'material using potassium acid phthalate as an internal standard is as follows: ' ;
, '67.7~ magnesium bis[t2-carboisopropoxy-4-car- .' : . ' boxylate-5-carbomethoxy7~3-oxapentane]
; ~ 19.6%.magnesium bis~methyl maleate) : 20 : 9.3~ magnesium maleate ,, ..
The ether extract containing a'portion o~ the mono--acid of the desired 'salt is.evaporated to dryness and 4 grams of solld col-. lected which contains 48.2.~ of the mono-acid. This mono-acid can be converted to the desired salt product by dissolvin~ the solid in water and adding ~Mg tOH) 2 to a pH of 7.3. The total yield of product assuming 100% conversion of the mono-acid is 70%.-' .
.
: 23~
.
~ ~ ~ S 2~i7 C.6~7 Canada ~ .
EXAMPLE IV
A. PREPAP~TION OF SODIU~ METHYL MALEATE
1 mole of maleic anhydride is dissolved in 1000 mlmethanol and 0.5 mole of sodium carbonate is added. The S solution is filtered and the me~hanol is distilled off under pressure. After drying the product in a vacuum oven 152 g of sodium methyl maleate is obtained.
B. PREPARATION OF SODIUM [(1 CARBOISOPROPOX~-3-CARBOXYLATE-4-CARBoMETHoXY)--2-OX~BUTANE
. .
160 grams ( 1.3 moles) of isopropyl glycolate and 50 grams (0.43 moles) of sodium methyl maleate re~erred in A above are heated to reflux for 2 hours, then the excess glycolate is distilled off under vacuum. The residue is dissolved in methanol and steam distilled to remove both the methanol and traces of isopropyl glycolate. The result-.. . :
ing water solution is evaporated to dryness and the ViSCQUS
material obtained is taken up in isopropanol, a portion of the matexi~l-dissolves and another portion precipitates. The solid precipitate is filtered and 21 grams recovered. NMR
analysis of the solid shows a mixture of disodium maleate and product. The isopropanol is evaporated of from the filtrate and the viscous liquid remaining is dissolved in water and neutralized to pH 8.3 using O.lN sodium hydroxide.
The solution is then evaporated down to dryness to give a residue of 35O3 grams cont~ining 52.1% sodium (l-carboiso-propoxy-3~carboxylate-4-carbomethoxy)-2-oxabutane (by ~MR).
The total yield of the desired sodium salt obtained is 27.8%
of theory.
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~5~7 C.6~7 Canada EXAMPLE V
PREPARATION OF CALCIUM BIS r (l-~ARBOISOPROPOXY-3-CARBOXYLATE-4-CARBOMETHOXY~-2-THIABUTANE]
A solution of 8 g (.053 moles~ of calcium bis-(methyl maleate) prepared as in Example I and 25 g of iso-propyl mercaptoace~ate (.19 moles) is refluxed for one hour.
Excess mercaptoacetate is distilled o~f under vacuum and ether is added to the resldue to precipitate the produce and ~ extract,residual mercaptoacetate ester. The product, calcium bis[(l-carboisopropoxy-3-carboxylate-4-carbomethoxy)-2-thia-, butane], is,obtained in 95~ yield (14.3 g). The structure is confirmed by NMR analysis.
The following compounds are similarly prepared by the above procedure: magnes um bis~(1-carboisopropoxy-3-carboxylate-4-carbomethoxy)-2-thiabutane and sodium ~
, carboisopropoxy-3-carboxylate-4-carbomethoxy)-2-thiabutane]
hy'substituting,magnesium bis(methyl maleate) prepared as in Example II(A) and sodium methyl maleate prepared in Example IV(A) respectively in place of calcium bis(methyl maleate).
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5287 c. f~67 Canada EX~PLE VI
. .
CALCIUM BIS r (l-CARBOISOPROPOXY-3-CA~BOXYLATE-4 CARBOMETHOXY)-2 -AZABUTANE ]
Calcium bis(methyl maleate) prepared as in Example I(A~, 10 grams (.067 moles) and 28 grams (.15 moles) of iso-propyl glycinate are heated for one hour at 80C. After re-- moving the excess glycinate ester by distilling under vacuum, the reaction mixture is extracted with ether. The resulting etXer insoluble solid material is filtered and immediately placed in a vacuum oven since it is hygroscopic. Nine grams -of solid product, 50% yield, of calcium bis[(l carboisopro-poxy-3-carboxylate-4-carbomethoxy)-2-azabutane] is obtained.
The structure of the product is confirmed by NMR.
The following compounds are similarly prepared by the above procedure: magnesium bis[(l-carboisopropoxy-3-carboxylate-4-carbomethoxy)-2-azabutane] and sodium [(1-carboisopropoxy-3-carbomethoxy~-2-azabutane] by substitut-ing mag~esium bis(methyl maleate) prepared as in Example II(A) and sodium methyl maleate prepared as in Example IV(A) , , . . :' respectively in place of calcium bis(methyl maleate).
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~ 2~7 c. GG7 Can~da EXAMPLE VII
PREPARATION OF CALCIUM BIS~METHYL l-PHENAZASUCCINATE]
_ : -2 1 ~
CH2 - CH - NH - 0 Ca ~ ~ :
- 7.0 grams (0.05 moles) of calcium bis(methyl maleate) preparedas in Example I(A) and 25 gxams (0.27 moles)o~ aniline are heated to 100C for one hour, cooled to 25C and either is added to precipitate out solid. 9.5 grams of calcium bls-[methyl l-phenazasuccinate] is obtained m 38% yield.
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C.667 Canada ~ 52~i~
EXAMPLE VIII
PREPARATION OF CALCIUM BIS[(l CARBOISOPROPOXY-3-CARBOXYLATE-4-CARBOMETHOXY)-2~0XABUTANE~
4 grams 10.027 mole) of calcium histmethyl maleate) prepared as in Example I(~) is added to 13 grams ~0.11 moles) of-isopropyl glycolate, 100 grams of dimethylformamide (DMF) solvent and 1 gram of Ca(OH)2. The mole ratio of maleate to glycolate is 0.25 to 1. The solution is stirred at room tem-perature for 3 hours, residual Ca(OH)2 is filtered out and the DMF and excess glycolate are distilled o~f under reduced pres-sure. The residue is dissolved in acetone and ether is added "'~
to precipitate the desired salt. This product is filt'ered and dried in a vacuum oven; 3 grams (26~ yield) are recovered.
Analysis of the product by NMR using a potassium acid phthalate internal standard is as follows:
' 62.7% calcium bis~ carboisopropoxy-3-carboxylate- ' ' 4-carbomethoxy)-2-oxa~utane] -' 22.7% calcium maleate '' A confirmation analysis was run utilizing G.L.C. (gas ~i~uid chromatography). The salt, i.e. the calcium bis[(l-carboiso- " "'' propoxy-3-carboxylate-4-carbomethoxy)-2-oxabutane] is dis-solved in methanol, acidified with concentrated H2S04 and re--' fluxed for 3 hours.' The solution is netltralized, filtered ''~ and the methanol removed by distillation'~mder reduced pres-sure. The G.L.C. analysis shows: ~ -' ' 54.7~ of the trimethyl ester of carboxymethyloxy-' succinic acid .
25.8% dimethyl maleate ' .
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.
~152~7 ~ . G6~ Canada 5.3% dimethyl fumarate The retention time of this material is identical to that of the authentic triester preparec' according to method disclosed in Belgium Patent 802,356 (application nu~ber 133495) granted January 14, 1974.
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~5f~7 C.6~7 Canada EXAMPLE IX
~REPARATION OF CALCIUM BIS[(l-PHENYL-l-CARBOISOPROPOXY-3-CARBOXYLATE-4 CARBOMETHOXY) 2-OXABUTANE~
- ~ H2 - CH - O - CH - 0 ~ Ca OOCH3 COO COOCHtcH3)2 2 12 grams (.08 moles) of calcium bis(methyl maleate) prepared as in ~xample I(A) and 60 grams (0.3 moles) of iso-propyl mandelate are mixed and heated to 130C for 2 hours.
The solution is cooled to room temperature. The ether is 1~ added (at 25C) and the ether insoluble solid precipitates and is filtexed offO 12.5 grams of product is obtained.
Since the solid is water insoluble 8 grams hydrochloric acid is added to the suspended solid in H2O to convert the product to the a-cid form in order to separate it from other impurities and in order to dissolve it in CDC13 for NMR analysis. A water immiscible liquid separates out and is extracted out with .
- ether. 4 grams of the mono-acid precursor of calcium bis~(l-phenyl-l-carboisopropoxy-3-carbo~ylate-4-carbomethoxy)-2-oxa-butane3, i.e. 12.5% yield is obtained.
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. ' ~5Z~7 C-667 ~anad~
EXAMPL~ X
. . .
PREPARATION OF CA~CIUM BIS[(3~CARBOISOPROPOXY-5-CARBOXYLATE-
C~2 - CH - O-CHCOOCH(CH3)2 Mg Five grams (0.028 moles) of magnesium bis(methyl .maleate) prepared as in Example II(Al is pl'aced into 32 grams (0.27 moles) 1sopropyl lactate. The solution is heated to 110-115C for two hours and the isopropyl lactate distilled off under reduced pressure. The residue is extract.ed twice with ether. Seven grams of ether insoluble solid magnesium bisE(2-carboisopropoxy-4-carboxylate-5-carbomethoxy)-3-oxa-pentane].is obtained. The NMR analysis of this'material using potassium acid phthalate as an internal standard is as follows: ' ;
, '67.7~ magnesium bis[t2-carboisopropoxy-4-car- .' : . ' boxylate-5-carbomethoxy7~3-oxapentane]
; ~ 19.6%.magnesium bis~methyl maleate) : 20 : 9.3~ magnesium maleate ,, ..
The ether extract containing a'portion o~ the mono--acid of the desired 'salt is.evaporated to dryness and 4 grams of solld col-. lected which contains 48.2.~ of the mono-acid. This mono-acid can be converted to the desired salt product by dissolvin~ the solid in water and adding ~Mg tOH) 2 to a pH of 7.3. The total yield of product assuming 100% conversion of the mono-acid is 70%.-' .
.
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.
~ ~ ~ S 2~i7 C.6~7 Canada ~ .
EXAMPLE IV
A. PREPAP~TION OF SODIU~ METHYL MALEATE
1 mole of maleic anhydride is dissolved in 1000 mlmethanol and 0.5 mole of sodium carbonate is added. The S solution is filtered and the me~hanol is distilled off under pressure. After drying the product in a vacuum oven 152 g of sodium methyl maleate is obtained.
B. PREPARATION OF SODIUM [(1 CARBOISOPROPOX~-3-CARBOXYLATE-4-CARBoMETHoXY)--2-OX~BUTANE
. .
160 grams ( 1.3 moles) of isopropyl glycolate and 50 grams (0.43 moles) of sodium methyl maleate re~erred in A above are heated to reflux for 2 hours, then the excess glycolate is distilled off under vacuum. The residue is dissolved in methanol and steam distilled to remove both the methanol and traces of isopropyl glycolate. The result-.. . :
ing water solution is evaporated to dryness and the ViSCQUS
material obtained is taken up in isopropanol, a portion of the matexi~l-dissolves and another portion precipitates. The solid precipitate is filtered and 21 grams recovered. NMR
analysis of the solid shows a mixture of disodium maleate and product. The isopropanol is evaporated of from the filtrate and the viscous liquid remaining is dissolved in water and neutralized to pH 8.3 using O.lN sodium hydroxide.
The solution is then evaporated down to dryness to give a residue of 35O3 grams cont~ining 52.1% sodium (l-carboiso-propoxy-3~carboxylate-4-carbomethoxy)-2-oxabutane (by ~MR).
The total yield of the desired sodium salt obtained is 27.8%
of theory.
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~5~7 C.6~7 Canada EXAMPLE V
PREPARATION OF CALCIUM BIS r (l-~ARBOISOPROPOXY-3-CARBOXYLATE-4-CARBOMETHOXY~-2-THIABUTANE]
A solution of 8 g (.053 moles~ of calcium bis-(methyl maleate) prepared as in Example I and 25 g of iso-propyl mercaptoace~ate (.19 moles) is refluxed for one hour.
Excess mercaptoacetate is distilled o~f under vacuum and ether is added to the resldue to precipitate the produce and ~ extract,residual mercaptoacetate ester. The product, calcium bis[(l-carboisopropoxy-3-carboxylate-4-carbomethoxy)-2-thia-, butane], is,obtained in 95~ yield (14.3 g). The structure is confirmed by NMR analysis.
The following compounds are similarly prepared by the above procedure: magnes um bis~(1-carboisopropoxy-3-carboxylate-4-carbomethoxy)-2-thiabutane and sodium ~
, carboisopropoxy-3-carboxylate-4-carbomethoxy)-2-thiabutane]
hy'substituting,magnesium bis(methyl maleate) prepared as in Example II(A) and sodium methyl maleate prepared in Example IV(A) respectively in place of calcium bis(methyl maleate).
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5287 c. f~67 Canada EX~PLE VI
. .
CALCIUM BIS r (l-CARBOISOPROPOXY-3-CA~BOXYLATE-4 CARBOMETHOXY)-2 -AZABUTANE ]
Calcium bis(methyl maleate) prepared as in Example I(A~, 10 grams (.067 moles) and 28 grams (.15 moles) of iso-propyl glycinate are heated for one hour at 80C. After re-- moving the excess glycinate ester by distilling under vacuum, the reaction mixture is extracted with ether. The resulting etXer insoluble solid material is filtered and immediately placed in a vacuum oven since it is hygroscopic. Nine grams -of solid product, 50% yield, of calcium bis[(l carboisopro-poxy-3-carboxylate-4-carbomethoxy)-2-azabutane] is obtained.
The structure of the product is confirmed by NMR.
The following compounds are similarly prepared by the above procedure: magnesium bis[(l-carboisopropoxy-3-carboxylate-4-carbomethoxy)-2-azabutane] and sodium [(1-carboisopropoxy-3-carbomethoxy~-2-azabutane] by substitut-ing mag~esium bis(methyl maleate) prepared as in Example II(A) and sodium methyl maleate prepared as in Example IV(A) , , . . :' respectively in place of calcium bis(methyl maleate).
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~ 2~7 c. GG7 Can~da EXAMPLE VII
PREPARATION OF CALCIUM BIS~METHYL l-PHENAZASUCCINATE]
_ : -2 1 ~
CH2 - CH - NH - 0 Ca ~ ~ :
- 7.0 grams (0.05 moles) of calcium bis(methyl maleate) preparedas in Example I(A) and 25 gxams (0.27 moles)o~ aniline are heated to 100C for one hour, cooled to 25C and either is added to precipitate out solid. 9.5 grams of calcium bls-[methyl l-phenazasuccinate] is obtained m 38% yield.
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C.667 Canada ~ 52~i~
EXAMPLE VIII
PREPARATION OF CALCIUM BIS[(l CARBOISOPROPOXY-3-CARBOXYLATE-4-CARBOMETHOXY)-2~0XABUTANE~
4 grams 10.027 mole) of calcium histmethyl maleate) prepared as in Example I(~) is added to 13 grams ~0.11 moles) of-isopropyl glycolate, 100 grams of dimethylformamide (DMF) solvent and 1 gram of Ca(OH)2. The mole ratio of maleate to glycolate is 0.25 to 1. The solution is stirred at room tem-perature for 3 hours, residual Ca(OH)2 is filtered out and the DMF and excess glycolate are distilled o~f under reduced pres-sure. The residue is dissolved in acetone and ether is added "'~
to precipitate the desired salt. This product is filt'ered and dried in a vacuum oven; 3 grams (26~ yield) are recovered.
Analysis of the product by NMR using a potassium acid phthalate internal standard is as follows:
' 62.7% calcium bis~ carboisopropoxy-3-carboxylate- ' ' 4-carbomethoxy)-2-oxa~utane] -' 22.7% calcium maleate '' A confirmation analysis was run utilizing G.L.C. (gas ~i~uid chromatography). The salt, i.e. the calcium bis[(l-carboiso- " "'' propoxy-3-carboxylate-4-carbomethoxy)-2-oxabutane] is dis-solved in methanol, acidified with concentrated H2S04 and re--' fluxed for 3 hours.' The solution is netltralized, filtered ''~ and the methanol removed by distillation'~mder reduced pres-sure. The G.L.C. analysis shows: ~ -' ' 54.7~ of the trimethyl ester of carboxymethyloxy-' succinic acid .
25.8% dimethyl maleate ' .
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.
~152~7 ~ . G6~ Canada 5.3% dimethyl fumarate The retention time of this material is identical to that of the authentic triester preparec' according to method disclosed in Belgium Patent 802,356 (application nu~ber 133495) granted January 14, 1974.
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~5f~7 C.6~7 Canada EXAMPLE IX
~REPARATION OF CALCIUM BIS[(l-PHENYL-l-CARBOISOPROPOXY-3-CARBOXYLATE-4 CARBOMETHOXY) 2-OXABUTANE~
- ~ H2 - CH - O - CH - 0 ~ Ca OOCH3 COO COOCHtcH3)2 2 12 grams (.08 moles) of calcium bis(methyl maleate) prepared as in ~xample I(A) and 60 grams (0.3 moles) of iso-propyl mandelate are mixed and heated to 130C for 2 hours.
The solution is cooled to room temperature. The ether is 1~ added (at 25C) and the ether insoluble solid precipitates and is filtexed offO 12.5 grams of product is obtained.
Since the solid is water insoluble 8 grams hydrochloric acid is added to the suspended solid in H2O to convert the product to the a-cid form in order to separate it from other impurities and in order to dissolve it in CDC13 for NMR analysis. A water immiscible liquid separates out and is extracted out with .
- ether. 4 grams of the mono-acid precursor of calcium bis~(l-phenyl-l-carboisopropoxy-3-carbo~ylate-4-carbomethoxy)-2-oxa-butane3, i.e. 12.5% yield is obtained.
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. ' ~5Z~7 C-667 ~anad~
EXAMPL~ X
. . .
PREPARATION OF CA~CIUM BIS[(3~CARBOISOPROPOXY-5-CARBOXYLATE-
6-CARBOMETHOXY)-4-OXAHEXANE]
. .
_ O _ ¦ ¦ : fH - c OCH(CH3)2 Ca _COOCH3 COO CH2CH3 _ 2 6 grams (0.04 moles) of calcium bis(methyl maleate) prepared as in Example I~A) and 26.5 g of alpha-hydroxy iso-propyl butyrate are heated to 130C for 2 hours. The excess butyrate solvent is then removed under reduced pressure and is extracted with ether. The ether insoluble salt precipitates and is filtered out. Five grams of solid is collected~
The compound was converted to the sodium salt by addition o~ sodium carbonate in order to make it more soluble in D2O for NMR analysis. The analysis is as follows:
41.0% [t3-carboisopropoxy-5 carboxylate-6-carbo-methoxy)-4-oxahexane] which corresponds to ~ calculated as the desired calcium salt 16.4% calcium bis(methyl maleate) 21.1~ calcium maleate 11.4~ water , :, .
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C.667 Canada sæ~
EXAMPLE XI
PREPARATION OF CALCIIJM BIS[(l-HYDROXY-4-CARBOXYLATE-5-CARBO-METHOXY)-3-O~PENTANE3 [fH2 CH--CH2cH2H~
Seven grams (.047 moles) of calcium bis methyl male-ate prepared as in Example I(A) is dissolved in 25 grams (0.4 moles) of ethylene glyco~ and the reaction mixture heated to 105C for 3 hours. The solution is then cooled (some product is insoluble) and the solution is extracted 5-6 times with ace-tone until all of the ethylene glycol is extracted out. S.7 grams of crystalline solid is obtained (58% yield). This solid is converted to the sodium salt for NMR identification by dissolving the solid in D20 and adding sodium carbonate to precipitate the calcium as calcium carbonate.
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~5~7 C.6G7 C~n~lda EXAMPLE XII
A. PREPARATION OF CALCIUM BIS(ETHYL MALEATE) [COOEt COO 9 ] 2 Fifty grams of maleic anhydride is dissolved in 400 mls ethyl alcohol. Ca(OH)2 is added to a pH of 8.5, iltered and dried in a dessicator over P2O5.
The product is 99.1~ pure by NMR analysis.
B. PREPARATION OF,CALCIUM BIS~ CARBOISOPROPOXY-3-CARBOXYL-ATE-4-CARBOETHOXY)-2~0XABUTANE~ .
[fH2 IH OcH2coocH(cH3)2] C ++
COOEt COO ~ 2 Twelve grams (.07 moles) of calcium bis(methyL
maleate) Frepared as in Example XIII(A) above is added.to 40 grams.(.34 moles~ of isopropyl glycolate and the reaction .
mixture is heated to 140-150C for one hour. The glycolate ~.. ;.
: solvent is distilled off under reduced pressure and the resi-due.is extracted with ether. 6.2 grams of ether insoluble . solid calcium bis[(l-carboisopropoxy-3-carboxylate~4-carbo-ethoxy)-2-oxabutane] is.obtained. The ether layer contains 13 grams of a viscous liquid containing the product in the form of the acid which can be co.nverted to the desired saLt .
.~y dissolving in water and adding Ca(OH)2 to a pH o~ 8.6 then taking to dryness.and extracting with ether. The salt is ether insoluble. Both the solid.and the viscous liquid . :
are analyzed by NMR, the results are as follows: :
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c . ~j67 Canacla L5~
;
SOLID ANALYSIS
. .
90.8% of calcium bis[(l-carboisopropoxy-3-carboxyl ate-4-carboethoxy)-2-oxabutane]
. .
_ O _ ¦ ¦ : fH - c OCH(CH3)2 Ca _COOCH3 COO CH2CH3 _ 2 6 grams (0.04 moles) of calcium bis(methyl maleate) prepared as in Example I~A) and 26.5 g of alpha-hydroxy iso-propyl butyrate are heated to 130C for 2 hours. The excess butyrate solvent is then removed under reduced pressure and is extracted with ether. The ether insoluble salt precipitates and is filtered out. Five grams of solid is collected~
The compound was converted to the sodium salt by addition o~ sodium carbonate in order to make it more soluble in D2O for NMR analysis. The analysis is as follows:
41.0% [t3-carboisopropoxy-5 carboxylate-6-carbo-methoxy)-4-oxahexane] which corresponds to ~ calculated as the desired calcium salt 16.4% calcium bis(methyl maleate) 21.1~ calcium maleate 11.4~ water , :, .
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C.667 Canada sæ~
EXAMPLE XI
PREPARATION OF CALCIIJM BIS[(l-HYDROXY-4-CARBOXYLATE-5-CARBO-METHOXY)-3-O~PENTANE3 [fH2 CH--CH2cH2H~
Seven grams (.047 moles) of calcium bis methyl male-ate prepared as in Example I(A) is dissolved in 25 grams (0.4 moles) of ethylene glyco~ and the reaction mixture heated to 105C for 3 hours. The solution is then cooled (some product is insoluble) and the solution is extracted 5-6 times with ace-tone until all of the ethylene glycol is extracted out. S.7 grams of crystalline solid is obtained (58% yield). This solid is converted to the sodium salt for NMR identification by dissolving the solid in D20 and adding sodium carbonate to precipitate the calcium as calcium carbonate.
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~5~7 C.6G7 C~n~lda EXAMPLE XII
A. PREPARATION OF CALCIUM BIS(ETHYL MALEATE) [COOEt COO 9 ] 2 Fifty grams of maleic anhydride is dissolved in 400 mls ethyl alcohol. Ca(OH)2 is added to a pH of 8.5, iltered and dried in a dessicator over P2O5.
The product is 99.1~ pure by NMR analysis.
B. PREPARATION OF,CALCIUM BIS~ CARBOISOPROPOXY-3-CARBOXYL-ATE-4-CARBOETHOXY)-2~0XABUTANE~ .
[fH2 IH OcH2coocH(cH3)2] C ++
COOEt COO ~ 2 Twelve grams (.07 moles) of calcium bis(methyL
maleate) Frepared as in Example XIII(A) above is added.to 40 grams.(.34 moles~ of isopropyl glycolate and the reaction .
mixture is heated to 140-150C for one hour. The glycolate ~.. ;.
: solvent is distilled off under reduced pressure and the resi-due.is extracted with ether. 6.2 grams of ether insoluble . solid calcium bis[(l-carboisopropoxy-3-carboxylate~4-carbo-ethoxy)-2-oxabutane] is.obtained. The ether layer contains 13 grams of a viscous liquid containing the product in the form of the acid which can be co.nverted to the desired saLt .
.~y dissolving in water and adding Ca(OH)2 to a pH o~ 8.6 then taking to dryness.and extracting with ether. The salt is ether insoluble. Both the solid.and the viscous liquid . :
are analyzed by NMR, the results are as follows: :
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c . ~j67 Canacla L5~
;
SOLID ANALYSIS
. .
90.8% of calcium bis[(l-carboisopropoxy-3-carboxyl ate-4-carboethoxy)-2-oxabutane]
7.4~ calcium maleate 1.8% water VISCOUS LIQUID ANALYSIS
56.8~ of calcium bis[(l-carboisopropoxy-3-carboxyl-. ate-4-carboethoxy)~2-oxabutane](as the acid) The total yield of the product assuming 100% conversion of the acid to Lhe desired salt is 7~%.
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' -C.667 Canada i;7 E~AMPLE XIII
... .
ATTEMPTED PREPARATION OF TRIETHYL CARBOXYMETHYLOXYSUCCINATEVIA THE NORMAL MICHAEL REACTION
Into 100 grams ethanol is placed 0.2 g sodium until the reaction is complete. 10.6 g ethyl glycolate is added and the ethanol distilled under reduced pressure. 15 g diethyl maleate is added the reaction mixture heated~to 45C for one hour.
The product is taken up in ether and the insoluble - solid is filtered. The solution is dLstilled under reduced pressure to remove ether and unreacted glycolate. Recovered 16 grams of product(s).
; GLC analysis (~ by weight) 6~0 ethyl glycolate 87.6 diethyl fumarate 1.2 diethyl maleate 1.9 triethyl carboxymethyloxysuccinate. Corresponds to a 7.5~ yield.
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~5Z~7 C, 6G7 Canada EXAMPLE XIV
A. PREPARATION OF BARIUM BIS(METHYL MALEATE) [CH- - CH ~ +~
Thirty grams of maleic anhydride is dissolved in 400 moles of methanol and Ba(OH)2 is added ~o a pH of 8Ø
The solution is filtered and is taken down to dryness. NMR
analysis is as follows: `
79.1% of barium bis(methyl maleate) 20.9% water B. PREPARATION OF BARIUM BIS[ (l-CARBOISOPROPOXY-3-CARBOXYL-ATE-~ -CARB OMETI-IOXY)-2-OX~BUTANE L . _ rTH2 1H_OCH2COOCH(CH3)2 1 lCOOCH3 OO ~ 2 Nineteen grams (0.08 moles) of barium bis(methyl ; maleate) prepared as in ~ above is placed into 55 grams (0~47 moles) of isopropyl glycolate and the solution is heated to 140-145C (some solid remained undissolved).
~ .
The g~ycolate solvent is removed under reduced pres~
sure and the residue is extracted with ether and filtered.
2.5 grams of ether insoluble barium bis[(l-carboisopropoxy-3-carboxylate~4-carbomethoxy)-2-oxabutane] is filtered off.
The ether solution is- taken to dryness and 30.3 g of a highly ,' viscous liqui~ is obtained. NMR analysis using potassium acid phthalate as a standard gives the ollowing results:
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C,fiG7 Canada i SOLID
90.8% barium bis[(l-carboisopropoxy-3-carboxylate-4-carbomethoxy)-2-oxabutane]
' 7.4% barium maleate ' ~ 5 1.8% water ' ~ VISCOUS LIQUID .
35.7% (-1-carboisopropoxy-3-carboxylic acid-4-carbo-: methoxy)-2-oxabutane 54.7% barium maleate.
- ' , , .
' 9.6% isopropyl' glycolate . , , : , The acid can be converted to the desi'red'product by : raising the pH of the liquid to 8v5 with`Ba(OH)2. The total yield assuming 100~ conversion of the acid to the salt is 56.7%~ ' ' :
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' ~ 7 C. G~ Ca~da EXA~LE XV
. A. PREPARATION OF CALCIUM BIS(EIEXYL MALEATE~
rC~ Ca L OOHexyl COO 2 40 grams (0.4 moles) of maleic anhydride is dis-- solved in 200 grams hexanol and Ca(OH)2 is slowly added with stirring until a pH of 8.5-8.6 is reached. The solution is - iltered and taken to dryness. The residue is taken up in -acetone and the fîrst crop of solid is filtered. ~This crop is contaminated with calcium maleate.) The second crop of crystals which slowly precipitates out is filtered and dried.
The calcium bis(hexyl maleate) is 90% pure by NMR analysis.
B. PREPARATION OF CALCIUM BIS[(l-CARBOISOPROPOXY-3-CARBOXYL-ATE-4-CARBOHEXYLoXY~-~-OXABUTANE]
j 15 10 grams (.04 moles based on 90% purity~ of the product produced in A above is dissolved in 35 grams (0.3 moles~ of isopropyl glycolate and the mixture heated to 1~0-150C for 45 minu-tes. The excess glycolate solvent is clis-tilled of under reduced press~ire and the viscous lic~uicl ex-tracted twice with 200 grams of water to remove any dissolved ; glycolate. 15 grams of a very viscous liquid are collected containing 42.4% of calcium bis~ carboisopropoxy-3-carboxyl-ate-4-carbohexy-oxy)-2-oxabutane]. The yield is 49%.
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.5:2~7 c. (;G7 Canada EXAMPLE XVI
A. PRF:PARATION OF STRONTIUM BIS (~lETHYL) ~LEATE
[ C33 COO ]~
Thirty-five srams (0.35 moles) of maleic anhydride - is dissolved in 300 grams methanol and Sr~OH)2 is added slowly with stirring to a pH of 8.5. The solution is evaporated under reduced pressure to a tacky residue. 100 mls of meth- -anol is added and the first crop of crystals filtered. To the methanol solution is added 200 mls acetone and 300 mls ether and the resulting solution is stirred for five minutes.
The solvent is decanted and the residue triturated with 100 mls methanol, 200 mls acetone and 200 mls ether. The solid remained is filtered, washed with acetone and dried in the vacuum oven. Forty-six grams of strontium bis ~methyl)maleate is obtained having a purity of 85.6~ by NMR analysis using potassium acid phthalate as an internal standard.
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B. PREPARATION OF ST~ONTIUM BIS[(l~CARBOISOPROPOSY-3-CARBOXYL-ATE- 4-CARBOMETHOXY~-2-OXABUTANE]
~ rfH2 Cl H-ocH2coocHtcH3) 21 ++
':
; 17.5 grams (0.09 moles based on 85~6% to purity) of ~ the product of A above is placed into 51 grams (0.~3 moles) .
of isopropyl glycolate and the solution heated to 140-150C
for one hour. The isopropyl glycolate i5 distilled off under r~duced pressure and the residue is e~tracted with one liter .
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~ 7 C. ~67 Canada of ether. The solid e~her insoluble product i~ dried in a vacuum oven to constant weight. 17.8 grams of strontium bis[(l-carboisopropoxy-3-carboxylate-4-carbome~hoxy)-2-oxabutane] is obtained~ The ether layer is taken down to dryness and 13.8 grams of liquid is obtained. This liquid is the mono-acid of the desired salt and can be converted to the desired salt by dissolving it in water, adding Sr(OH)2 to a pH of 8.5, evaporatlng to dryness and extract-ing with ether. The solid and liquid were analyzed by NMR
as ~ollows:
SOLID
77.5~ strontium bis[(l-carboisopropoxy-3-carboxyl-ate-4 carbometho~:y)-2-oxabutane]
10.1~ strontium maleate 10~5% strontium bis(methyl)maleate . :
LIQUID
3a . ~ (1-carboisopropoxy-3-carboxylic acid~4-carbo-methoxy)-2-oxabutane 70.0~ isopropyl glycol~te .
The yield is 70.8% based on 100~ conversion of the mono-acid present to the desired salt product. ~ -, ~ .
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C.667 Canada 5~ 7 This invention has been described with respect to certain preferred embodiments, and various modifica-tions and - variations in the light thereof will be suggested to persons skilled in the art and are to be included within the spirit S and purview of this application and ~he scope o~ the appended claims.
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56.8~ of calcium bis[(l-carboisopropoxy-3-carboxyl-. ate-4-carboethoxy)~2-oxabutane](as the acid) The total yield of the product assuming 100% conversion of the acid to Lhe desired salt is 7~%.
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' -C.667 Canada i;7 E~AMPLE XIII
... .
ATTEMPTED PREPARATION OF TRIETHYL CARBOXYMETHYLOXYSUCCINATEVIA THE NORMAL MICHAEL REACTION
Into 100 grams ethanol is placed 0.2 g sodium until the reaction is complete. 10.6 g ethyl glycolate is added and the ethanol distilled under reduced pressure. 15 g diethyl maleate is added the reaction mixture heated~to 45C for one hour.
The product is taken up in ether and the insoluble - solid is filtered. The solution is dLstilled under reduced pressure to remove ether and unreacted glycolate. Recovered 16 grams of product(s).
; GLC analysis (~ by weight) 6~0 ethyl glycolate 87.6 diethyl fumarate 1.2 diethyl maleate 1.9 triethyl carboxymethyloxysuccinate. Corresponds to a 7.5~ yield.
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~5Z~7 C, 6G7 Canada EXAMPLE XIV
A. PREPARATION OF BARIUM BIS(METHYL MALEATE) [CH- - CH ~ +~
Thirty grams of maleic anhydride is dissolved in 400 moles of methanol and Ba(OH)2 is added ~o a pH of 8Ø
The solution is filtered and is taken down to dryness. NMR
analysis is as follows: `
79.1% of barium bis(methyl maleate) 20.9% water B. PREPARATION OF BARIUM BIS[ (l-CARBOISOPROPOXY-3-CARBOXYL-ATE-~ -CARB OMETI-IOXY)-2-OX~BUTANE L . _ rTH2 1H_OCH2COOCH(CH3)2 1 lCOOCH3 OO ~ 2 Nineteen grams (0.08 moles) of barium bis(methyl ; maleate) prepared as in ~ above is placed into 55 grams (0~47 moles) of isopropyl glycolate and the solution is heated to 140-145C (some solid remained undissolved).
~ .
The g~ycolate solvent is removed under reduced pres~
sure and the residue is extracted with ether and filtered.
2.5 grams of ether insoluble barium bis[(l-carboisopropoxy-3-carboxylate~4-carbomethoxy)-2-oxabutane] is filtered off.
The ether solution is- taken to dryness and 30.3 g of a highly ,' viscous liqui~ is obtained. NMR analysis using potassium acid phthalate as a standard gives the ollowing results:
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C,fiG7 Canada i SOLID
90.8% barium bis[(l-carboisopropoxy-3-carboxylate-4-carbomethoxy)-2-oxabutane]
' 7.4% barium maleate ' ~ 5 1.8% water ' ~ VISCOUS LIQUID .
35.7% (-1-carboisopropoxy-3-carboxylic acid-4-carbo-: methoxy)-2-oxabutane 54.7% barium maleate.
- ' , , .
' 9.6% isopropyl' glycolate . , , : , The acid can be converted to the desi'red'product by : raising the pH of the liquid to 8v5 with`Ba(OH)2. The total yield assuming 100~ conversion of the acid to the salt is 56.7%~ ' ' :
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' ~ 7 C. G~ Ca~da EXA~LE XV
. A. PREPARATION OF CALCIUM BIS(EIEXYL MALEATE~
rC~ Ca L OOHexyl COO 2 40 grams (0.4 moles) of maleic anhydride is dis-- solved in 200 grams hexanol and Ca(OH)2 is slowly added with stirring until a pH of 8.5-8.6 is reached. The solution is - iltered and taken to dryness. The residue is taken up in -acetone and the fîrst crop of solid is filtered. ~This crop is contaminated with calcium maleate.) The second crop of crystals which slowly precipitates out is filtered and dried.
The calcium bis(hexyl maleate) is 90% pure by NMR analysis.
B. PREPARATION OF CALCIUM BIS[(l-CARBOISOPROPOXY-3-CARBOXYL-ATE-4-CARBOHEXYLoXY~-~-OXABUTANE]
j 15 10 grams (.04 moles based on 90% purity~ of the product produced in A above is dissolved in 35 grams (0.3 moles~ of isopropyl glycolate and the mixture heated to 1~0-150C for 45 minu-tes. The excess glycolate solvent is clis-tilled of under reduced press~ire and the viscous lic~uicl ex-tracted twice with 200 grams of water to remove any dissolved ; glycolate. 15 grams of a very viscous liquid are collected containing 42.4% of calcium bis~ carboisopropoxy-3-carboxyl-ate-4-carbohexy-oxy)-2-oxabutane]. The yield is 49%.
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.5:2~7 c. (;G7 Canada EXAMPLE XVI
A. PRF:PARATION OF STRONTIUM BIS (~lETHYL) ~LEATE
[ C33 COO ]~
Thirty-five srams (0.35 moles) of maleic anhydride - is dissolved in 300 grams methanol and Sr~OH)2 is added slowly with stirring to a pH of 8.5. The solution is evaporated under reduced pressure to a tacky residue. 100 mls of meth- -anol is added and the first crop of crystals filtered. To the methanol solution is added 200 mls acetone and 300 mls ether and the resulting solution is stirred for five minutes.
The solvent is decanted and the residue triturated with 100 mls methanol, 200 mls acetone and 200 mls ether. The solid remained is filtered, washed with acetone and dried in the vacuum oven. Forty-six grams of strontium bis ~methyl)maleate is obtained having a purity of 85.6~ by NMR analysis using potassium acid phthalate as an internal standard.
. ' ~ ' ~ ' ' ' . .
B. PREPARATION OF ST~ONTIUM BIS[(l~CARBOISOPROPOSY-3-CARBOXYL-ATE- 4-CARBOMETHOXY~-2-OXABUTANE]
~ rfH2 Cl H-ocH2coocHtcH3) 21 ++
':
; 17.5 grams (0.09 moles based on 85~6% to purity) of ~ the product of A above is placed into 51 grams (0.~3 moles) .
of isopropyl glycolate and the solution heated to 140-150C
for one hour. The isopropyl glycolate i5 distilled off under r~duced pressure and the residue is e~tracted with one liter .
-39- ~
~':
l' .. . ... . . . ... . .. . . . . ..
~ 7 C. ~67 Canada of ether. The solid e~her insoluble product i~ dried in a vacuum oven to constant weight. 17.8 grams of strontium bis[(l-carboisopropoxy-3-carboxylate-4-carbome~hoxy)-2-oxabutane] is obtained~ The ether layer is taken down to dryness and 13.8 grams of liquid is obtained. This liquid is the mono-acid of the desired salt and can be converted to the desired salt by dissolving it in water, adding Sr(OH)2 to a pH of 8.5, evaporatlng to dryness and extract-ing with ether. The solid and liquid were analyzed by NMR
as ~ollows:
SOLID
77.5~ strontium bis[(l-carboisopropoxy-3-carboxyl-ate-4 carbometho~:y)-2-oxabutane]
10.1~ strontium maleate 10~5% strontium bis(methyl)maleate . :
LIQUID
3a . ~ (1-carboisopropoxy-3-carboxylic acid~4-carbo-methoxy)-2-oxabutane 70.0~ isopropyl glycol~te .
The yield is 70.8% based on 100~ conversion of the mono-acid present to the desired salt product. ~ -, ~ .
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C.667 Canada 5~ 7 This invention has been described with respect to certain preferred embodiments, and various modifica-tions and - variations in the light thereof will be suggested to persons skilled in the art and are to be included within the spirit S and purview of this application and ~he scope o~ the appended claims.
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Claims (21)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A compound of the general formula wherein R is a primary alkyl group of one to six carbon atoms, wherein M1 is H, Ca, Mg, Ba, Sr, Na, K or L1, wherein x is 1 or 2 and is equivalent to the valency of M1, wherein Y is oxygen or sulphur or amino (NH), and wherein Z is 1) an ester moiety of the general formula:
wherein R1 is isopropyl or secondary butyl, and when Y is oxygen or sulphur, R2 is hydrogen, methyl, ethyl or phenyl, and when Y is NH, R2 is hydrogen, methyl, ethyl, isopropyl, isobutyl, secondary butyl, benzyl, p-hydroxybenzyl or 2-(methylthio) ethyl, or 2) 2-hydroxyethyl or 3-hydroxypropyl.
wherein R1 is isopropyl or secondary butyl, and when Y is oxygen or sulphur, R2 is hydrogen, methyl, ethyl or phenyl, and when Y is NH, R2 is hydrogen, methyl, ethyl, isopropyl, isobutyl, secondary butyl, benzyl, p-hydroxybenzyl or 2-(methylthio) ethyl, or 2) 2-hydroxyethyl or 3-hydroxypropyl.
2. A compound as defined in claim 1 having the formula wherein said M1 and x are as previously defined.
3. A compound as defined in claim 1 having the formula wherein said M1 and x are as previously defined.
4. A compound as defined in claim 1 having the formula
5. A compound as defined in claim 1 having the formula
6. A compound as defined in claim 1 having the formula wherein said x and Ml are as previously defined.
7. A process for preparing a polyfunctional compound of the general formula wherein Y is oxygen, sulphur or imino (NH), wherein R is a primary alkyl group of one to six carbon atoms, wherein M is Ca, Ba, Mg, Sr, Na, K or Li, Wherein x is 1 or 2 and is equivalent to the valency of M, and wherein Z is 1) an ester moiety of the general formula:
wherein R1 is isopropyl or secondary butyl, and when Y
is oxygen or sulphur, R2 is hydrogen, methyl, ethyl or phenyl, and when Y is NH, R2 is hydrogen, methyl, ethyl, isopropyl, isobutyl, secondary butyl, benzyl, p-hydroxy-benzyl or 2-(methylthio)ethyl, or 2) 2-hydroxyethyl or 3-hydroxypropyl, comprising reacting by heating a salt of a monoalkyl ester of maleic acid of the general formula wherein said x, R and M are as previously defined, with an active hydrogen containing compound of the general formula H - Y - Z
wherein said Y and Z are as previously defined.
wherein R1 is isopropyl or secondary butyl, and when Y
is oxygen or sulphur, R2 is hydrogen, methyl, ethyl or phenyl, and when Y is NH, R2 is hydrogen, methyl, ethyl, isopropyl, isobutyl, secondary butyl, benzyl, p-hydroxy-benzyl or 2-(methylthio)ethyl, or 2) 2-hydroxyethyl or 3-hydroxypropyl, comprising reacting by heating a salt of a monoalkyl ester of maleic acid of the general formula wherein said x, R and M are as previously defined, with an active hydrogen containing compound of the general formula H - Y - Z
wherein said Y and Z are as previously defined.
8. A process as defined in claim 7 wherein said reaction takes place in the liquid phase.
9. A process as defined in claim 7 wherein said reaction takes place under substantially anhydrous conditions.
10. A process as defined in claim 7 wherein said reaction is accomplished at a temperature of about 25°C to 200°C.
11. A process as defined in claim 7 wherein said reaction is accomplished at a temperature of about 100°C to 160°C.
12. A process as defined in claim 8 further comprising dispers-ing said monoalkyl ester salt in a sufficient quantity of said active hydrogen containing compound to enable said active hydrogen containing compound to function as both a reactant and a solvent for said reaction.
13. A process as defined in claim 8 further comprising dissolv-ing said monoalkyl ester salt and said active hydrogen contain-ing compound in a cosolvent prior to said reacting.
14. A process as defined in claim 13 wherein said reaction takes place at a temperature of about 25°C to 100°C.
15. A process as defined in claim 13 wherein said cosolvent is dimethylformamide, dimethylacetamide, dimethylsulfoxide or mixtures thereof.
16. A process as defined in claim 7 further comprising:
1) recovering said polyfunctional compound, and 2) hydrolyzing said recovered compound with an aqueous solution of an alkali or alkaline earth metal hydroxide to form a compound of the general formula wherein said Y is oxygen, sulphur or imino (NH), said M
is Ca, Ba, Mg, Sr, Na, K or Li, said x is 1 or 2 and is equivalent to the valency of M, and wherein Z is 1) a carboxylate moiety of the general formula wherein when Y is oxygen or sulphur R2 is hydrogen, methyl, ethyl or phenyl, and said M and x are as pre-viously defined, and when Y is NH,R2 is hydrogen, methyl, ethyl, iso-propyl, isobutyl, secondary butyl, benzyl, p-hydroxybenzyl or 2-(methylthio)ethyl, or 2) 2-hydroxyethyl or 3-hydroxypropyl.
1) recovering said polyfunctional compound, and 2) hydrolyzing said recovered compound with an aqueous solution of an alkali or alkaline earth metal hydroxide to form a compound of the general formula wherein said Y is oxygen, sulphur or imino (NH), said M
is Ca, Ba, Mg, Sr, Na, K or Li, said x is 1 or 2 and is equivalent to the valency of M, and wherein Z is 1) a carboxylate moiety of the general formula wherein when Y is oxygen or sulphur R2 is hydrogen, methyl, ethyl or phenyl, and said M and x are as pre-viously defined, and when Y is NH,R2 is hydrogen, methyl, ethyl, iso-propyl, isobutyl, secondary butyl, benzyl, p-hydroxybenzyl or 2-(methylthio)ethyl, or 2) 2-hydroxyethyl or 3-hydroxypropyl.
17. A process as defined in claim 16 wherein said compound produced by said hydrolysis has the formula wherein said M and said x are as defined in claim 16.
18. A process as defined in claim 16 wherein said compound produced by said hydrolysis has the formula wherein said M and said x are as defined in claim 16.
19. A process as defined in claim 7 further comprising:
1) recovering said polyfunctional compound, and 2) hydrolyzing said recovered compound with an aqueous solution of a mineral acid to form a compound of the general formula wherein said Y is oxygen, sulphur or imino(NH), Z is 1) a carboxylic moiety of the general formula , wherein when Y is oxygen or sulphur, R2 is hydrogen, methyl, ethyl or phenyl and when Y is NH, R2 is hydrogen, methyl, ethyl, iso-propyl, isobutyl, secondary butyl, benzyl, p-hydroxybenzyl or 2-(methylthio)ethyl, or 2) 2-hydroxyethyl or 3-hydroxypropyl.
1) recovering said polyfunctional compound, and 2) hydrolyzing said recovered compound with an aqueous solution of a mineral acid to form a compound of the general formula wherein said Y is oxygen, sulphur or imino(NH), Z is 1) a carboxylic moiety of the general formula , wherein when Y is oxygen or sulphur, R2 is hydrogen, methyl, ethyl or phenyl and when Y is NH, R2 is hydrogen, methyl, ethyl, iso-propyl, isobutyl, secondary butyl, benzyl, p-hydroxybenzyl or 2-(methylthio)ethyl, or 2) 2-hydroxyethyl or 3-hydroxypropyl.
20. A process as defined in claim 19 wherein said compound pro-duced by said hydrolysis has the formula
21. A process as defined in claim 19 wherein said compound produced by said hydrolysis has the formula ,
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/642,838 US4058554A (en) | 1975-12-22 | 1975-12-22 | Novel ester derivatives of ether polycarboxylic acids and process for making same |
| US642838 | 1975-12-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1115287A true CA1115287A (en) | 1981-12-29 |
Family
ID=24578246
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA268,030A Expired CA1115287A (en) | 1975-12-22 | 1976-12-16 | Ether polycarboxylate compounds and the production thereof |
Country Status (2)
| Country | Link |
|---|---|
| US (3) | US4058554A (en) |
| CA (1) | CA1115287A (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4663071A (en) * | 1986-01-30 | 1987-05-05 | The Procter & Gamble Company | Ether carboxylate detergent builders and process for their preparation |
| US4798907A (en) * | 1988-02-26 | 1989-01-17 | The Procter & Gamble Company | Controlled temperature process for making 2,2'-oxodisuccinates useful as laundry detergent builders |
| US5332505A (en) * | 1992-10-02 | 1994-07-26 | Betz Laboratories, Inc. | Method for inhibiting silica and silicate deposition |
| CN115557847A (en) * | 2021-06-30 | 2023-01-03 | 湖南师范大学 | Succinic acid monoester/amide amino acid surfactant containing ester/amide amino and preparation method thereof |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2062917A (en) * | 1933-09-14 | 1936-12-01 | Du Pont | Polycarboxylic acid esters |
| US2120688A (en) * | 1935-04-25 | 1938-06-14 | Monsanto Chemicals | Method of manufacturing substituted succinic acids and esters thereof |
| US2341846A (en) * | 1941-06-24 | 1944-02-15 | American Cyanamid Co | Polyhydric alcohol ethers of aliphatic polycarboxylic acid esters and their preparation |
| US2377246A (en) * | 1942-03-02 | 1945-05-29 | Monsanto Chemicals | Alkoxy-substituted aliphatic carboxylic acid compounds |
| US2438091A (en) * | 1943-09-06 | 1948-03-16 | American Cyanamid Co | Aspartic acid esters and their preparation |
| US3278593A (en) * | 1965-07-21 | 1966-10-11 | Eastman Kodak Co | Polyoxyalkylene ethers of citric acid |
| US3700599A (en) * | 1970-09-25 | 1972-10-24 | Economics Lab | Composition for mechanically cleaning hard surfaces |
| US3775475A (en) * | 1971-04-28 | 1973-11-27 | Shell Oil Co | Telomer products |
| DE2220295C3 (en) * | 1971-04-30 | 1981-11-12 | Unilever N.V., Rotterdam | laundry detergent |
| US3862219A (en) * | 1971-10-20 | 1975-01-21 | Ethyl Corp | Process for the preparation of alkali-metal salts of carboxyalkoxy succinates |
| US3943165A (en) * | 1972-07-14 | 1976-03-09 | Lever Brothers Company | Esters of carboxymethyloxysuccinic acid and derivatives thereof |
| US3935257A (en) * | 1974-03-18 | 1976-01-27 | Monsanto Company | Chemical compounds |
-
1975
- 1975-12-22 US US05/642,838 patent/US4058554A/en not_active Expired - Lifetime
-
1976
- 1976-12-16 CA CA268,030A patent/CA1115287A/en not_active Expired
-
1977
- 1977-07-07 US US05/813,733 patent/US4145558A/en not_active Expired - Lifetime
- 1977-09-09 US US05/832,031 patent/US4133960A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| US4058554A (en) | 1977-11-15 |
| US4133960A (en) | 1979-01-09 |
| US4145558A (en) | 1979-03-20 |
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