Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-07-17
2002-07-16
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S152000, C564S123000, C560S009000, C560S013000, C560S016000, C560S027000, C560S030000, C562S430000, C562S432000, C562S443000
Reexamination Certificate
active
06420603
ABSTRACT:
The present invention relates to a novel process for the preparation of N,N′-bis[2,3-dihydroxypropyl]-5-[(hydroxyacetyl)methylamino]-2, 4,6-triiodo-1,3-benzenedicarboxamide of formula (I), commonly known as Iomeprol, a novel non-ionic contrast agent which shows excellent safety and contrast effectiveness.
The synthesis of the compound of formula (I) was described first in EP 26,281, but the subsequent EP 365,541 suggested a different synthetic route, based on a Smiles' rearrangement reaction of 5-alkoxy-2,4,6-triiodo-1,3-benzenedicarboxamide derivatives in basic aqueous conditions, to give the corresponding 5-(hydroxyacyl)amino derivatives, according to Scheme 1 (see below).
The advantages of the latter synthesis over that described in EP 26,281 mainly derive from avoiding some reagents and solvents such as: thionyl chloride, acetic anhydride, methyl iodide, methylene chloride and chloroform, as well as reactions (such as the catalytic reduction with hydrogen), which under industrial production conditions are environmentally and toxicologically dangerous therefore requiring specific operative conditions.
The key intermediate of this synthetic route is the compound of formula (VII), which is synthesized as described in EP 185,130 and reported in Scheme 1.
The process comprises the use of 5-hydroxy-1,3-benzenedicarboxylic acid as starting compound, which is esterified under usual conditions with MeOH and acidic catalysis to methyl diester of formula (II). The latter is hot amidated with 1-amino-2,3-propanediol (commonly named isoserinol), with a 100% reagent excess. Methanol formed during the reaction is distilled and the amine excess is removed by means of a strong cationic resin to give the compound of formula (III). The resulting diamide is iodinated in aqueous basic solution with a 2.5M KICl
2
solution to give the compound of formula (IV).
No details are given concerning the recovery conditions of compound (IV) which is transformed into the corresponding sodium salt (V), then reacted while hot is methyl bromoacetate in dimethylacetamide to give, after recrystallization from methanol, the compound of formula (VI), which is subjected to amidation with hot methylamine to yield compound (VII). EP 185,130 discloses compound (VII) as an intermediate for the synthesis of a number of contrast agents deriving from N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-hydroxy-1,3-benzenedicarboxylic acid amide.
Scale-up of this process shows, however, unexpected technical problems, thus summarized:
in the formation of dimethyl ester of formula (II), as it is well known in literature, due to the characteristics of methanol, a non-catalytic amount of H
2
SO
4
is needed to shift the equilibrium towards the formation of the ester. Under these conditions, monomethyl sulfate forms as a side-product which, analogously to the well-known dimethyl sulfate, is dangerous for the health;
compound (IV), as well as the sodium salt of formula (V), has to be isolated from the aqueous solution;
the alkylation of compound (V) with methyl bromoacetate has to be carried out in dimethylacetamide, which should be recycled for economic reasons;
compound (VI) has to be purified by crystallization from methanol;
in the described iodination conditions, an excess amount of iodine has to be used, to the detriment of the subsequent synthetic step, in that such an excess can act as an oxidizer towards the alcohol moiety present in the amides at the 3- and 5-positions to give the following compound
which is hardly separable from compound (IV) and which, after the subsequent synthetic steps, produces an impurity which contaminates the final product, Iomeprol. This impurity is considerably toxic and its formation should therefore be prevented as much as possible.
For the purpose of making industrial syntheses more environmentally safe, avoiding the use of organic solvents as much as possible, while preventing the formation of side-products dangerous for health, a safe alternative process for the preparation of (VII) has been searched for.
It is therefore the object of the present invention a novel process for the preparation of Iomeprol, comprising the steps represented in the following Scheme 2:
a) esterification with butanol and acidic catalysis to give 5-hydroxy-1,3-benzenedicarboxylic acid butyl diester (VIII);
b) amidation of compound (VIII) with an isoserinol excess, to give an aqueous solution of N,N′-bis-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzene-dicarboxamide (III);
c) iodination of compound (III) with ICl, in stoichiometric amounts or in a 1% excess, to give N,N′-bis-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide (IV);
d) alkylation of compound (IV) with compound (IX), 2-chloro-N-methyl-acetamide, in aqueous solution, to give N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[2-(methylamino)-2-oxoethoxy]-1,3-benzene-dicarboxamide (VII), which is used as humid product; finally,
e) Smiles' rearrangement of compound (VII) in basic conditions and subsequent purification to give Iomeprol (I).
A further object of the present invention is the process for the preparation of compound (VII), an useful intermediate for the preparation of iodinated contrast agents as described in EP 185,130, comprising steps a), b), c) and d), and further the final drying (VII).
Contrary to what disclosed in EP 185,130, the process of the present invention is characterized in that all synthetic steps b) to e), including the preparation of the alkylating agent of formula (IX), are carried out in aqueous solution, in that organic solvents are avoided and in that the recovery of the single intermediates is no longer necessary, but it is possible to operate continuously directly on the solutions of the intermediates themselves.
In step a) the formation of the butyl diester of formula (VIII) allows to successfully overcome the problems cited above. In fact operating according to the process of the invention it is possible to use a catalytic amount of H
2
SO
4
, preferably corresponding to 6% by mol on 5-hydroxy-1,3-benzenedicarboxylic acid.
Alternatively, a catalytic amount of p-toluenesulfonic acid monohydrate can be used, preferably in amounts equivalent to 6% by mol on 5-hydroxy-1,3-benzenedicarboxylic acid. The esterification reaction can also be carried out in the hot and operating under gradually decreasing reduced pressure, instead at atmospheric pressure.
Compound (VIII) can be recovered either by direct crystallization form the final reaction mixture, previous concentration, or by precipitation from an alkali aqueous solution, previous elimination of the organic solvent. In the first case, the final crystallization is carried out in the cold (T of about 5° C.), and more crops have to be recovered through repeated concentrations of mother liquors, or mother liquors of the first crop have to be recycled and used for a subsequent esterification reaction. In the second case (recovery from an alkaline aqueous solution) the reaction mixture is concentrated to a residue, which is subsequently treated with an aqueous solution of an inorganic base (preferably sodium or potassium hydroxide or ammonia): by controlled cooling of the resulting emulsion, compound (VIII) is obtained as a partially crystalline solid. Compound (VIII) can be filtered or centrifuged or filter-pressed and dried.
Alternatively, compound (VIII) can be redissolved in n-butanol and the resulting solution can be used in the subsequent step b). The advantages of the direct use of the solution are the possibility to avoid the recovery step of the humid product as well as, above all, the drying step, which requires a prolonged treatment in static dryer under vacuum at 30-40° C., compound (II) being a low-melting solid.
Step b) is substantially equivalent to that described in the above Patent, and consists in the amidation of compound (VIII) with isoserinol.
The reaction is carried out in the melted state, (i.e. in a 120% isoserinol excess), at a temperature of 90-95° C., for a time o
Alessandroni Laura
Ambrosetti Patrizia
Argese Maria
Geremia Renato
Moretti Enrico
Bracco International B.V.
Killos Paul J.
Reyes Hector M.
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