This paper goes a long way to explaining why our doctors thought that this chemical was safe at the time of its' introduction. It should also be noted that this paper was published at the height of WWII, if there were doubts about it, investigation would be a subject best left on the "back burner" until peace re-established itself in the post-war, US dominated, world. (MF)

 

Soc.Chem.Ind 63-223(1944)
THE PREPARATION OF IODINE-CONTAINING X-RAY CONTRAST SUBSTANCES.
IV. ETHYL IODOPHENYLUNDECOATE (PANTOPAQUE)
Authors: Wilson Baker, E.E.Cook, and (in part) W.G.Leeds

A detailed process is described for the preparation of ethyl-iodophenyundecoate (I), an x-ray contrast substance for the visualisation of the spinal canal and other bodily cavities. Undecenoic acid and benzene are condensed to give phenylundecoic acid, which is directly iodinated in acetic acid solution in presence of iodic acid and the product enterified(sic). The overall yield of purified material is 70%.

Until recently the only compounds available for the X-ray visualisation of the spinal canal have been iodised vegetable oils, in particular iodised poppy-seed oil which contains about 40% of iodine. These iodised oils are of variable quality and are unsatisfactory in clinical practice.

Owing to the reactive nature of the iodine atoms which are in aliphatic combination, samples are often unusable owing to free iodine, or they may slowly decompose in the body with liberation of iodine, causing toxic symptoms particularly in contact with diseased or inflamed tissues.

This instability is especially objectionable in the spinal canal, where that portion of the oil which cannot be withdrawn, may be finally absorbed only after a period of years. For this reason there is considerable reluctance to use iodised poppy-seed in myelography.

A clinically satisfactory, non-toxic oil containing chemically inert aromatic iodine has been described by Strain, Plati and Warren.

This is ethyl p-iodophenylundecoate (I)1 C4H4I(CH2)I10CO2Et, a product which has been prepared by the Eastman Kodak Company under the name of "Pantopaque", but it is not yet generally available. It has the advantages over iodised poppy-seed oil of being more fluid and more rapidly absorbed without toxic symptoms after intrathecal injection. The iodine content is about 30%, so that it is rather less radio-opaque than iodised poppy-seed oil.

The ethyl iodophenylundecoate was prepared by the American workers by the condensation of iodobenzene with ethyl undecenoate in presence of aluminium chloride, and is probably a mixture consisting mainly of (I) with a smaller quantity of p-C8H4I CHMe(CH2)10CO2Et, and doubtless traces of the ortho-isomeride. The yield claimed is 40%.

Some of the ethyl iodophenylundecoate was prepared by the method of Strain, Plati and Warren, and, although clinically satisfactory, the yield was only 10%, and no higher yield could be obtained either under the original or modified conditions, or by the use of other condensing agents or solvents.

It became clear that a considerably improved method for preparing ethyl iodophenylundecoate would have to be found if it was to be produced technically on the large scale, and amongst the methods investigated since 1942, in this laboratory only the direct iodination of phenylundecoic acid or ester showed promise.

Close study of the reaction led ultimately to the process now described, by which clinically usable ethyl iodophenylundecoate is prepared in 88% yield from phenylundecoic acid, or 70% overall yield from undecenoic acid and benzene.

After the present process had been worked out a second paper by Plati, Strain and Warren (Ibid 1943, 65,1273) described the direct iodination of simpler phenyl-fatty acids using sodium nitrite as oxidising agent, but the yields were not good (14-50%). It seems clear that the experiments were initiated because "a method for the direct iodination of phenyl-fatty acids was essential" in order to avoid the poor yield in the condensation of iodobenzene with unsaturated esters.

In the present process phenylundecoic acid is prepared by the condensation of benzene with undecenoic acid in presence of aluminium chloride. This product is probably the a-phenyl derivative, but it may contain the isomeride with the grouping CHPhMe.

The phenylundecoic acid is then iodinated in acetic acid solution in presence of iodic acid and a little water. Under these conditions the iodine substitutes almost wholly into the nucleus, undoubtedly mainly in the p-position, but a very small amount of iodine appears to enter the side-chain in the a-positive to the carboxyl group.

It is considered essential that this aliphatic iodine should be removed if the final material is to be completely stable in the body. The crude iodinated acid is, therefore, first refluxed with aqueous alcoholic sodium hydroxide, and then oxidised with excess of potassium permanganate in acetone, thus degrading any unsaturated or hydroxy-acids to homologues with one or two fewer carbon atoms, so that the iodinated acid as isolated contains small quantities of iodophenyldecoic and iodophenylononoic acids. Finally the saturated iodinated acids are esterified with alcohol and sulphuric acid and the esters distilled.

The fact that the final product is not entirely homogeneous is no disadvantage in X-ray diagnosis. The material prepared as described here has been tested in myelography by Professor H.W.B.Cairns, F.R.S and doctor F.H.Kemp at the Radcliffe Infirmary, Oxford and found to be completely satisfactory.

In bulk it possesses a pale yellow colour which is difficult to remove, but in analysis and physical properties it is otherwise extremely similar to "Pantopaque".

Both products may be sterilised in scaled tubes at 100 degrees without alteration, but should be stored in the dark as they develop a light brown colour when exposed to sunlight.

The iodination of phenylundecoic acid in presence of persulphates, in particular potassium persulphate, has also been investigated. In these cases only about half the iodine enters the nucleus, and it is possible to introduce two atoms of iodine into the molecule, and then to remove the aliphatic iodine by hydrolysis and oxidation. Although the material thus prepared is satisfactory the yield is only about 30% from phenylundecoic acid.

Experimental

Phenylundecoic acid (cf. Fourneau and Baranger): Powdered aluminium chloride (310g;1.5mols. optimum quantity) is added to anhydrous benzene (1200cc; purified by concentrated sulphuric acid) in a 3litre flask fitted with a dropping funnel and mercury-scaled stirrer and cooled in an ice-salt mixture.

During 45 minutes a solution of undecenoic acid (284g;1mol.)in benzene (200cc) is run into a well-stirred mixture, the temperature being kept between 5 and 10 degrees. The mixture is then warmed slowly to 10 degrees (sic), stirred for a further half-hour, poured into crushed ice (800g) and concentrated hydrochloric acid (500cc) with stirring and the benzene layer separated.

The aqueous layer is extracted twice with a little benzene and the united extracts are shaken with dilute hydrochloric acid, then water, dried over calcium chloride, and distilled, yielding phenylundecoic acid (318g;78%), h.p. 210-235/21 mm.

Iodination of phenylundecoic acid. In this process all-glass apparatus must be used or corks protected by asbestos. A 3 litre flask is fitted with a 2 foot length of glass tubing 1 inch in (diameter) cooled externally by a 1 inch spiral of thin lead piping through (which) cold water is passed.

The flask contains phenylundecoic acid (200g;1mol) (sic) (150g;1.5atoms(sic)), a solution of iodic acid (60g) in water (sic) glacial acetic acid (1litre) and is heated on a sand-bath (sic) deposition of iodine in the condenser refluxing must be gentle (about 3 hours and then vigorous for a further 13 hours. The (?) acid and excess of iodine are now removed under reduced pr(?) a water-bath, the residue in the flask is diluted with (?) (1litre) and extracted several times with benzene. The (?) extract is freed from iodine by shaking with a saturated solution of sodium bisulphite, then with water, dried over calcium (?) chloride and the benzene removed by distillation.

Removal of aliphatic iodine. To a solution of the iodinated (?) alcohol (1litre) is added sodium hydroxide (150g) in water (?quantity) the homogeneous mixture heated on the water-bath for (? time) and then most of the alcohol removed under diminished (?). The product is diluted with water, acidified with hydrochloric acid(?) and extracted with benzene. The extract is washed with (?) and dried over calcium chloride, the benzene removed under di(?) pressure, and the residue dissolved in alcohol free acetone (?) in a 3 litre flask fitted with a mercury-sealed stirrer and c(?). Powdered potassium permanganate (10 or 40 g.(?)) is added and the mixture(?) stirred and refluxed on a water bath for 1 hour when excess(?) permanganate(?) is still present. The acetone is removed by distillation(?), water added, and sulphur dioxide passed to remove mercuric(?) dioxide and liberate the iodinated acid as the upper layer(?) of(?) the(?) mixture is well extracted with benzene, the extracts are washed(?) and (?) the benzene and traces of water removed by distillation (?) under (?) reduced pressure from a water-bath.

Esterification of iodophenylundecoic acid. The iodophenylundecoic acid is refluxed with alcohol (500cc) and concentrated sulphuric(?) acid (50cc) for 16 hours, the alcohol removed under reduced(?) pressure(?), and the product poured into water and extracted thoroughly(?) using(?) ether. The combined extracts are washed with saturated ______(?) bisulphate solution, then aqueous sodium bicarbonate, and distilled(?) water. After drying over anhydrous sodium sulphate the e____(?) is(?) shaken with charcoal which removes most of the colour, the(?) _______(?) removed , and the product distilled from an air.bath. ________(?) fraction of b.p. up to 190degrees/0.8mm, was discarded and the fraction(?) of(?) b.p. 190-210 degrees/0.8mm (280g) was collected. The b.p. is(?) _____(?) mainly 218-220degrees/0.5mm, by distillation over a free(?) _____(?). Found: C 55.6,55.7: H 7.6,7.6: I 30.2, 31.2%: n(?) ________ (?) d 25 over 25(?) 1.2560. Calc(?) for
C19H2902I 30.5%.

C and H values may indicate the presence of some iodinated ______(?) carbon: the iodine values vary owning to the difficulty with(?) ______(?) when(?) these compounds are oxidised.

The pale yellow colour of the product may be further reduced(?) by(?) dissolving in dry light petroleum (600cc;b.p.40-60 degrees(?)). Then(?) filtered(?) for half an hour with charcoal and the filtrate shaken with Merc(?) (?)mann alumina(?), filtered, and the solvent removed under di(?) pressure in the water bath.

The Dyson Perrins Laboratory
Oxford University
Received May(?) 1944

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