The present invention relates to a novel process for preparing 2-bromoglutaric acid
diesters.
5
α-Haloglutaric acids and esters thereof are useful basic building blocks in organic
synthesis, which make it possible to incorporate, into a complex molecule, an αglutaric acid fragment via a simple nucleophilic substitution reaction.
10 EP 1 931 673 describes novel gadolinium complexes derived from PCTA, which have
applications as contrast agents in the field of medical imaging. The side chains of some
of these complexes, notably of gadopiclenol, include an α-glutaric acid fragment. The
synthesis of gadopiclenol, in the form of a mixture of all its stereoisomers, as described
in EP 1 931 673, involves the alkylation of pyclene with diethyl 2-bromoglutarate,
15 resulting in an intermediate hexaester, which is then hydrolyzed to give the
corresponding hexaacid, which is then complexed with a source of gadolinium. The
gadopiclenol prepared according to the process described in EP 1 931 673 is finally
obtained by reacting the gadolinium hexaacid complex with 3-amino-1,2-propanediol.
20 Synthesis of gadopiclenol
3
Diethyl 2-bromoglutarate (referred to as EBG hereinbelow) is a relatively unstable
compound, which degrades over time, under the effect of the temperature or in the
presence of water. More precisely, this particular α-haloglutaric ester has a tendency
to become hydrolyzed or to cyclize and thus to lose its bromine atom. Attempts to
5 purify commercial EBG, or to develop novel synthetic routes for obtaining it with
improved purity, and thus preventing its degradation, have been unfruitful.
The inventors thus sought an alternative to EBG, which would be more stable than it,
while at the same time being sufficiently reactive to achieve the synthesis of
10 gadopiclenol, for example. Thus, chloro derivatives of glutaric acid, which meet the
criterion of improved stability relative to EBG, do not constitute a satisfactory option,
insofar as they do not have sufficient reactivity. Iodo derivatives are, for their part,
more reactive than their bromo analogs, but are also more unstable. The investigations
conducted by the inventors enabled them to select di-(C3-C6)-alkyl 2-bromoglutarate
15 compounds as an alternative to EBG, in particular in the synthesis of gadopiclenol.
However, the corresponding commercial products do not have a high enough degree of
purity to be used in the preparation of a pharmaceutical product intended for human
administration, such as gadopiclenol.
20 It is thus necessary to develop a novel process for preparing di-(C3-C6)-alkyl 2-
bromoglutarate compounds, which enables them to be obtained with a sufficient
degree of purity, and which can be performed efficiently on an industrial scale.
Now, the synthesis of 2-bromoglutaric acid diesters is very sparingly described in the
25 literature. Patent CS 209266 B1, granted in 1983, is, to the inventors’ knowledge, the
only document that mentions the preparation of these compounds. It relates in general
to a process for preparing an α-haloglutaric acid or an alkyl diester thereof of formula
R’O2CCH2CH2CH(X)CO2R’’, in which R’ and R’’ are (C1-C5)alkyl groups and X corresponds
to a bromine or chlorine atom, the emphasis however being clearly placed on the
30 preparation of the chloro derivatives. Said derivatives are obtained by chlorination of
the glutaric acid diester in the presence of an antimony-based catalyst. Although said
document asserts that the method described makes it possible to perform
monochlorination in the α position with better selectivity than in the processes of the
prior art, the fact remains that appreciable amounts of β-chloro or α-dichloro and
35 trichloro derivatives are formed, the selectivity with respect to the α-monochloro
4
product ranging between 63.16% and 86.1% depending on the nature of the antimonybased catalyst, the degree of conversion of the starting ester itself oscillating between
86.10% and 98.9%. It should be noted that the conditions for which the degree of
conversion of the starting material is the highest allow the α-monochloro product to
5 be obtained with a selectivity of only 79%. Another major drawback of this process is,
moreover, the use of antimony, which is extremely toxic.

1. A process for preparing the 2-bromoglutaric acid diester of formula (I) below:
(I)
5 in which R represents a (C3-C6)alkyl group,
comprising the following steps:
(b) formation of the 2-hydroxyglutaric acid diester of formula (II)
(II)
by reaction of butyrolactone acid of formula (BA)
10 (BA)
with the alcohol of formula ROH, in the presence of an acid such as sulfuric acid; and
(c) bromination of the 2-hydroxyglutaric acid diester of formula (II), by sparging with
gaseous hydrobromic acid, leading to the 2-bromoglutaric acid diester of formula (I).
15 2. The process as claimed in claim 1, characterized in that step (b) is performed in the
presence of the acetate of formula CH3COOR.
3. The process as claimed in claim 1 or 2, characterized in that, during step (b), the
water is removed by vacuum distillation.
20
4. The process as claimed in any one of claims 1 to 3, characterized in that in step (b),
butyrolactone acid of formula (BA) and the alcohol ROH are introduced in amounts
such that the ROH/BA mole ratio is between 2 and 10.
25 5. The process as claimed in any one of claims 1 to 4, characterized in that, on
conclusion of step (b), the reaction medium is cooled to a temperature below 15°C
and is left to separate by settling after addition of water so as to obtain the formation
of an organic phase and a separate aqueous phase, said aqueous phase then being
removed and said organic phase being dehydrated by vacuum distillation and/or
30 concentration under vacuum before being subjected to step (c).
22
6. The process as claimed in any one of claims 1 to 5, characterized in that step (c)
comprises the following cycle of steps:
- setting the temperature of the reaction medium to a value of between 5°C and 40°C,
5 - introducing gaseous hydrobromic acid in an amount of between 1 and 1.5 mol. eq.
relative to the amount of butyrolactone acid (BA) used in step (b),
- vacuum distillation for a time advantageously between 3h and 8h so as to remove
water from the reaction medium,
- restoring the temperature of the reaction medium to a value of between 5°C and
10 40°C,
said cycle of steps being advantageously repeated from 3 to 8 times.
7. The process as claimed in any one of claims 1 to 6, characterized in that it comprises
a first step (a) of forming butyrolactone acid of formula (BA) by reacting L-glutamic
15 acid with sodium nitrite in aqueous solution.
8. The process as claimed in any one of claims 1 to 7, characterized in that the reaction
mixture obtained on conclusion of step (c) is subjected to the following additional
steps:
20 (d) introduction of the reaction mixture obtained on conclusion of step (c) into a basic
aqueous solution, the solution obtained having a pH typically between 7.5 and 9.5;
(e) separation by settling of the solution obtained in step (d), so as to obtain the
formation of an organic phase and a separate aqueous phase, said aqueous phase being
then removed;
25 (f) concentration under vacuum of the organic phase obtained in step (e), until a
temperature of between 65°C and 75°C is reached, followed by drying under vacuum;
(g) optionally, filtration; and
recovery of the 2-bromoglutaric acid diester of formula (I).
30 9. The process as claimed in any one of claims 1 to 8, characterized in that the 2-
bromoglutaric acid diester of formula (I) obtained on conclusion of step (c), (f) or (g)
is subjected to an additional racemization step by adding a bromine salt, such as LiBr
or tetrabutylammonium bromide.
23
10. The process as claimed in any one of claims 1 to 9, characterized in that R
corresponds to an n-butyl group.
11. The process as claimed in any one of claims 3 to 10, characterized in that the
5 vacuum distillation operations taking place during steps (b) and (c) are azeotropic
distillations.
12. A compound of formula (I) below:
(I)
10 in which R represents a (C3-C6)alkyl group, preferably a butyl group,
with a degree of purity, determined by HPLC analysis, of greater than or equal to 90%.
13. The compound as claimed in claim 12, characterized in that R corresponds to an
n-butyl group.
15
14. The compound as claimed in claim 12 or 13, characterized in that its degree of
purity is greater than or equal to 95%.
15. The compound as claimed in any one of claims 12 to 14, characterized in that its
20 degree of purity is greater than or equal to 97%.