Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1998-06-17
2003-08-26
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
Reexamination Certificate
active
06610885
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a process for the preparation of iodinated X-ray contrast agents, in particular non-ionic N-alkylated-acylamino-triiodophenyl compounds such as iohexol, iodixanol, iopentol and ioxilan.
BACKGROUND OF THE INVENTION
Non-ionic iodinated X-ray contrast agents have achieved great commercial success over the past twenty years and accordingly improving the efficiency of their manufacture is of great importance.
The manufacture of non-ionic contrast agents includes production of the chemical drug substance (primary production), followed by formulation to drug product (secondary production). The drug substance is usually made in a multistep chemical synthesis, and is thoroughly purified before formulation. As with any commercial drug production it is important to optimize yield, process time and demand for expensive equipment. All these parameters depend both on the chemical reaction conditions and the work-up between each step. The number of steps in the overall synthesis will of course be of great importance and if the work-up between individual process steps could be omitted significant improvement in efficiency can be obtained, provided that sufficient quality and yield are maintained for the final product.
Omitting the work-up between two process steps means that the second step will be performed in the crude reaction solution resulting from the previous step. Potential major advantages includes:
higher yield (through avoidance of loss of the intermediate in the work-up);
elimination of isolation, purification, drying and analysis of the intermediate;
significant reduction in equipment demand (eg. reactors, filters, driers, etc.); and
significant reduction of the process time.
Despite these potential advantages, in practice intermediates are usually worked up between successive process steps. The reasons for this often include the facts that impurities may carry through the process and that the optimum solvent for the first reaction is usually not the same as for the second reaction.
The present multistage preparation of certain non-ionic X-ray contrast agents requires successive acylation and N-alkylation reactions. Thus for example in the production of iohexol (as described in SE-7706792-4 and by Gulbrandsen in Kjemi No. 6/90, pages 6-8), 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodophthalamide (hereinafter 5-Amine) is acetylated to produce 5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodophthalamide (hereinafter 5-Acetamide) which is then N-alkylated to produce 5-[N-(2,3-dihydroxypropyl)-acetamido]-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodophthalamide (iohexol).
Similarly, in the production of iopentol as described in NO-160918, 5-Amine is acetylated to yield 5-Acetamide which is N-alkylated to produce 5-[N-(2-hydroxy-3-methoxypropyl)acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodophthalamide (iopentol).
In the production of iodixanol described in NO-161368, 5-Amine is acetylated to yield 5-Acetamide which is then reacted with a bifunctional alkylating agent, a coupling agent, to yield 1,3-bis(acetamido)-N,N′-bis[3,5-bis(2,3-dihydroxypropylaminocarbonyl)-2,4,6-triiodophenyl]-2-hydroxypropane (iodixanol).
In the preparation of iohexol described above, the acylation is effected in acetic anhydride in the presence of a catalytic amount of sulphuric acid followed by concentration and addition of methanol. Thereafter water and sodium hydroxide (to pH 10-11) are added, base hydrolysis (to remove O-acyl groups) proceeds for 4-5 hours and 5-Acetamide is isolated from the reaction mixture by cooling and neutralization with hydrochloric acid. The precipitated 5-Acetamide is filtered, washed with water and dried. The 5-Acetamide is then dissolved in propylene glycol with the addition of sodium methoxide, the resulting methanol is stripped off and the N-alkylating agent (1-chloro-2,3-propanediol) is added. After the N-alkylation reaction is complete, the reaction mixture is evaporated to dryness and further purification steps (involving crystallization from a further solvent, butanol) are performed to yield the purified iohexol in a form suitable for use in secondary production.
The 5-Amine to 5-Acetamide acylation described for the preparation of iopentol in NO-160918 is similar, with the 5-Amine being acylated in acetic anhydride in the presence of a catalytic amount of p-toluene sulphonic acid. After cooling the reaction mixture, a precipitate forms which is filtered off and suspended in a mixture of methanol and water and hydrolysed under basic conditions (pH 11.5). The 5-Acetamide product is filtered off after cooling to ambient temperature, neutralization with HCl and further cooling to 30° C. The 5-Acetamide is washed with water and dried before being suspended in propylene glycol. Sodium hydroxide is added and when all solid material has dissolved, the N-alkylating agent (here 1-chloro-3-methoxy-2-propanol) is added. After the alkylation is quenched, several purification steps are again required before satisfactorily pure iopentol is obtained.
For the synthesis of iodixanol described in NO-161368, 5-Acetamide is prepared and worked up as described for iopentol above. It is then suspended in water and dissolved therein with the addition of sodium hydroxide. The N-alkylating agent, the coupling reagent epichlorohydrin, is then added. After the reaction is complete it is quenched with dilute hydrochloric acid and further purification steps are carried out in order to obtain satisfactorily pure iodixanol.
SUMMARY OF THE INVENTION
It has now been surprisingly found that the work-up of the 5-Acetamide before the subsequent N-alkylation may be avoided without unacceptable loss in yield or purity of the acylated, N-alkylated product and without undue complication of the purification procedure for that product.
Thus viewed from one aspect the invention provides a process for the preparation of an N-alkyl-acylamino-phenyl-carboxylic acid or carboxylic acid derivative by liquid phase acylation and subsequent N-alkylation of a corresponding amino-phenyl-carboxylic acid (or carboxylic acid derivative) characterised in that said N-alkylation is effected by addition of an alkylating agent to a solution containing the reaction products of said acylation, ie. those that remain in solution during the liquid phase acylation.
Viewed from an alternative aspect the invention provides a process for the preparation of an N-alkyl-acylamino-phenyl-carboxylic acid or carboxylic acid derivative compound comprising acylating an amino-phenyl-carboxylic acid (or carboxylic acid derivative) in a liquid phase, base hydrolysing the acylated product to remove O-acyl groups from the N-acyl-amino intermediate and, maintaining the liquid phase at a basic pH, N-alkylating the N-acylamino intermediate.
DETAILED DESCRIPTION OF THE INVENTION
In the process of the invention, the aminophenyl carboxylic acid or carboxylic acid derivative starting product is preferably a compound having a total of three amino and carboxyl groups on the phenyl ring, eg. an aminoisophthalic acid or derivative or a diaminobenzoic acid or derivative. By carboxylic acid derivative is meant for example a salt, ester or amide, eg. an CONHR* or COOR* group where R* is optionally hydroxylated alkyl preferably optionally hydroxylated C
1-6
alkyl. Furthermore the starting compound is preferably a triiodophenyl compound, particularly an alkylamino-carbonyl-triiodophenyl compound and most particularly a 2,4,6-triiodo-2,5-bis(alkylamino-carbonyl)-aniline, such as 5-Amine for example. The alkyl moiety of any alkylaminocarbonyl group will preferably carry one or more hydroxyl groups and will typically contain up to 6, preferably up to 4 carbon atoms.
The acylation of the starting compound may be effected using any convenient acylating agent, eg. an acetylating agent such as for example an acid halide or more preferably acetic anhydride.
Following the acylation, which is conveniently acid catalysed, the product is base hydrolysed, eg. at p
Gulbrandsen Trygve
Holmaas Lars Terje
Ingvoldstad Odd Einar
Amersham Health AS
Bacon & Thomas
Killos Paul J.
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