descrih n c n compounds in tliis scric.:, as \\ell as i i d The amino acid was tested for its ability to inhibit tlerived from ~.'-(y-clilor~~propyl~-. p-( 7 the growth of E . coli, ,Z'FCC 9723, a i d S. c c ~ ~ i ~ i s i u t ~foiiyliircas , htrain 13!1, accordiiig to the method of Ilittnier, cf ( ~ 1 . ' ~ iiictliou~pi~opyl)-, aiid p-ryaiioltrii~ciic,siilEoii:iiiiiti(~ I 110 1:i-t t l i i w iiiciitioiied Iin\ 1 ) c ~ t i\yiitiic4/(~1!I('It \\-ah inactive on both the yeast .tixiii a i i d O I I tlw ( * : i i w ol f I i e i i ;tiialogy to tlie acti\.rl urea.: tlclri\ ( ~ J 1i o I i i li:. w l i u p to 100y 7 i d . of inc~liuiii. p-c I I I ( ) i ) - :I I I (1 p - n i t 1 I ouyt wi izeri wi I 1fo i I ani I d ExperimentalG 'l'lic wlfoiiyliii.(w~M we p i q x ~ r cit1it.i ~l l)y reactioii I)etwrii an ai~ylsulfoiianiide and :tii alkyl isocyaiiatc i i i 3-Trifluoromethylbutyric Acid. -4-TriRuoromethrlcrotonic thc preseiice of potassium carl)oiiute (mctliocl 1) UI 1)y :icitl (100 g,, 0.65 mole) \vas hydrogenated with 3.0 g. of 5';;. I,:ill:tdiurii-on-charc.oal at a n init,ial pressure of 4.22 kg./cni.2 tlic> pyi olysi5 01 ail aniinc salt of a11 uiylsulioii~lcaiI,:r.\fter the theoretical absorption of hydrogen W:LS completed (0.7.5 mate jinethod 11i . .\lethod I \ \ 0 1 . k ~~nlootllly l aii(1 hr.), the catalyst w:is renioved by filtration, the solution rr:r,s y a w liigh yield11~ t h all ~ u l f o n : i ~ i i ~ ~ ~ d ~ \\ . ~ 1 1I~ ~ 1 ~ washed with chloroform, and the combined filtrate was distilled inetliotl 11 f:iiltd i i i ~ m vabt's o to p r o d u ~t l i t ' c.xpr.rtct to yield 00.5 g. (SOYo)of product,, t1.p. 90--01" ( 2 5 mrn.), nZ1n resiilts. S -( p - ('yaiiobc.rizencsiilfoii~1~ - 1'hiityluic~ 1.35s0. Anul. Chlcd. for CsHYF302: C', 3S.17; H, 4.52. Found: \vah obtainecl froni tlic appropriatt. caritaiiiatc., \I l i c i ( ?&.64; H, 4.64. tllP S'-cyclohrxyl r.ompoIlnd r.O~Ildnot I)(> pi ('pal' Ethyl 2-Bromo-3-trifluoromethylbutyrate.-A mixture of 50 g. I I I t l i i b waj. (0.32 mole) of 3-triftuoroniethglbutyric acid, 41 g. (0.3 mole) of I he preparation of p-ac.ctyl and p-propioiiyll)eiixc~ii(~phosphorus trichloride, and 80 g. (0.5 mole) of bromine \vas 1icX:tted for 20 hr. :it 125". The excess t)rornine and phosphorus ~ulfoiianiide accortliiig to *\Iecrwein, el C L ~ . ,s~t u tiiig tric:hloride were removed in vacuo and 17 g. (1.0 mole) of abso1ut)e from the p-amirioacylphciioiics liaa bec.11 descri1)cd. o t h:invl WLS added droprrise with stirring. The mixture wa.s IVc used tliis method to prepare p-butyryl- aiid p distilled through a Wheeler column to yield 2X.S g. (40(,4) of ethyl \ u l e yll~enzeiiesiilforia~nidc. ~ 11- (y-C'liloroprop~l)l~cii:~-trifluoromettiylbutyrate, b.p. 136-137, n ? 4 ~1.3631, d"', aiid ~-(y-nietIiosypropyl)be~izcric~1.14s; and 3'7.1 g. (325;) of a-bromoester, t).p. 180", n 2 2 . : r ~ ) drnesulfoiianiide 1.4071, GPO., 1.465, MRD 14.11 (calcd. 43.83). >iilfoiianiidr n-ere prepared try the c'nlorosulforiatioii 01 Anal. Calcd. for C7H9BrF302:c', 31.95; H, Found : t h c appropriat,cly substituted benzene derivat>ive fol(', 31 .BT; H, 4.12. io\\ 1.d hy t reatnicnt of the resulting sulfoiigl chloriclc Ethyl 2-Azido-3-trifluoromethylbutyrate.-Tlie bromo ester with ilminoiiia. (27 g., 0.1 mole), 100 g. (1.5 moles) of sodium azide, 50 ml. of ethyl alcohol, and enough Tvater to dissolve the sodium azidtb T h e evaluatioii of the hypoglycemic activity \\ as were refluxed for 127 hr. The reaction mixture was steam discai-rid oiit with male rats weighing 150-1 GO g. T h o tilled, heavily salted, and extractrd with ether. The extract 1 ~ : ~ s aninids \wro fasted 20 hr. prior to testing arid then dried over sodium sulfate and stripped i n vacuo. Distilla WI-P treated orally with 100 nig. kg. of the testt coni5 g. ( 2 2 % ) of product, h.p. 69-70" ( I t nim.), n yielded poiiiidh. Blood glucoic levels w r c determined eiizy1.4000; dao41.230; $111~44.33 t c a l ~ l44.6*5 . !. 4,4,4-Trifluorovaline.--The azido ester ( 5 g. 0.22 mole) in 10 iiiatically, ii.ing four rats per group, tolbutamide aiid 1111. of ethanol was hydrogenated for 22 hr. a t 4.43 kg./cm.* with S-(ppi~opio~i~lbcrizc~i~si~lfoiiyl) - S ' - r y c lo hexyl 11rea 5%,Dalladium-on-charc,(i~l. The catalyst was filtered and washed YtLrviiig as standards. Tlic results obtained FI it 11 with ether. Dry hydrogen c'hloride gas w:is bubbled into the p-acylbcrize~iesrilforiylureassliou that only conipouiids solution and the solvent was evaporated in cucuo. The resulting p:tste was refluxed for 23 hr. with 30 nil. of concentrated HC1. \vith a11 acetyl or propionyl residue possess hypoglycemic T h e mixture was evaporated to dryness i n vacz~o,and absolute acti\*ity. \\ liile vsleryl-suhstituted compounds arc i l l ethanol was added and again evaporated to dryness in z~acuo. :wti\-c1. I I I t l i r srri of p - p r o p i o ~ i y l b c n ~ ~ ~ r ~ ~ s u l f o i ~ ~ l The resulting solid was dissolved in absolute ethanol, neutralized I I I Y Y L ~ tlir highest ar ity ~ r n so t ) s e i ~ ~\\-hcii d N' \vas refrigemted. There was obtained 2.1 g. .;iil)\titutc.tl I)?. c~~c~l011e~yl. I t q h c i n g the Iattclr 1)) lly pure :mino :tcid. Recryst,allizsati a,ve white plates, m.p. 239" de(.., Rf (SO cyclopcntyl, lie~ali~drohc11zy1, or 13y cyclolieptyl I 1,ut:inol and 20c7, acetic acid) 0.61 ; Xt (65':; pyridine and 26 hiilted in gradually tliminislicd activity. T l w txiizyl water) 0.94. The product gave a positive ninhydrin test. iii:i(*tivc>aiid thc phenctliyl- aiid tht. /lnuZ. Calcd. for C6H8F3NO2: C, 35.09; H, 4.74: S , 8.18. Iic~xylurr~ii of tlik g i ~ i i p~ w r Iivperglyccniic~. e (", 35.20: H, 4.87: T! 8.0.;. I3'ound: r ,
(%
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r ,
(1-
Acknowledgment.-We n-ish to express our sincerc appreciation to Ilr. Karl Ditkmer ant1 his staff for the micmhiological assay. Itwin, : m i S. .J. ('riqiol. ,I.
.Aril.
taken o n a Nalge-.\xelro(l melting point ap1iar.zBoiling points are uncurrectd. Analysrs w r v IIPTfortnr
