963
SOTES
September 196'7 action was complete, 2-chloromethyl-5-niethoxy--1H-pyra1~-4-one (II! (37.2 g, 0.212 mole), was added and the reaction mixture wab &red for 24 hr a t room temperat,nre. The DMF was distilled in vacuo. and the solid residne wa* extracted wit'h hot CHCI3-ethanol 180:20) and filtered. The filtrate was taken to dryless in vacuo. aiid the dark residue was recrystallized twice with charcoal trearnieiit from ethanol-water. The resulting white needles weighed 33.7 g and had mp 179.5-181" iuncor). d n a l . Calcd for Cl4Hd206: C, 54.54; 3,5.23; S , 9.09. Foiind: C, 54.55; H, 4.91; N, 8.99. ~~-4-Hydroxy-5-methoxy-2-pyridylalanine (IV).-A mixture of 28.0 g of I11 and 60 g of concentrated NH,OH was placed in a -tainless steel bomb; the bomb was sealed and placed in an oveu a t 85-90' for 2.5 hr. The r e a d o n mixt'ure, a dark liquid, I n - then concentrat,ed in uacuo, and the residual S H I O H wab removed by taking up the viscous residue in methanol and again concentrating in z'acuo. T h e concentrate was ninhydrin positive (dark blue), but repeated attempts to effect crystallization were uiisuccessful. Hydro1 of this residue was effected by heating 28.0 g of the residue under reflux several hours in a suspension of 45 g of Ba(OH), in 200 ml of water. After removal of solid Ba(OH by filtration, the filtrate was neutralized by the addition of CO? (Dry Ice). The BaC03 which precipitated n-as removed by filtration, and the filter cake was washed with water to remove any adsorbed amino acid. Remaining B a 2 + was removed from the filtrate by addition of 10% H2S04until Bas04 no longer precipitated. After filhation the filtrate was concent'rated in oacuo, aiid the light brown residue was recrystallized (after decolorizati(iii by charcoal treatment) from ethanol-water to yield 14.0 g o f white, hygroscopic crystalline material, mp 252-255" dec. Paper chromatography of the product with BuOH-ACOH-H~O (4: 1 : 1) gave a single ninhydrin spot (light brown), Rr 0.13. Anal. Calcd for C9H12N204.0.5H40: C, 48.87; H, 5.92; N> 12.66. Found: C, 48.78; H, 6.10; N, 12.53. 1)~-4,5-Dihydroxy-2-pyridylalanine(V).--S solution of 1.0 g of IV and 3 ml of concentrated HI was heated under reflux for 3.5 hr. The I11 was then removed in vacuo,and the residue wab taken up in a small volume of water. The resulting solution was neutralized with concentrated N H 4 0 H , whereupon a precipit'ate of the amino acid formed (the amino acid is sparingly soluble in water). Complete removal of the amino acid from solution was effected by the addition of ethanol, and the crystalline material was collected by filtration. After decolorizing with charcoal, the amino acid was finally recrystallized from ethanolwater, and after drying overnight a t 80" (vacuum desiccator, P,Oj) weighed 0.90 g, mp 236-241' dec. Paper chromatography of the amino acid in BuOH-AcOH-H20 (4: 1: 1) gave a single ninhydrin spot (light brown) with an Rf of 0.13. The amino acid reacted with FeC18 to produce a deep purple color, indicating cleavage of the methoxy groiip in the 5 po4tion of the pyridine ring. -Anal. Calcd for C811,0N204.H20: C, 44.45; H, 5.60; N, 12.96. Found: C, 44.23; H, 5.58; N, 12.82. Ultraviolet absorption spectrum showed a t p H 3, A,, 270 mp, X,,in 256 mM; a t pH 12,,,,A 294-296 mp, A,!, 250-252 mp. These absorption maxima and minima were identical with those of a sample of 4,5-dihydroxy-2-hydroxymethylpy~idine.
Synthetic Biologically Active Poly-niers. IV. N'- Acylsulfanilamide-Formaldehyde Copolymers
amide (la), sulfabenzamide (Ib): and sulfacetamide (IC)wit,h formaldehyde. NH2
I
1
SO,NHR
SO,NHRJ~
IIa, R = H IIb, R = C,H,CO IIc. R = CH,CO
Ia.R=H Ib, R = C,H,CO IC, R=CH,CO
,HCH,~--
111
IIb or IIc
H-o
TZi7
IIa
+
C6H5COLNa or CH,C02Na
IV
The copolymerizatioti processes were carried out, in general, by the method previously reported.la Hydrolysis of I I a with concentrated HC1 yielded 111. The structure of 111 was previously related'" to the structure of a polymer obtained by the sulfonation of an aniline-formaldehyde copolymer (IV). Basic hydrolysis of both I I b and IIc yielded IIa. Acidic hydrolysis of IIa, derived from both I I b and IIc yielded 111. Elemental analyses and infrared spectra seem to confirm the assigned structures. The copolymers appeared t o be monodisperse. The intrinsic viscosities of IIa. IIb, and IIc in dimethyl sulfoxide (DMSO) at 25' were found t o be 0.07. 0.24, and 0.10, respectively. I t was reported previousl) that a sulfapyridineformaldehyde copolymer exhibited antimalarial activity above that of sulfapyridine p e r se.la Therefore. copolymers IIa-c were vreened for antimalarial activity employing the procedure previously reported. la The screening results are summarized in Table I.
JOHK R. DOMBROSKI, L. GCYD O X ~ R C M ASD A ,JOHX Kazza~o~
Experimental Section
Department of Cheinzstiy, Clarkson College of Technology, Potsdam, S e w York
Sulfanilamide-Formaldehyde Copolymer (IIa).-A mixture containing 1.67 g (0,0097 mole) of sulfanilamide (Ia), 50 ml of water. 1mlof 4% aqueous HC1, and 1 ml of 377, aqueous formaldehyde solution was heated at reflux for 8 hr. A resin was depobited. The reaction mixture was cooled and filtered. The resin wab pulverized and extracted with boiling water several times to remove unreacted moiioniers. The yield of dry washed product was 1.03 g (57.8yc).The product softened at 187-190'. The intrinsic viscosity of the prodiict in IllISO was 0.07; infrared data (em-'): 3400 w,3250 P, 3100 s>2910 m, 2800 K, 2:NO w, 1650 m, 1570 s, 1490 s, 1390 TV, 1290 Y! 1140 8 , 1080 q > 090 m. 885 w, 820 P. A n d . Calcd for C,H,S,O,Y: C, 45.6; H, 4.37; S , 15.20; S, 17.40. Foiind: C, 43.95: H, 5.03: S , 14.80: S,16.00.
Kecetz erl .Ifarch 16. I S 6 ;
In continuing investigat,ions aimed at attempting to discern the effect of polymerizat,ion on drugs, we had occasion to study the copolymerization of sulfanil(1) For previoub pagers i n this series see: (a) L. G. Donaruma and J. Razaano, J . Med. Chem., 9, 2 5 8 11966): (b) R. J . Cornel1 and L. G. Donaruma. J . Polymer Sci., 3A, 82T (1965): J . .Wed. Chem., 8, 388 (1965). (2, This work was taken i n part from t h e thesis t o be submitted b y M r . J o h n Razzano in partial fiilfillment of t h e requirement3 f u r t h e Ph.D. degree.
of acetic a d a a z apparent, but quantitative i-olation. J>sleni
Dose le\ el, m y A #
Monomer act. (I)"
Polymer ;let. tII!"
IIa
SO Iiiactive Iiiac,livth 160 t nac.tive Inactive 320 Iiiact ivr .\ctive 640 Ciirativr .li*t.ive 1280 Ciirativr .lctive Ih, IIh 40 Iiiact ive Ciirative 160 Cur at ive 'rosic Toxic. 640 Curative IC, 111, 40 Inactive Clirative Ciirat ivr Clirative 160 640 Ciirativr ('iirat ive Aiitinialarial testing wit$ dolie by I)r. Leo I t m e at the Uiiiversity of Miami Medicit1 Srhool. Test, were carried out employing Plasmodium berghei in young ICIl/Ha Swiss mice. ', .%ctive = mice in a treated group survive at least 14 days: ciirative = mice in a treated group wrvive to :40 days: toxic = death- I JC riming through day 5 after infectioii arr attribiited t o d r ~ i p action: Control animal.*do n o t die M'ore d a y 6. I:t,
IKI
:ittempi ua. made to &chi?\ v
Acknowledgments.-Thib work n a b supported I I I part by Public Health Service Grant 5 ROl-AI06662. We are indebted t o Dr. ,J, P. TI instead of 1.1 nil of 3 i r i aqueou.i HCI. The yield of produo1 softening a t 230-235' rvaa g (14.2(; ). The iiitrinaic. vincosit). a1 25" was 0.10; infrared data 0 i,:32:30 s, 3050 ni, 2860 iv, 2610 1395 *, 1500 m, 1445 i n , l;3i5 w. 165 8 . 11.53 q, 1095 ni, 1000 n'. $150 n'.
L
J,
.Incc(. Calcd for Cgljj,83&S: C:. -17.77: I f , 4.45: S , !?.: leported previously for a sulfap ine-formaldehyde cwpolymer.
LThen the reactioii mixture was made basic, the odor of amnioni:i The solution mi- evaporated t o dryiies:;. after rencidification. The residue was thoroughly washed with water t o remove the salt present. The brown solid left w:i- ideiitiral with the sulfonic acid hylrol I $ the sulfapyridirie-formald Hydrolysis of 1Ib.--IIb (6.S g ) a a , dissolved ~ iii 30 nil of 10' ( aqueous NaOH and refluxed for S hr. The solutioii wah cooled a ~ i dthe p H was adjusted t o 8 with dilute aqueour HC1. The gunimy precipitate (3.5 g ) was washed with HC1 after filtratioii and dried. The infrared apectrum of thi.4 material was comparable to that of IIa, and acid hydrolysi3 of this productl" yielded 111. The filtrate a t p H 8 was made stroiigly acidic with HCI, anti 2.2 g (96'G) of benzoic arid (identified h>- infrared romparisoiil was precipitated. Hydrolysis of He.-IIc (2.0 g) byah dissolved ill 12 nil of 10( ( :iqueous NaOH arid refluxed 24 hr. The solutio11 was cooled and carefully neutralized to pH S. A preciipitate appeared which was collected by filtration, waahed with w-ttter, aiid dried t u yield 1.45 g of material h ng aii iiifrared spectrum comparable t o Ira, and acid hydrolj of this product yielded 111. The filtratr a ( pH 8 was made strongly acid with aqueous HCI. The ( I ~ I I I , was apparent.
;?j = intrinsic
-
viscosity
M =average molecular weight K a n d a = empirical constants
Iri order to differentiate between the two possibilities, or to recognize the presence of both structures ill the product) the purified reaction product was treated with aqueous nitrous acid t o diazotize any free amino groups present. 1-pori wirmirig the solution and vel11) This \vurk na;. 1akt.u 111 i n 1 1 f r i ~ i n[tie thesis to be submitGed b y X i . .John R a i z a n o in partial fitlfillnient of t h e reqiiirrments for t h e I ' k l l . {legree . V i I . Chcm., 8 , 388 (19ti5) , (,2) (a) K ,J, L'ornril a i d I.. G. I ~ u r i a r r u n a .1. €L J. Cornel1 and L. G. Iliinarunla. .I. P o l y m e r S c i . , SA, 827 (1HfiRI; ( h i I.. G . Donanim? a n d ,101 n R a r r a n o , .I. lJw/. Chpni.. 9 , 2.58 (1966).
