Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Patent
1999-10-04
2000-08-29
Barts, Samuel
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C07C20900
Patent
active
061111422
DESCRIPTION:
BRIEF SUMMARY
3-Amino-1,2-propanediol of formula (I), commonly known as isoserinol, is widely used as building-block of non-ionic iodinated X-ray contrast agents, as well as in the synthesis of antiinflammatories, analgesics and cosmetics. ##STR1##
The major industrial application of said products lies in the synthesis of a number of non-ionic X-ray contrast agents, such as: Iohexol, Iopentol, Iopromide, Ioversol, Ioxilan, Iodixanol.
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.
The high purity level of the compound of formula (I) is therefore extremely important in order to avoid formation of any by-products and assure high purity standards to the final products.
In literature, a number of methods for the purification of compound (I) are reported, the most widely used being distillation under vacuum (see, for example, EP 470004), and other procedures to remove water contained in the crude, always under reduced pressure (JP 3063251) or to decolourize the solution, again under reduced pressure (JP 3086851).
Nevertheless, said product is marketed with impurity contents ranging from 1% to 3% (see for instance the product marketed by ALDRICH or by MERCK).
The major starting syntons for the synthesis being glycidol or 3-chloro-1,2-propanediol, which are reacted with ammonia (see, by way of example, the following patents: JP 03063251 A2; DE 3830351A1; DE 3014129A1; DE 3014109A1; DE 3014098A1), the main organic impurities which can be expected, and in some cases described, are: glycerin, serinol, 3-chloropropane-1,2-diol, bis(2,3-dihydroxypropyl)amine, tert(2,3-dihydroxypropyl)amine.
In addition to these impurities, some inorganic acids, such hydrochloric and sulfuric acids, and by-products such as 5-amino-2,4,6-triiodoisophthalic acid should also be considered in case compound of formula (I) derives from recovery of contrast agents.
Different purification procedures can be selected depending on the type of and the content in impurities present in 3-amino-1,2-propanediol.
Among organic impurities, serinol is very difficult to remove completely, since it has chemical characteristics similar to those of the compound of formula (I).
The present invention relates to novel processes for the purification of compound of formula (I), which can be applied directly on the product both as the free base and its salts, depending on the impurities present in the starting product.
Object of the present invention is a process for the purification of compound of formula (I) to obtain products with a content in organic impurities <0.1% and in inorganic impurities lower than 0.05%, comprising the following steps: with (C.sub.1 -C.sub.5) straight or branched alcohols or alcohol solvents of formula Alc--OH wherein Alc is a (C.sub.3 -C.sub.7) straight or branched; from the group consisting of: oxalic acid, an X--Ph--COOH acid, wherein X is a substituent at the phenyl ring Ph such as H, Cl, NO.sub.2, Br and (C.sub.1 -C.sub.4) straight or branched alkyl, or p-toluenesulfonic acid; formula R--OH, wherein R is a (C.sub.1 -C.sub.6) straight or branched alkyl, or monoalkylether glycols of the class of (C.sub.3 -C.sub.7) alkylcellosolves, with water contents from 0.5% to 60%, depending on the used solvent; give compound of formula (I) as the free base; formula R--OH.
The extraction with solvents at 20.degree. C. to 50.degree. C. provides a first rough removal of the organic impurities from the water-dissolved or melted product.
Said procedure can be carried out continuosly on the industrial scale, thereby performing effectively a first rough removal of the impurities extracted by the organic solvent. The organic impurities present
Barts Samuel
Dibra S.p.A.
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