CA1159062A - N-[3-(1'-3"-OXAPENTAMETHYLENE-AMINO- ETHYLIDENEAMINO)-2,4,6-TRIIODOBENZOYL]-.beta.-AMINO- .alpha.-METHYLPROPIONIC ACID - Google Patents

Abstract

Abstract N-[3-(1'-3"-Oxapentamethyleneamino-ethylideamino)-2,4,6-triodobenzoyl]-.beta.-amino-.alpha.-methylpropionic acid.
The present invention relates to a pharmaceutical compound, N-[3-(1'-3"-oxapentamethylene-amino-ethylideneamino)-2,4,6-triiodobenzoyl]-.beta.-amino-.alpha.-methyl propionic acid, as prepared by a novel process comprising hydrolysis of N-[3-(1'-3"-Oxapentamethyleneamino-ethylideneamino)-2,4,6-triiodobenzoyl]-.beta.-amino-.alpha.-methylpropionitrile.

Description

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This application is a di.visional of copendin~
Canadian Patent Applica-tion 367,731 flled December 30, 1980.( N-~3~ 3"~0xapentamethyleneamino~ethylideneamino)-

2,~,6~triiodobenzoyl ~-amino- ~-methylpropionic acidc The p~esen-t invention relates to N-~3-(1',3~'o o~apentamethyleneamino-ethylideneamino)-2,4,6-triiodo benzoyl ~ ~-amino-~,-methyl.propionitrile,' which is a novel compound, and its use ~or the preparation o~`
N ~ 3-~ 3"_0xapentamethy~eneamino-ethylideneamino)-2,4,6~triiodobenzoyl~ amino-~ -methylpropionic acid, ~hich is known as'an active.compound in a~ents for per-oral ~apid cholecystography. . .. ' It is kno~n, ~ro~ Canadian Pa-tent 1,002,522 - . .
i~,sued December 28, 1977, that derivatives o~ 274,6-.
triiodobenzoyl-aminoalkanecarboxyiic acids which carry a substitu-ted amidino group in the 3-position oP.the b~nzene -~ucleus are X-ray contrast'media which are used for visuali-sation oP the gallbladder'and are particularly distin- .
15 ' guished b~ their ease oP absorption and their rapid eli-mination $rom the body. Amongst these comp~unds, .
N-~3~(19-3't-oxapentamethyleneam;no~ethylideneamino)-2,4,6-triiodobenzoyl~ amino- ~-met'nylpropionic acid ~iomorinic acid) of the ~ormula I~
. ' I . ' .
~ C0-N~I-CH2-lH~C000 I I - -;
N

3 / .
has achieved particular impor~ance and is used as a so~ .
called rapid cholecystoyraphy agent. A.~ter peroral admini5tration oP this compound, pre~erably in the ~orm oP the ~Ja salt, it is possib].e to obtain photo~raphs o~ the bile ducts within 60~90 minu~es and pictures oP
the gallbladder within 5 hours, so that it is possible Por the agent to be taken and the investigation to be carri. ed ou t in one day.

.. .. . .. ::

3 0 ~i 2 According to Canadian P~tent 1,002,522 referred to above, in order to prepare the compound o~ the ormula I9 3-amino-2,4,6-triiodobenzoyl chloride is re-acted ~ith N-ace-tylmorpholine and phosphorus o~ychloride in chloroform by boiling, and the resulting acid chlor-ide, containing the amidino grou~ which has been formed, is isola-ted as the salt~ After liberating the base, this can then be conver-ted into the compound of -the formula I by reac-tion with ~-amino-a-methylpropionic 10 aci~ esters, also under -the action o~` heat, and sub-sequent saponification.
This process has the disadvantage that, in the reaction of 3-amino-2,4,6-triiodobenzoyl chloride with acetylmorpholine 9 by-products which are insoluble in 15 acid and also, as another by-product, the morpholi~e of 3~ oxapentamethyleneamino-ethylideneamino)-2,~,6- ;
triiodobenzoic acid are formed. Thèse impuri-ties can only be separated o~f after the preparation of the end product, and their separation is very difficult be-20 cause the acid of the formula I crystallises poorly or no-t at all in the impure form and the p~ri~ica-tion is very wasteful and necessitates mul-tiple evaporation of mother liquors.
The Cana~npa-tent 1,002,522 also 25 gives the reaction of N-(3~amino-2,4,6--~riiodoben~oyl~-amino-alkanecarboxylic acid alkyl ester~ with N~acetyl-morpholine and phosphorus oxychloride, likewise whils-t boiling under reflux, as another proces~ variant.
The morpholide ~ormation can indeed be avoided in this 30 procedure, but the reaction nevertheless does not pro-ceed uni~ormly, and in this case also, by-products which are insoluble in acid are formed. ~ost of -these can indeed be separa-ted off by acidi~ying -the mix-ture to pH 1-1.5, but certain amounts o:E these by-products 35 remain in the product and make purification thereoE very di~ficult Finally, it is furthermore possible9 according to Canadian Patent 1,002,522, to carry out the preparation o.-E the compound of the Eormula I at room :, '9 1 5 UT ~3 ~) 2 3 ~
tempera-ture by reaction of N-(3-acetylamino-2,4~6-tri-iodobenzoyl)-~-amino-a-me-thylpropionîc acid methyl ester wi-th morpholine in the presence of phosphorus penta-chloride, but s-till more by-produc-ts are formed in this reaction procedure, so that -the yield of pure product is even lower and the purification is even more troublesome than in the case of the other kno~m processes.
~ compound which exhibits a good te~dency to crystallisation and, because of its good solubili-ty and lO stability in dilute aqueous acids and the sparing solu-bili-ty of the base in water, can be purified very read-ily and in a simple manner, could now be found in the ne~:.T nitrile of the compound of -the formula I ? which has the formula II:
, ~CO~ CH2--~ H--CN
15 ~ ~I C~3 II

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C~3-C-N

Although this compound can thus unhesitatingly be re~ -precipitated several -times for purification processes~
it can, surprisingly, be hydrolysed either with strong acids or in alkaline solution to give the acid of the 20 formula I without the arnidino group being attacked9 with the .~ormation of harmful impurities, or without iodine being split off. The discovery of this new sub-stance has thus opened a new and advantageous route for the preparation of the comp~und of the formula 13 since, 25 when -the pure nitrile of the formula II is subjected -to hydrolysis, -the acid of the formula I is obtained in such a pure form that at most one simple recrys-tallisa-tion, for example from methanol, which can be carrled.out without noticeable losses, is sufficient to obtain the 30 acid in a purity which can be used for pharmaceutical.
administration Since the waste.~ul puri.f:icatioll o~ the acid is thus eliminated, and furthermore both the , .. ,. . . .. -,;. . . .;
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3 :~ S ~ 2 prcpara-tion of -the nitrile o~ -the ~ormula II and its saponification take place with very good yields, i'~ is -therefore also possible to prepare iomorinic acid of the formula I in a considerably highèr yield than was hither-to -the case The presen-t inven-tion accordingly relates to the new ni-trile~of iomorinic acid, of the ~ormula II, and ..
its use for -the preparation o~ iomorinic acid of the formula I by hydrolysis~

:
For the preparation o~ the nitrile of the ormula II, ~-(3~amino~2,~,6-triiodobenzoyl)-~amino- -. a-methylpropionitrile can be reac-ted with N-acetyl-15 morpholine in an inert reaction medium in the presenceof phosphorus o~ychloride. By treating the resulting reaction mix-ture with water, before or during evapora-tion o~ the solvent used, an acid aqueous solution con-taining -the ni-trile of` the ~ormula II in the ~orm of a zo salt is ob~ained. Any by-products present which are insoluble in acid can then be separated off in -the form of a solid in a simple manner, for example by ~iltration.
I~ the clear acid solution is then neu-tralised and a pH
value of at least 8 is established, the sparingly solu-25 ble ni-trile separa-tes out, eit.her directly in crystal-line ~orm or as an oil which very rapidly crystallises completely, and can thus easily be isolated in solid ~orm~
However, it is also possible -to obtain the 30 nitrile of the formula II s-tarting from 3-(l'-3"-oxa-pen-tclmethyleneamino-ethylideneamino)-2,4,6-triiodobenzoyl chloride, by reaction with ~-aminoisobutyronitrile, likewise in an iner-t solvent. In this case, after evaporating off the solvent, the reac-tion produc-t must 35 first be dissolved by -treatment wi-th dilute ac.id and t~len precipitated by rendering the solution alkaline.
In carrying out the reaction of N-(3-amino-2,4,6-triiodobenzoyl)-~-amino-a-methylpropionitrile ~ith N--acetylmorpholine a~d phosphorus oxychloride, which is .

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~ 15'3~2 `-the pre~erred process varian~t 9 it is expedient to employ bo-th -the N-ace-tylmorpholine and the POC13 in excess com-pared with the nitrile. 1.5-3 rnols of N-acetyl-mol~holine and 2-6 mols of phosphorus oxychloride are appropria-tely employed per mol of the nitri.le. ~This excess o~ the t~o reactants suppresses the formation of by-products and increases -the yield, bet-ter resul-ts being achieved, ~lithin the limi-ts indica-tedg if at least one of -the t~o s-tarting materials is employed in an 10 . amoun-t corresponding to the upper region of the range indica-ted Less than 59' of by-products, and yields of ni~rile o~ the formula II greater than 95% are ob-tained if 3 mols of I~-acetylmorpholine and 2-6 mols of POCl~ are employed per mol of N-~3~amino~2,4,6-triiodo-benzoy~ ar~lino-~-methylpropionitrile~ In contrast, if only 2 mols of ~-ace-tylmorpholine are used, 6 mols o~
POC13 are required per mol of N-~-amino-2,4,6--triiodo-benzoyl)-~-ami.no-a~methylpropionitrile in order to achieve optimu~ results. The bes-t resul-ts are ob~
tained wi-th a molar ra-tio o~ 1:3:6.
The reac-tion temperature is preferably kept as lo~Y as possible, and in par-ticular in the range between 0C and about 2CC, It is particularly favourable to adjust the temperature to abou-t 0C when the reactan-ts - 25 are mixed -to~ether, and to allo~ the temperature -to rise to abou-t 20C only in order to bring the reaction to completion Since the reaction is exothermic, the mix-ture mus-t be cooled. However9 it is also possibIe to allow the reaction -to go to completion at a higher temperature, ~or example a-t the boilin~ point of the reaction mixture, especially if shorter reaction -times are desired.
The fac-t that by-products are also formed, in addition to the nitrile oE -the formula II, indeed has an e:E~ec-t on the yield, but is of no significance for the success o:E -the process or ~or -the puri-ty o~ the end pro-duct o.f the formula I This is because, on -the basis o~ i-ts solubili-ty charac-teristics, the nitrile of the formula II can be purl~ied in an excellent manner~

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This means -that even when -the process is carried out under conditions under which more than 55' of by-products are ob-tained, purification of -the nitrile pre-sents no dif~iculties and the purity of the end product o.~ the ~ormula I is thus nevertheless sa-tisfactory.
The reaction of ~-(3-amino~2,4,6 triiodobenzoyl)-~-amino-~-methylpropionitrile wlth N-acetylmorpholine and POC13 is carried ou-t in an iner-t reaction medium, and it is expedient to use an inert organic solventO Since the nitrile used as the star-ting ma-terial is scarecely soluble in the customary organic solvents, the reac-tion is in most cases carried ou-t in solventsin which the complex which ~orms from N-ace-tylmorpholine and phos-phorus oxychloride is indeed soluble, bu-t -the nitrile is insoluble. Such solvents are, for example, dioxane, tetrahydrofuran, acetonitrile and chlorinated hydro-carbons, such as chloro~orm or methylene chloride. In spi-te of the fac-t -that the reaction is carried out in a heterogeneous phase sys-tem, -the yield is su~prisingly very good.
The solubility o~ the complex of acetylmorpholine and POC13 is moreover no prerequisite at all for the success of the process according to -the inventionO
- The reaction also proceeds smoothly in those organic solvents, such as aroma-tic hydrocarbons, in particular toluene, in which the complex of ace-tylmorpholine and POC13 is also insoluble and only suspended therein.
The reaction can also be carried out in excess POC13 as the solvent. It is expedien-t also to puri~y, by adding active charcoal, the acid solution formed when the reaction product is taken up in water The base of the formula II is then precipitated by rendering the solution alkaline with any water-soluble base which is sufficiently alkaline to ensure that a pH value of at least 8 is achieved. ~mmonia is pre~erably used I~ more by~produc-ts are present, a second puri~ication can be carried out without dif~iculty or losses~ by dis-solving the ni-trile of the ~ormula II once more in dilute acid, i~ necessary -treating the solution once more .

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wi-th active charcoal, and precipi-tating the nitrile again by rendering the solu-tion alkaline The second process varian-t, -that is to say the reac-tion of -the acid chloride 9 in which the amidino group has already been formed9 ~i-th ~~aminoisobutyro nitrile, is also likewise carried ou-t in an inert sol-vent 9 such as dioxane 9 chloroform or tetrahydrofuran, it being expedient to warm the mix-ture. In -this case also, the by-products which are insoluble in acid can easily be separated off as a resul-t of the advantageous properties of -the nitrile of the formula II. In this case also, purification is carried ou-t9 if necessary9 by repea-tedly dissolving the product in acid~ treating the solution with active charcoal and precipi-tating the r~tril~ with alkalis, preferably ammonia, Surprisingly, -the saponfica-tion o~ the nitrile of t~le formula II obtained in a pure form in this manner pro-ceeds entirely smoothly. I-t can be carried out by treatment with concentra-ted inorganic acids, such as -2Q hydrochloric acid or sulphuric acid. Howe~er~ it can also be carried ou-t with -the aid o~ alkaline agents, for example wi-th alcoholic-a~ueous alkali ~etal hydrox-ide solutions, such as NaOH or KO~. Finally, how-ever, i-t is also possible first -to prepare the corres-ponding imido-ester by -the action of acids in an alco-holic medium, for example wi-th meth~nolic hydrochloric acid, and to split this es-ter by treatmen-t wi-th wa-ter.
The free compound of the formula I, which is ampho~eric in character, is bes-t precipitated from -the saponifica-tion solution at -the isolelectric point, whereupon it is obtained in pure form in almost quan-ti-tative yield.
The N-(3-amino-2,4,6-triiodobenzoyl)-~-~nino-a- '~
methylpropionitrile required as -the starting material can be obtained in yields of over 90% in a simple manner, by acylating ~-aminoisobutyroni-trile with ~-amino-2,4,6-triiodobcnzoylchloride ~-~ninolsobutyronitrile is likewise prepared in a simple manner, by addition of ammonia onto methacrylonitrile, and can easily be ob-tained in a pure form by distilla-tion.

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, 3 ~o~ ( Example 1:
77 4 g (0.6 mol~ of N-acetylmorpholine are added to 18~.6 g (102 mols) of phosphorus oxychloride in 500 ml of chloro:~orm at a tempera-ture of 0CO During this addition, the tempera-ture rises to abou-t 8C, in spite of further cooling. After the temperature has fallen to 0C again, 116.2 g (0.2 mol) of N-(3-amino-2,4,6-tri-iodobenzoyl)-~-amino-a-me-thylpropionitrile are added and the suspension is then stirredg without further cooling.
Af~er 40 hours, the chloroform suspension is poured in-to 800 ml of wa-ter, and in par-ticular at a rate such that the chloroform distils off con-tinuously and a clear aqueous phase is formed. In order to dri~e off las-t residues of chloroform, the aqueous solution is subsequently boiled up for a short time. It is then cooled and filtered with charcoal and the acid solution is first brought to pH 6 with ~10% streng-th aqueous sod-ium hydroxide solution and then rendered alkaline with concentrated aqueous ammonia. The ni-trile of the ~ormula II which separates out, partly i~l the form of an oil 9 becomes solid and fil-terable when -the aqueous-ammoniacal solu-tion is warmed to 85C and s-tirred vig-orously ~or a short time. The produc-t is ~iltered off and dissolved once more in 1.2 1 of water containing 0.4 mol of hydrochloric acid and the solution is treated with charcoal and rendered alkaline with ammonia9 as described above, and the produc-t precipitated, 137 g of N-C3-(1'-3''-oxapentame-thyleneamino-e-thylideneamino)-2,4,6-triiodobenzoyl]-~-amino-a-methyl-propioni-trile of melting point 129-130C, tha-t is to say 98/9% of theory, are obtainedO
The N-(3-amino-2,4,6-triiodobenzoyl)-p-amino--methylpropionitrile re~uired as the s-tar-ting material is prepared as follows:
106 6 g (0.2 mol) of 3-amino-2,4,6--triiodoamino-benzoyl chloride in 500 ml of chloroform are koiled under reflux with 17.6 g of ~-aminoisobutyronitrile and 21~2 g o~ triethylamine for several hours. The N-(3-amino-2,4,6-triiodobenzoyl)-~-amino-a-methylpropionitrile , ", '1 -~:
.:

~15~ 2 g already star-ts -to crystallise out during hea-ting. In order to bring -the crystallisation -to comple-tion~ 200 ml of chloroform are distilled off from -the reaction mix--ture and -the mixture is then left to stand a-t room -temperaturec hfter fil-tration, 10804 g (93O~%) of -the ni-trile are obtainQd, Af-ter washing the chloro-form mo-ther liquor ~li-th water and then concentrating it to 40 ml, a fur-ther 6~3 g (5O4~) are ob-tained~ Melt ing poin-t~ 187C, 10 Example 2:
183.6 g (1.2 mols) of phosphorus oxychlori~e and 77,4 g (0.6 mol) of N-acetylmorpholine are introduced in-to 500 ml of dioxane at 0C and a solution of 116.2 g ~0,2 mol3 of N-(3-amino-2,l~,6-triiodobenzoyl)-~-amino-a-15 methylpropioni-trile in 500 ml of dioxane is then added.
After s-tirring -the mix-ture overnight, the dioxane is d:is-tilled off in vacuo, the residue is taken up in about 1 1 of water, ~le aqveous mixture is filtered o~er charcoal and the N-~3-(1'-2"-oxapen-tame-thyleneamino-20 ethyliden~amino)-2,4,6-triiodobenzoyl~-~-amino-a-methyl-propionitrile is precipita-ted at pH 8.5 by adding ammonia.
Af`-ter filtration~ the still mois-t produc-t is taken up in 1.2 1 of ] N HC] and the mixture is fil-tered over char-coal. The nitrile is pracipitated again from -the fil-25 trate9 which is no~ clear, with alkali and is now fil-tered off. 121 g (87.5~o of theory) of N-[3](1'-3"-oxapenta-methyleneamino-ethylideneamino)-2,4,6-triiodobenzoyl J - ~-amino-~-me-thylpropionitrile of melting poin-t: 129-130C
are obtainedO
30 Example ~:
19 g of N-acetylmorpholine are added to 250 ml of phosphorus oxychloride at 0C. In spite of cooling, -the temperature -thereby rises to 10C. After 5 min-utes, 29 g of N-(~-amino-2,~l,6-triiodobenzoyl)-~-amino-~-~5 methylpropionitrile are added at 5C, whils-t fur-ther cooling and whilst stirring, Stirring is continued overnight at 20C, whereupon an almost clear so:lu-tion is f orrlle d .
For working up, the phosphorus oxychloride is as ~, .. .
.

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1 l~9~B2 far as possîble distilled of~ in ~acuo, the evaporation residue is dissoived in 150 ml of chloroform and the solution is poured into 300 ml of water. The mixture is then further worked up as described in Example lo 33 g (95.~l% of theory) of N-~3~ 3"~oxapenta-methyleneamino-e-thylldeneamino~-2,4,6-triiodobenzoyl~
amino-~-me-thylpropionitrile of melting point: 129-130C
are obtained.
Example 4:
19.4 g of N-acetylmorpholine are added -to ~6 g o~ phosphorus oxychloride in 200 ml of toluene at 0C, whils-t coolingO After a short time, a white precipi~
ta-te ~orms in the solu-tion. 29 g of N-(3-amino-2,4,6-triiodobenzoyl)-~-amino-a-methylpropionitrile are then 15 added, whilst stirring, and stirring is continued for 40 hours at 20C The oily reaction product thereby ~ormed is taken up in 400 ml of water and the slightly turbid solution is ~iltered over charcoal. The N- -~3-(1'-3"-oxapentamethyleneamino-e-thylldeneamino)-2,~,6-20 triiodobenzoyl]-~-amino-a-me-thylpropionitrile is precipi-tated from -the clear acid fil-trate by adjus-ting the pH
value to 8. 33.2 g are obtained, that is to say g6%
of theory. Melting poin-t: 129~1~0C.
Example 5:
183.6 g (1.2 mols) of phosphorus oxychloride are rnixed ~ith 77.4 g (0.6 mol) of N-ace-tylmorpholine and 116.2 g (0.2 mol) of N-(3-amino-2,4,6-triiodobenzoyl)-~-amino-a-methylpropionitrile a-t a tempera-ture o~ 0C as described in Example 1, and the mixture is then boiled 30 under reflux ~or 1~ hours. Working up is carried out as described in Example 1.
121.3 g o~ N-C3-(1'-2''-oxapentamethylenea~ino-ethylideneamino)-2,4,6-triiodQbenzoyl]-~~amino~ methyl~
propioni-trile, that is to say 87.6% o~ theory, are 35 ob-tained. Melting point: 129-130Co Exar~ple 6:
3~ g of 3 (1'-3"-oxa~entamethylenearnino-ethyli-deneamino)-2,4,6-triiodobenzoyl chloride hydrochloride ~prepared according to the ins-tructions in Canadian Pat~nt . .

9 ~ ~i 2 Spe_i~ica-tion -- ~ppl.Ser.No~l76.658 are suspended---in chloro~orm.
Tne base is liberated by adding triethylamine 9 af-te~
~ich 5 g of ~--aminoisobu-tyroni-trlle are added and the mi~ture is boiled under reflux for 3 hours~ The c'nloroform solution thus ob-tained is -then e~apora-ted in VaC~10, -the oily residue is taken up in 4 N hydrochloric acid9 -the mi~ture is trea-ted with aot:ive charcoal and the ac-tive charcoal is liltered off. The acid fil-trate is -then brought to pH 6 by adding 40C~o s-treng-th 10 N 0~, and the pH ~alue is then adjus-ted -to 8.5 wi-th con-centra-ted aqueous ammonia. The precipi-tate ~hich has thereby separated out is left to s-tand at 60C for some time and is then filtered off and dried. 34.5 g of N~ (1'-3"-oxapentamethyleneamino-ethylidenearnino)-i5 2~4~6-triiodobenzoyl]~~~amino-~-methylpropionitrile~
tha-t is to say 93.6% of -theory, are obtained.
Ex~mple 7: `
1~7 g of the N-~3~ oxapentamethyleneamino-ethylideneamino)-2,4,6--triiodobenzoyl~-ami~o-~-methyl--20 p~opionitrile obtained in the preceding éxamples are dis-solved in 300 ml of concentrated hydrochloric acid and the solution is hea-ted to 80C. After 2 hours, the hydrolysis has ended and the aqueous-hydrochloric acid solution is evapora-ted in vacuo The residue is dis-25 solved in aqueous sodium hydroxide solvtion and insolublec onstituents are filtered off~ The acid is precipi-tated from the filtrate by adjus-ting -the pH value to 4 5 123 g (87.6% of theory~ of N-[3-(1'-2"-oxapentamethylene-amino-e-thylideneamino)-2,4,6-triiodoben~oyl~-~-amino-~- ;
;30 metllylpropionic acid are obtained. ~ further 16 2 g of acid (11.5%) are obtained by cQncen-trating the mother liquor Af-ter recrystallising -the combined products from methanol, 12l~ g of pure crystalline acid'of mel-tin~
point: 202-205C are obtained, tha-t is to say 87.2% of 35 -theory, relative -to N-(3-amino-2,L~,6-triiodobenzoyl)-~amino-~-methylpropionitrile, i~ the prepara-tion proced~
ure according to Example 1 was used ~or the preparation of the nitrile.

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12 _ Example 8-34.5 g of N--[3~ -3"-oxapenta~ethyleneamino-ethylidenearnino)-2,4,6--triiodobenzoyl]-~-amino-a-methyl propionitrilc are dissolved in 1 1 of ho-t 96% s-treng-th alcohol and7 a ter adding 20 g of 20~o s-treng-th sodium hydroxide solu-tion, the mixture is boiled under reflux ~or 2 hours The alcohol is then s-tripped off and the residue is diluted wi~h wa-ter -to 500 ml and adjus-ted to pH 1 with hydrochloric acid. The flakes which there-by separate out.are filtered offO The acid is pre-cipitated from the clear filtrate by adjusting -the pH to ~.5, and is filtered off. After recrystallising from methanol, 25 g of pure crystal-ine ~-[3-~ 3"-oxapenta-methyleneamino-ethylideneamino)-2,4,6~triiodobenZo~
arnino-a-methylpropionic acid of rnelting poin-t: 202 205C
are ob-tained, that is to say 72~' of theory, relati~e to ~-(3-amino-2,4,6-triiodobenzoyl)-~-amino-a-me-thylpro-pi.onitrile if the preparation of -the nitrile was carried out according to Example 1.
20 Example 9:
30 g of N [3-(li-3"-oxapentame-thyleneamino-ethylideneamino)-2,4,6-triiodobenzoyl]-~-amino-a-rnethyl-prop.ionitrile are boiled under reflux in 150 ml of 10 N
methanolic HCl for 2 hours. All the rnethanolic hydro-chloric acid is dis-tilled off, the evaporation residue is taken up in 300 ml of water, the a~ueous mixture is boiled up for a shor-t time and insoluble constituents are fil-tered off. The acid is precipitated by adjusting the pH value to 4.5, and is isola-ted. Af-ter recrystal-30 lising from methanol~ 24 2 g of N-[3-(lt-3"-oxapen-ta-methyleneamino-ethylideneamino)-2,4,6-triiodobenzoylJ-~-amino-a-methylpropionic acid of melting poin-t: 202-205C
are obtained. The yield is 785' of theory, re:lative to N~(~-amino-2,4,6-triiodobenzoyl)-~-arnino-a-rnethyl-35 propionitrile, on the basis of the preparation of then.i-trile in accordance with the method of Exclmple 1.

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Claims (4)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. Process for the production of N-[3-(1'-3"-oxapenta-methyleneamino-ethylideneamino)-2,4,6-triiodobenzoyl]-.beta.-amino-alpha-methyl-propionic acid having the formula I, which comprises using N-[3-(1'-3"-oxapentamethyleneamino-ethylideneamino)-2,4,6-triiodobenzoyl]-.beta.-amino-alpha-methyl-propionitrile of the formula II, as starting material and hydrolysing said compound by heating with i) a strong acid or ii) an alkaline hydrolysing agent in aqueous medium.

2. Process as claimed in claim 1 in which for hydrolysis the nitrile compound is at first heated with a strong acid in an alcoholic medium in order to form the corresponding imidoester, this imidoester is then split off to form the free N-[3-(1'-3"-oxapentamethyleneamino-ethylideneamino)-2,4,6-triiodobenzoyl]-.beta.-amino-alpha-methylpropionic acid by treatment with water.

3. Process as claimed in claim 1 in which the nitrile compound as starting material is purified before hydrolysis and after hydrolysis the resulting acid is treated for purification by one simple recrystallization,

4. Process claimed in claim 2 in which the nitrile compound as starting material is purified before hydrolysis and after hydrolysis the resulting acid is treated for puri-fication by one simple recrystallization.