FR2697249A1 - Process for the preparation of bis (1,3-dihydroxypropylamide) of L-5- (2-acetoxypropionylamino) -2,4,6-triiodoisophthalic acid. - Google Patents

Abstract

There is described an improvement to a process for preparing L-5- (2-acetoxypropionylamino) -2,4,6-triiodo-isophthalic acid bis (1,3-dihydroxypropylamide) by reaction of L-acid dichloride -5- (2-acetoxypropionylamino) -2,4,6-triiodo-isophthalic with 2-amino-1,3-propanediol in the presence of a base, in a solvent which is acetone or a lower alcohol.

Description

The present invention relates to a process for preparing a product

  intermediate of organic synthesis and, more specifically, a process for the preparation of the bis- (1,3-dihydroxypropylamide) compound of L-5- (2-acetoxypropionylamino) -2, 4,6-triiodo- acid

  isophthalic (hereinafter referred to as "compound A").

  Compound A, described for the first time by the Swiss company Savac AG, for example in British patent No. 1,472,050, can be used as an intermediate product of organic synthesis, by the

  that, by deacetylation, it gives the compound bis-

  (1,3-dihydroxypropylamide) L-5- (2-

  hydroxypropionylamino) -2,4,6-triiodo-isophthalique, which is also described in the aforementioned British patent and can in turn be used in diagnosis as a non-ionic substance of X-ray contrast. To our knowledge, the industrial synthesis of compound A remains that which is described in the abovementioned British patent and comprises the following stages: 1 preparation of the starting substance, namely 5-amino-2,4,6-triiodoisophthalic acid (compound B), by iodination of 5-amino-isophthalic acid;

  2 preparation of 5-amino-2,4,6- acid chloride

  triiodoisophthalic (compound C); 3 reaction of compound C with L-2-acetoxypropionic acid chloride (acetyllactic acid

  to give the acid dichloride L-5- (2-

  acetoxypropionylamino) -2,4,6-triiodo-isophthalic (compound D);

  4 reaction of compound D with 2-amino-l, 3-

  propanediol in dimethylacetamide and in the presence of a base, to give compound A. Other synthetic methods have also been proposed, such as for example a variant which consists in reversing the order of steps 3 and 4, c is to say

  reacting compound C with 2-amino-1,3-

  propanediol to obtain the compound bis- (1,3-

  dihydroxypropylamide) 5-amino-2,4,6-triiodo- acid

  isophthalic or a protected form thereof (compound E) and reacting the latter with L-2-acetoxypropionic acid chloride to obtain compound A; but, to our knowledge, these syntheses have not been

  applied on an industrial scale.

  The reaction of step 4 is described in the example

  1, section A of the aforementioned British patent.

  This reaction is carried out by the addition of a solution of 2-amino-1,3-propanediol in dimethylacetamide to a solution of L-5- (2-acetoxypropionylamino) -2,4,6-triiodoisophthalic acid dichloride.

  and tributylamine in dimethylacetamide.

  The ratio of L-5- (2-

  acetoxypropionylamino> -2,4,6-triiodo-isophthalic (compound D), 2 amino-1,3-propanediol and the base

  (tributylamine) is, in equivalents, 1: 2.5: 2.

  The reaction is carried out at 50 ° C. and gives, after a few hours, the desired product with a yield of 92%. The subsequent treatment of the reaction mixture, described in Example 1-A of British Patent No. 1,472,050 , includes evaporation of dimethylacetamide (hereinafter referred to as DMA), suspension, with vigorous stirring, of the oily residue in methylene chloride and recovery of the precipitate with

  hot methylene chloride in batches.

  By repeating the preparation described above, we have noted various drawbacks which make such synthesis on an industrial scale difficult. The vacuum distillation of the solvent at the end of the reaction is an operation which proves to be very difficult on an industrial scale, by the fact that DXA is a

  high boiling point solvent (l C 5 'C).

  Purification of the product, precipitated with methylene chloride from the residue from the distillation of DNA, involves several treatments with hot methylene chloride; besides that such an operation is long and laborious, it does not rid the product of the residual 2-amino-1,3-propanediol, since the latter is also insoluble in methylene chloride. Even if the crude product is obtained following said operations with a yield which corresponds to what is reported in the patent, it has a quite poor purity (titer of 80% 5, because it contains significant amounts of hydrochloride butylamine and

  2-amino-1,3-propanediol or its hydrochloride.

  The use of DNA in the reaction of step 4 certainly facilitates the reaction itself, but it is nevertheless accompanied by the abovementioned drawbacks, namely the painful elimination of the DNA, the complicated subsequent treatment of the mixture and the low purity of

desired product.

  Despite this, DNA is, to our knowledge, the solvent used in industry in the reaction of step 4 It could therefore be concluded that the use of DKA or an equivalent solvent such as dimethylformamide is absolutely necessary in

performing such a reaction.

  Now it has been discovered with surprise that if the reaction is carried out in acetone or in a lower alcohol, the desired product A is obtained with yields comparable to those of the state of the art, but only at the same time, all the drawbacks relating to the further treatment of the reaction mixture and the

  purity of the desired product are eliminated.

  The subject of the present invention is therefore, in a process for the preparation of bis (1,3-dihydroxypropylamide)

  L-5- (2-acetoxypropionylamino) -2,4,6-triiodo- acid

  isophthalic by reaction of acid dichloride L-5- (2-

  acetoxypropionylamino) -2,4,6-triiodo-isophthalic with 2-amino-1,3-propanediol in the presence of a base, the improvement consisting in using acetone or a

  lower alcol as reaction solvent.

  By the term "lower alcohol" is meant an alcohol

  in C 1-C normally used as an industrial solvent.

  Among them, C 3-C alcohols are preferred, and

  particularly isopropanol, sec -butanol and t -

butanol.

  From the use of acetone or a lower alcohol as solvent, the following practical advantages are obtained,

  whose industrial importance is evident by it-

  same: es i 4 eqlfii, A to, ve =: A ') rv,: inis 4 rt r 4 +: A-ra separated by filtration, rather than by distillation of the solvent as in the case of DMA; 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 should be emphasized how elimination of 2-amino-1,3-propanediol is one of the major problems in synthesis according to the aforementioned British patent; the desired product is obtained in yields comparable to those obtained using DNA as solvent, but the purity of the product is clearly higher (titer greater than 95% and even equal to 99%); the use of a lower alcohol or acetone as solvent is also suitable in the variant of the process described above, namely the reaction between

  Compound C, optionally protected, and 2-amino-

  1,53-propanediol. From a practical point of view, the reaction according to the present invention can be carried out by the addition of 2-amino-1,3propanediol to a solution containing both compound D and the base, preferably tributylamine, in a alcohol (preferably isopropanol or dry -butanol) or in acetone, maintained with stirring at temperatures included

  between 20 and 100 C, preferably between 40 and 60 'C.

  At the end of the reaction, the mixture is cooled to -15 ° C., the compound A which precipitates is separated by

  filtration and cold washed with alcohol and / or acetone.

  The yield is high and the product is of high purity. The following examples are given in order to better

  illustrate the present invention without limiting it.

Example 11 e 1-

  2-amina-1,3-propanediol (0.451 g; 4.96 mmol) has

  added to a solution of L-5- acid dichloride (2-

  acetoxypropionylamino) -2,4,6-triiodo-isophthalic (1.6 g; 2.25 mmol) and tributylamine (0.92 g; 4.96 mmol) in isopropyl alcohol (8 ml), maintained

  with stirring at 50 ° C. and under a nitrogen atmosphere.

  The mixture was kept stirring at 50 ° C for 16-18 h and the reaction was monitored by thin layer chromatography (CCG) (silica gel;

  eluent, methylene chloride: methanol = 10: 3).

  At the end of the reaction, it was cooled to 15 ° C. and kept stirring for 1 h. The product was filtered under a nitrogen atmosphere, washed with isopropyl alcohol at 15 ° C. (2 × 2 ml) and dried. under vacuum

(50 C, 25 mm Hg).

  1.5 g of bis (1,3-dihydroxy-

  isopropylamide) L-5 acid (2-acetoxypropionylamino) - 2,4,6-triiodoisophthalic (HPLC titer 99%; yield

81%), p f = 187-190 C.

  The mother liquors still contained 0.15 g of the product (for a total yield of 89.6%) recoverable by evaporation of the solvent and conventional subsequent treatment, such as treatment with solvents or mixtures of solvents and chromatographic processes taking account for the higher solubility of compound A

in water.

  Example 2 2-amino-1,3-propanediol (0.28 g; 3.07 mmol) a

  added to a solution of L-5- acid dichloride (2-

  acetoxypropionylamino) -2,4,6-triiodo-isophthalic (1.6 g; 2.25 mmol) and tributylamine (1 g; 1.4 mmol) in dry butanol (4 ml), maintained with stirring at

'C and under a nitrogen atmosphere.

  The mixture was kept stirring at 50 C for 18 h 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 stirring for 1 h. The product was filtered under a nitrogen atmosphere, washed with dry -butanol (2

  ml) and dried under vacuum (50 ° C, 25 mm Hg).

  0.99 g of bis (1,3-dihydroxy-

  isopropylamide) L-5 acid (2-acetoxyprbpionylamino> -

  2,4,6-triiodoisophthalic (title by HPLC 99%;

yield 84.1%).

  The mother liquors still contained 0.069 g of the

  product, for a total yield of 90.1%.

  2-amino-1,3-propanediol (0.28 g; 3.07 mmol) has

  added to a solution of L-5- acid dichloride (2-

  acetoxypropionylamino) -2,4,6-triiodo-isophthalic (1 g; 1.4 mmol) and tributylamine (0.57 g; 3.07 mmol) in acetone (4 ml), maintained under agitation

'C and under a nitrogen atmosphere.

  The mixture was kept stirring at 50 ° C for 18 h and the reaction was monitored by thin layer chromatography (CCX) (silica gel;

  eluent, methylene chloride: methanol = 10: 3).

  At the end of the reaction, it was cooled to 15 ° C. and kept stirring for 1 h. The product was filtered under a nitrogen atmosphere, washed with acetone (2 × 2

  ml) and dried under vacuum (50 ° C, 25 mm Hg).

  0.76 g of bis (1,3-dihydroxy-

  isopropylamide) L-5- (2-acetoxypropionylamino) acid -

  2,4,6-triiodoisophthalic (titer by HPLC 98%;

yield 64.6%).

  The mother liquors still contained 0.31 g of the

  product, for a total yield of 91.4%.

Example 4

  2-amino-1,3-propanediol (0.28 g; 3.07 mmol) has

  added to a solution of L-5- acid dichloride (2-

  acetoxypropionylamino) -2,4,6-triiodo-isophthalic (1 g; 1.4 mmol) and diazabicyclooctane (0.172 g; 1.53 mmol) in isopropyl alcohol (4 ml), maintained

  with stirring at 50 ° C. and under a nitrogen atmosphere.

  The mixture was kept stirring at 50 ° C for 18 h and the reaction was monitored by thin layer chromatography (CCX) (silica gel;

  eluent, methylene chloride: methanol = 10: 3).

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

  Hg). 0.85 g of bis (1,3-dihydroxyisopropylamide) of L-5- (2-

  acetoxypropionylamino) -2,4,6-triiodo-isophthalic (title by HPLC 95%; yield 70%).

  The mother liquors still contained 0.184 g of the product, for a total yield of 86%.

Claims (2)

  1. Process for the preparation of bisl (1,3-   dihydroxypropylamide) L-5- (2-   acetoxypropionylamino) -2,4,6-triiodo-isophthalic by   acid dichloride reaction L-5- <2-   acetoxypropionylamino) -2,4,6-triiodo-isophthalic with 2-amino-1,3propanediol in the presence of a base and in an inert solvent, characterized in that acetone or a lower alcohol is used as reaction solvent.   2 Method according to claim 1, characterized in that the alcoholic solvent is chosen from   isopropanol, sec -butanol and t -butanol.