Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid anhydrides
Reexamination Certificate
2000-07-31
2002-02-12
Geist, Gary (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid anhydrides
C562S888000
Reexamination Certificate
active
06346650
ABSTRACT:
The present invention relates to a process for manufacturing mixed anhydrides represented by the general formula (I):
in which:
R
1
represents H or CH
3
; and
R
2
represents an alkyl, alkenyl, aryl, alkaryl or aralkyl residue, according to which process an alkali metal (meth)acrylate of general formula (II):
in which:
R
1
is as defined above; and
M is an alkali metal, is reacted with a chloroformate of general formula (III):
in which R
2
is as defined above.
Mixed anhydrides are mild acylating agents, the use of which has been described in peptide synthesis in place of conventional anhydrides
and acid chlorides
In audition, the only by-products generated by the mixed anhydrides of formula (I) in the acylation reactions are CO
2
and the alcohol R
2
OH, which are easier to remove than (meth)acrylic acid or HCl.
The processes for synthesizing the non-acrylic mixed anhydrides which have been described in the literature are mostly based on the method described by Vaughan in J. Am. Chem. Soc. 73, 3547, 1951: the mixed anhydride is synthesized by equimolar reaction between an alkyl chloroformate and a tertiary amine carboxylate, at low temperature (generally less than 0°), in a solvent medium (tetrahydrofuran, acetone, toluene, chloroform, etc.). Besides the need to work in a solvent medium, at very low temperature, one of the main constraints of the process lies in the fact that it is necessary to separate off by filtration the trialkylammonium chloride which precipitates in the medium.
In Bull. Chem. Soc. Jap. 1968, 41, 2521-3, Harada and Kondo describe, among the examples, the synthesis of carboethoxymethacrylic anhydride:
by reaction between potassium methacrylate and ethyl chloroformate, in a solvent medium (chloroform), at 0° C., in the presence of pyridine.
The synthesis of carboethoxymethacrylic anhydride is also described in French patent application FR-A-2 212 340, starting with triethyl-ammonium methacrylate and ethyl chloroformate in a solvent medium (acetonitrile).
The synthesis of non-acrylic mixed anhydrides is described in German patent DE-C-1 133 727 by reaction between a carboxylate and a chloroformate in a chloroformate/carboxylate molar ratio of between 0.95 and 1.10.
The processes described in the literature mostly relate to non-acrylic mixed anhydrides and present, depending on the case, many drawbacks, the chief ones being the use of solvents and the use of amines in stoichiometric amount relative to the carboxylic acid or in catalytic amount. The need to separate out the alkylammonium chloride by filtration also constitutes a drawback.
In most of the processes described in the literature, the reagents (II) and (III) are used in equimolar proportions or between 0.95 and 1.1. Under these conditions, it is possible to obtain a mixed (meth)acrylic anhydride
containing little symmetrical anhydride
R
1
being as defined above. This is particularly inconvenient when it is desired to synthesize carboxyalkoxy (meth)acrylic anhydride containing very little methacrylic anhydride.
It has been discovered, surprisingly, that these problems can be solved by modifying the conditions of the reaction between compounds (II) and (III), and in particular by carrying out this synthesis with a compound (III)/compound (II) molar ratio of greater than or equal to 1.15.
A subject of the present invention is thus a process for preparing a high-purity mixed (meth)acrylic anhydride (I), by reaction between the abovementioned compounds (II) and (III), characterized in that the said reaction is carried out in an aqueous medium and in the absence of amines, the chloroformate (III)/alkali metal (meth)acrylate (II) molar ratio being at least equal to 1.15.
In general, the reaction is carried out with compounds (II) and (III) in which:
R
2
is chosen from C
1
-C
40
alkyl, C
2
-C
40
alkenyl, phenyl, phenyl (C
1
-C
40
alkyl) and (C
1
-C
40
alkyl) phenyl residues; and
M represents Na or K.
The mixed anhydrides of formula (I) in which R
2
represents C
1
-C
40
alkyl, such as ethyl, n-propyl, isopropyl, n-butyl or isobutyl, are of particular interest and constitute a family of preferred mixed anhydrides of the invention. These are mild acylating agents which can very advantageously replace methacrylic anhydride or (meth)acryloyl chloride which generate methacrylic acid or hydrochloric acid in acylation reactions.
In the process of the present invention, the chloroformate (III)/alkali metal (meth)acrylate (II) molar ratio can be between 1.15 and 2, preferably between 1.5 and 1.7, in order to limit the formation of by-products of the type
for example. At and above 1.15, a substantial improvement in the selectivity and yields are observed; thus, when the synthesis of carboethoxymethacrylic anhydride is carried out by reaction between sodium methacrylate and ethyl chloroformate, a reduction in the formation of methacrylic anhydride and by-products is observed. Moreover, a high molar ratio is favourable in terms of selectivity, but is penalizing with respect to the production efficiency.
The reaction according to the present invention is advantageously carried out at a temperature of between −10 and +30° C., preferably between +10 and +20° C.
In accordance with one specific embodiment of the present invention, the alkali metal (meth)acrylate (II) is prepared in aqueous solution by neutralizing (meth)acrylic acid with the hydroxide MOH, the MOH/(meth)acrylic acid molar ratio being between 1 and 1.5, in particular between 1 and 1.1, and the water/alkali metal (meth)acrylate (II) weight ratio being between 1.5 and 7, in particular between 1.5 and 2, after which the chloroformate (III) is reacted with the alkali metal (meth)acrylate (II).
In accordance with one particularly advantageous characteristic of the present invention, the reaction between the alkali metal (meth)acrylate (II) and the chloroformate (III) is carried out in the presence of a phase-transfer catalyst, dissolved or fixed to a polymeric support such as a styrene-divinylbenzene copolymer or a crosslinked polyvinyl-pyridine resin and used in particular in a proportion of from 0.001 to 0.02 mol, in particular from 0.005 to 0.01 mol, per mole of alkali metal (meth)acrylate (II).
The phase-transfer catalyst is advantageously chosen from quaternary ammonium salts, phosphonium salts and crown ethers.
As examples of quaternary ammonium salts
mention may be made of those in which:
R
4
to R
7
each represent C
1
-C
40
alkyl, such as CH
3
, C
2
H
5
, C
4
H
9
, C
8
H
17
and C
16
H
33
, or aryl such as phenyl, or aralkyl such as benzyl;
X represents one from among Cl, Br, I, OH and HSO
4
;
and, in particular, tetramethylammonium chloride, benzyltrimethylammonium chloride, benzyltri-n-butylammonium chloride, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, methyltrioctylammonium bromide and tetra-n-butyl-ammonium hydrogen sulphate;
as examples of phosphonium salts, mention may be made of (C
4
H
9
)
4
P
⊕
Cl
⊖
, (C
4
H
9
)
4
P
⊕
Br
⊖
, (C
8
H
17
)
3
C
2
H
5
P
⊕
Cl
⊖
, (C
4
H
9
)
3
C
6
H
5
P
⊕
Cl
⊖
; and
as examples of crown ethers, mention on may be made of 18-crown-6 and dibenzoyl-18-crown-6.
Working in the presence of a phase-transfer catalyst increases the reaction substantially (3 to 5 hours as opposed to 15 hours without catalyst).
The reaction according to the invention is generally carried out with stirring in a thermostatically-controlled jacketed reactor while rigorously controlling the temperature. The crude reaction mixture separates out into two phases by settling if the stirring is stopped (or into three phases if a phase-transfer catalyst is used, fixed to a polymeric support). The reaction progress is monitored by regularly taking samples of the aqueous phase and assaying the residual alkali metal (meth)acrylate (II). The reaction is considered as complete when the degree of conversion of the alkali metal (meth)acrylate (II) is greater than 95%.
At the end of the reaction, the phases of the two-phase or three-phase reaction mixture
Fabis Frédéric
Paul Jean-Michel
Rault Sylvain
Riondel Alain
Atofina
Deemie Robert W.
Geist Gary
Millen White Zelano & Branigan P.C.
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