2,4,6-TRIIODOISOPHTHALAMIDE DERIVATIVE

The present invention relates to new compounds, to radiological compositions containing such compounds and to the use of such radiological compositions.

i0 Non-ionic contrast agents for intravascular and centra! nervous system visualization are complex molecules. As is known, the iodine in the molecule provides opacification tO the x-rays. The remainder of the molecule provides the framework for transport of the iodine atoms. However, the structural arrangement of the molecule is important in providing stability, solubility and biological safety in various organs. A stable carbon-iodine bond is achieved in most compounds by attaching it to an aromatic nucleus. An enhanced degree of solubility as well as safety is conferred on the molecule by the addition of suitable solubilizing and detoxifying groups.

Several of the features that are desirable for intravascular and central nervous system non-ionic contrast agents are often incompatible so that all such agents represent compromises. In searching for the best compromise, the controlling factors are pharmacological inertness, i.e., in vivo safety, and high water solubility. Thus, the idea! intravascular or central nervous system non-ionic agent represents a compromise in an attempt to obtain the following criteria:

l. Maximum opacification to x-rays 2. Pharmacological inertness 3. High water solubility - 2îÆ98739 4. Stability 5. Selective excretion 6. Low viscosity 7. Minimal osmotic effects An object of the present invention is to provide a non-ionic x-ray contrast agent. Another object of this invention is to provide a non-ionic x-ray contrast agent meeting substantially all the foregoing criteria.

i0 This invention relates to N,N'-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6triiodoisophthalamide. N,N'-Bis(2,3-dihydroxypropyl)-5N-(2-hydroxyethyl)glyco!amido-2,4,6-triiodoisophthalamide is subject to a number of different types of isomerism as is explained below. The present invention extends to all isomers thereof. As used herein, the term N,N'-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)- glycolamido-2,4, 6-triiodoisophthalanùde means N, N ' -his ( 2,3-dihydroxypropyl ) - 5-N- ( 2-hydroxyethy i ) - glycolamido-2,4, 6-triiodoisophthalamide and all isomers thereof.

Exo and endo isomers exist due to restricted rotation of the N-CO bond caused by steric hindrance and the presence of the hydroxyethyl group. These isomers tend to equilibrate in solution but are sufficiently stable to be separated by thin layer chromatography.

In addition, there are two forms for each isomer due to restricted rotation of the N-(2-hydr0xYethy1)-Ar bond. The compounds of the present invention also exist in racemic, optically active and meso forms.

uz. z'. D - 31ï90. .39 Individual stereoisomers of the compounds of the invention can be obtained by conventional methods.

N,N'-bis-(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiodoisophthalamide may be used as an x-ray contrast agent. The agent may be used in various radiographic procedures including those involving cardiography, coronary arteriography, aortography, cerebral and peripheral angiography, arthrography, intraveneous pyelography and urography as well as myelography. Mixtures of isomers of this invention may also be used as x-ray contrast agents.

A further feature of the present invention is a radiological composition containing N,N'-bis-(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6triiodoisophthalamide as an x-ray contrast agent together with a pharmaceutically acceptable radiological vehicle.

Pharmaceutically acceptable radiological vehicles include those that are suitable for injection such as aqueous buffer solutions, e.g., tris(hydroxymethyl)aminomethane (and its salts), phosphate, citrate, bicarbonate, etc., sterile water for injection, physio!ogical saline, and balanced ionic solutions containing chloride and/or bicarbonate salts of normal blood plasma cations such as Ca, Na, K and Mg. Other buffer solutions are described in Remington's Practice of Pharmacy, Eleventh Edition for example on page 170.

The vehicles may contain a chelating agent, e.g. a small amount, of ethylenediaminetetraacetic acid, the calcium disodium sà1 t or other pharmaceutically acceptable chelating agents.

î'íg 739 The concentration of N,N'-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiodoisophthalamide in the pharmaceutically acceptable vehicle, for example an aqueous medium, varies with the particular field of use. A sufficient amount is present to provide satisfactory x-ray visualization.

For example, when using aqueous solutions for angiography the concentration of iodine is generally 140-400 mg/ml and the dose is 25-300 ml.

The radiological composition is administered so that the contrast agent remains in the living animal body for about 2 to 3 hours, although both shorter and longer residence periods are'normally acceptable.

N,N'-Bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)- glycolamido-2,4,6-triiodoisophthalamide may thus be formulated for vascular visualization conveniently in vials or ampoules containing I0 to 500 ml. of an aqueous solution.

The radiological composition may be used in the usual way in x-ray procedures. For examples in the case of selective coronary arteriography, a sufficient amount of the radiological composition to provide adequate visualization, is injected into the coronary system and then the system is scanned with a suitable machine, for example a fluoroscope.

N, N'-Bis (2,3-dihydroxypropyl)-5-N- (2-hydroxy - ethyl)glycolamido-2,4, 6-triiodoisophthalamide may be prepared in accordance with the procedures set out below. All" temperature designations are in degrees centigrade.

i0 1i9 739 EXAMPLE I Preparation of N,N'-Bis(2,3-dih_ydroxypropyl)-5-N- ( 2-hydroxyethyl ) glycol am:id,0-2,4, 6-tri iodoi sophthalamide (11).

A. Preparation of 5-Amino-2,4,6-triiodoisophthaloyl Chloride (2) C02H I +SOC12 H2N CO2 H EtOAc COCl H2NI@ 0C1 I 1 2 5-Amìno-2,4,6-triiodoisophthalic acid (6.73 Kg, 12.04 mol) was charged and EtOAc was added. SOCl2 (5.73 Kg, 48.17 mol) was added to the slurry in one portion and the mixture was heated at reflux for 4 hours. After the reaction, 24.2 L of unreacted SOC12 and the solvent were distilled (64-77°, 7 hrs.

distillation time). The product started to precipitate when the reaction solution cooled to 55°; the slurry was stirred overnight, allowing it to cool to room temperature. The solids were collected, washed with cold EtOAc (5°, 3.8 L), suction-dried for 3 hours and air-dried at room temperature to give the desired product 2 (3.525 kg, 49.2% yield).

The filtrate (about 25 L) was distilled to a volume of L and cooled to 2° overnight. The precipitated product was collected, washed with cold EtOAc (5°, 1.5 L), suction-dried and air-dried to give a second crop of the product 2 (0.83 kg, 11.6% yield). The two crops of the product were combined, 4.355 kg (60.8% yield). The product showed one spot by tlc analysis (C6H5CH3/CH3OH; 9/1).

UZZb B. Preparation of 5-Amino-N,N'-bis(2,3-dihydroxvpropyl)-)x 2,4, 6-triiodoisophthalamide (4) Nf :OCI +HnNCHoCH-CHo+NaoC0 DMF L! j L 3 > OH OH H CONHCHoCH-CHn LI I L OH OH ,oCH-CHo x OH OH 2 4 Pulverized 5-amino-2,4,6-triiodoisophthaloyl chloride (4.35 Kg, 7.347 mol) was dissolved in DMF (6 L). The solution was cooled to 20° and Na2CO3 (2.33 Kg) was added: the temperature remained at 20°. To -the reaction mixture was added, drop-wise, a solution of 3-amino-l,2-propanediol 3 (1.67 Kg, 22 mol) in 2.14 L of DMF with cooling (ice-bath) at 34-35° over a period of 1.5 hour. After the addition, the reaction mixture was stirred at room temperature for 24 hours; the solid was filtered and washed with MeOH (3 x 500 ml). The filtrate and the MeOH wash were combined and evaporated under vacuum at 60-63° (water bath) to give 4.5 L of a dark syrup. The warm syrup (50-60°) was poured into a mixture of 45 L of water and 4 L of concentrated HCI with rapid stirring. The solution was stirred for minutes, and evaporated under reduced pressure at 65-70° (water-bath) to a volume of 28 L, washed with EtOAc (2 x 9 L) and further evaporated under reduced pressure at 65-70° (water bath) to a volume of 12 L. The solution was diluted with 24 L of MeOH, seeded With an authentic sample of 4 (4-5 g) and stirred at room temperature for 2 days. Off-white solids precipitated during the stirring period. The solids were collected, washed with MeOH, suction-dried, and transferred to a tray and oven- - v-- Æ198ç '39 dried at 70° for 24 hours to give the desired product 4.

(2.582 Kg, 49.85% yield). The product showed one spot by tlc analysis (EtOAc/MeOH/AcOH; 10/5/1). LC purity:

98.5% (peak height) ( C18, H2 0/CH3 CN; 60/40, flow 1 mL/min, retention time 3 minutes).

C. Preparation of 5-Amino-N,N'-bis(2,3-diacetoxypropyl) 2,4,6-triiodoisophthalamide (5) CONHCHoCH-CHo OE,j <i OH o [ 0 ] H N"V "CONHCH«CHCH H ŒE OH OH CONHCH2CH-ïH2 I .. OAc 0Ac CH-CH 211 2 0 OAc Compound 4 (2.58 Kg, 3.66 mol) was slurried in pyridine.

Acetic anhydride (1.7 Kg, 16.65 mol) was added, drop-wise, to the slurry with stirring and cooling (ice-bath) over a period of 1.25 hours. The slurry temperature during this period was maintained at 33-34°.

After the addition the stirred slurry was allowed to cool to room temperature. During this time the slurry gradually became clear and the resulting solution was al!owed to stir at room temperature for 17 hours The reaction solution (5.24 L) was diluted with EtOAc (i0 L); ice water (7°32 L) was added and Che mixture was stirred for 15 minutes. A mixture of ice water (7.32 L) and concentrated HCI (1.464 L) was added and the mixture was stirred for 45 minutes. The layers were separated (separation time 15 minutes) and the brown organic layer (bottom layèr) was collected. The aqueous layer was extracted with EtOAc (2x5 L) and each time the organic layer (top layer) was collected. The organic layers were combined (25 L) and washed with the following i0 ii98 39 U/- £,-) solutions: I. A mixture of water (3.66 L) and concentrated HCI (0.366 L); 2. A ndxture of water (3.66 L) and concentrated HCI (0.18 L) and 3. 10% NaCI solution (4 L). The organic layer was then dried over anhydrous Na2S04 (800 g) overnight. The solution was filtered and evaporated under reduced pressure at 60° (water bath) to give 5 as a yellow, glassy product. The product was then dried under vacuum at 60° for 13 hours, 3.21 kg (theory: 3.19 kg, > 100% yield, due to the presence of HOAc).

The product showed one spot by tlc analysis (EtOAc/ CH2C12; 30/20, Rf: 0.36); ic purity: 97-98%.

( C18, H2 0/CH3 CN; 60/40, flow 1.0 mL/min, retention time 9.8 mìn); two minor peaks occurred before and one minor peak after the main peak.

D. Preparation of Acetoxyacetic Acid (Acetylglycolic Acid) (7) HOCH2CO2H + CH3COCI -- CH3CO2CH2CO2H 6 7 Acetyl chloride (778.3g, 9.91 mol) was slowly (30 min.) added to glycolic acid (493 g; 6.48 mo!) with cooling and stirring. The temperature was kept at 15-25° After the addition was complete, the mixture was stirred at room temperature for 0.5 hour at which time a violent expulsion of HC1 gas occurred causing the reaction to set up solid. Toluene (i L) was added, and the mixture was heated to 70° in order to dissolve the solid. The solvent was removed under reduced pressure resulting in an oil to which toluene (2 L) was added.

After the mixture was allowed to stand overnight, the solids were collected, washed with toluene (i L) and air-dried to give 568.75 g (74°3%) of m.p. 65-66.5° (lit. 67-70°). The pmr spectrum was consistent with the assigned structure.

E. Preparation of Acetoxyacetyl Chloride (8) CH3CO2CH2C02H + SOCl2 -- CH3CO2CH2COCl 7 8 The acetoxyacetic acid (568.75 g, 4.82 mol) and thionyl chloride (759.19 g, 6.38 mol) were combined and heated with stirring at 65-70° for 1 hour. The solution was then heated 1 hour at 70-75° nd lastly 1 hour at 77° (reflux). The thionyl chloride was removed under reduced pressure and the residue was vacuum distilled.

The fraction boiling at 53-60° (12-15 mm) was collected giving 85°6% of 8. The ir spectrum was consistent with the assigned structure.

F. Preparation of 5-Acetoxyacetamido-N,N'-Bis(2,3diacetoxypropyl)-2,4,6-triiodoisophthalamide (9) CONHDAP " DMAC I, +CH3CO2CH2COCl > H2N ONHDAP ÇONH CONHDAP I CONHDAP I 8 9 DAP=-CH2CHOAcCH2OAc Compound 5 (349.32 g, 0.4 mol) and DMAC (1050 ml) were combined. The stirred mixture was cooled to 5° The i0 acid chloride (163.85 g, ].2 mol.) was added slowly keeping the temperature at 5-10° When the addition was complete the reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. Water (36 ml) was added to the reaction mixture. The temperature rose to 48° and then began to fall. The mixture was added to water (5 L) which was extracted with ethyl acetate (4 x I000 ml). The combined organic extracts were washed with 10% NaHCO3 solution (2 x i000 ml), water (I000 ml) dried over Na2SO4 and evaporated under reduced pressure to give 321.26 g (82.5%) of 9. The pmr spectrum was consistent with the assigned structure.

G. Preparation of N,N'-Bis(2,3-dihydrox propyl)-5-glycolamido-2,4,6-triiodoisophthalamide (i0) CONHDAP CONHDHP OHN H2 OAc CONHDAP +NaOH MeOH CONH i OH I CONHDHP lO DAP=-CH2CHOAcCH2OAe DHP= -CH2 CH---OHCH2 0H Compound 9 (321.26 g, 0.33 mol) and MeOH (1650 ml) were combined and stirred until all solids dissolved. To this solution was added IN NaOH (1650 ml, 1o65 mol).

The mixture was stirred for 30 min; HCI (137.5 ml, 1.65 mol) was then added. The solution was evaporated under reduced pressure to give a residue which was carried on to the next step without purification.

1198739 0225 - Il - IIOCH2 H. Preparation of N,N'-Bis(2,3-dihydroxylpropyl)-5N-(2-hydroxyethyl)glycolamido-2,4,6-triiodoisophthalamide (II) CONHDHP I +NaOH+CICH2CH2OH CONHDHP i0 DHP = - CH2 CHOHCH2 0H HOCH.

CONHDHP I I CONHDHP I Il The residue I0 (251.82 g, 0.33 mol; assume theory) was mixed with IN NaOH (412 ml, 0.412 mol). The mixture was stirred at room temperature until all solids dissolved, then the solution was stirred for 1 hour. 2-Chloroethanol (40.25 g, 0.5 mol) was added and stirring was continued for three days. To the mixture was added IN NaOH (330 m!, 0.33 mol); and after the mixture was stirred for 1 hour, 2-chloroethanol (32.2 g, 0.4 mol) was added. After three more days, another portion of IN NaOH (150 ml, 0.15 mol) was added. After being stirred 1 hour, a final quantity of 2-chloroethanol (16.1 g, 0.2 mol) was added. The solution was stirred overnight and then was evaporated to dryness under reduced pressure. The residue was triturated with MeOH (i L) for 1 hour. The precipitated solids were filtered off and the mother liquor was concentrated in vacuo. The crude product was purified by preparative liquid chromatography to give 127 g (47.7%) of Ii; m.p.186-198°; tlc (CHCI3 /MeOH/HOAc, 70/30/2; Merck silica gel plate)-one spot (Rf - 0.51); ic (H2 0/THF:

99.75/0.25; ibar-II, OEichrosorb RP-18,10 um, I0°) -two components (chromatographic purity: 97.3%); the ir and pmr spectra were consistent with the assigned structure Cal. for CI8 H2 413 N309; C:26.78, H:3.00; I:47.17; N:5.21 Found: C:26.47; H:3.23; I:46.83; N:5.12 »J ' * Trade Mark EXAMPLE I I RADIOGRAPHIC OBSERVATIONS l0 A male mouse (23 g) was anesthetized with sodium pentobarbital (40 mg/kg, i.p.; Nembuta!@, Abbott Laboratories). The N,N'-bis(2,3-dihydroxypropyl)-5-N- (2-hydroxyethyl)glycolar do-2,4,6-triiodoisophthalamide prepared by method of Example i, was administered at a dose of I0,000 mg I/kg (40% I solution) via a lateral tai! vein of the mouse at a rate of 1 ml/minute. Whole body radiographs in the ventrodorsal position were taken immediately and 5 minutes after administration with opacification of the liver and cardiovascular and renal excretory systems.

A pentobarbital-anesthetized male rat (234 g) received an intracisternal injection of 137 mg I/kg (40% I solution) of the N,N'-bis(2,3-dihydroxypropyl)-5N-(2-hydroxyethyl)glycolamido-2,4,6-triiodoisophthalamide, prepared by method of Example i. A lateral radiograph of the head and thorax, obtained immediately after administration, demonstrated good visualization of the cisterna magna, basal cisterns, and cervical subarachnoid space.

1198 39 EXAMPLE III The following pharmacological studies were conducted on N,N'-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl )glycolamido-2,4, 6-triiodoisophthalamide (PRODUCT), prepared by the method of Example I.

i0 i. Acute Intravenous Toxicity in Mice A solution of the PRODUCT (40% I) was injected into the lateral tail vein of young adult male and female Swiss mice at a rate of 1 ml/min. Following injections, the animals were observed for immediate reactions and then daily throughout a seven day observation period.

Lethality data were as follows:

DOSE DOSE NUMBER OF MORTALITIES/ (m@ I/kg) (mg/kg) NUMBER DOSED 18,500 39,220 0/8 20,000 42,400 5/8 21,500 45,580 i0/I0 Thus the LD50 value is probably about 20,000 mg i/kg.

2. Acute Intracisternal Toxicity in Rats:

The technique described by Melartin, et al. (Invest.

Radiol. 5: 13-21, 1970) was utilized to evaluate lethal effects of a solution of the PRODUCT after injection into cerebrospinal fluid at the cisterna magna. Young adult male Sprague Dawley rats were used. After dosing, the animals were housed individually and observed for immediate reactions and periodically for a two day observation period. The LD50 value was calculated by the method of Litchfield and Wilcoxin (J. Pharmacol.

Exp. Therap. 96: 99-113, 1949) with the following results:

CONCENTRATION (m I!kg) 45O LD50/(95% Confidence Limits) mg I/kg m k i,i00 2,332 (874-1,385) (1,853-2,936) i0 3. Acute Intracisternal Neurotoxicity in the Dog:

Three dogs (2 male, 1 female) were briefly anesthetized with thiopental sodium (20 mg/kg, iv., Nembutal®, Abbott Laboratories) and single doses of 314 (i dog) or 320 Mg I/kg (2 dogs) of the PRODUCT (50% I solution) were administered into cerebrospinal fluid at the cisterna magna. The dogs were observed thereafter for neurotoxicity. The animals displayed moderate CNS depression but no signs of convulsive or preeonvulsive behavior.

DOSE (m /Heart) 1,480 HR CF 4. Intracoronary Cardiotoxicity in the Isolated Perfused Rabbit Heart.

Four female New Zealand albino rabbits (3o4 - 4.3 kg) were employed for this study. Rabbits were sacrificed by cervica! dislocation, the hearts excised and coronary perfusion was performed via the aortic root using an oxygenated physiological salt solution heated to 37°C. A solution of PRODUCT (37% I) was warmed to 37°C and intracoronary bolus injections (4 ml) were made via a sidearm of the perfusion apparatus. The heart rate (HR), ...............

contractile force (OF), and electrocardiogram were recorded and results were as follows:

Mean % Change from Control HR and CF - at Various Times after PRODUCT Administration Arrhythmias 0-15 sec 15-30 sec 1 min 2 min 4 min. Observed -5 5 3 3 -2 None 49 48 62 2 -36 SUPPLEMENTARY DISCLOSURE It has now been found that the compound of this invention can be prepared by alternative additional processes. It is therefore a further feature of this invention to prepare said compound of this invention, which is N,N'-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiodoisophthalamide of the formula:

CONHCH2CHOHCH20H I I HOCH2CO CONHCH2CHOHCH2OH HOCH2CH2/ I i0 by a process which comprises either a) alkylating a compound of the formula:

CONHCH2CHOHCH2OH HOCH2CO-NH I CONHCH2CHOHCH2 0H with ethylene oxide or a compound of the formula:

HOCH2CH2 -X wherein X is halogen'or another leaving group to provide the desired compound of the formula:

- 16i198'Z89 CONHCH2CHOHCH20H I HOCH2CO N HOCH2CH2° I CONHCH2CHOHCH2OH I or b) alkylating a compound of the formula:

CONHCH2 HCH20-COCH3 I I O-COCH3 I O-COCH3 with ethylene oxide or a compound of the formula:

ROCH2CH2-X wherein X is halogen, or an= other leaving group, R is hydrogen, acetyl or another" alcohol protecting group to provide a compound of the formula:

CONHCH2 HCH20-COCH3 I CH3C0OCH2 CO N I O-COCH3 CONHCH2íHCH20-COcH3 ROCH2CH2/ I O-COCH3 and then hydrolyzing said latter compound to • !l - 17 - î198789 provide the desired compound of the formula:

I CONHCH2CHOHCH2OH I HOCH2CO N HOCH2CH2/ 2CHOHCH20H or c) alkylating a compound of the formula:

CONHCH2CHORCH2OR I ROCH2CO-N I CONHCH2CHORCH20R with ethylene oxide or a compound of the formula:

R'OCH2CH2-X wherein X is halogen or another leaving group, R is acetyl or another alcohol protecting group and R' is the same as R, to provide a compound of the formula:

CONHCH2CHORCH2OR I I iP CONHCH2CHORCH2 OR ROCH2COìIH CH2CH2OR' I - 18OE198'739 and then hydrolyzing said latter compound to provide the desired compound of the formulå:

CONHCH2CHOHCH20H I I HOCH2CO N CONHCH2CHOHCH2OH HOCH2CH2/ I i0 The substituent X may be halogen, for example chlorine or bromine« or another leavT - ing group, for example a p-toluenesulfon loxyl, methanesulfonyloxy, dimethylsulfonium, diethylsulfonium or pyridinium group. The substituent R may be hydrogen or acetyl or another alcohol protecting group, for example tetrahydropyranyl, trityl, ethoxycarbonyl (-C00C2H5), benzyl or allyl (-CH2 CH=CH).

The alkylation procedure may be carried out in the presence of a base, for example sodium methoxide, sodium ethoxide, sodium hydride, sodium carbonate or potassium carbonate. The reaction may also be carried out in the presence of a diluent or solvent such as methanol, ethanol, dimethylsulfoxide (DMSO), dimethylacetamide (DMAC) or propylene glycol.

In the process (b) or (c), the hydrolyzing procedure may be carried out by use of a hydro!yzing agent which may be, for example, sodium methoxide in methanol, ammonia in methanol, trifluoroacetic acid in aqueous methanol, aqueous sodium carbonate, aqueous sodium hydroxides aqueous potassium hydroxide, aqueous hydrochloric acid, aqueous hydrobromic acid or an ion exchange resin in the presence of water, such as an Amberlite resin, for example Amberlite IR-120 HCP resin.

These processes are illustrated further, but not limited thereby, by the following additonal examples.

r ' * Trade Mark - 19î19 EXAMPLE IV Preparation of N N'-Bis(2,3-dihydroxypropyl) - 5-[N-(2-hydroxyethyl)glycolamido]- 2,4,6-triiodoisoæhthalamide Step I: Preparation of 5-[N-(2-acetoxyethyl)- acetoxyacetamido]-N,N'-bis(2,3-diacetoxypropyl)-2,4, 6-triiodoisophthalamide (Hexaacetate) CONHDAP CONHDAP I I BrCH2 CH2 OAc/DMSO I l I coc co - i I CH2 CH2 OAc (Pentaacetate) (Hexaacetate) (DAP= -CH2 CHOAcCH2 OAc) .i0 Dimethylsulfoxide (i00 ml) was charged to a flask and there was added thereto, with stirring, 100 g of 5-acetoxyacetamido-N,N'-bis(2,3-diacetoxypropyl)-2,4, 6-triiodoisophthalamide (pentaacetate) [95.71 g based on assay]. The mixture was stirred and warmed to to 45°C until all pentaacetate dissolved. The solution was cooled to 35 to 38°C and 28.40 g of powdered anhydrous potassium carbonate was added as quickly as possible to keep the reaction dry. Stirring at 35 to 38°C was continued for 15 minutes and then 20.59 g of 2-bromoethyl acetate was added in one portion and the reaction temperature maintained at 21 to 23°C by cooling. The reaction mixture was then stirred very vigorously at 35 to 38°C for 14 to 15 hours. 4.42 G of 2-bromoethyl acetate was added with vigorous stirring 20I198 39 and stirring was continued for an.additional 17 to hours. Ethyl acetate (206 ml) was added to the re-' action mixture which was then filtered to collect the salts and the salts were washed with 200 ml of ethyl acetate and then discarded. The combined filtrate and washing was diluted with 520 ml of ethyl acetate and then 450 m! of 5% sodium chloride was added and stirred for 20 minutes. The ethyl acetate layer was separated and retained. The water layer was extracted with 514 ml of ethyl acetate and the combined ethyl acetate layer and extract was stirred for i0 minutes with 750 ml of a 5% sodium chloride solutions The layers were separated and the ethyl acetate layer was dried over 100 g of anhydrous magnesium sulfate. After filtering and washing with 200 ml of ethyl acetate, the combined filtrate and washing was concentrated to 180.5 g (about ii0 g of crude hexaacetate present). Ethyl acetate (250 ml) and toluene (750 ml) were added and the solution was stirred for 19 hours. The mixture was filtered and the solid was washed with I00 ml of an ethyl acetate-toluene mixture (44:100) o The solid product was dried at 25 to 40°C and there was thus obtained 85.5 g (82% yield based on the assay of pentaacetate) of 5-[N-(2-acetoxyethyl)-acetoxyacetamido]-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide (hexaacetate).

The HPLC purity is 94-97%.

Step 2: Preparation of N,N'-bis(2,3-dihydroxy_propyl ) -5- [N- ( 2-hydroxyethyl ) glycolamido] -2,4,6-tri-.

iodoisophthalamïde CONHDAP CONHDHP I i_n NaOMe I I MeOH/-I° to 4°C> HOCH2CON I CONHDHP AcOCH2CON ONHDAP (Hexaacetate) (DAP= -CH2CHOAcCH2 OAc ) (DHP= -CH2 CHOHCH2 OH) - 21ii98739 A mixture of 427.5 ml of methanol and 85.5 g of hexaacetate (obtained as above) was stirred until solution was complete and the solution was then cooled to -I°C. There was added thereto 8.07 ml of a sodium methoxide solution (freshly prepared from 0.72 g of sodium metal dissolved in 30 ml of methanol). The reaction mixture was stirred at -i° to 4°C for 3 to 4 hours and then quenched with 0.484 ml of acetic acid.

The reaction mixture was evaporated to near dryness at 60°-75°C leaving a very thick oil which was then diluted with 290 ml of water to give about 20% w/v of solution. The solution was adjusted, if necessary, to pH 4.5 to 5.0 by addition of acetic acid. The solution was then either concentrated to 81.4 ml (about 80% w/v) in vacuo at 60°-75°C or it was evaporated to dryness to obtain crude desired compound. The yield of crude compound is 66.34 g (101.8% on a dry weight basis) containing some sodium acetate and Methanol.

The HPLC purity of this crude compound, N,N'-bis(2,3dihydroxypropyl)-5-[N-(2-hydroxyethyl)glycolamido]- 2,4,6-triiodoisophthalamide, is 94 to 98%.

EXAMPLE V Hydrolysis of hexaacetate to N,N'-Bis(2,3dihydroxypro yl)-5-[N-(2-hydroxyethyl)- Hlycolamido]-2,4,6-trïiodOisophthalamide by use of aqueous resin CO DAP CO OHP _ 00oc > Ac°c 2 l "co DA HOCH2 CON' I CON DHP CH2CH2 OAc CH2CH2 OH (Hexaacetate) (DAP= -CH2 CHOAcCH2OAc) (DHP= -CH2 CHOHCH2 0H) 98739 A reaction mixture of water (20 ml), hexaacetate (5.4 g) and Amberlite IR-120 HCP ion exchange resin' (20 ml) is stirred and heated at 100°C for 3 hours.

The mixture is then cooled to ambient temperature and filtered and the resin is washed with water (20 ml).

The filtrate was evaporated to dryness and there was thus obtained N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2hydroxyethyl)glycolamido]-2,4,6-triiodoisophthalamide having a purity of 92% to 98%. The crude material was purified by chromatography.

* Trade Mark - 23II',)87 9 The embodiments of the invention in which an exclusive property or privilege is claimed are dei fined as follows:

l° A process for the preparation of N,N'- bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiodoisophthalamide of the formula:

CONHCH2CHOHCH2OH I I -- -- CoN cR C o cH oH HOCH2CH// I 2 2 which comprises either a) alkylating a compound of the formula:

CONHCH2CHOHCH2OH I with a compound of the formula:

HOCH2CH2-X wherein X is halogen, to provide the de-- sired compound of the formula: