Title of Invention

A PROCESS FOR THE PREPARATION OF 5-AMINO-2,4,6-TRIIODO-1,3-BENZENE DICARBOXYLIC ACID

Abstract

The present invention referes to e process for the preparation of 5- amino-2,4,6-triiodo-1, 3 - benzenedicarboxylic (67) Abtract acid ooaprisaing the following steps a) Catalytic hydrogenatlon of 5-nitro-1t 3 - benzenedicarboxylic acid in basic environment, which gives an aqueous solution of 5-amtno-1, 3-benzenedicarboxylic acid sodlun salt; b) direct iodination of the 5-amino-1, 3 - benzenedicarboxylic acid sodium salt solution deriving from step a) without further purification, with a solution of ICl in Hcl, being the 5-anino-l, 3-benzenedlcarboxylic acid sodium salt solution previously added with HCl and H2SO4 The title compound is recovered from the reaction mixture by known methods*

Full Text

This invention refers to a new process for the synthesis of 5-amino-2,4,6-triiodo-l,3-benzenedicarboxy-lic acid of formula (I) The compound of formula (I) is useful as intermediate for the preparation of iodinated X-ray contrast media, in particular non-ionic ones. This compound is cited in Beilstein and Chemical Abstracts and its preparation has been described for the first time in patent US 2820814 (Schering Corp., 1955; CA 52: 16305; GB-A-785670), by using an excess of iodine monochloride in hydrochloric acid at room temperature. The 5-amino-isophthalic acid (or 5-amino-l,3-benzenedicarboxylic acid) can be directly triiodinated, although one can stepwise iodinate whereby the intermediate mono- or dihalogenated substance is isolated and subjected to further iodination. The resulting reaction yield of 60% is unsatisfactory for the industrial exploitation and, as showed from the example of the above patent, it is necessary a purification step, consisting of a treatment with cnarcoai ana iuriner reprecipitciLion by addition of concentrated hydrochloric acid, thus lowering the final yield. In a more recent article (J. Org. Chem, 59, 1344, 1994), Ranganathan et al. describe the iodination of the 5-amino-l,3-benzenedicarboxylic acid following a method already known in literature (Larsen et al., J. Am. Chem. Soc, 78, 3210, 1956), using KIC12 generated in situ by reaction between KIO3 and KI in presence of hydrochloric acid. The reaction is carried out at neutral pH and at a temperature of 55-60'C with a resulting yield of 74%, always after purification with charcoal and successive reprecipitation by acidification and crystallization by methanol. In both cited references the purification is necessary since in the final product there are traces of mono- or diiodinated products, as well as the presence of coloured by-products. Both cited processes operate at an extremely low concentration of the starting material. More recently, some Japanese patent applications have been published (Mitsui Toatsu Chemical Ltd., JP-A-3197451, JP-A-1224203, JP-A-1224202, JP-A-1201002, JP-A-1201003, JP-A-1047746, JP-A-1047745, JP-A-1047744) relative to the preparation and purification of 5-amino-2,4,6-triiodo-l,3-benzenedicarboxylic acid, and the iodine recovery from the mother liquors. A first patent application JP-A-1047744 describes an improvement of the reaction yield under iodination conditions according to Schering patent, carrying out the reaction at a higher temperature (80-100'C), with a resulting declared yield of 97.7%. As deduced from the prior art citea in tne successive patent application JP-A-3197451, the resulting product purity is not enough and this application describes the preparation of the above compound by treating 5-aminoisophtalic acid with IC1 in presence of H2S04 or H3P04 as catalyst, to solve this problem. The acid catalyst is added in amount of 0.1-20 mol%, preferably 1-10% respect to the acid. The concentration of the acid is 1.0-15 wt%, preferably 2.0-10 wt.%. Iodine monochloride is used 3.0-4.5 mol equivalent, preferably 3.0-3.9 mol equivalent to the precursor. The reaction is preferably carried out at 50-100°C for 1-5 hours. The final product is obtained with high purity (99.5%) and high yield (98.1%). The problem which the above application overcomes is the contamination of the product by the intermediates of mono- or di-iodination. The target is achieved by catalysis with sulfuric or phosphoric acid and even without using hydrochloric acid as a solvent to IC1. The patent application does not suggest anything on how to avoid the formation of coloured impurities, which are mentioned in the previous documents and were also present in the product we obtained under the conditions described by the application. In the experimental section of both applications, the concentration of the substrate has been increased if compared to the previous prior-art references, but is still low if the industrial productivity is taken into account. In all these references the starting product is isolated 5-amino-l,3-benzenedicarboxylic acid in its indissociate form. The process of this invention is characterized by the fact that the iodination reaction is carried out directly on 5-amino-1, 3-benzenedicarboxy1ic acid sodium salt, which derives from the catalytic hydrogenation in basic environment of 5-nitro-1, 3-benzened i carboxy1ic acid, with a solution of IC1 in HCl , which is previously added with HCl and H2SO,. Accordingly the present invention therefore provides a process for the preparation of 5-amino-2,4,6-triiodo-1, 3-benzenedicarboxy1ic acid comprising the following steps: a) catalytic hydrogenatioh of 5-nitro-l, 3-benzenedicarboxy1ic acid in basic conditions to produce aqueous solution of 5-amino-l, 3-benzenedicarboxy1ic acid sodium salt; b) direct iodination of the 5-amino-l, 3-benzenedicarboxy1ic acid sodium salt solution deriving from step a), after acidifying the same with HCl and H2S04 without further purification, with a solution of ICl in HCl, and recovering the 5-amino-2,4,6-triiodo-1,3-benzenedicarboxy1ic acid by known method. Particularly preferred are the following iodination conditions according to which the process of this invention operates : the ratio of the total acid equivalents coming from HCl and H2SO. to the moles of 5-nitro-1,3-benzenedicarboxylic acid ranges from 2.5:1 to 3.5:1; the ratio of HCl equivalents to 5-nitro-l, 3-benzenedicarboxy1ic acid moles ranges from 0:1 to 2:1, preferably from 0.5:1 to 1.5:1; the ratio of H2S04 equivalents to 5-nitro-l, 3-benzenedicarboxy1ic acid moles ranges from 0.5:1 to 3.5:1, being preferably from 2.0:1; the molar ratio to ICl and 5-nitro-l, 3-benzenedicarboxy1ic acid ranges from 3.0:1 to 3.5:1; the molar ratio of HCl to IC1 in the IC1 solution in HCl ranges from 0.4:1 to 1.2:1; the temperature of iodination ranges from 75 to 110°C, preferably from 70 to 95°C. tT For the first time, due to the presence of the acids in the amounts previously described, it is possible to obtain the desired product as white (hydrate form) or yellow (anfhydrous ■i form) crystals with excellent yields and high purity, free from dark coloured compounds, without further purification. Another remarkable advantage of the presence of sulfuric acid in the amounts previously described, extremely important for the industrial productivity, is the possibility of performing the iodination under conditions of substrate concentration higher than usual standards in the absence of sulfuric acid, with the same yield. In the experimental section are showed an example, in which 3 equivalents of hydrochloric acid without addition of sulfuric acid are added, and an example where only sulfuric acid is added. In the first case a decisively low yield is achieved while in the second case the yield is satisfactory but the final product is dark-brownish, thus requiring a successive purification. The following examples of the practice of the present invention are meant to be illustrative and are in no way limiting the scope of the invention. EXAMPLE 1> A) 5-amino-l,3-benzenedicarboxylic acid 325 g 5-nitro-l,3-benzenedicarboxylic acid (product available on the market) are loaded into a reactor with 2.8 1 of water. It is heated to 60-70°C and the starting product dissolved by addition of 410 g of 30% NaOH. Then 10 g of charcoal are added; the slurry is filtered and the filter is washed with 200 ml of water. 8 g of Pd/C 5% (product available on the market) are then loaded and conditioned with approx. 0.01 m3 nitrogen. 0.1 m3 hydrogen are added under a pressure of 30 kPa. The temperature spontaneously reaches 50"C and is kept by cooling. When the hydrogen consumption stops, the solution is kept under pressure for 1 h and then the residual hydrogen is removed by washing with 0.02 m3 of nitrogen. The suspension is filtered and the filter washed with 100 ml of water giving approx. 3.85 kg of solution containing 5-amino-l,3-benzenedicarboxylic acid sodium salt. B) 5-amino-2,4,6-triiodo-l,3-benzenedicarboxylic acid In a reactor loaded with 2.75 1 of water, are added in sequence 0.08 kg of HC1 (34% w/w), 3.85 kg of solution of 5-amino-l,3-benzenedicarboxylic acid sodium salt coming from the previous reaction and 375 g of H2S04 (1:1 aqueous solution). The content is heated to 70°C, and during 3 hours 1.35 kg of a solution of IC1 in HC1 (44.5% iodine, molar ratio IC1:HC1=1:1) (product available on the market) is added. When the addition is complete the solution is heated to 90'C and the temperature kept for 6h. Then the content is cooled to 60°C and transferred to another reactor, where it is cooled to 30"C. The slurry is decolourised by adding 45 g of sodium bisulfite under stirring, then centrifuged and the product washed with 0.3 kg of water thus giving 935 g of the desired wet product. After drying, 830 g of the desired product are obtained. Total yield of the two steps (on the anhydrous product): 95.0% Water content: 2% Potentiometric assay: 99.3% 1-H-NMR, 13C-NMR, IR and MS spectra are consistent with the structure. EXAMPLE 2 Comparative example of 5-amino-2,4,6-triiodo-l,3-benzenedicarboxylic acid preparation in presence of 3 HC1 equivalents. According to the procedure described in EXAMPLE 1, 3.85 kg of a solution of 5-amino-l,3-benzenedicarboxylic acid sodium salt are reacted with IC1 in presence of 0.48 kg of HC1 (34% w/w). Total yield on two steps on anhydrous product: 82.0% The chemical-physical characteristics are in accordance with those previously described. EXAMPLE 3 Comparative example of 5-amino-2,4,6-triiodo-l,3-benzenedicarboxylic acid preparation in presence of 3 H2S04 equivalents. According to the procedure described in EXAMPLE 1, 3.85 kg of solution of 5-amino-l,3-benzenedicarboxylic acid sodium salt are reacted with IC1 in presence of 450 g of H2S04 (1:1 aqueous solution). Total yield of the two steps on the anhydrous product: 91.0% The chemical-physical characteristics are in accordance with those previously described, but the product is dark-brownish. Comparative example: 5-amino-2,4,6-triiodo-I,3-benzenedicarboxylic acid preparation according to the method described in Example 1 of JP-A-3197451, scale multiplied by 3. In a jacketed reactor equipped with a stirrer are loaded 57.2 g of 5-amino-l,3-benzenedicarboxylic acid (5% water content, titre 95%, equal to 0.3 mol), 1440 g of water, 1.47 g of sulfuric acid. It is heated to 70°C and 306.9 g (0.945 mol) of a 50%wt-ICl solution in 35% HC1 are dropped during 1 h. The reaction is completed by keeping it under stirring at 70°C for 4 h. It is cooled to 10°C, the precipitate is filtered and concentrated under reduced pressure. We obtained 144 g (86%) cf a brownish crystalline solid formed by 5-amino-2,4,6-triiodo-1,3-benzenedicarboxylic acid containing 0.8% w/w of water and 1% of impurities coming from incomplete iodination. EXAMPLE 5 Comparative example: 5-amino-2,4,6-triiodo-l,3-benzene¬dicarboxylic acid preparation according to the method described in Example 1 of JP-A-3197451, but without isolation of 5-amino-2,4,6-triiodo-l,3-benzenedicar¬boxylic acid. The procedure of example 4 is repeated but instead of the isolated 5-amino-l,3-benzenedicarboxylic acid, an equivalent amount (580 g) of the solution containing 5-amino 1,3-benzenedicarboxylic acid sodium salt obtained at the end of hydrogenation is loaded. When the reaction is completed, a black suspension is given from which, through filtration, a modest amount (70 g) of a black solid formed by 5-amino-triiodo-l,3-benzenedicarboxylic acid heavily contaminated by impurities probably due to WE CLAIM : 1. A process for the preparation of 5-amino-2,4,6- triiodo-1, 3-benzenedicarboxy1ic acid comprising the following steps: a) catalytic hydrogenation of 5-nitro-l, 3-benzenedicarboxy1ic acid in basic conditions to produce aqueous solution of 5-amino-l, 3-benzenedicarboxy1ic acid sodium salt; b) direct iodination of the 5-amino-l, 3-benzenedicarboxy1ic acid sodium salt solution deriving from step a), after acidifying' the same with HCl and H-SO4 without further purification, with a solution of ICl in HCl, and recovering the 5-amino-2,4,6-triiodo-1 , 3-benzenedicarboxyIic•acid by known method. 2. A process according to claim 1, wherein the ratio of the total equivalents of acids provided by HCl and H2SO4 to the moles of 5-nitro-l, 3-benzenedicarboxy 1 ic iacid ranges from 2.5:1 to 3.5: 1 . i 3. The process according to claim 2; wherein the ratio of the equivalents of H2SO, to the moles of :5-nitro-l, 3-benzenedicarboxyIic acid ranges from 0.5:1 to 3.5*1. 4. The process according to claim 3, wherein the ratio of the equivalents of H2SO4 to the moles of ;5-nitro-l, 3-benzenedicarboxy1ic acid is 2.0:1. 5. The process according to claim 1, wherein the ratio of ICl to the moles of 5-nitro-l, 3-benzenedicarboxylic acid ranges from 3.0:1 to 3.5:1. 6. The process according to claim 1, wherein the molar ratio of HCl to ICl in ICl solution in HCl ranges from 0.4:1 to 7. The process according to claim 1, wherein the temperature of step b), ranges from 75 to 110 C, preferably from 70 to 95°C. 8. A process for the preparation of 5-amino-2,4,6-triiodo- 1, 3-benzenedicarboxy1ic acid substantially as herein described and exempli fied.

Documents:

860-mas-1996 abstract.pdf

860-mas-1996 claims.pdf

860-mas-1996 correspondence -others.pdf

860-mas-1996 correspondence -po.pdf

860-mas-1996 description (complete).pdf

860-mas-1996 form-2.pdf

860-mas-1996 form-26.pdf

860-mas-1996 form-4.pdf

860-mas-1996 form-8.pdf

860-mas-1996 petition.pdf