PROCESS FOR THE MANUFACTURING OF IODINATED CONTRAST AGENTS

Abstract: A process for the preparation of compounds of general formula (I) characterized in that the corresponding derivatives of general formula (II) are reacted with the compounds of general formula (III).

Description: PROCESS FOR THE MANUFACTURING OF IODINATED CONTRAST AGEHXS This invention refers to a new synthetic procesε especially for the manufacturing of derivatives of diamides of 5-alkoxy-2,4,6-triiodo-l,3-benzenedicarboxy- lic acids of general formula (I) wherein which can be the same or different are, independently, H or a linear or branched ( C 1 -C 10 ) alkyl group, optionally substituted by 1-6 hydroxy and/or alkoxy groups, or a polyoxyalkyl group comprising from 1 to 10 oxygen atoms and from 3 to 30 carbon atoms, or R^ and R2 or R3 and R 4 , taken together, form a (C2~Cg) chain optionally interrupted by one or more N, 0, S atoms; is the group Rg and Rg, which can be the same or different are, independently, H or a (C^-Cg) alkyl, hydroxyalkyl, alkoxyalkyl or alkoxyhydroxyalkyl group, R 7 is H or a (C 1 ~C 3 ) alkyl, hydroxyalkyl or alkoxyalkyl group, characterized in that the corresponding derivatives of general formula (II) wherein R^ , R 2 R3 and R 4 are as previously described and the hydroxy group on the benzene ring can be also present as salt of an alkali metal or alkaline- earth metal or a (C2~Cg) trialkylamine, are reacted with the compounds of general formula (III) Z is halogen atom or a reactive residue of a sulfonic acid or a cation -N + (R 9 ) 3 wherein R g is a (C^- Cg) alkyl group and R R 7 and R g are as previously described. The preparation of the compounds of general formula (I) has been previously described in patent EP 185130, which describes the synthesis of the above compounds starting from phenol precursors or from their salts according to Scheme 1. SCHEME 1 The above patent foresees the reaction of the phenol groups in the free form or the reaction in the salified form with alkali or alkaline-earth metals with a reactive compound R 5 '-Z', preferably containing an alkoxycarbonylalkyl group and a reactive group Z', with the same meaning for Z in this invention and the successive transformation of the ester group into amido group, by reaction with ammonia or with differently substituted amines. The resulting products of formula 2 can be useful also as intermediates as described in patent EP 365541, for the preparation of X-ray contrast media by Smiles rearrangement. Differently from patent EP 185130, the process of this invention, foresees only one step for the production of the desired product, i.e. the direct reaction of phenol precursors with a reactive compound already containing the desired amido group, as from Scheme 2. SCHEME 2 (I) (ID The use of an amido derivative in the reaction of nucleophilic substitution to give derivatives of general formula (I) instead of an ester derivative, as described in patent EP 185130, leads to a considerable decrease in the number of synthetic steps required to obtain the final compounds of general formula (II). The application of the process of this invention is particularly interesting for the preparation of an intermediate in the synthesis of S-N,N'-bis[2-hγdroxy-l- (hydroxymethyl)ethylJ-5-[(2-hydroxy-l-oxopropyl)amino]- 2,4,6triiodo-l,3-benzenedicarboxamide, commonly known as IOPAMIDOL, which is one of the world best-seller in the field of non-ionic X-ray contrast media. The synthesis method described in EP 365541, foresees the formation of intermediate 3, according to the procedure described in the already cited EP 185130, followed by Smiles rearrangement, as shown in Scheme 3. A more straightforward preparation for iopamidol can be carried out by the sequence of reactions shown in Scheme 4 and described in Examples 1, 2 and 4. ♦ 2 More generally, in order to carry out the process of this invention, the salts of phenol derivatives of general formula (II) are particularly suitable for the reaction of etherification, in particular their sodium, potassium and calcium salts. The reactive group Z in compounds of general formula (III) is as definition a halide Cl, Br and I, or a reactive residue of a sulfonic acid (for instance methanesulfonyloxy (MeS0 2 0 " ), benzenesulfonyloxy (PhS0 2 0 ~ ), nitrobenzenesulfonyloxy (p-N0 2 PhS0 2 0~), toluenεulfonyloxy (TsO~), and so on), preferably toluenesulfonyloxy, or a N + (Rg) 3 cation wherein R g iε as previously defined. Particularly preferred are the following reaction conditions for the process of this invention: the sodium salt of the phenol compound of formula ( II); the stoichiometric ratio compound of formula (III)/compound of formula (II) is equal to 2; - the formation of a ether bond between the compounds of general formula (II) and the compounds of general formula (III) is carried out at a temperature comprised between room temperature and 120*C, preferably 60-100'C; - the use of protic and dipolar aprotic solvents, preferably water, H 2 0/EtOH mixture, dimethylacetamide (DMA), methyl cellosolve and ethyl cellosolve. The ether bond formation between the compounds of formula (II) and those of formula (III) implies a nucleophilic substitution reaction which involves inversion of configuration when in the compound of general formula (III) a chiral carbon is present. In view of the resultε of this invention, we can desume that, considering the same leaving group in the compound of general formula (III), aε the protonating ability of the εolvent increaεeε (i.e. the capacity of the εolvent of donating protons for the formation of hydrogen bonding), the most optically pure product iε obtained. The reεulting amideε can be uεed in Smiles rearrangement reactions, under the conditions cited in patent EP 365541 to obtain diagnostic compounds, such as Iopamidol (Examples 1, 3 and 4). The isolation of the compounds of general formula (I) is carried out according to the methods known in the practice of organic chemistry. Often, through the use of ion exchange resinε, or electrodialyεiε or tangential filtration techniqueε uεing filtration membranes, the saltε, baεeε or acidε εhould be removed from the reεulting water-εoluble compoundε. The following exampleε are meant for the illuεtration of the beεt poεεible experimental conditionε in order to carry out the proceεε of thiε invention. EXAMPLE 1 vO R = CONHCH(CH 2 OH) 2 Z* Solvent Lactate/ Recovery Optical Chemical 1 → 3 fenate yield in 2 purity purity (mol/mol) steps 1 TsO DMA 2 40 67 96 2 TsO Methylcell. 2 40 96 99 - continue - - continue - a: with the addition of KI (0.15 mol equiv. with respect to phenoxide) as catalyst EXAMPLE 2 (S)-5-(2-amino-l-methy1-2-oxoethoxy)-N,N'-biε[2-hydroxy- 1-(hydroxymethyl)ethyl3-2,4,6-triiodo-1,3-benzenedicar- boxamide To a solution of 21.8 g of N,N*-bis[2-hydroxy-l- (hydroxymethyl)ethyl]-5-hydroxy-2,4,6-triiodo-1,3-benze- nedicarboxamide sodium salt (prepared according to the procedure described in patent EP 185130) (0.03 mol) in 70 mL of methyl cellosolve, heated to 80 β C, 14.6 g of R- 2-C[(4-methylphenyl)sulfonyl]oxy]propanamide (prepared according to the procedure described in Markert, F. Chem. Ber. 1927, 60, 2456) (0.056 mol) are added and the resulting mixture is kept under stirring in the same conditions for 8 h. After removing methyl cellosolve by evaporation under reduced preεεure, the oily reεidue is treated with CH 2 C1 2 (2x250 mL). The solid, filtered and dried is dissolved in abs. EtOH (190 mL) and after filtration of sodium p-toluensulfonate, the εolution iε concentrated to dryneεε. The treatment is repeated with abs. EtOH (150 mL) and after evaporation the resulting residue is crystallized from abs. EtOH (75 mL). 10.5 g of the desired product (0.0135 mol) are recovered. Yield: 45% m.p.: IIO'C [α]D Q = -22.90' (c 5%, CH3OH) TLC: silica gel plate 60F 254 Merck Eluent: CHCI3 : CH3OH : NH 4 OH 25% = 6 : 3 :1 Detector: soluble εtarch and UV light R f = 0.22 1 H-NMR, 13 C-NMR, IR and MS spectra are consiεtent with the εtructure. EXAMPLE 3 Preparation of IOPAMIDOL εtarting from (S)-5-(2-amino-l- methyl-2-oxoethoxy)-N,N'-biε[2-hydroxy-l-(hydroxyme¬ thyl)ethyl3-2,4,6-triiodo-1,3-benzenedicarboxamide To 10.1 g of (S)-5-(2-amino-l-methyl-2-oxoethoxy)- N,N'-biε[2-hydroxy-l-(hydroxymethyl)ethyl3-2,4,6-triio- do-l,3-benzenedicarboxamide (prepared according to the procedure deεcribed in EXAMPLE 2) (0.013 mol) diεsolved in 50 mL of MeOH, and maintained under reflux, are swiftly added 56 mL of KOH IN in MeOH (0.056 mol) then the mixture is refluxed for 2 h. After cooling to room temperature, MeOH is removed by vacuum distillation. The solid residue is diluted in water (100 mL) and percolated on cation exchange resin Amberlite^ IR 120 and anion exchange resin Duolite® A 30B eluted with water. After evaporation of the aqueous solution the residue iε crystallized from EtOH (35 mL) to give 8.9 g of the desired product (0.0114 mol). Yield: 88% Sample purity: 99.8% [α3 20 = +137.00 * (c = 1.25% w/v aε Cu(II) complex), 436 optical purity 96% [literature [α3 20 = +142.28* + 0.13*3 436 ^-NMR, 13 C-NMR, IR and MS εpectra are conεiεtent with the εtructure. EXAMPLE 4 Preparation of IOPAMIDOL starting from N,N'-bis[2-hydro- xy-1-( ydroxymethyl)ethyl3-5-hydroxy-2,4,6-triiodo-1,3- benzenedicarboxa ide To a solution of 17.20 g of N,N'-bis[2-hγdroxy-l- (hydroxymethyl)ethyl3-5-hydroxy-2,4,6-triiodo-1,3-benze- nedicarboxamide sodium salt (prepared according to the procedure described in patent EP 185130) (0.0236 mol) in 60 mL of a H 2 0/EtOH 4/1 mixture, heated to 80*C, 11.5 g of R-2-[[(4-methylphenyl)εulfonyl3oxy3propanamide (prepared according to the procedure deεcribed in Markert, F. Chem. Ber. 1927, 60, 2456)(0.056 mol) are added and the reεulting mixture iε kept under εtirring for 8 h. After removal of the εolvent by evaporation under reduced preεεure, the oily reεidue is treated with CH 2 C1 2 (2x250 mL). The solid, filtered and dried, iε diεεolved in abε. EtOH (190 mL) and after filtration of εodium p-toluenεulfonate, the εolution iε concentrated to dryneεε. To the εolution of the reεidue (70 mL MeOH) refluxing, 81 mL on IN KOH in MeOH (0.0811) are εwiftly added and the heating iε kept during 2h. After cooling to room temperature, MeOH iε removed by vacuum diεtillation. The reεidual εolid iε diluted in water (100 mL) and percolated on a cation exchange resin Amberlite® IR 120 and on an anionic exchange resin Duolite® A 30B eluted with water. After evaporation of the aqueous solution the reεidue iε cryεtallized from EtOH (50 mL) to give 10.2 g of the desired product (0.0131 mol). Yield: 56% yield in two steps [α3 D = +138.88 * (c = 1.25% w/v as Cu "11 ) complex), 20 optical purity 96% [literature [α3 20 = +142.28 * ± 0.13*3 436 ^-NMR, 13 C-NMR, IR and MS spectra are consiεtent with the εtructure.

Claims: CLAIMS 1. A process for the preparation of compounds of general formula (I) wherein R^, R 2 , 3/ R4 which can be the same or different, are, independently, H or a linear or branched (C 1 -C 10 ) alkyl group, optionally subεtituted by 1-6 hydroxy and/or alkoxy groups, or a polyoxaalkyl group comprising from 1 to 10 oxygen atoms and from 3 to 30 carbon atoms, or R^ and R 2 or R and R 4 , taken together, form a (C 2 -C 8 ) chain optionally interrupted by one or more N, 0, S atomε, Rg iε the group wherein Rg and Rg which can be the εame or different, are, independently, H or a (C^-Cg) alkyl, hydroxyalkyl, alkoxyalkyl or alkoxyhydroxyalkyl group, R 7 is H or a (C 1 -C 3 ) alkyl, hydroxyalkyl or alkoxyalkyl group, characterized in that the corresponding derivatives of general formula (II) wherein R^, R 2 , R 3 and R 4 are as previously defined and the hydroxy group on the benzene ring can be also present as salt of alkali metal or alkaline-earth metal or a (C2-C6) trialkyla ine, are reacted with the compoundε of general formula (III) wherein Z iε halogen atom or a reactive reεidue of a sulfonic acid or a -N + (R 9 ) 3 cation wherein Rg iε a ( c l" c 6) aikyl group and Rg R 7 and Rg are aε previouεly defined. 2. A proceεε according to claim 1, wherein the compound of formula (II) iε in the form of εodium εalt. 3. A proceεs according to claim 1, wherein the stoichiometric ratio of the compound of formula (III) and the compound of formula (II) is equal to 2. 4. A process according to claim 1, wherein the ether bond formation between the compounds of general formula (II) and the compounds of general formula (III) is carried out at a temperature comprised between room temperature and 120 * C, preferably between 60-100*C. 5. A process according to claim 1, wherein the reaction solvent iε selected from the group consisting of protic εolventε and dipolar aprotic εolventε, preferably H 2 0, H 0/EtOH mixture, dimethylacetamide (DMA), methyl celloεolve and ethyl celloεolve.

Inventors: ANELLI PIER LUCIO, BROCCHETTA MARINO, GAZZOTTI ORNELLA, UGGERI FULVIO, ANELLI, PIER, LUCIO, BROCCHETTA, MARINO, GAZZOTTI, ORNELLA, UGGERI, FULVIO
Applicants: ANELLI PIER LUCIO, BRACCO SPA, BROCCHETTA MARINO, DIBRA SPA, GAZZOTTI ORNELLA, UGGERI FULVIO, ANELLI, PIER, LUCIO, BRACCO S.P.A., BROCCHETTA, MARINO, DIBRA S.P.A., GAZZOTTI, ORNELLA, UGGERI, FULVIO
Application year: 1996
Main classification: C07C231
IPC codes: C07C231, C07C235, C07C237