Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1999-04-30
2001-07-17
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C424S009452, C564S142000
Reexamination Certificate
active
06262303
ABSTRACT:
The present invention relates to a process for the preparation of S-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxo-propyl)amino]-2,4,6-triio-do-1,3-benzenedicarboxamide of formula (I), more commonly known as Iopamidol, one of the most widely marketed iodinated contrast, comprising a novel step for the synthesis of the intermediate S-N,N′-bis[2-hydro-xy-1-(hydroxymethyl)ethyl]-5-[(2-(acetyloxy)-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide of formula (II).
The synthesis of Iopamidol was first described in GB 1,472,050 and it involves the steps represented in the following Scheme:
and precisely the reaction of S-(−)-5-[[2-(acetyloxy)-1-oxopropyl]amino]-2,4,6-triiodo-1,3-benzenedicarboxylic acid dichloride of formula (III) dissolved in dimethylacetamide (DMAC) with a slight excess of 2-amino-1,3-propanediol (commonly named serinol) also dissolved in dimethylacetamide, in the presence of tributylamine, to give compound (II), S-N,N′-bis[2-hy-droxy-1-(hydroxymethyl)ethyl]-5-[(2-(acetyloxy)-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide.
The ratio between compound (II), serinol and tributylamine is 1:2.5:2 expressed in equivalents. The reaction is carried out at 50° C., yielding, after some hours, the desired product in a 92% yield.
The work up of the reaction mixture, described in the cited Patent, comprises evaporating dimethylacetamide, suspending the oily residue in methylene chloride, repeatedly taking up the precipitate with hot methylene chloride.
The resulting residue is then hydrolysed to Iopamidol with NaOH, the subsequent treatment of the resulting solution with a cationic and an anionic resin allows to purify it from the salts before recrystallizing from ethyl alcohol.
The main problems with this process are the following:
the distillation of the solvent under vacuum at the end of the reaction is a quite troublesome operation from the industrial point of view, DMAC being a high boiling product (165° C.);
the use of DMAC gives rise to N-[2-hydroxy-1-(hydroxymethyl)ethyl]-N′-dimethyl-5-[(2-hydroxy-oxo-propyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide, (hereinafter referred to as impurity I).
one of the seven impurities of Iopamidol described in Pharmeuropa, vol. 6, no.4, December 1994, pages 343-345, which is ascribable essentially to the production of dimethylamine by DMAC during the work up of the reaction;
moreover, the use of such a high boiling solvent is quite troublesome and difficult so that solvent traces remain in the recovered solid product, which traces, however, have not to exceed 650 ppm (USP limit for Iopamidol).
A first attempt to replace DMAC was made by GB 2,272,218 (priority 27.10.1992), in which the preparation of only compound (II) is described, using solvents different from DMAC, i.e. acetone or lower (C
1
-C
4
) alcohols, in the presence of a base, preferably tributylamine.
As acknowledged by the inventors themselves in the subsequently published patent application GB 2,311,524, which will be discussed in the following, Iopamidol obtained from intermediate (II), in spite of his having an acceptable purity grade, also had different impurities instead of the impurity I.
Physicians and the authorities which grant drug marketing authorizations, require drugs with very low levels of impurities in order to minimize any involved risks of side-effects or toxic effects for the patient.
As far as iodinated contrast agents are concerned, such a requirement is due to the total amount of administered product, which is much higher than that of other medicaments. By way of example, the injected dose of contrast agent can reach and even exceed 150 g.
Iopamidol has, in fact, recently undergone a change in its pharmacopoeia requirements, (Italian Pharmacopoeia IX, 3rd revision 1994; US Pharmacopoeia XXIII, 5th revision, Nov. 15, 1996) and it has now to contain at most 0.25% of impurities.
The recently published British patent application GB 2,311,524 (priority 29.03.1996), discloses an alternative approach to obtain Iopamidol with such purity characteristics.
GB 2,311,524 describes the preparation of compound (I), using N-methylpyrrolidone as reaction solvent, in the presence of a base, preferably selected from serinol, tributylamine, triethylamine or an inorganic carbonate, claiming a higher purity of the obtained compound (II), which is reflected in the final purity of Iopamidol.
The preferred process involves the reaction of compound (III) with serinol in N-methylpyrrolidone, in the presence of previously purified triethylamine or of sodium carbonate. The subsequent treatment of the resulting crude through a battery of ion exchange resins (strong cationic, weak anionic, strong anionic, weak anionic, as described in GB 2,287,024) yields the final compound Iopamidol, with a declared purity in accordance with the revisioned pharmacopoeia requirements.
It is therefore evident from the study of the prior art the impelling exigency of:
avoiding the presence of DMAC, thereby also improving the profile of the impurities present in Iopamidol as well as the carrying out of the industrial process;
easily removing the reaction solvent: N-methylpyrrolidone belongs, in fact, to the same class of dipolar aprotic solvent as DMAC and, having a similar high boiling point, is therefore difficult to remove completely.
We have now surprisingly found that Iopamidol fulfilling the pharmacopoeia requirements can be prepared by the process of the invention comprising:
a novel method for the preparation of compound (II);
the easy transformation of the resulting compound (II) into Iopamidol without involving basic hydrolysis neither complex chromatographic treatments.
It is therefore the object of the present invention the preparation of compound (I) comprising the formation of compound (II) by reacting compound (III) with only serinol in a solvent selected from a lower alcohol and monoalkyl ether glycols of the class of alkylcellosolves and cyclic, straight or branched alkyl ethers.
“Lower alcohol” means a straight or branched C
2
-C
5
alcohol, preferably a secondary alcohol. Particularly preferred are t-butanol and sec-butanol.
Glycols are preferably comprised from C
3
and C
7
, ethoxyethanol and methoxyethanol being particularly preferred.
Cyclic, straight or branched alkyl ethers are C
4
-C
10
, and they are preferably selected from the group consisting of: dioxane, diglyme and methyl tert-butyl ether.
We have surprisingly found that the reaction carried out without the addition of a base, in particular tributylamine as in the prior art, and in an alcoholic or ether solvent, allows to effectively overcome the above mentioned problems related to the presence of DMAC, at the same time providing a final product with the purity characteristics in accordance with, or even better than, the present pharmacopoeia requirements.
As already discussed in GB patent application 2,311,524 (as well as described in WO 9214539) it was already known in the prior art that the reaction can be carried out without the use of a base, using more than 4 equivalents of serinol, which thus acts as an acceptor of the hydrochloric acid formed during the reaction itself. The reaction is, however, carried out in DMAC, thus involving the problems mentioned above.
GB 2,311,524 itself envisages the possible use of a serinol excess as a base (see Example 1, serinol/compound (II) molar ratio=4.36:1), but the solvent is anyway N-methylpyrrolidone and in all the described examples the reaction is carried out under nitrogen atmosphere, which is not a condition easy to reproduce industrially, and the subsequent hydrolysis process to Iopamidol involves a troublesome step through different ion exchange columns.
We have surprisingly found that when serinol is added in a molar ratio to compound (III) ranging from 6 to 25, preferably from 8 to 15, the addition of a base for the subsequent hydrolysis of compound (II) to Iopamidol is no longer nece
De Santis Nicola
Incandela Salvatore
Dibra S.p.A.
Kumar Shailendra
Nixon & Vanderhye
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