21
Yol. ii
Synthesis of Derivatives of Isophthalamic Acid as X-Ray Contrast Agents
Chenizcal Resenith Department) J f r d i c i n u l Ilinzsaon, ilfallznch r o d (‘hemztnl Il’orks, St. Louis, iIf o
Recezved
B i ~ y i i s t$5, 1‘162
A number of derivatives of 5-aniino-2,5,6-triiodoisophthalnmic acid have been synthesized. Prelirninarv pharmacological evaluation indicates that the salts of the Ion-er nieinbers of t,his series are among the least toxic iodinated organic compounds known.
For the past several years we have engaged in a research project directed toward the development of less toxic iodinated organic compounds t o be screened as X-ray contrast agents in intravascular radiography. Our approach has been t o 1-ary substituents in the 3and 5-positions of the 2,4,B-triiodobenzoic acid nucleus in a search for functional groups which ~ ~ - o uimpart ld both higher \rater solubility 2nd lower toxicity. As a part of this program a number of derivatives of 3-amino-2,4,6-triiodoisophthalamicacid h a w been synthesized. ThCl syntheses were carried out as outlined in the flow diagram. With ammonia and the lower primary nlkylamines, ammonolysis of methyl hydrogen 2nitroisophthalate (Method A) gnrc the desired Salkyl 5-nitroisophthalamic acid (111) in good yield. With the higher primary alkylamines and with dimethylamine, the simple ammonolysis procedure failed and it was necessary to synthesize the desired monoamides (111)using the acid chloride (T*I-Method B).
I
I1
1
VI
R3COCl
I
/
I
\ R2
Va, RI = H, Rn= Rd= CH,
VI11
\
(isothalamic acid3) has shown to be the most promising compound in the series and, therefore, has been selected for clinical evaluation.2b
Experimental* Ilimethyl 5-nitroisophthalatc ( I ) was prepared from 5-nitroisophthalic acid by the method of Beye+ or by the reaction of 5nitroisophthaloyl chloride with excess methanol; m.p. 120.3 122.3’ (lit., 121 .5’,58 12lo,5b 123’5” 1. Hydrogen Methyl 5-Nitroi~ophthalate(II).--Xormal aqueous sodium hydroxide (0.02 eq. ) was added at room temperature with rapid sn-irling to a solution of dimethyl 5-nitroisophthalate (4.8 g., 0.02 mole) in acetone-methanol (100 nil. each). After standing overnight, the solvents were evaporated a t steam bath temperature and the residue ext,racted with warm water (50 ml.), The unsaponified diester (0.23 g., 4 2 r & n1.p. 115-117’) R:LS filtered and the filtrate acidified with dilute hydrochloric acid t,o precipitate crude 11; yield, 3.4 g. (75‘53),m.p. 170.5-175.5’. The preparation \vas also carried out on a larger scale esscnt’ially as described above by adding 42.6 g. (0.76 mole) of potassium hydroxide in 500 ml. of methanol to 182 g. (0.76 mole) of tho diester dissolved in 1900 nil. of acetone; yield, is%, m.p. 175.179’; m.p. pure 11, 179.5-181.0°. d m l . Calcd. for C~HTSOG:iieiit. equiv., 223. Found: neut. erpiv., 222. N-Methyl-5-nitroisophthalamicAcid (111, R I = IT, Rz = CH,). --Crude methyl hydrogen 5-nitrojsophthalate (46.3 g., 0.21 mole j was dissolved in 35’5 aqueous methylamine solution (500 ml.). The reaction mixture was evaporated overnight on a steam bath, the cooled residue treated with 50 ml. of water and the solution acidified with hydrochloric acid. The crude matrrial ims purified by reprecipitntion from dilute ammonia solution (after charcoal treatment a t pH 5.2) followed by recrystallization from SOYo aqueous ethanol. 5-Amino-N-methylisophthalamic Acid.-Crude X-methyl-5nitroisophthalamic acid (neut. rquiv. 216, 11.2 g., 0.05 mole) in 250 ml. of methanol was shaken with hydrogen and 5 % Pd/C in a Parr loir pressure hydrogenator. After the theoretical quantity of hydrogen for reduction of the nitro group had been absorbed, the solution n-asfiltered to remove t,he catalyst and the solvent evaporated under reduced pressure to give a white residue of crude 5-amino-S-methylisophthalamic acid, m.p. 227-230‘. (For the synthesis of all other compounds in this series, the amino intermediate was used in the iodination step immetiiately after cvnporation of the solvent and Tyithout further purification.)
Rz
Certain members of this series of compounds (as their sodium or S-methylglucamine salts) have been found to be less toxic and more mater soluble than previously known radiopaque medi8.I The solubilities and acute toxicities obtained for these compounds are listed in Table 111 -46 a rrsult of additional pharmacological testing,?a ~~-acctamido-2,4,G-triiodo-S-mrthJ.lisophthalamic acid (1) J 0 Hoppe, A n n \ 7’ l r i c d S ( i , 78, 7 2 7 (1959), ani1 other references therein (2) (a) J K Kodama. I T 11 Butler 1 I\ Tusing and F. P. Hallett, t o be published, (b) C T Dotter I< R Q t i L U ~ C11 I< Bilbao, and F C Hinck, Northuest I l e d z c z n r 61, 41 11982)
(3) OfTiciaI generic name. Early clinical testing was carried o u t under t h e generic name “metlialaniic acid.” (-1) h l l melting points are corrected. Neutral equivalents were determined by potentiometric titration of a weighed sample of acid u-ith standard sodium hydroxide solution using a Beckman LIodel €12 pH meter. T l ~ r solvent system used for these titrations was a mixture of dimethylformamiile ( 2 vol., added first), absolute ethanol (8 vol.) and distilled water (10 vol.). Elemental analyses were made by D r . IT,J. Larson and his staff of t h e T h partment of Chemical Control, LIallinckrodt Chemical Works, or by A h . Iackseg of this department,. The infrared absorption spectra of t l i ? majority of the rompounds reported here were taken using t h e Perkin-Elmer Bpectrophotoineter Rlodel 2 1 (potassium bromide disc). All spectra mere consistent witti the gostulated s t r u c t u r e ~ . T h e assistance of Mr. R. 1). Field and staff of the Depart,rnent of Chemical Control in determining and interpreting these spectra is arknowletiged. c.5) (a) B. Bryer, J . prakt. Chem., ( 2 ) 25, 490 (1882): (b) J. B. Cohen anii D. AIcCandlish, J . Chin. Soc.. 87, 1269 f1905): (r) E. Alullrr. B e r . , 42, 133 (1909), footnote.
January, 1963
I O D I X i l T E D ISOPHTHALAMIC
ACIDDERIVATIVES TABLEI1
TABLEI
5-~4MIi%O-2,4,6-TRIIODO-~-ALKYLISOPHTHALAMIC ACIDS
5-NITROISOPHTHALAMIC ACIDS
C02H
CO,H
Yield,
25
i?l.p.,
-Neutral-equivalent Calcd. Found
Rz Method % OC. H A 78 238.6-239.6 210 A 89 251.0-252.5 224 H CHI B 72* 211.3-213.3 238 CH3 CHI H C?Hs A 80 206.0-208.0 238 Anal. Calcd. for CeHsNzOe: N, 12.5. Found: Yield by hydrolysis of corresponding methyl ester. Ri
a
Yield,
R1
Ri
%
H
H 74.6" H CH3 72",54' H C2Hj 61b CH3 CH3 74" Prepared using ICI-HCl.
208 222" 238 238 N, 12.3.
hl.p., OC.
cSeutral-equivalent Calcd. Found
284.1-285.1dec. 558 266-268 dec. 572 586 242.5-244.5 274.9-275.9dec. 586 Prepared using KIClz.
'
555 568 578 573
TABLEI11 5-ACYLAMINO-2,4,6-TRIIODO-N-ALKYLISOPHTHALAMlC ACIDS
COZH
Solubility,= Yield,
RI
%
H H CH3 H
640 76c 6OC 79" 32c 87c
m p . , "C.
Neutral equivalent Calod. Found
-Iodine, Calcd.
%Found
g./lOO
ml. soln.
IVLD~~~ mice (mdkg.)
84 21,200e 293d 600 63.5 63.4 602 19,2ooe 85 62.0 61.8 285 dec. 614 619 20,5OOe 103 296.1-297.1d 60.6 59.9 628 630 18,600' 43 300.1-301.Id 60.6 60.6 627 628 H 17,800' 59.1 292.6-293.6d 54 59.3 646 642 H 6,160' 34 56.9 56.6 668 275' 670 h H ... 56.9 56.0 291.8-292.8' ... 672 670 19,8OOe 60.6 60.5 H 74c 80 294d 623 628 H 40 3,710e 54.6 54.1 695 340 301-303 698 62.0 61.6 281.(2-282. Od H 614 50 ... 609 530 58.0 H 271.7-272.id 57.9 ... ... 653 33" 656 a Determined by equilibrating a t 25O, a saturated solution of the sodium salt with sodium salt crystals and then determining t h e sodium salt concentration in the supernatant liquid. b Administered to mice as the sodium or N-methylglucamine salt in aqueo us solution, wherein the salt concentration was adjusted so that each solution contained 300 mg. I/ml. Ref. 2a. c Using R&O C1 as tke acylating agent. Decomposition. e Sodium salt. f iY-Methylglucamine salt. Prepared by Method B. Usi ng (RjC0)20 as the acylating agent.
5-Amino-2,4,6-triiodo-N-methylisophthalamic Acid (IV, R1 = H, R2 = CH3).-The following two experiments are illustrative of the iodination procedures used. (a) Using Iodine Monochloride.6-Crude 5-amino-N-methylisophthalamic acid (9.7 g., 0.05 mole) was dissolved in 18.5% hydrochloric acid (200 ml.) and this solution was diluted t o 1 1. with water. Iodine monochloride (27.4g. of 957, ICl, 0.16 mole) in 30 ml. of concd. hydrochloric acid was added in one portion to the stirred solution a t 54". After 2 hr. of heating on a steam bath (go"),the solution was diluted to 1.5 1. and after 3 hr. of heating, titration of an aliquot sample indicated that 507, of the IC1 had been consumed. Precipitation of a solid began after 3.75 hr. Intermittent heating and stirring was continued for 4 days, 10 g. of 95y0 IC1 being added during the third day. After 4 days, titration of an aliquot sample indicated that 967, of the theoretical quantity of iodine monochloride had been consumed. The precipitated solid was filtered, washed with water and dried a t 75" under reduced pressure yielding 20.6 g. (727,) of product. (b) Using Potassium Iododichloride.7-Potassium iododichloride solution (1144ml., 2.22 moles) was addedduring0.5 hr., to a stirred suspension of 5-amino-N-methylisophthalamicacid (196 g., 1.01 mole) in 2.5 1. of water. After 3 hr. of additional stirring, a solution of sodium hydroxide (88 g., 2.2 moles in 200 ml. of water) was added. Then, additional 1.95M KIClz solution (522 ml., 1.01 mole) was added during 0.5 hr. The reaction mixture was stirred overnight after which the crude product was collected
(6) V. H. Wallingford, H. Decker and M. Kruty, J . A m . Chem. Soc., 74, 4366 (1952). (7) A. A. Larsen. C. RIoore, J. Sprague, B. Cloke, J. Moss, and J. 0. H o m e , ibid., 78, 3210 (1956).
and purified by crystallization of the ammonium salt and conversion to the free acid by reaction with hydrochloric acid, yielding 310 g. (547,) of product. 5-Acetamido-2,4,6-triiodo-N-methylisophthalamicAcid (Va, R1 = H, RZ = R3 = CH3).-Acetyl chloride (17 ml., 0.24 mole) was added in portions to a stirred slurry (room temperature) of 5-amino-Z,4,6-triiodo-N-methylisophthalamic acid (5i.2 g., 0.1 mole) in dimethylacetamide (120 ml.). Solution occurred in 0.5-1 hr. and after a total of 1.5 hr., 20 ml. of water was added and the reaction mixture evaporated to a thick slurry. The product was purified by twice dissolving it as its sodium salt and precipitating the free acid by the addition of mineral acid. The nearly colorless Va decomposed a t about 285" but did not melt below 300",yield, 47 g. Acetylation could also be carried out using acetic anhydride in dimethylacetamide with 1-2 drops of concd. sulfuric acid as catalyst. The ethyl ester (VIII, R ' = CPH,, R1 = H, RP = R3 = CHI) was prepared by adding a solution of potassiuni hydroxide (22g., 0.33 mole) in absolute ethanol (500 ml.) to a stirred slurry of 5acetamido-2,4,6-triiodo-N-meth~lisophtha1amic acid (205g., 0.33 mole) in 500 ml. of absolute ethanol. Diethyl sulfate (45 ml., 0.33 mole) was added to this solution and after 2 hr. of stirring, the solution had become almost solid with crystals. After standing overnight, water (500 ml.) was added and the crystals --ere collected. The mother liquor was evaporated to dryness and the rwidue combined with the previously collected crystals. The combined solids were stirred into 800 ml. of wa*.er containing a slight excess of sodium hydroxide. The solution was acidified slightly (pH 5) and the undissolved ester collected. The crude ester was recrystallized by dissolving in 400 ml. of hot dimethylformamide, filtering, and diluting the filtrate with 400 ml. of water; yield, 102 g. (48%), m.p. 297.5-298.0' dec.
A i u l . Calcd. for Ci3H1313X;204: I, 59.3; S , 4.33. F o u n d : I, 59.3; 1,4.30. 3-Carbomethoxy-5-nitrobenzoyl Chloride ~VI).-Hytlr~ig.en methyl 5-nitroisophthalate (11, 241 g., 1.07 mole) :iiid phospliurus pontachloride (230 g,, 1.07 mole) lvcre niisrd in t,olutw~(100 1111. j :tt room teniperature. The reaction proreedrd sloivly for 17..5 Iir. aftcr nhich heat (steam bath) t v : ~applied to coinplrte solution in itn additional 45 inin. The toluenr ivas c.vaporated untlrr reduccd pressure whereupon the rrutle product cryst:tllizctl. Addition of carbon tetrachloride :inti cwiporat ion uiitlcr rtducrrl pressure gave VI, n1.p. i2.4--i-lo. :lnal. Calcd. for C9HsClS() 5 : rierit. yriiv.. 244. l ~ o u n ( l : neut. cquiv., 238 (drterniined Ijy :dcoholysis of thr chloroforni~-l group and titration of the lihrratetl hydrochloric acid). Methyl N,N-Dimethyl-5-nitroi,cophthalamate(VII, R I = R, = CH,).----One hundred granis of VI (0.41 niolr) was :idtl(:tl during 0.5 hr. to :i well-stirrrd solution of tlinit:thylaniiiie 181 g. of a ‘25‘; aqueous solution, 0.45 n i o l ( ~ :~iid ) sodium 1)icark)onatc. (69 g., 0.82 niolc) in water (500 nil.), ni:iirit:~,ined at 0-5”. \Vheri the rc3:iction appeared coniplete. the uiidissolved ni:ttclri:tl \ V M collected, slurrird xvith sotliuni biearl~oriatcsolution, and :tguiii collected: washtd and air drictl: y k l d of crudr VI1 (111 = Ill. = CH,), 00 g. (87l j. rii.ii. G1.:I-7O.:i0. .I portion of t h t s crutlrl product was rc.cryst,allizrtl twicc, froiii nic~tli:iriol. ni.I). 89.:3 91 ..io. N,N-Dimethyl-5-nitroisophthalamicAcid (111, 111 = R, = CIli).--?*Iethanol (‘LOO nil.) was added to 80 g. of crude methyl N,N-diniethyl-5-nitroisophthalaniate ttnd then 300 nil. witcsr. Sodium cttrhonate (36.5 g.) was added in portions t o t h r w.:trmcd niixture (pH S-!)). After filtr:ttion arid acidification n-ith ki>,drocliloric acid, the resulting precipitate was collected and dried. yielding 54 g. of crude 111 (111 = IS-C-C-COS1amino). B-idimpthylamino) and (?-(1rimethylammonium) suhstitnted diethylpropionamid~.b(I’ig. I ) . Sc,\t, t hr pronoimccd difference hetn w i i iridiict~\-(~ vff ( ~ 1 y elicited by \om(’ yuhstituents on a- and P-c~art)on~ of aliphatic acids,’ prompted II\ to c’xamine the. 1,ioc.hrmicaal rebpoiiic~ of thc w(arglalky1amino) ~ u b ~ t i t i i l t d analogs (Fig 2 ) of the previously itudied Ll-(arylalkyl:tmino)propionic. acid diethylamides?; th(3 fact that t l i c v I\\ o W I I C \ ot (wmpouiidi a110 (mild I)(> \ i ~ \ i ~ t l \(I\ ~ ’ I ~ I ~ I I C~ oI i~ j I~~ n J d
t i ~ iXvu i
iiiii
Yorh N I
(1 O i w n i r ( l c c s r u i b t t \ l‘lbi r) 3bL.
iiil~(ilt1
