812
NOTES
Sulfanilamidoquinazolines
A long-act ing sulfanilamide, 2-methoxy-f-sulfaiiilaii i i doquinazolirie (111), was prepared' in low yield f i oiii 2.1-diiiietlioxyyuiiiazolirle (I) aiid sodiuiii sulfaiiilaiiiide (11) using 2-iiiethoxyethaiiol as the. reaction solvent. The present report deals with hoiiie of t h e results obtained duriiig a study of the process descrihed i i i the patent.* Gas chroiiiatographic anal iwwtioii distillate shon ed suhbtaiitially iiiorc thaii tlw theoretical 1 iiiolc of iiicxthaiiol expected frotii the 1111vleophilic displaceiiieiit of the reactive, estcr-like, 4iiicthoxy group. Replacenieiit of the lesy reactivc 2-niethoxy group by the solvent alcohol m s coiisidercd a likely possibility, although such a replacenlent had not beeii previously reported. The formation of '1(2-inethoxyethoxy) -~-sulfariilaniidoquiiiazoliiie (IT-) was later confiriiied by its subsequent isolation froii i process iiiother liquors I t was identical nith tho product formed froiii sodiuiii sulfariilaniide arid 2,4di (2-niethoxyethoxy) quiiiazolii io. OCH,
1;
11
+I
:;H,0CH2CH 011
CH IOCHLCH201ia
I
(
H,O( ~l,ClliOll
OCH~CHLOCH 3
a*' . .AO~
1;
$hol
+ N KPOCH,
\
H,c H,O c H
c
IV
H N S O ~-- - @ - H . C$?O('H-CHJJH
iiiadvortciitly obtaiiicd cJarlic>rill an attempt to prcpilrcl 111 by a iiiodified procedurc. This procedure iiivolvcd the reactioii, in liquid aiiuiionia. between sulfanilaiiude arid 2,-l-dicliloroquiiiazoliiic iii the presericc of 2 q u i \ - . of lithiiiiii aillid(>.follon-cd by treatiiient of the t~csiiltiiig '1-chlor o de1 ivativc \\ itli sodiiiin niethouide also ohtaiiied hy the I cwtioti of C'oiiipoiiiid I~ulfaiiilaiidrwith 2,f-dirhloi oquiiiazoliti(~iii acetone, follon-cd by the rcplacc~iiiciit of the 2-chloro group by iiietho\j 1 Sonic irirtlirr \I oil\ o i l the iiucleopliilic*displaceiiieiit of the 4-iiiethoxy group of I bv sulfonaiiiide aiiioiis has s h o n i i t liat thc t,eiizciiesulforiaiiiide aiiiori reacts with I to give the c.upected yield of thc -I--hciizeiiesulfoiiaii~ido clci ivatir T\ hilc tlic S-iiictlipli~erizenesulfoiiaiiiide itii1011 piodiic~zlittlc, if any, product The priiiiary ~ ( ~ I I /(.iiesiilfotiaiiiid(, aiiioii pcwiiits tlic' splittiiig out 01 iiiethat iol. a. 13i*etschiieidei atid Idotzer" point out for au aiialogoas i eart ioii of sulfanilainide iiriioii with triiiictlioxy-,.-triaziiic~, while tlic S-iiiethylbeiizeiieiulfoiia~iiidcaiiiou docs iiot. Antibacterial Results.-Thc ailtibacterial activitics ot 111. its S4-ncctyl tlcii\ % t i \v q arid several related Coiiipoiiii(1a. 1ia1-c~beeii rcpoited.7 liccriitly tlie aiitibacterial activity of I \ 7 \\-as determnied and found t o 1)ciiifciioi, to 111. Acute Toxicities.--'l'lic~acute toiicitics for 2-iiict ti.-3-sulfaiiilamidocjiiiiiazoliii(~ (I1I) aiid its isoi , 'it - (2-1iict h(1xv-4-(1uii iamlyl)~ulfaiiilaiiiidc (Y) dc3tci.iiiiiic.d i i i g o u p of 10 iiialc albitic) iiiire8 g wig hi I T to 30 g .I sodiuiii halt solution of ear11 coiiipold 111 S - d i t i c l nab ucliiiiiiistcied iiitravenously at a ratr of 0.3 1111. i i i i i i T l i c ~pH of tlie I11 solution was 8.**)9.0 a i d of t h ( JI' solutioii \\as 12-12 5 . (L
111
+
I1
H2
L
~
'
& - O C H ~ C H , O C H~
IV
The latter coiiipourid was prepared by alcoholysis of I with 2-iiiethoxyethanol. Here again the 2-riiethoxy group was replaced by tlic 2-met hoxyethoxg ginup, contrary to 1itei.atut.e indications. It has berri wported2 that replaceiiieiit of ai1 alkoxy group (OR) by a different alkoxy group (OR') takes place only at position 4 of quinazoliiie with position 2 being unaffected. A literature search likewise failed to reveal aiiy previous cxainples of alcoholysis of a %alkoxyquinazoliiie. (hi the other haiid thr ester-like character of 4-alkoxyquinazolines has beeii clearly demonstrated hy hydrolysis. alcoholysis, and ainnionolysis. Arma-
.
( 5 ) \\. I I i r i i i d i e j u i n \d\dnces In Heterocbciic C tienilstr> \ (11 1 1. 11 I\atnt/L, 1 d \radernic Press Ye!$ I o r k V. \ . 106J I, 2~54. ( 6 ) TI Hretsclinr!iter i n i l I\ K l o t i e r IT. G. Patent 2 7 T i 738 I D < ( 18 I(45hl. ( 7 i I 11,ir I I Ii \ \ p i h t . l I/ 4 i i l z m r , r o ? ~ ~ldy p n f s ( h ( w o f i r ,l,Iil ilti 119 (8) \\eIlbf~~ itr.1 11 < t r i l i ( t obtained floln 1 aburdior) $urwi! t> Iiididnapiilie I n d
.
NOTES
November, 1964 A median lethal dose (LD50)for I11 was 460 mg./kg. (432490) with a median toxic dose (TD50) of 24 mg./ kg. (20.0-28.8).9 The LD50 for V mas 320 mg./kg. (264.4-387.2) and the TD,, was 12 mg./kg. (9.2-15.7). Ataxia (2/10) at 18 mg./kg. was the minimal toxic effect observed with I11 and occurred about 23 min. after treatment. Additional effects a t the highest dose level that was not lethal to 20 mice (400 mg./kg.) consisted of depression and an increase in respiratory depth within 2 min. after treatment. These effects were followed by Straub's tail reaction, opisthotonos, and clonic convulsions accompanied by a rolling movement. Deaths at 440- and 500-mg./kg. dose levels were apparently the result of respiratory failure and started to occur 14 min. after drug administration. The minimal toxic response to V was also ataxia which occurred at 7 mg./kg. (2/10) within 2 min. after treatment. Responses t o V at the highest dose level that was not lethal to 10 mice (150 nig./kg.) and a t lethal dose levels (300 and 400 nig./kg.) were similar to those observed with I11 at corresponding levels of toxicity. The onset of clonic convulsions was slightly faster with V. Recovery from side effects was evident within 15-20 hr. after treatment with either I11 or V. Experimental 10
2-Methoxy-4-sulfanilamidoquinazoline (III).'-Metallic
sodium (121 g., 5.26 g.-atoms) was carefully dissolved in 2 l. of methanol in a 12-1. flask. The reaction system was purged with nitrogen and 4.7 1. of 2-methoxyethanol (Fisher, purified), 903 g. (5.26 moles) of sulfanilamide, and 1 kg. (5.26 moles) of 2,4dimethoxyq~inazoline~ were added with stirring to the solution. The mixture was heated to reflux (84') and maintained a t this temperature for 72 hr." After cooling to 10-20°, 850 ml. of 6 N HCl was added over 1.5 hr. The crude product was collected, washed with 1 1. of methanol, and dried; yield, 721 g. (41.5%). Efficient slurrying of the crude product with warm methanol gave 706 g. (40.67,) of off-white product, m.p. 227228'. nnal. Calcd. for C1~Hl4X403S: K, 16.96; S, 9.71. Found: K, 16.93; S, 9.58.
2 4 2-Methoxyethoxy)-4-sulfanilamidoquinazoline (IV) Monohydrate.'-This compound was first isolated, with difficulty, in 10%; crude yield from t'he mother liquors of 111. I t was identical with material synthesized as follows for confirniation of structure. 2,4-Di(2-methoxyethoxy)quinazoline (10.8 g., 0.0388 mole), 8.22 g. (0.042 mole) of sodium sulfanilamide, and 80 ml. of 2methoxyethanol were heated a t 85-90' for 1 week. The reaction mixture was concentrated, the residue was dissolved in water, and the aqueous solution was washed with ether and acidified to produce 9 g. (59%)12 of tan solid. Four recrystallizations from 50y0aqueous 2-methoxyethanol gave a cream solid of m.p. 129.5-138' ( a sample dried a t 85-90' in vacuo presumably lost water of crystallization because the melting point rose to ca. 1820). (9) Median lethal and toxic doses were calculated according t o the method of J. T. Litchfield and F. Wilcoxon, J . Pha~macol.Ezptl. Thrrap., 96, 99 (1949). (10) T h e melting points are corrected (Thomas-Hoover capillary apparatus). We gratefully acknowledge the cooperation of Dr. Lewis J. Throop. 3Iessrs. John G . Schmidt, Clarence Kennedy, and Charles 32. Combs of O U T Control Laboratories for the analytical, chromatographic, and instrumental data. T h e infrared spectra of all the described compounds were consistent a i t h the assigned structures. (11) I n another run using only 2-methoxyethanol a s the solvent the ternperature was raised t o l l O o , following the reaction period. and t h e distillate was collected. Approximately 10% of the solvent volume %-as distilled. Gas chromatographic analysis of the distillate showed 1.4 equiv. of methanol indicating partial displacement of the 2-methoxy group. (12) Alcoholysis of t h e %alkoxy group could not lead t o by-products; therefore, a relatively higher yield than in the case of I11 was obtained.
813
Anal. Calcd. for C17HlsNIOdl.H20: C, 52.03; H, 5.14; N, 14.28; S, 8.17; HzO, 4.58. Found: C, 52.42; H , 5.33; N, 14.38: S, 8.30; H20,4.22. N*-Acetyl-"- [2-(2-methoxyethoxy)-4-quinazolyl]sulfanilamide.-The two samples of IV with acetic anhydride gave the same N4-acetyl derivative, m.p. 210.5-212' after sintering at 190'. Anal. Calcd. for C19H2~N4OSS: C, 54.80; H , 4.84; N, 13.45; S, 7.70. Found: C, 54.54; H, 5.08; X, 13.12; S, 7.86. The n.m.r. spectra of this compound and I V were consistent with the structures. 2-Methoxyquinazolin-4(3H)-one was obtained in approximately 12y0 yield from I11 reaction mother liquors. It gave no melting point depression when mixed with an authentic sample prepared according to the literature, l 3 m.p. 229-230". Anal. Calcd. for CsHsNzOZ: C, 61.36; H, 4.58; N, 15.90; OCH3, 17.60. Found: C, 61.54: H, 4.66; S, 16.07; OC&, 17.73. 2,4-Di(2-methoxyethoxy)quinazoline. A.-A mixture of 19 g. (0.1 mole) of 2,4-dimethoxyquinazoline and 190 ml. of 2methoxyet,hanol containing 2.7 g. (0.117 g.-atom) of dissolved sodium was stirred and heated a t 85" for 3 hr. The solution was concentrated under reduced pressure, diluted with 100 ml. of water to separate a red oil, and ext.racted lvith ether (three 100ml. portions). The ether extract' was dried and concentrated to yield 3.7 g. (13%) of solid. Recrystallization from ethyl acetat,e-Skellysolve B (1:8) gave a white product, m.p. 45-46'. Anal. Calcd. for C14Hl&n04: C, 60.42; H, 6.52; S , 10.06. Found: C, 60.72; H, 6.59; S, 9.98. The product was identical with that prepared in 437, yield from 2,4-dichloroquinazo!ine and sodium 2-methosyethylate (method B). 2-(2-!Methoxyethoxy)quinazolin-4(3H)-one was precipitated from t,he aqueous mother liquor of the above preparation (method B) by neutralization with acetic acid. A tan solid, weighing 4.6 g. (217c), ?vas obtained. Three recrystallizations from ethyl acetate gave a white product, m.p. 117.5-118.5D. Anat. Calcd. for CllHll?;ZO,: C? 59.99; H, 5.49; N, 12.72. Found: C,60.20; H, 5.54; 9,12.73. N4.(2-Chloro-4-quinazolyl)sulfanilamide.-Lithium amide was prepared by slowly adding 1.6 g. (0.23 g.-atom) of lithium wire to 200 ml. of liquid ammonia containing 0.2 g. of ferric nitrate. Sulfanilamide, 17.2 g. (0.1 mole), was then added portionwise to the lit,hium amide suspension, followed by 19.9 g. (0.1 mole) of 2,4-dichloroquinazoline. The resulting mixt,ure was allowed to stir for 2.25 hr. and the liquid ammonia was then evaporated with the aid of a steam bath. The solid residue was mixed with 200 ml. of water and a small amount of undissolved solid was filtered off. Acidification of the filtrate with acetic acid precipit,at,eda solid which was collected and dried a t room temperature. The solid was then triturated with methanol and dried at 55'; rrude yield, 20.8 g. (62%). A sample recrys1,allizedtwice from io%, aqueous dimethylformaniide gave the purified compound. Attempts to melt the compound resulted in evolut,ion of HCl with no melting up to 360". However, when a sample was introduced in a bath a t about 260", melting occurred immediately with deconiposition. Ana?. Calcd. for C14HllC1N402S:C, 50.22; H, 3.31; C1, 10.59. Found: C, 50.11; H,3.49; C1, 10.40. N4-(2-Methoxy-4-quinazolyl)sulfanilamide(V) was originally prepared by heating under reflux for 26 hr. a mixture of 6.8 g. (0.02 mole) of the above crude chloro intermediate and 125 ml. of methanol containing 2 g. (0.087 g.-atom) of dissolved sodium. The solution was cooled and acidified wit,h 17 ml. of acetic acid to give a whit,e precipitat,e which was collected, washed with methanol, and dried overnight at 50-55'; yield, 4.8 g. (72%). Anal. Calcd. for C1&4N40$S: C, 54.53; H, 4.27; N, 16.96; S,9.71. Found: C, 54.50; H, 4.51; N, 16.97; S, 9.76. V was also obt,ained as follows. A mixture of 19.9 g. (0.1 mole) of 2,4-dichloroquinazoline,34.4 g. (0.2 mole) of sulfanilamide, and 250 ml. of acetone wa,s stirred t o give a pale yellow solution as the temperature rose to 35". After 5 hr. a solid had formed. The solvent was removed in V ~ C Z L O . A stirred mixture of the residual solid and 450 ml. of methanol containing 23 g. (1.0 g.-atom) of dissolved sodium was heated underreflux for20 hr., filtered t o remove insoluble material, and the filtrate was acidified t o precipitate 6.5 g. (20%) of V. Recrystallization from di(13) R. H. hIcKee, J . prakt. Chem.. [21 84, 821 (1912); Chem. Abstr., 6, 991 (1012).
metlig-lformamid~~-ater gave an off-white solid, ii1.p. 225.5230.5" dec. (resolidifies at ca. 232' itlid remelts at cn. 286.52890). Anal. Found: C, 54.62; H, 4.20; 3, 16.89. This product WBP stion-ii to be identical with the origiiial ample by mixture melting point and iiifrared spectrum, aiid by spectrophotometric and p a p ~ r c~1irr~m:~tograpliic coirip:Lrisons. Compound V gave a negative l~r~tt,toii~-SIltrsliall test. N-( 2-Methoxy-4-quinazo1yl)benzenesulfonamidewas prepired from I and sodium berizeiiesulfonniiiide i r i Zi:70 yield by the procedure give11for 111; n1.p. 2 3 0 L Anal. Calcd. for C l a H 1 3 S 3 ') ~ { S :S ,1:l.X); 5: 10.17. Fomid: s,13.11; 8, 10.25. When it similar reaction was n i i i witli sodiuiri S-iueLli\ll)eiizenesulfoiiainitle and I, no product \v:ts isolated. 'Thr uuly c.rysta1line solid isolated was 2 - ~ ~ e ~ l 1 c . 1 ~ ~ ~ ~ i 1 i 1 1 ~ i ~ ~ 1 l i i i - ~ ~ ~ ~ l i ~ - ~ 1 1 1 ~ ~ .
Acknowledgment.-\\'e
\visli to tliaiik tlic followiiig
who ga\c their assistancct: A\Iessrs. I). 11. Causey,
W. AI. Coatcs, ,J. 1'. Elkiiis, \V. 13. Laccficld, 1). I(Table I). In some cases, with EOF, the correspondiiig hydrazidines, i.e., the S,S'-his(arylaiiii~io)fol.mamidiiie~ (11),inay also be formed a5 by-products. The presence of the ethoxy group in I is proved by their reactivity with aniline and with arylhydrazinea. In this case conipounds I1 are produced again.
I'
It AIPL"N=COC.H, I
.li S H Y - C I I S H S H . 1 1 I1
1'henylhydra~ine a i d tlic tolylhydrazine hydrochlorides premit, hon.eve18, a completely diff erelit (1) l'aper V of tliis series: ( ' . R u n t i , t;. Nisi, and I,. Sindell C'him., 5 1 , 71g (1961). ( 2 ) R . Stcd14, . I . p r n b f . Cheni.,[ 2 ] 68, i i i i (l$lO.31: see also C'. I'. .Illen and -1.Rell, "(Jrjanir Rgntlirses." C h ~ l l .Y t J . 111, .JoIiri n'iley m r l Sons, Inr.. N e w T l j r k , N. P..IUS%, 1). 9Li. (:4) 1.. ('l:iisen, d l l n . , 287, 300 f1695:. (4) I:. v . J\'xItlier, .J. p m k t . Chem., 121 53, 475 (ISCJG;. ( 5 ) Only t n o r:xanipies uf conipoiinds of tliis type. cbtaineil by [Ret-., 47, 2345 (1814) 1 by reaction between plienylliydrazine liydruchloride :ind an i i i i i i i o i.tlier, arc: nientioned in l i t e r a t u r e . t o our knoaledne. ( ~ e i i c r ally itiiinc others and arylhydrazines rea1.t to give icmmzans anil/ur xiiiidrxzunes [ w e .L \V Nioeltuiii, Chem. A'ei'., 6 6 , 33.5 ( I V O S ) ] .
1
_ ,
I:+:,i - - R v; i
listctl in 'l'ablc 11. 'l'he structurc of conipouiids I\- is rat,lier uncspectcd, since they are t,riazoliuiii derivatives in which ;I ciuaternary nitrogcii is h u i i d t,o ail arylaiiiino group. Thcy present in the infrared spect~ruiiia rather broad absorption band at 1810 ( > i i i . - - I , attributable t o the structural cleiiieiit 3 S + - I I jiiiiiiioiiitliii band).6 The coiiipounds possess surfac*c-act8ivch properties (conceiitratioii .1 iiig. ' 100 1111. a t 2 . j o ) , e v ~ i tliougli i iiiuch l o \ ~ e rt'liaii mi equicoilcentrated solutioii of dodecyl-p-t'olyltriii~ethylaiiiiiiouiu i n n icthylsu 1fat P. 13. I\.itkoK, .J. i3. I' ~ C B .J. I'.I ' u t t r . ( 7 ) I)esogen$, (til
(1!152):
