Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-05-14
2002-08-27
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S139000, C564S416000, C564S418000
Reexamination Certificate
active
06441235
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The process relates to an improved method of preparing 5-amino-N,N′-bis(R)isophthalamides, where R is 2,3-dihydroxy propyl or 1,3-dihydroxyisopropyl, which compounds are useful as intermediates in preparing iodinated diagnostic agents.
2. Description of the Prior Art
Nyegaard & Co. British Patent 1,548,594, published Jul. 18, 1979 describes a process for preparing 5-amino-N,N′-bis(2,3-dihydroxypropyl)isophthalamide as follows:
Dimethyl 5-nitro-isophthalate and 2.4 molar equivalents of 1-amino-2,3-propanediol were refluxed in methanol for twenty hours and the resulting 5-nitro-N,N′-bis(2,3-dihydroxypropyl)isophthalamide was isolated in 84% yield. The latter compound was suspended in aqueous hydrochloric acid and hydrogenated in the presence of a palladium oxide/charcoal catalyst. The resulting 5-amino-N,N′-bis(2,3-dihydroxypropyl)-isophthalamide was not isolated but the acid solution containing it was iodinated with sodium iodine dichloride to obtain 5-amino-2,4,6-triiodo- N,N′-bis(2,3-dihydroxypropyl)isophthalamide in 71% yield from the nitro compound (over-all yield of 59.5% from dimethyl 5-nitroisophthalate). Subsequent reactions are described for the preparation of 5-[N-(2,3-dihydroxy-propyl)acetamido]-2,4,6 triiodo-N,N′-bis(2,3-dihydroxypropyl)isophthalamide, useful as an X-ray contrast agent.
Felder et al. U.S. Pat. No. 4,001,323, issued Jan. 4, 1977 describes (Example 7) the reaction of 47.9 g. (0.2 mole) of dimethyl 5-nitroisophthalate and 22.8 g. (0.25 mole) of 1,3-dihydroxyisopropylamine (serinol), 5 hours at 140-150° C. and the isolation of 57.2 g. of 5-nitroisophthalic acid di(1,3-dihydroxypropylamide). This represents an apparent 80% yield based on the starting ester; however it is stoichiometrically impossible to obtain this amount of product in view of the deficiency in the amount of serinol since the reaction requires two moles of amine for every mole of ester. Felder et al. further describe the hydrogenation of the nitro bis-amide in ethanol solution in the presence of palladium-carbon catalyst and iodination of the resulting 5-aminoisophthalic acid di(1,3-dihydroxy-propylamide) in 75% over-all yield.
SUMMARY OF THE INVENTION
The invention relates to an improvement in the preparation of a compound of the formula
where R is CH
2
CH(OH)CH
2
OH or CH(CH
2
OH)
2
, which comprises reacting a di-lower-alkyl 5-nitroisophthalate with at least two molar equivalents of a compound of the formula RNH
2
in a solvent comprising a lower-aliphatic alcohol containing a basic catalyst to obtain a solution containing 5-nitro-N,N′-bis(R)isophthalamide, and, without isolating the latter, catalytically hydrogenating said solution to obtain a solution of 5- amino-N,N′-bis(R)-isophthalamide.
DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS
The starting material for the process of the invention is a di-lower-alkyl 5-nitroisophthalate wherein lower-alkyl preferably has from one to four carbon atoms. The conversion of the di-lower-alkyl 5-nitroisophthalate to 5-nitro-N,N′-bis(R)-isophthalamide takes place in a solvent comprising a lower-aliphatic alcohol containing a basic catalyst. The lower-aliphatic alcohol solvent is preferably a lower-alkanol or lower-alkoxyalkanol of one to four carbon atoms, for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methoxyethanol, 2-ethoxyethanol or 3-methoxypropanol. The basic catalyst is a strong base preferably derived from the addition of an alkali metal to the lower-aliphatic alcohol solvent. The amide formation is carried out at a temperature between about 65 and 150° C. depending upon the solvent used and conveniently at approximately the boiling point of the solvent, and the reaction is complete in a few hours.
The amine reactant, H
2
NCH
2
CH(OH)CH
2
OH, has an asymmetric carbon atom and thus exists in the racemic form and in its optically active dextro or levo forms. The process of the invention can be carried out with either the racemic form or one of the optically active forms.
No isolation of the intermediate 5-nitro-N,N′-bis(R)-isophthalamide is effected, and the solution thereof is directly hydrogenated in the presence of a catalyst effective in the reduction of aromatic nitro groups to amino groups. Exemplary of such catalysts are platinum or palladium or the oxides thereof, preferably supported on carbon. The hydrogenation reaction can be initiated at room temperature or above. Hydrogenation is complete in about one hour's time. The resulting 5-amino-N,N′-bis(R)isophthalamide can be isolated in the free base form by filtering off the catalyst and removing the solvent by evaporation or distillation; or in the form of an acid-addition salt by the addition of a strong inorganic or organic acid to the product solution whereby the respective acid-addition salt separates in crystalline form from the solution. Appropriate acid-addition salts are the hydrochloride, hydrobromide, methanesulfonate and the like.
The process of the instant invention possesses several distinct advantages over the processes disclosed in the prior art. The process disclosed and claimed herein can be carried out on a large scale in yield of 96.9-99.6%. This represents an improvement of 13-15% in yield over that (84%) described in British Patent 1,548,594 even assuming a quantitative yield in the catalytic hydrogenation reaction of the reference patent. Furthermore, the instant process can be carried out in a period of five hours effective reaction time as compared with 44 hours in the process of the British patent (20 hours for the amidation and one day for the hydrogenation). Finally, it has been found possible to use only a 5% excess of expensive 2,3-dihydroxypropyl-amine to obtain a nearly quantitative yield of product by the instant process as compared to a 20% excess in the process of the British patent.
REFERENCES:
patent: 4001323 (1977-01-01), Felder et al.
patent: 4256729 (1981-03-01), Lin
patent: 1186305 (2002-03-01), None
patent: 1 548 594 (1979-07-01), None
Gelotte Karl Olaf
Parady Edward David
Amersha, Health AS
Chisholm Robert F.
Kumar Shailendra
Ronning, Jr. Royal N.
Ryan Stephen G.
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