GB2272218A

GB2272218A - Process for the preparation of l-5-(2- - acetoxy-propionylamino)-2,4,6-triiodoisophthalic acid bis-(1,3-dihydroxy-propylamide)

Info

Publication number: GB2272218A
Application number: GB9320888A
Authority: GB
Inventors: Marco Villa; Antonio Nardi; Fabio Benedetti
Original assignee: Zambon Group SpA; Zambon SpA
Current assignee: Zambon Group SpA; Zambon SpA
Priority date: 1992-10-27
Filing date: 1993-10-11
Publication date: 1994-05-11
Anticipated expiration: 2013-10-11
Also published as: NL194271C; ITMI922451A0; GB2272218B; ES2073370B1; GB9320888D0; CH688147A5; NL194271B; FR2697249A1; NL9301822A; FR2697249B1; IT1256163B; DE4336154A1; ES2073370A1; ITMI922451A1

Abstract

The known process for the preparation of L-5-(2-acetoxy-propionylamino)-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxypropylamide), which consists of reacting L-5-(2-acetoxy-propionylamino)-2,4,6-triiodo- isophthalic acid dichloride with 2-amino-1,3-propanediol in the presence of a base, is improved by carrying it out in acetone, or a lower alcohol, especially isopropanol, s.butanol or t.butanol, as reaction solvent. The recovery of the product is simplified. Using the same process the preparation of 5-amino-2,4,6-triiodo- isophthalic acid bis-(1,3-dihydroxypropylamide) or a protected form thereof is also claimed.

Description

2272218 TITLE:

Process for the preparation of L-5-(2-acetoxy-propionylamino)-2,4,6triiodo-isophthalic acid bis-(1,3-dihydroxy-propylamide) DESCRIPTION:

The invention relates to a process for the preparation of L-S-(2-acetoxypropionylamino)-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxypropylamide) (hereinafter "compound All).

Compound A, described in British Patent Specification No. 1472050 is useful as an intermediate in the synthesis by desacetYlation of L-S-(2hydroxypropinylamino)-2,4,6-triiodo-isophthalic acid bis-(1,3dihydroxypropylamide), also described in the above cited British Patent Specification. The latter compound can be used in diagnostics as a nonionic X-ray contrast medium.

To our knowledge, the industrial synthesis of compound A remains that described in the aforesaid British Patent Specification and consists of the following steps:

1. the starting material, 5-amino-2,4,6-triiodo- -isophthalic acid (compound B), is prepared by iodination of 5-amino- isophthalic acid; 2. compound B is converted to 5-amino-2,4,6-triiodo- -isophthalic acid dichloride (compound C); 3. reaction of compound C with the chloride of L-2- -acetoxy-propionic acid (acetyl-lactic acid) to give L-5- (2-acetoxypropionyl amino) -2, 4, 6-triiodo-isophthalic acid dichloride (compound D); 4. reaction of compound D with 2-amino-1,3- -propanediol in dimethylacetamide in the presence of a base to afford compound A.

Other synthetic methods have been described. For example, an alternative synthesis involves the inversion in the order of steps 3 and 4, namely the reaction of compound C with 2- amino-1,3-propanediol to give 5-amino-2,4,6-triiodo-isophthalic acid bis- (1,3-dihydroxypropylamide) or a protected form thereof and its reaction with L-2-acetoxypropionic acid chloride to give compound A. To the extent of our knowledge, however, these alternative syntheses have not been industrially applied.

The reaction of step 4 as described in Example 1, part A of the abovementioned British Patent- Specification comprises adding a solution of 2-amino-1,3-propanediol in di methyl acet amide (hereinafter I'DMA") to a solution of compound D and tributylamine in DMA. The equivalence ratio between compound D, the 2-amino-1,3-propanediol and the base (tributylamine) is 1:2.5:2. The reaction is carried out at 50C and provides, after a few hours, the desired product with a 92% yield. The work-up of the reaction product comprises the evaporation of the DMA, the suspension under vigorous stirring of the oily residue in methylene dichloride and the repeated recovery of the precipitate with hot methylene dichloride.

Repetition of this preparation in our laboratories revealed various drawbacks that would make such a synthesis troublesome from an industrial point of view. The distillation under vacuum of the solvent at the end of the reaction would need several hours because DMA is a high boiling solvent (165'C). The purification of the product, precipitated by methylene dichloride from the residue of DMA distillation, comprises several treatments with hot methylene dichloride; such an operation besides being long and industrious, does not provide the purification of the product from the residual 2-amino-1,3-propanediol since it too is insoluble in methylene dichloride. The crude product which is obtained after these operations, even if with a yield reflecting that reported in the aforesaid British Patent Specification, ll 3in practice has a quite low purity (80% titre) as it contains relevant quantities of butylamine hydrochloride and of 2-amino-1,3-propanediol or its hydrochloride.

The use of DMA certainly facilitates the reaction itself but, nevertheless, presents the above described drawbacks of the troublesome removal of the DMA, the complicated work-up of the mixture and the low purity of the desired product. Despite these drawbacks, to the extent of our knowledge, DMA is still the solvent used industrially. Thus, it could be concluded that the use of DMA, or of an equivalent solvent such as dimethylformamide, is absolutely necessary in carrying out such a reaction.

we have surprisingly found that, by carrying out the reaction in acetone or in a lower alcohol, the desired compound A is obtained in yields comparable to those of the prior art but, at the same time, all the drawbacks in the work-up of the reaction mixture and the purity of the desired product are overcome.

In a process for the preparation of L-5-(2-acetoxy -propionylamino)-2,4,6-triiodo-isophthalic acid bis-(1,3 -dihydroxypropylamide) by reacting L-5-(2-acetoxy -propionylamino)-2,4,6-triiodo-isophthalic acid dichloride with 2-amino-1,3-propanediol in the presence of a base, the improvement of the invention consists in using acetone or a lower alcohol as reaction solvent.

By the term lower alcohol we ref er to C 1- C 4 alcohols normally used as industrial solvents. Among them C 3-C4 alcohols are preferred and, in particular, isopropanol, s.butanol and t.butanol.

With respect to the use of acetone or a lower alcohol as a solvent, the following practical advantages, whose industrial importance is selfevident, are obtained:

the desired product (compound A precipitates and can be separated by filtration rather than by distillation of the solvent as in the case of DMA; the compound A is purified by cold washing with alcohol or acetone since the organic base and 2-amino-1,3-propanediol can be removed with cold solvent. It is important to point out how the elimination of 2-amino-1,3- propanediol is one of the main problems in the synthesis according to the abovementioned British Patent Specification; the desired product is obtained in yields comparable to those obtained using DMA as a solvent, but the purity of the product is definitely higher (titre higher than 95%, even equal to 99%); the use of a lower alcohol or acetone as a solvent is equally suitable in the alternative above described process, namely the reaction between compound C, optionally protected, and 2-amino1,3-propanediol.

From a practical point of view the reaction according to the invention can be carried out by adding 2-amino-1,3-propanediol to a solution containing both the compound D and the base, preferably tributylamine, in alcohol (preferably isopropanol or s.butanol) or in acetone, kept under stirring at temperatures between 20 and 1000C and preferably between 40 and 60C. At the end of the reaction the mixture is cooled at 10-150C, the compound A which precipitates is filtered off and cold washed with alcohol and/or acetone. The yield is high and the product is highly pure.

The following Examples illustrate the invention.

Example 1

2-Amino-1,3-propanediol (0.451 g; 4.96 mmol) was added to a solution of LS-(2-acetoxy-propionylamino)-2,4,6-triiodo-isophthalic acid dichloride (1. 6 g; 2.25 mmol) V 1 i and tributylamine (0.92 g; 4.96 mmol) in isopropyl alcohol (8 ml), kept under stirring at SO'C and under nitrogen atmosphere. The mixture was kept under stirring at 5CC for 16-18 hours and the reaction was monitored by thin layer chromatography on silica gel, eluting with methylene dichloride: methanol 10:3. At the end it was cooled at 150C and kept under stirring for 1 hour. The product was filtered under nitrogen, washed with isopropyl alcohol at 15'C (2 X 2 ml) and dried under vacuum (50'C, 25 mm/Hg).

1.5 g of L-5-(2-acetoxy-propionylamino)-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxy-isopropylamide) were obtained (99% HPLC titre; 81% yield), m.p. = 187-190C.

Mother liquors contained further 0.15 g of product for an overall 89.6% yield recoverable by evaporation of the solvent and conventional work-up, such as treatment with solvents or mixtures of solvents and chromatographic methods keeping into account the higher solubility of compound A in water.

Example 2

2- Amino- 1, 3-propanedi ol (0.28 g; 3.07 mmol) was added to a solution of L-S-(2-acetoxy-propionylamino)-2,4,6-triiodo-isophthalic acid dichloride (1 g; 1.4 mmol) and tributyltin (0.57 g; 3.07 mol) in s. butanol (4 ml), kept under stirring at SOOC and under nitrogen atmosphere. The mixture was kept under stirring at 50C for 18 hours and the reaction was monitored by thin layer chromatography on silica gel, eluting with methylene dichloride:methanol 10:3. At the end it was cooled at 15C and kept under stirring for 1 hour. The product was filtered under nitrogen pressure, washed with s.butanol (2 mi) and acetone (2 x 2 ml) and dried under vacuum (500C, 25 mm/Hg).

0.99 g of L-S-(2-acetoxy-propionylamino)-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxy-isopropylamide) were obtained (99% HPLC titre; 84.1% yield). Mother liquors contained further 0.069 g of product for an overall 90.1% yield.

Example 3

2-Amino-1,3-propanediol (0.28 g; 3.07 mmol) was added to a solution of L5-(2-acetoxy-propionylamino)-2,4,6-triiodo-isophthalic acid dichloride (1 gT 1.4 mmol) and tributylamine (0.57 g; 3.07 mmol) in acetone (4 ml), kept under stirring at 50C and under nitrogen atmosphere. The mixture was kept under stirring at 5VC for 18 hours and the reaction was monitored by thin layer chromatography on silica gel, eluting with methylene dichloride:methanol 10: 3. At the end it was cooled at 15'C and kept under stirring f or 1 hour. The product was filtered under nitrogen pressure, washed with acetone (2 x 2 ml) and dried under vacuum (50cC, 25 mm/Hg).

0.76 g of L-5-(2-acetoxy-propionylamino)-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxy-isopropylamide) were obtained (98% HPLC titre; 64.6% yield). Mother liquors contained further 0.31 g of product for an overall 91.4% yield.

Example 4

2-Amino-1,3-propanediol (0.28 g; 3.07 mmol) was added to a solution of L5-(2-acetoxy-propionylamino)-2,4,6-triiodo-isophthalic acid dichloride (1 g; 1.4 mmol) and diazabicyclooctane (0.172 g; 1.53 mmol) in isopropyl alcohol (4 ml), kept under stirring at 5CC and under nitrogen atmosphere. The mixture was kept under stirring at 50C for 18 hours and the reaction was monitored by thin layer chromatography on silica gel, eluting with methylene dichloride: methanol 10:3. At the end it was cooled at 150C and kept under stirring for 1 hour. The IQ -7product was filtered under nitrogen, washed with isopropyl alcohol (2 x 2 ml) and dried under vacuum (SO'C, 25 mm/Hg).

0.85 g of L-S-(2-acetoxy-propionylamino)-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxy-isopropylamide) were obtained (95% HPLC titre; 70% yield). Mother liquors contained further 0.184 g of product for an overall 86'I'l. yield.

Claims

1. A process for the preparation of L-5-(2-acetoxy-propionylamino)-2,4,6triiodo-isophthalic acid bis-(1,3-dihydroxy-propylamide), the process comprising reacting L-5-(2-acetoxy-propionylamino)-2,4,6-triiodoisophthalic acid dichloride with 2-amino-1,3-propanediol in the presence of a base and in acetone or a lower alcohol as reaction solvent.

2. A process for the preparation of '5-amino-2,4,6 -triiodo-isophthalic acid bis-(1,3-dihydroxypropylamide) or a protected form thereof, the process comprising reacting 5-amino-2,4,6-triiodo-isophthalic acid dichloride or a protected form thereof with 2-amino-1,3 -propanediol in the presence of a base and in acetone or a lower alcohol as reaction solvent.

3. A proess according to claim 1 or claim 2 in which the alcoholic solvent is isopropanol, s.butanol or t.butanol.

4. A process for the preparation of L-5-(2-acetoxy-propionylamino)-2,4,6triiodo-isophthalic acid bis-(1,3-dihydroxypropylamide), the process being substantially as described herein with reference to any of the Examples.

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