[ e I 3 O D -3.3" ( e 2, acetic acid) [ l i t . 6 nip 112-113', [ e I 2 ' D -3.7' Myelographic Agents 111. (c 2, acetic acid)]. Glycol Iodobenzoatesl A solilt,ioli of 1.5 g of this e-ter in 7 . 5 ml of glacial acetic acid !vas treated with 7.5 ml of 4 .\- HBr-acetic acid and the mixture JAMES E. SIGGIZS .ISD J.MESH. ACKERM 1s wa; kept a t room temperature for 1 hr. Excess HBr and acetic acid lvere removed in vacuo at 20" and the residue, after washing Sterling-Winthrop Research Institufe, Rensseluer, Sew Y Ok/ with dry ether, was discolved in water, treated with triethylanline to pH 8, aiid extracted with ethyl acetate, and the extract Received A p r i l 1, 1966 was worked iip to give 0.8 g of 1.-alanyl-D-glutamic acid dibeiizyl ester ad an oil (Xi (a) 0 . 8 2 which wa? iised for coildensation I n cwiitiriuation of oiir study of contrast agents for X-ray withoiit any fiirther purification. 2 4 1 -O-Benzyl-2-acetamido-4,6-O-benzylidene-2-deoxy-3-visualization of the spinal cord, we have prepared some reverse esters (Table I) analogous to the series previoudy reported.2 0-o-glucopyranosy1)acetyl-L-alanineBenzyl Ester (HI).-To a K e v-ere able to realize oiir hope that this small nioleciilar stirred suspension of 100 mg of ?j-ethyl-5-phenvIi.osazolium ;3'-mlfouate (Woodward's reagent K)' in 10 nil of d modification would permit rapid elimination from the spinal canal. -4fter cisteriial administration into cats and dogs, the at OD, a solution of 200 mg of I :tiid 0.6 ml of tri 21) ml of aretoilitrile was added. T h e mixture was stirred a t esters enabled details of the spinal caiial to be viaiialized and were 0" until a clear solution was obtained (40 miri). A cold solution eliminated from the animals in period> raiigiiig from a few weeks to a fexv months. Of benzyl alaninate (obtained by treating 155 mg of the ptolueneeulfonic acid salt of benzyl alaninate in 15 ml of acetonitrile with 0.05 ml of triethylamine) was added, and the mixture Experimental Section3 wah stirred for aii a d d i t i o i d 1 hr at 0" aud kept overnight a t room temperature. The solvent was removed i n caczto and t'he o-Iodobenzoyl chloride and sodinm p-iodobeiizuate xvere preresidiie was washed wit,h 0.5% N a H C 0 3 solution. The precipipared as previously described2 from commercially available iodotate wai extracted with ethyl acetate, the extract was washed benzoic acids. Aliphatic acid chlorides, ethylene chlorohydrin, hiiccessively with 0.55; Xa2COa,5% citric acid, water, and satiiand trimethylene chlorohydrin were commercial prodiictr used rated YaC1 sollition. The organic phase was dried ( l I g S 0 ~ ) as obtained. Tetramethylene chlorohydrin (Mathemn Coleman nlld evaporated, and the residue wa:, washed with et,her arid aiid Bell) was distilled before use, bp 82-84' (11 mm), nZ6g crystallized from ethyl acetate-petroleum ether or ethanol, 1.4511. mp li2-1i3". 2-Hydroxyethyl acetate (Eastman Kodak Co., practical) 2-Acetamido-3-O-carboxymethyl-2-deoxy-~-glucose.-~ne?c- was stirred with ice-cold 2555 aqiieoiis &C03 and the mixture pected difficulty was experienced in the hydrogenolytic splitting was extracted with chloroform. Washing with water, drying of the blocking groups aiid an aqueous medium seemed to be (Sa2SOa),removal of solvent, and distillat ion gave 'I-hydroxyfavorable for this step. Iri view of the insolubilitj- of the blocked ethyl acetate satisfactory for our purposes, bp '38" (23 mm), n z 5 D caompouiids in wat,er removal of the blocking groups had to be 1.4190. carried out either stepwise, i , ~ .first , acid cleavage to remove the Chloroalkyl A1kanoates.-The standard reactioii between a n benzylidene group followed by hydrogenation in aqueous methacid chloride and an alcohol was used to prepare these c>omanol, or in one step by carrying out the hydrogenation in a pounds, n i t h the exception of 3-chloropropyl 2-metho~yacetate.~ vigorously st,irred mixture of ethyl acet,atearid water. The latter was prepared by the toluenesiilfonic acid catalyzed Method A. Stepwise Removal of Blocking Groups.--A reaction b e h e e n methoxyacetic acid and trimethylene chlorosolutioii of 340 mg of I in a mixture of 12 ml of glacial acetic acid hydrin. arid 8 nil of water was rhaken i u a closed flask for 2.5 hr a t room The reaction of hexanoj-1 chloride n-ith trimethylene chlorotemperature. The solveiits were removed in m x o a t 60-7O0, hydrin in hexane gave a 74% yield of 3-chloropropyl heranoate, the residue was evaporated to drynebs after bp 134" (23 mm), 72% 1.4373. remove the last traces of acetic acid, dissolved Snal. Calcd for CgHiiC102: C, 56.10; H, S.89; C1, 1S.40. water, and filtered. A part of the aqueous s Found: C, 56.42; H , 9.0i; C1, 18.78. philized to give presumably benzyl 2-acetamido-3-O-carbox~-1-Chloro-2-propyl Valerate.-Commercial l-i.hloro-L'-I,ropaiiol methyl-2-dec)xy-e-I)-glucoside, nip 153-157" (from ethyl aretate): (Matheson Coleman aiid Bell) as fractionally diatilled through yield 70?i,. a 15-cm Vigreux column t o give a forerun, bp 49-51' (28 mm), ,Inal. Calid for CljI12aSOq: C, 33.21J: 11, G.2:3; S, 3.97. which was discarded and a colorless fraction, bp 51' (28 mm), n z 5 ~ 1.4355. Forty-reven grams (0.5mole) of thi,. alcohol waas then hydrogenat ed ii>iiig added dropwise to a stirred solution of 59 ml (0.3 mole) of butyrj.1 1OC; Pii-C for ;i-G hr at ordinary temperature and pres-ive, the chloride in hexane. After evolution of HC1 had .*ub.cided, catalyst waq filtered, aiid the aqiieoiis phare was lyophilized to the mixture was heated under reflux for 2 hr, cooled, wished with give the desired compoiind as a colorless hygrcisc-opic powder. 5s NaHCO3, and dried (Na2S04). The 3olveiit was removed In the cave of compoiiiids containing a benzyl e>ter a': well, and the oil was fractioiially dihtilled throiigh a 15-cm \?greiis the compounds were first hydrogenated ill methaiiol arid x ~ t h column to give 34.8 g (80%) of the ester, bp 110' (30 mm), heqiiently in water. n% 1.4290. Method B. One-Step Removal of Protecting Groups.Anal. Calcd for CBHlICIOL:C, 53.77; 11, 8.46; Cl, 19.84. Conipound I (300 mg) was dissolved ill excess moist ethyl acetate Found: C, 53.54: H, 8.56; C1, 19.80. (itppros 200 ml), by warming if riecexhary, aiid 50 ml of distilled Method A. 2-Acetoxyethyl p-Iodobenzoate (l).-To a soluwater and (1.3 g of 10yc Pd-C were added. T h e mixture was tion of 62.0 g (0.250 mole) of p-iodobenzoic acid in 360 nil of vigorously stirred and hydrogeiiated a t ordinary temperature dimethylformamide was added 35 ml (0.25 mole) of triethyland prehsure until n o more hydrogen was absorbed (5-6 hr). The amine, followed by 30.8 g (0.252 mole) of 2-chloroethyl acetat>e. vatalyst w a s filtered arid the aqueous phase was extracted twice The browii mixture Tvas stirred 24 hr a t 115". After cooling aiid with ethyl acetate. The aqueous extract was now stirred for removal of Et&. HCl by filtration, the mixture was poured into :30 miri with 4 g of Dowes 50 ( H + form), the water and the aqueous pha.-e was extracted with CHCb. The the filtrate waq lyophilized, mid the residlie wa combined organic extract w i s washed successivel!- x i t h cwld L: mixtiire of methanol-ethyl :icet ate. The co 5% KzC03, HrO, cwld 3';; HC1, H20, :tiid aaturated S:tCl. tical in all respect3 with that ohtailled by method -1. Drying over Drierite, decolorizing with charcoal, mid removal of 2 4 2-Acetam~do-2-deoxy-3-O-~-gIucopyranosyl)acetyl-~-ala-solvent gave an oil which amounted to 42.5 g (51c,~c) of 1 after nine ( X ) was prepared from I11 according to method B dedistillation. Thirj product .solidified after cooling in D r y Ice. scribed above for the hydmgenolysis.
Acknowledgment.-We xish to express our t,hanks to DI. 11.L. Dhar, Director, for his interest in this work a i d to 1\11.. ,J. Sara11arid his iisiiwistes f o r niicronii;tlyie~, ~
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1 5 . \ \ ' u u d n a r d , It. .\, Olufaun, alii1 11. A l ; i > e r , J . . I m . C'/tem. Siic., 83, 1010 ( I ! J G I ) ,
(1) Paper 11: J. H. Ackerman, V. Akullian, C. Moore, and h. .iLarsen. . J . .Wed. Chem., 9 , 165 (1966). ( 2 ) J. E. Siggins, J. H. .ickerman, and A . .I. Larsen, ibid., 8 , T28 (1965). (3) Melting point- w r e takrii i n a modified Hwsliberg alNbiaratiia and are
~uirorrected. (4) Eiriar .J. M i n i and It. Leiuiu, . S u u ~ c , i h ~ c m i s l i / ~ h20B, / ~ . 4:i (1947) ; C / , ~ r nA. b u l r . , 42, W S I g (1918).
