US3178473A - Process for the n-alkylation of acyl anilides halogen substituted in the nucleus - Google Patents

Description

United States Patent 3,178,473 PROCESS FOR THE N-ALKYLATION 0F ACYL ANILIDES HALOGEN SUBSTITUTED JN THE NUCLEUS Hugo Holtermann, Hovik, Baerum, Leif Gunnar Haugen, Grefsen, Oslo, Vegard Nordal, Smedstad, Oslo, and Johan Lyder Haavaldsen, Oslo, Norway, .assignors to Nyegaard &'Co. A/S, Oslo, Norway No Drawing. Filed Mar. 2, 1962, Ser. No. 176,894

Claims. (Cl. 260--519) This invention relates to the preparation of compounds of the general Formulas A and B wherein R is a substituted or unsubstituted alkyl group, such as for example methyl, propyl, carboxymethyl, carbalkoxymethyl or hydroxyethyl, X is hydrogen or iodine atoms at least two of them being iodine and, Y designates hydrogen or a desired substituent such as a carboxyl, carbalkoxyl, amino, acylamino or the group and wherein Z designates the residue of a substituted or unsubstituted aliphatic or aromatic carboxylic acid, for example an acetyl group.

"Particularly the invention relates to those compounds of the above general formula in which X is iodine and where R, Y and Z have the meanings given above.

The practical importance of the invention is apparent from the fact that new and valuable compounds can be prepared by the process, especially X-ray'contrast agents, in which case the compounds which are acids may be used in the form of their non-toxic salts, and intermediates in their production. Thus, for instance, the new X-ray agent N-methyl-3,5-diacetamido-2,4,-triiodobenzoic acid (I) is made easily available by means of this invention, and also methyl N-methyl-3,5-diacetarnido-2,4,6-triiodobenzoate (II and 3 (N methylacetamido) 5 amino- 2,4,6-triiodobenzoic acid (III), the latter two compounds (II and III) being important intermediates in processes for the production of (I) The novelty and characteristic inventive feature of the process is a simple and eificient method of making compounds of the above general Formula A or B whereby the N-substituted-acylamido group (RAIL-z of the above general Formula A or B is formed.

It will be seen that the compounds of the above general Formula A are derivatives of N-alkyl-acylanilides, thus, Compound I for example, is a 2,4,6-triiodo-3-acetamido-5-carboxy-N-methylacetanilide.

The general methods of organic chemistry for making N-alkylacylanilides are the following, as exemplified by N-methylacetanilide:

(1) Aniline is methylated by means of a methylating agent (dimethyl sulphate, methyl p-toluene sulphonate,

3,i?8,473 Patented Apr. 13, 1965 "Ice (2) Aniline is reacted with p-toluenesulphonic acid chloride (or benzene-sulphonic acid chloride), the p-toluenesulphonanilide formed is methylated, the N- methylated reaction product hydrolysed under drastic conditions (strong mineral acid, heat) yielding 'N-methylaniline, which is finally acetylated:

IYIH: Imam-@011,

(3) Acetanilide is converted to the sodium salt by heating it with powdered metallic sodium in a high boiling inert solvent, for example Xylene, followed -by treatment of the sodium salt with a methylating agent (for example methyl iodide) AclTIH AclTT-Na ITTHCH; AeIIT-CH;

A CIIL- 0 H3 It is true that methylaniline according to procedure 1 above can technically be separated from the other reaction products and from unreacted aniline by fractional distillation or by fractional crystallization of the hydrochlorides, but these are special separation procedures not generally applicable and are in any case irrelevant for the present analysis.

The present invention is characterised by the discovery that the N-substituted acylanilides of the above general Formulas A or B are prepared by N-substitution in alkaline aqueous solution (for example sodium hydroxide solution), alkaline aqueous-organic solution (for example alkaline aqueous methanolic solution) or organic solution in the presence of a base (for example ethoxide in ethanol) of the acylanilides of the general Formula C according to the general reaction:

HIYT- Z RIFT Z X X X X Y Y Y Y 3 bromoacetic acid, ethyl bromoacetate, ethylenebromohydrin, etc.)

We have thus found that while acylanilides in general are not alkylated in solution in the presence of alkali or sodiumalkoxides, this is the case when two or more halogens are introduced into the ortho and para positions relative to the nitrogen atom of the anilide.

This may appear the more surprising when one con siders the steric hindrance known to operate in the neig boring positions of aromatic bound halogens and which is quite formidable in the case of iodine. It is furthermore noteworthy that reaction mechanism studies indicate that the alkylation reaction is proceeded by enolization and ionization of the acylamido group of the anilide to be alkylated, in spite of the work of Neudert and Ropke (Chem. Ber., 87, 659-667 (1954)) who found no indication of a tendency of enolisation or dissociation of the acetamido group in their ultraviolet absorption studies on adipoyl bis (2,4,6-triiodo-3-carboXy-anilide) (IV) which is easily methylated in aqueous alkali according to the invention to the N,N-dimethyl derivative (V) I I I I -NH 0 (013940 OHN (IJO H 11 I I I I NC 0 (011,) 0 ON I H H I Furthermore we have found that the general method (method 3 above) of alkylating anilides by successive treatment with metallic sodium and an alkylating agent is not generally applicable on the polyhalo-anilides of the invention (general Formula C above). It has thus for instance not been possible in our hands to N-alkylate methyl 3,5-diacetamido-2,4,6-triiodobenzoate by successive treatment with metallic sodium and methyl iodide (or dimethyl sulphate) in boiling xylene (or dioXan) although the alkylation proceeds rapidly at room temperature and below in aqueous alkali.

We have also found that an ordinary alkylation (according to method 1 above) of amino-nitrogen prior to the introduction of the acyl group of the compounds of the general Formula C is not generally applicable and has failed completely in our hands for example in the case of 3,S-diamino-2,4,6-triiodobenzoic acid which could not be N-methylated by means of methyl iodide or dimethyl sulphate. This is taken advantage of in the present invention according to which compounds of the general Formula C in which one Y is an amino group and the other Y is an acetamido group can be alkylated exclusively on the amide-nitrogen as in the following reaction:

(I) 0 2H (I: 0111 I I I H N- -NHAc H N -NAc (III) where no trace is found of a derivative carrying a methyl group on the amino nitrogen, and where the yield of the desired Compound III is nearly quantitative. This reaction is of great importance because the intermediate (III) can easily by acetylation be converted to the valuable N- methyl-3,5-diacetamido 2,4,6 triiodobenzoic acid mentioned above.

Method 2 above is not generally feasable because of the extraordinary resistance to hydrolysis of polyhalogen substituted anilides, and would of obvious reasons constitute an unnecessary and laborious complication.

The present invention therefore is founded on the discovery that acyl anilides of the above general Formula C (1) Can be N-alkylated in alkaline aqueous or organic solution as easily as sulphonanilides, contrary to other ordinary acylanilides and that (2) The ordinary method of N-alkylation of anilides is not generally applicable to the compounds of the invention.

As to the interpretation of the general Formulae A and C it should be stated clearly that they are intended to cover also compounds which contain two or more acyl anilido groups in the same or in different aromatic nuclei, thus the following compounds and reactions fall within this invention:

I I I I AcHN NHAc AcHN NAc I I Hz AcN NAc is, I in.

I I I NHOO (CH2)4CONH ([JOZH 00111 I I I I NCO (CH2)4CON I CH (1H I It has furthermore been found that certain compounds of the general Formula C of the invention can be further alkylated when suitable groups (for example carboxyl groups) are present as substituents, and that in such cases it is usually possible to lead the reaction so as to give the one or the other reaction product. It is thus possible according to the invention to methylate 3,5-diacetamido- 2,4,6-triiodobenzoic acid to either the N-monomethyl acid, the N,N-dimethyl acid or the N,N-dimethyl-methyl ester as illustrated by the following formula:

(iJOzII (IJOQH I I I I AcHN- NHAc AcHN- NAc I I Ha (IJO H 00 011 I I I I AcN NAc .AcN- NAc H3 I H5 (EH3 I H3 and while this reaction sequence takes place in aqueous media, N-alkylation taking place more rapidly than esterification, the following sequence is predominant in nonaqueous media, esterification taking place more rapidly TABLE ICI1ti1111ed than N-methylation: ion: 00,11 HOOC-(CH hCOlFI-R (10211 2 3 I I I I I I 5 I I I I NCO(CH;)4CON AeHN- NHAc AcHN- NHAe I CH3 I I I I R=H, CH3 R=CH3, CQH5, 03H? ooze (|302CH3 $0211 F I I I I I I I AoHN- -NAc ACN NAO I i b I R I R I H H 1 H3 In some such cases it may be an advantage to carry the reaction to the completely N-methylated ester stage and I I I I then convert the N-methylated ester to the acid if the latter compound is desired. AcylHN NAcyI 1 IL I It has furthermore been found that in the cases Where the N-methylated acylanilides of the invention carry an HZCOOH iodine atom in both ortho positions to the acylamido group a new type of isomerisrn occurs which is due to re- GO H 003E I stricted rotation of the acyl group around the axis .con- I I I necting the carbonyl carbon-atom with the nitrogen atom, making two thermodynamically preferred orientations of A 1 A the acyl group possible, one in which the carbonyl of the c} Cy c N Ac I J; J, acyl group points inwards towards the aromatic nucleus R I R H010 I HICOflH (endo form) and another in which it points outwards away from the aromatic nucleus (exo form), the two forms adopting their thermodynamical equilibrium rapidly above 70 C.

The process of the invention is very simple and is carried out in the following Way. The acyl-polyhalo-anilide is dissolved in aqueous alkali eventually by the help of I 1110331011 an organic solvent (for example acetone, methanol, di- C'H CH OH oXan etc.), or it is dissolved in an organic solvent towhich is added strong alkali or an alkali alkoxide or some other 40 TABLE II suitable base, and the alkylating agent (for example di- AcylNgflaqozR methyl sulphate, methyl p-toluene sulphonate, propyl I I I I iodide etc.) is added preferably in portions withstirring, I I I I I I 1 dissolved in some solvent which will give a' homogeneous solution. Stirring and cooling are usually advantageously I I I I vA N NAG employed in the case of the very reactive alkylating agents.

The compounds of Table II below are examples-of compounds which can be prepared according to the invention, those of Table I comprise those which have actually been 01120013 01129013 prepared. TABLE I NC 0 (CH -G O N AeylN (CH Il-N Aeyl I CH -ITI-A0 Join (303R I I 3 I I I i I I r r r I I I I I 1 -NAO HZN --NAc R =H, alkyl 1 1 Jam 1 on,

I I I I I r .I I

AcHN NAe AcN -NAc R =alkyl I R =11, alkyl R =alkyl I I I I r r 'I r I I R =allq71 R =H, alkyl TABLE IIContinued C R 0 OgR I I I I lTT-Acyl HzN- -N-Acyl I R I R R =H, alkyl R =H, alkyl R =alkyl R =alky1 O 0 R 0 0 R I I I I HzN -IIIC 0 (CH2) 4C ON -NH, OH; (EH; I R=H, CH;

I I I Acyl HN lTT-Acyl .AcHN NAc I R I 6111 C 0 2R R=H, alkyl R, R=H, alkyl R: alkyl I I I I AcHN -NAc Acyl-N- N-Aeyl I HzCHgOH R I R 11:13 1k 1 R=H alk l a y R'=R'"=ik 1 0 0 B C 0 R I I I I AeN- NAe AcN NAc J; I HgCOgR' l I HgCHzOH HzCOgR' HzCHzOH R, R=alkyl R=alky1 EXAMPLE 1 N-methyl-Z,4,6-triiod0acetanilide Triiodoacetanilide (3.9 mmol., 2 g.) was suspended in 20 ml. of ethanol and brought into solution by means of 2 ml. of N methanolic sodium hydroxide. Dimethyl sulphate (6.4 mmol., 0.6 ml.) was added while stirring and placed on a water bath at 60 C. After about minutes N-methyl-2,4,6-triiodoacetanilide crystallised and was filtered after 12 hours standing and washed on the filter with 5 ml. of ethanol. The pistol dried product (0.6 g., 78% of theory) melted at 183l90 C. (Mixture of the acetexo and acetendo forms.)

EXAMPLE 2 N-mezhyl-3-acclamid0-2,4,6-trii0d0benzoic acid 3-acetamido-2,4,6-triiodobenzoic acid (0.147 mol., 82 g.) was dissolved in a mixture of water (80 ml.) and 5 N sodium hydroxide (3.7 eqv., 110 ml.). The solution was cooled to about 15 C. and dimethyl sulphate (1.2 eqv.), dissolved in acetone (17 ml.) was added with stirring at a relatively slow rate. After 45 minutes stirring the N- methyl-3-acetamido-2,4,6-triiodobenzoic acid was precipitated by addition of hydrohcloric acid (1:1) to pH about 0.5. The moist acid, containing the exo and endo isomers in about equal proportions was dissolved as their ammonium salts in about 400 ml. of water and the solution kept in boiling water bath for about 45 minutes in order to convert the thermodynamically less stable isomer (endo compound) into the more stable (exo compound), whereafter the solution was treated with active carbon, filtered, cooled and precipitated by means of hydrochloric acid 7 0 (1:1), stirred for about 1 hour, filtered, washed with water and dried. Exo-N-methyl-3-acetamido-2,4,6-triiodobenzoic acid was obtained in 94% yield (79 g.).

EXAMPLE 3 5-amino-3-(N-methylacetamido)-2,4,6-triiod0benz0ic acid Methyl 5 -amino-3 (N-mcthylacetamido) -2,4,6- triiodobenzoate 3-acetamido-5-amino-2,4,6-triiodobenzoic acid (2 g.) was suspended in water (2 ml.) and dissolved by adding 7.8 m1. of 5 N potassium hydroxide. Dimethyl sulphate (1.8 ml.) dissolved in acetone (l.8 ml.) was added in portions with stirring at 50 C. The insoluble methyl 5- .amino 3 (N-methylacetamido) 2,4,6-triiodobenzoate which precipitated was filtered, washed with dilute acetic acid and with water and dried (2.0 g.).

EXAMPLE 5 Methyl N-methyl-3,5-diacctamid0-2,4,6-trii0dobenzoate Methyl 3,S-diacetamido-2,4,6-triiodobenzoate (50 g; 0.08 mol.) was suspended in water (150 ml.) and dissolved by adding 5 N potassium hydroxide (38 ml.; 2.4 eqv.). Acetone (5 ml.) was added with stirring followed by dimethyl sulphate (8 ml.; 1.05 eqv.) dissolved in acetone (10 ml.) slowly at about 15 C. After 1% hours insoluble methyl N,N'-dimethyl-3,5-diacetamido-2,4,6- triiodobenzoate (2.9 g.) was separated by filtration. The filtrate was acidified by means of concentrated hydrochloric acid (about 20 ml.) and the precipitated material filtered, Washed with water, redissolved in strong alkali to a concentration of about 10% ester, filtered from a small amount of N,N-dimethyl-mcthylester, the filtrate reacidified and the practically pure methyl N-methyl-3,5-diacetamido-Z,4,6-triiodobenzoate filtered, washed with water and dried.

EXAMPLE 6A N-methyl-3,5-diacetamido-2,4,6-triiod0benzoic acid 502.4 g. (0.8 mol.) of methyl 3,5-diacetamido-2,4,6-triiodobenzoate is dissolved in 800 ml. 5 N aqueous potassium hydroxide (4 mol.) by mechanical agitation and gentle heating. All material dissolves and the solution is cooled to room temperature whereafter 1600 ml. of molar methanolic methylsulphuric acid is added with stirring. The mixture is heated on boiling water bath for 10 minutes under reflux cooling. Then the heating continues on the boiling water bath with descending condenser. After about 2 hours about 1420 ml. has distilled over at 72- 82". Some solid substance has precipitated, and a further 200 ml. (1 mol.) 5 N potassium hydroxide and 22 g. of solid (85%) potassium hydroxide are added, after which heating on boiling water bath continues with descending cooler. After minutes a sample of the mixture gives, after addition of glacial acetic acid to pH about 4.5, no longer any precipitate. Altogether about 1560 ml. distillate has been collected.

The heating is suspended and to the darkbrown mixture is added 500 ml. of water. After cooling to room temperature, the precipitated substance is filtered by suction on a glass filter and washed with 250 ml. of water.

The two filtrates are combined and filtered. To this clear, brown, filtered liquid (1920 ml.) is added with mechanical stirring 970 ml. of dilute hydrochloric acid (1 :2) to pH about 4. After standing over night the solution is filtered from a voluminous, chocolate-brown precipitate, which is washed with 400 ml. water. Filtrate and washings .are combined and 70 g. of carbon (index 35) added, heated to boiling and filtered. The filtrate is washed with about 1000 ml. of water and the two filtrates combined. To the tea-coloured solution is added about 2150 ml. dilute hydrochloric acid (1:2) with mechanical stirring to pH 10.5. After agitation over night it is filtered on a sintered plate (G4) and the precipitate washed twice with water (500 ml. and 300 ml.), and dried to constant weight over phosphorous pentoxide in vacuum. The slightly yellowish substance weighs 378 g. (76.6%) and consists of approx. 85% N-methyl-3,5-diaeetamido-2,4,6- triiodobenzoic acid, admixed with about 5% 3,5-diacetamido-2,4,6-triiodobenzoic acid and about 15% N,N-dimethyl-3,5-diacetamido-2,4,6-triiodobenzoic acid. 3 g. of this product is extracted twice with pyridine-containing alcohol. The undissolved pyridine salt is treated with diluted hydrochloric acid, washed and dried, whereby 56% chromatographically pure N methyl 3,5 diacetamido- 2,4,6-triiodobenzoic acid is obtained. By processing of the alcoholic mother liquors the yield of this compound can be increased.

EXAMPLE 6B N-m'ethyl-3,5-diacetamid0-2,4,6-trii0dobenzoic acid 3,5-diaoetamido-2,4,6-triiodobenzoic acid g.) is suspended in water (-10 ml.), 5 N potassium hydroxide (4.3 eqv.) is added and the mixture cooled to about C. Dimethyl-sulphate (0.5 eqv.) dissolved in an equal volume of acetone is added drop by drop while stirring. After the reaction mixture has been stirred for about 1 hour hydrochloric acid (1:1) is added, with stirring to pH about 0.5. The precipitate is filtered, washed and suspended moist in 4 parts of water, concentrated ammonia is added to pH about 7 and the ammonium salt solution is isomerized at 90100 C. for about half an hour whereafter additional ammonia is added to pH about 9 followed by solid ammonium chloride (about 10% weight/volume) and the solution stirred over night and the excess of 3,5-diacetamide-2,4, 6-triiodobenzoic acid recovered as ammonium salt on the filter. The filtrate is precipitated by means of hydrochloric acid (1:1) at pH about 0.5 and the N-methyl-3,5-diacetamido-2,4,fi-triiodobenzoic acid collected on a filter, washed and dried.

EXAMPLE 7 Methyl N,N'-dimethyl-3,5-diacetamid0-2,4;6 .triiodobenzome 50 g. of methyl 3,5-diacetamido-2,4,fi-triiodobenzoate is dissolved in a mixture of 50 ml. 5 N potassium hydroxide and 200 ml. of water by careful heating under mechanical stirring. At 4850 21.5 ml. of dimethylsulphate is added under constant stirring, 12-16 drops per minute. After the solution has become neutral, it is heated for '5 minutes to 55-65. The product is filtered ott, extracted hot for a few minutes with '2 N potassium hydroxide, cooled, filtered, washed and dried, whereby 50.0 g. (94%) pure N,N-dimethyl-3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester is isolated.

EXAMPLE 8 N,N -dimethyl-3 ,5 -diacetam id0-2,4, 6 triiodobenzoic acid 3,S-diacetamido-2,4;6-triiodobenzoic acid (10 g.) is sus pended in -10 m1. of water and 5 N potassium hydroxide (6 eqv.) added and the mixture cooled to about 15 C. Dimethyl sulphate (1.4 eqv.) dissolved in an equal volume of acetone is added drop by drop with stirring. The product is precipitated by the addition of hydrochloric 10 acid, collected on a filter, resuspended moist in about 4 volumes of water and dissolved by the addition of alkali to pH about 7. The solution is now isomerised by heating to 90-100" C. for about 1 hour, cooled and reprecipitated by means of hydrochloric acid, filtered, washed and dried in the ordinary way, yielding about 10 g. of dry N,N-dimethyl-3,5-diacetamido-2,4,6-triiodobenzoic acid.

EXAMPLE 9 Propylation of 3,5-diacetamid0-2,4,6- triiodobenzoic acid 3, 5-diacetamido-2,4,6-triiodobenzoic acid (5 g.; 8.2 mmol.) was suspended in water (5 ml.), and brought into solution by means of the addition of 5 N potassium hydroxide (6.5 ml.; about 4 eqv.). n-Propyl iodide (0.8 ml.; 8.2 mmol.) dissolved in acetone (1 ml.) was added and the mixture heated under reflux and mechanical stirring on the boiling water .bath for about 1 hour. The temperature was then decreased to between 60 and C. and the .solution was stirred at this temperature for another hour. The mixture was then cooled to room temperature and acidified by means of hydrochloric acid (1:1) .to pH about 0.5.. The precipitate was filtered, washed with water and dried yielding a product (4.8 g.; yield) having a M.P. 215 C. (decomp) and which by comparative chromatography of unisomerised and isomerised samples indicated a mixture of about 50% starting material, 30% N-propyl-3,5-diacetamido-2,4,6- triiodobenzoic acid and about 20% of N,N'-dipropyl-3,5- diacetamido-Z,4,6-triiodobenzoic acid.

EXAMPLE 10 Propylation of methyl 3,5-diacetamido-2,4,6- triiodobenzoate Methyl 3,S-diacetamido-2,4,6-triiodobenzoate (5 g.; about 8 mmol.) was suspended in water (5 ml.), and then brought into solution by means of 5 N potassium hydroxide (6.5 ml.; 4 eqv.). Propyl iodide (0.78 ml.; 8.0 mmol.) dissolved in acetone (1 ml.) was added. The mixture was heated under reflux and mechanical stirring on the boiling water bath for about 1 hour. And then for a further hour at 60 80 C. A precipitation occurred during heating and the precipitated methyl N,N-dimethyl- 3,5-diacetamido 2,4,6-triiodobenzoate weighed 1.3 g. and melted at 220 C. (decomp.). A sample was converted to the corresponding acid by means of aminolysis and a chromatogramme showed it to be pure dipropyl compound.

The filtrate was acidified with concentratedhydrochloric acid-topH about 0.5, and filtered, and washed by suspending it twice in 50 ml. each time of 0.5-M sodium carbomate, and filtered a new. After final washing with a little water the methyl N-propyl-3,S-diacetamido-2,4,6-triiodobenzoate' weighed dry 3.0 g. and melted 'at 220 C. (decomp.). A sample of this product was converted to the corresponding acid and chromatographed, the chromatogramme showing that it consisted of the monopropyl compound with only traces of starting material and dipropyl compound present.

EXAMPLE 11 N,N-dimethyl-adip0yZ-bis- (3-carb0m'etlz0xy2,4,6- triiodaanilide) Adipoyl-bis-(3-carboxy-2,4,6-triiodoanilide) (29.8 g.) was dissolved in potassium hydroxide (60 ml.; 2.5 N) and dimethyl sulphate (18 ml.) added with stirring in the course of 5 minutes. The temperature rose to 40 and the solution became cloudy. Successively more potassium hydroxide (60 ml.; 5 N) and .dimethyl sulphate (72 ml.) were added in portions whereby the temperature rose further. After stirring for about 1 hour the N,N-dimethyl-adipoyl-bis-(3 carbomethoxy 2,4,6 triiodoanilide) (25 g.) was obtained after filtration, washing and drying.

1 1 EXAMPLE 12 N ,N '-dimethyl-adi poy l-bis- (3 warmly-2,4,6- triiodoanilide) Adipoyl-bis-(3 carboxy-Z,4,6-triiodoanilide) (1.28 g.) Example 2:

React. React. Yield, Melting Example Compound Alkylating agent temp, time, Percent point,

0. hrs. C.

15 N-ethyl-3-acetamido-2,4,6- Ethyl iodide 65 2% 66 210-235 triiodobenzoic acid.

16 N-n-propyl-3-acctamido-2,4,6 n-Propyl iodide 00 1 95 1 132-140 triiodobenzoic acid.

17 N-n-butyl-3-acetamido-2,4,6- n-Butyl iodide 80-90 2 triiodobenzoic acid.

was dissolved in water (2 ml.) and acetone (1 ml.) and potassium hydroxide (2 ml.; 5 N) added. Dimethyl sul- At these reaction temperatures the conversion of the less stable isomers is not necessary.

phate (0.28 ml.; 1.4 eqv.) was added with stirring, where- The following compounds were prepared according to by the temperature rose from 21-31 C. in the course of Example 3:

React. React. Yield, Melting Example Compound Alkylatlng agent temp, time, Percent point,

C. hrs. C.

18 5-amino-3-(N-ethy1aceta Ethyl iodide 65 1% 92 200-250 midio)-2,4,6-triiodobenzoie aci 19 5-amino-3-(N-n-propyl-acetan-Propyl iodide 90 1% 100 240-262d migo)-2,4,6-triiodobenzoic aei 20 5-amino-3-(N-n-butyl-acetan-Butyl iodide 00 2 80 155-160 Inigo)-2,4,6-triiodobenzoie aei 21 5-amino-3-(N-n-pentyl-acetan-Pentyl iodide 90 2 47 141 mligo)-2,4,6-triiodobenzoie ac 22 5-amino-3-(N-methyl propaf Dimethyl sulphate.-. l5 1 95 156-160 migo(-2,4,6-triiodobenzoic aci 23 5-amino3-(N-ethyl-propa Ethyl iodide 65 1% 95 Inigo)-2,4,6-triiodobenzoio aei 24 5-amino-3(N-n-propyl-propan-Propyl iodide 90 1% 75 migo)-2,4,6-triiodobenzoic ac 25 5-amino-3(N-methyl-butyra- Dimethyl sulphate..." 15 1 97 mi 1(i1o)'-2,4,6-triiodobenzoic aci about seconds. After about 20 minutes the reaction product was precipitated by means of strong hydrochloric acid (pH 0.5), filtered, washed and dried, whereby 1.15 g. of chromatographically pure N,N'-dimethyl-adipoy1- vbis-(3-carboxy 2,4,6 triiodoanilide) was obtained as a completely colourless product.

EXAMPLE l3 N,N'difi-hydroxyethyl) -3,5-diacetam hie-2,4,6- triiodobenzoic acid 3,5-diacetamido-2,4,6-triiodobenzoic acid (24 g.) was suspended in warm water (70 ml.) and dissolved by adding 10 N sodium hydroxide (3O rnl.). Ethylenebromohydrin (16 ml.) was added to the still warm solution and left at room temperature over night.

The acid was then precipitated by means of concentrated hydrochloric acid to pH about 0.5, filtered, washed with water, dried and crystallised from ethanol/ethylacetate.

Yield 17.5 g. (64%). Melting point l96-l97 C. Toxicity in mice LD :17.0 g. acid/kg.

EXAMPLE 14 N-(fi-hydroxyethyl)3-acetamid0-2,4,6- triiodobenzoic acid The compound was prepared from 3-acetamido-2,4,6-

From these compounds the following diacyl-derivatives have been prepared:

EXAMPLE 26 N,N'diethyl-3,5-diacetamido-2,4,6- triiodobenzoic acid 3,5-diacetamido-2,4,6-triiodobenzoic acid (20 g.) was suspended in water (20 ml.) and 10 N sodium hydroxide 13 (22.8 ml.) added andthe mixture heated to about 65 C. Ethyl iodide (8.1 ml.) was added with stirring. After 1% hours at 65 C. the solution was cooled and the product precipitated by means of hydrochloric acid (1:1) to pH about 0.5, filtered, washed with water and dried.

Yield 18.3 g. (83.5%). Melting point 248-253" C.

EXAMPLE 27 N,N-dimethyl-3,5-diprpamid0-2,4,6-trii0d0benzoic acid Sodium 3,5-dipropamido-2,4,6-triiodobenzoate (15 g.) dissolved in water (30 ml.) was added 5 N sodium hydroxide (18 ml). Dimethyl sulphate (6.5 ml.) dissolved in acetone ml.) was added the cooled solutionwith stirring. After 1 hour the product was precipitated with concentrated hydrochloric acid, filtered, washed with water and dried.

Yield: g. (96%), melting point 230232 C.

EXAMPLE 28 N,N-dipr0pyl-3,5-dipr0pamid0-2,4,6-triiod0benz0ic acid This compound was prepared as described in Example 27 by using propyl iodide as alkylating agent and the reaction temperature being 90 C.

Yield 53%, melting point 265-270 C.

EXAMPLE 29 N-carboxymethyl-fi-acetamido-Z,4,6-trii0d0benz0ic acid 3-acetamido-2,4,6-triiodobenzoic acid (1 g.) was suspended in water (1 ml.) and 5 N sodium hydroxide (3 ml.) added. Bromoacetic acid (1.01 g.) dissolved in water (1 ml.) was added drop by drop with stirring to the solution which had been heated to 50 C. After about 30 min. at 5-'0-60 C. the product was precipitated by means of concentrated hydrochloric acid to pH about 0.5, filtered, washed withwater and dried.

Yield 82%, melting point 255 C.

EXAMPLE 30 N ,N '-dicarb0xymethyl-3 ,5 -diacetamid0-2,4,6- zriiodobenzoic acid This compound was prepared from 3,5-diacetamido-2, 4,6-triiodobenzoic acid as described in Example 29.

Yield: 26%, melting point 150-180 C.

EXAMPLE 31 3-(N-carboxymethylacetamido) -5-amin0-2,4,6- triiodobenzoic acid This compound was prepared from- 3-acetamido-5- amino-2,4,6-triiodobenzoic acid as described in Example 29.

Yield: 90%, melting point: 160-161 C.

EXAMPLE 32 N-methyl-2,4,6-trii0d0-/3-carboxypropanilide EXAMPLE 33 N-ethyl-2,4,6-trii0d0-[i-carboxypropanilide The compound was prepared as described in Example 32, using ethyl iodide as the alkylating agent. 'The reaction temperature was 70 C.

Yield: 77%, melting point: 146-149 C.

EXAMPLE 34 N-n-propyl-2,4,6-trii0d0-,8-carboxypropanilide The compound was prepared as described in Example 32. Using 'n-propyl iodide as the .alkylating agent. The reaction temperature was 90 C.

Yield: %,.meltingpoint 167-178 C.

We claim:

1. A compound selected from the group consisting of a compound of the formula in which R is a member selected from the group consisting of lower carboxyalkyl, lower carbalkoxyalkyl and lower hydroxyalkyl, Z is lower alkanoyl, Y is a member selected from the group consisting of hydrogen, amino, lower alkanoylamido and and R is a member selected from the group consisting of hydrogen and lower alkyl; a compound of the formula 0 o 0 R O o o R I I I I f r Y III(CHz)4-ll Y I R R I I I in which Y, R and R have the same meaning as above; and nontoxic salts of the compounds of both of said formulas in which R is hydrogen.

2. N,N-di-(fi-hydroxyethyl) 3,5 diacetamido-2,4,6- triiodobenzoic acid.

3. N-(fl-hydroxyethyl) 3 acetarnido 2,4,6 triiodobenzoic acid. 7

4. A process for the preparation of a compound selected from the group consisting of a compound of the formula COOR in which R is a member selected from the group consisting of lower carboxyalkyl, lower carbalkoxyalkyl and lower hydroxyalkyl, Z is lower alkanoyl, Y is a member selected from the group consisting of hydrogen, amino, lower alkanoylamido and and R is a member selected from the group consisting of hydrogen and lower alkyl and a compound of the formula o o R 30 0 R I -I I- I 0 0 II U Y 1TIo(0H.)i I?T -Y R R I I I in which Y, R and R have the same meaning as above, comprising reacting the corresponding compound in which "15 1 0 R is hydrogen with a compound selected from thegroup 2,776,241 1/57 Priewe 260471 consisting of lower haloalkanoic acids, lower alkyl esters 3,048,626 8/62 Wallingford 260-562 XR of lower haloalkanoic acids and lower alkylene halohy- FOREIGN PATENTS drins in the presence of an aqueous alkaline medium.

5. The process of preparing N,N'-di(B-hydroxyethyl) 5 820,661 9/59 Gmat Bntam' 3,5-diacetamido-2,4,6-trii0dobenzoic acid, comprising re- 576,507 5/59 Canadaacting 3,5 diacetamido 2,4,6 triiodobenzoic acid with 321,121 12/02 ethylenebrornohydrin in the presence of an aqueous solu- OTHER REFERENCES of sodium hydroxlde' Migrdichian: Organic Synthesis, vol. II, (New York 10 References Cited by the Examiner 1957) 1440' UNITED STATES PATENTS LEON ZITVER, Primary Examiner.

2,060,851 11/36 Calcott et a1 260-584 DUVAL T. MCCUTCHEN, DANIEL D. HORWITZ, 2,611,786 9/52 Wallingford 260-471 Examiners.

Claims (2)

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA

4. A PROCESS FOR THE PREPARATION OF A COMPOUND SELECTED FROM THDE GROUP CONSISTING OF A COMPOUND OF THE FORMULA