NL9301822A - Process for the preparation of the compound L-5- (2-acetoxy-propionylamino) -2,4,6-triiodoisophthalic acid bis- (1,3-dihydropropylamide). - Google Patents

Description

Title: Process for the preparation of the compound L-5- (2-acetoxy-propionylamino) -2,4,6-triiodoisophthalic acid bis- (1,3-dihydropropylamide).

The present invention relates to a process for the preparation of an intermediate for organic synthesis and, more particularly, to a process for the preparation of the compound L-5- (2-acetoxy-propionylamino) -2,4, 6-triiodoisophthalic acid bis- (1,3-dihydro-propylamide) (hereinafter referred to as compound A).

The compound A, which was first described by the Swiss company Savac AG, for example in British Patent No. 1,472,050, can be used as an intermediate for organic synthesis, because it leads to the compound L- by deacetylation 5- (2-Hydroxypropionyl-amino) -2,4,6-triiodoisophthalic acid bis- (1,3-dihydroxypropyl-amide), also described in the above British patent, which in turn can be used in diagnostic techniques such as non-ionic X-ray contrast media.

To the best of our knowledge, the industrial synthesis of compound A is limited to that described in the aforementioned British Patent and consists of the following steps: 1. the starting material, 5-amino-2,4,6-triiodoisophthalic acid (compound B), is prepared by iodination of 5-aminoisophthalic acid; 2. preparation of 5-amino-2,4,6-triiodoisophthalic acid chloride (compound C); 3.reaction of compound C with L-2-acetoxy-propionic acid chloride (acetyl-lactic acid) to give L-5- (2-acetoxy-propionylamino) -2,4,6-triodoisophthalic acid dichloride (compound D );

4. reaction of compound D with 2-amino-1,3-propanediol in dimethylacetamide and in the presence of a base to give compound A

Other synthesis methods have also already been described, such as, for example, an alternative synthesis involving reversal of the order of steps 3 and 4, namely the reaction of compound C with 2-amino-1,3-propane diol to to give the compound 5-amino-2,4,6-triiodoisophthalic acid bis- (1,3-dihydroxypropylamide) or a protected form thereof (compound E) and its reaction with L-2-acetoxy-propionic acid chloride to give compound A, but as far as we know these syntheses are not used industrially.

The reaction of step 4 is described in Example 1 point A of the above British patent.

Such a reaction is carried out by adding a solution of 2-amino-1,3-propanediol in dimethylacetamide to a solution of L-5- (2-acetoxy-propionyl-amino) -2,4,6-triiodoisophthalic acid dichloride and tributylamine in dimethylacetamide.

The ratio of L-5- (2-acetoxy-propionylamino) -2,4,6-triiodoisophthalic acid dichloride (compound D), 2-amino-1,3-propanediol and the base (tributylamine) is in equivalents, Is2, 5s2.

The reaction is carried out at 50 ° C and, after a few hours, provides the desired product in 92% yield.

The further processing of the reaction mixture described in Example 1-A of British Patent No. 1,472,050 involves the evaporation of dimethylacetamide (hereinafter referred to as DMA), the suspension stirring vigorously the oily residue in methylene chloride and the recovery of the precipitate with hot methylene chloride several times.

In repeating the preparation described therein, we noted several drawbacks that make such synthesis difficult from an industrial point of view.

The vacuum distillation of the solvent at the end of the reaction is an operation which poses many problems in an industrial application since DMA is a high boiling solvent (165 ° C).

The purification of the product, precipitated by methylene chloride from the precipitate of the DMA distillation, because different treatments with hot methylene chloride; such an operation has the drawbacks that it is not only long and laborious, but also does not provide for purification of the product from the precipitated 2-amino-1,3-propane-diol because it is not soluble enough in methylene chloride.

The crude product obtained after various operations, even if the yield corresponds to the data of the patent, has in practice a low purity (80% titer) since the relevant amounts of butylamine hydrochloride and 2-amino-1,3-propanediol or the hydrochloride thereof.

The use of DMA in the reaction of point 4 certainly facilitates the reaction itself, but nevertheless provides for the disadvantages described above, namely the difficult removal of the DMA, the complicated work-up of the mixture and the low purity of the desired product.

Nevertheless, as far as we know, DMA is the solvent that is used industrially is the reaction according to point 4.

In this way, it can be deduced that the use of DMA, or an equivalent solvent such as dimethylformamide, is absolutely necessary in carrying out such a reaction.

Surprisingly, it has now been found that by carrying out the reaction in acetone or in a lower alcohol, the desired product A can be obtained in yields comparable to those of the prior art, but at the same time all drawbacks related to work-up of the reaction mixture and the purity of the desired product is eliminated.

It is therefore an object of the present invention to provide a process for the preparation of L-5- (2-acetoxy-propionylamino) -2,4,6-triiodoisophthalic acid bis- (1,3-dihydroxypropylamide) by L-5- (2-acetoxy-propionylamino) -2,4,6-triiodoisophthalic acid dichloride to react with 2-amino-1,3-propanediol in the presence of a base, the improvement being that acetone or a lower alcohol is used as the reaction solvent.

By the term lower alcohol is meant C 1 -C 4 alcohols normally used as an industrial solvent. From this group, the (C3-C4) alcohols are preferred, and especially isopropanol, sec-butanol and t-butanol.

With regard to the use of acetone or a lower alcohol as a solvent, the following practical advantages are obtained, of which the industrial importance is obvious: - the desired product (compound A) precipitates and can be separated by filtration instead of by distillation of the solvent as in the case of DMA; compound A is purified by cold washing with alcohol or acetone because the organic base and 2-amino-1,3-propanediol can be removed with cold solvent. It is important to indicate how the elimination of 2-amino-1,3-propanediol is one of the major problems in the synthesis of the above-mentioned British Patent; - the desired product is obtained in yields comparable to those obtained using DMA as a solvent, but the purity of the product is clearly higher (titre higher than 95%, even equal to 99%); the use of a lower alcohol or acetone as a solvent is likewise suitable in the alternative embodiment of the above-described process and in particular for the reaction between compound C, optionally protected, and 2-amino-1,3-propanediol.

From a practical point of view, the reaction of the present invention can be carried out by adding 2-amino-1,3-propanediol to a solution containing both compound D and the base, preferably tributylamine, in alcohol (preferably isopropanol or sec.butanol) or in acetone, kept under stirring at temperatures between 20 and 100 ° C and preferably between 40 and 60 ° C.

At the end of the reaction, the mixture is cooled to 10-15 ° C, the precipitating compound A is filtered off and washed cold with alcohol and / or acetone.

The yield is high and the product has a high purity.

For the purpose of better illustrating, without limiting, the present invention, the following examples are given.

Example 1 2-Amino-1,3-propanediol (0.451 g; 4.96 mmol) was added to a solution of L-5- (2-acetoxy-propionyl-amino) -2,4,6-triododoisophthalic acid dichloride ( 1.6 g; 2.25 mmol) and tributylamine (0.92 g; 4.96 mmol) in isopropyl alcohol (8 ml), kept under stirring at 50 ° C and under a nitrogen atmosphere.

The mixture was kept under stirring at 50 ° C for 16-18 hours and the reaction was monitored by thin layer chromatography (TLC) (silica gel, eluent methylene chloride 1 methanol = 10: 3).

At the end of the reaction, it was cooled to 15 ° C 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-triiodoisophthalic acid bis-1,3-dihydroxy isopropylamide) were obtained (99% HPLC titer; 81% yield) melting point 187-190 ° C.

The mother liquor further contained 0.15 g of the product in a total yield of 89.6%, recovered by evaporation of the solvent and usual work-up such as treatment with solvents or mixtures of solvents and chromatographic methods, taking into account the higher solubility of compound A in water.

Example 2 2-Amino-1,3-propanediol (0.28 g; 3.07 mmol) was added to a solution of L-5- (2-acetoxy-propionyl-amino) -2,4,6-triiodo- isophthalic acid dichloride (1g; 1.4mmol) and tributylamine (0.57g; 3.07mmol) in sec.butanol (4ml), with stirring and kept under nitrogen atmosphere at 50 ° C.

The mixture was kept under stirring at 50 ° C for 18 hours and the reaction was followed by thin layer chromatography (TLC) (silica gel, eluent methylene chloride methanol = 10: 3).

At the end of the reaction, it was cooled to 15 ° C and kept under stirring for 1 hour. The product was filtered under nitrogen pressure, washed with sec-butanol (2 ml) and acetone (2 x 2 ml) and dried under vacuum (50 ° C, 25 mm / Hg).

0.99 g of L-5- (2-acetoxy-propionylamino) -2,4,6-triiodophthalic acid bis-1,3-dihydroxy isopropylamide) was obtained (99% HPLC titer; 84.1% yield).

The mother liquor further contained 0.069 g of product, making the total yield 90.1%.

Example 3 2-Amino-1,3-propanediol (0.28 g; 3.07 mmol) was added to a solution of L-5- (2-acetoxy-propionyl-amino) -2,4,6-triiodo- isophthalic acid dichloride (1 µg 1.4 mmol) and tributylamine (0.57 g; 3.07 mmol) in acetone (4 ml), under stirring and kept under nitrogen atmosphere at 50 ° C.

The mixture was kept under stirring at 50 ° C for 18 hours and the reaction was monitored by thin layer chromatography (TLC) (silica gel, eluent methylene chloride: methanol = 10: 3).

At the end of the reaction, it was cooled to 15 ° C and kept under stirring for 1 hour. The product was filtered under nitrogen pressure, washed with acetone (2 x 2 ml) and dried under vacuum (50 ° C, 25 mm / Hg).

0.76 g of L-5- (2-acetoxy-propionylamino) -2,4,6-triiodophthalic acid bis-1,3-dihydroxy isopropylamide) were obtained (98% HPLC titer; 64.6% yield).

The mother liquor further contained 0.31 g of product, making the total yield 91.4%.

Example 4 2-Amino-1,3-propanediol (0.28 g; 3.07 mmol) was added to a solution of L-5- (2-acetoxy-propionylamino) -2,4,6-triiodoisophthalic acid dichloride ( 1 g; 1.4 mmol) and diazabicyclo-octane (0.172 g; 1.53 mmol) in isopropyl alcohol (4 ml), kept under stirring at 50 ° C and under a nitrogen atmosphere.

The mixture was kept under stirring at 50 ° C for 18 hours and the reaction was monitored by thin layer chromatography (TLC) (silica gel, eluent methylene chloride: methanol = 10: 3).

At the end of the reaction, it was cooled to 15 ° C and kept under stirring for 1 hour. The product was filtered under nitrogen, washed with isopropyl alcohol (2 x 2 ml) and dried under vacuum (50 ° C, 25 mm / Hg).

0.85 g of L-5- (2-acetoxy-propionylamino) -2,4,6-triiodoisophthalic acid bis-1,3-dihydroxy isopropylamide) was obtained (95% HPLC titer; 70% yield ).

The mother liquor further contained 0.184 g of product, making the total yield 86%.

Claims (2)

1. Process for the preparation of L-5- (2-acetoxy-propionylamino) -2,4,6-triiodophthalic acid bis-1,3-dihydroxy-propylamide by L-5- (2-acetoxy-propionylamino) -2,4,6-triiodoisophthalic acid dichloride to react with 2-amino-1,3-propanediol in the presence of a base and an inert solvent, the improvement being that acetone or a lower alcohol is used as the reaction solvent . The method of claim 1, wherein the alcoholic solvent is selected from the group consisting of isopropanol, sec-butanol and t-butanol.