RESEARCHES ON QUINAZOLINES.
1071
acetate, aniline and nitrobenzene. Saponification yielded 23. I per cent. formic acid. A pure monoformate should yield 2 4 . 2 per cent. i\ttempts made to introduce more formic acid radicles into the cellulose molecule by raising the temperature a t which acylation was carried on gave only negative results. These experiments essentially go to confirm the results of Berl and Smith. Less agreement c::n be noted with the product described by Bemberg.' According to this patent i t should be possible by essentially the same procedure as t h a t outlined above to prepare a formate soluble in moderately concentrated aqueous acids. I t is further stated that if cellulose he first soaked in formic acid and then pressed to a 100per cent. gain in u7eight and placed in benzene containing from 3 per cent. to I O per cent. of sulphuric acid a fihrous formate of cellulose may be obtained. It was not found possible to duplicate these results, but as the formation of a fibrous formate would have possessed considerable interest, experiments were made in which several other diluents were used instead of benzene. The latter seems particularly unsuitable for the purpose because it is not practicable to prepare a homogeneous mixture of the three liquids in the proportions suggested. Instead of benzene, experiments were made with ether, ethyl acetate, glacial acetic acid, acetone and a mixture of benzene and ether. All results The were negative as far as the production of a fibrous formate was concerned. following experiment was typical. Two grams of hydrated cellulose dried a t 1000 were treated with 20 grams formic acid (sp. g. I . Z Z ) , z grams sulphuric acid (sp. g. 1.836) and 5 grams ethyl acetate. The cellulose was unattacked and insoluble in formic acid after standing for three days. I n a similar mixture which contained only z grams of ethyl acetate the cellulose partly dissolved but the fibrous portion was not soluble in formic acid. These experiments seem to show that the addition of even a small amount of a neutral solvent practically puts a stop to acylation, while, when the quantity of diluent is still further reduced, some acylation takes place but the product dissolves in the reacting mixture. MASSACHUSETTS INSTITUTE O F TECHNOLOGY, BOSTON,M A S S .
[CONTRIBUTIONS FROM THE
HAVEMEYER LABORATORIES No. 169.1
OF COLUMBIA UNIVERSITY,
RESEARCHES ON QUINAZOLINES (TWENTY-THIRD PAPER). ON 6-METHYL-7-AMINOQUINAZOLONES, 7-NITROQUINAZOLONE-6-CARBOXYLIC ACIDS, AND I ,3,7,9NAPHTHOTETRAZINES.2 B Y MARSTON
TAYLOR BOGERT AND ALFRED H. KROPFF. Received
--, 1909.
I n a recent conim~nication~ the authors described the preparation and properties of certain amino and nitramino derivatives or' benzoic, nz-toluic and m-phthalic acids of anthranilic structure, i. e . , with an amino group adjacent to a carboxyl, and the present paper deals with some of the quinazoline condensations obtained from these anthranilic acids. I n general, these condensations depend upon the intermediate formation 1
LOC.
Cit.
* Read a t the meeting of
the New York Section, May 14,1909.
*THISJOURNAL, 31, 841 (1909).
ORGANIC A N D BIOLOGICAL.
1072
of an acylanthranilamide, which then forms the miazine cycle by loss of water, /".COR C6H + C6H4/" : CR -t H,O, \CO.NR~ "\CO.SHR~ the acylanthranilamide being conveniently formed by the action of primary amines upon acylanthranils or acylanthranilic esters :
/ N--CO R C,H4\ i
;L".COR R ' S H , == C,H,/
co
C$,/
H. co \COOR
\CO .XH R'
-+ R'NH,
+
C6H, ROH \CO. N H R ~
--
The intermediate amides were iiot separated, the reaction being carried through to the quinazoline. For the formyl condensation products, the reaction of Niementowski' is the most con\-enient :
d- H,N.COH --+C,H[
C b K /xF12
\COOH
,NH.COH
+
\COONH, ,NH.COH C,H,'
\CO.NH,
-
/N : C H CF,(
I
CO. N H
For diketotetrahydro compounds, the uraniino acids or their esters were used : / N H . CO I C,H, C6H4 /".Co"z \CO.NH \COOH
-
LVhen the acylanthranils were condensed with hydrazine, N-aminoyuinazolones resulted which, like other unsymmetrical secondary hydrazines, undergo the Bdlow condensation? with diacetosuccinic ester, giving pyrrole derivatives : C,H,/N
:
yR
\CO. N/-
.
ianiinoterephtlialic acid. j
H,N
‘\/\/’
( I , 3,6,S-Sdp ht 110te t razi n e 11ucleus )
XH2
N
N
/\ /\A\
I I
~
HOOC/\/\COOH (4,6-Dianiino-m-pht~ialic acid )
I
\A/‘\/
IN
(1,3,i.g-Naphthotetrazinenucleus. )
Experimental.
-
z,6-Dzmethyl- 7 ncetamzno-4-quinazolone (z,6-I~inzetlryl-7-aretamzno-~-ii) tlto t) q i u q i azo 1in e) ,
I1
O
I OH
-I-Methyl-2-acetamino-4, j-acetanthranil wis added to dilute ammonium hydroxide and the solution heated to boiling. The anthranil gradually dissolved and soon thercafter the quinazolone separated from the boiling solution. On boiling out the excess of ammonia and cooling, the quinazolone was obtained in colorless needles, m, 1). ahout 3 3 0 ~ . Found: PI’, 18.4. Calculated for C,,H,,O,N,: N , 18.18. I t is easily soluble in dilute caustic alkalies, and is reprecipitated from such soluticins by acidification with acetic acid. 2,6-Dimetlzyl-7-amino-~-quilzaz010~ze (~,6-Uiinethyl-7-anzino-~-hydroryquinazoliize) .The above acetyl derivative was boiled for a few minutes with IO per cent. potassium hydroxide solution, the solution filtered, and the filtrate saturated with carbon dioxide. The aminoquinazolone thus precipitated was purified by re-solution in potassium hydroxide solution and re-precipitation with carbon dioxide. Found: N, 2 2 . 4 . Calculated for C,,H,,OI,: N , 2 2 . 2 2 . Colorless solid, melting above 3 0 0 ~ ;soluble in alcohol or in dilute hydrochloric acid. a,6-Dimetlzyl-~-phei~yl-~-acetam~no-#-qu~~ia~olo1ie, CH,CONH N : C.CH, ‘COH’, I , CH,/ \CO.N.C,H,
‘THISJOURNAL, 27, 1 1 2 j and 1302 (19oj). Ibid., 29, 729 (1907).
I075
RESEARCHES ON QUINAZOLINFS.
was prepared by heating the acetanthranil with excess of aniline. On cooling, the quinazolone separated. It was freed from aniline by washing with dilute acetic acid, and was then crystallized from dilute alcohol. Found: N, 13.75. Calculated for C,,H,,O,N,: N, 13.68. Beautiful, glistening, diamond-shaped plates, m. p. 271 O (uncorr.). r-Methyl-~-nitro-q-quinazolone-6-carboxylic Acid (a-~~ethyE-~-nitro-4-hydroxyquinazoline-6-carboxylicaczd), 0,N / N : C.CH, O,N\ /N : C.CH, C,H, I ‘CP, -HOOC \c(oH):N HOOC’ \CO.NH
-
,
-4-Xitroacetanthranil- j-carboxylic acid was added to a n excess of dilute ammonium hydroxide solution, the solution boiled for a few minutes, evaporated to dryness, the residue dissolved in dilute potassium hydroxide solution, filtered from impurities, and the quinazolone precipitated by careful neutralization with hydrochloric acid. Recrystallized from water, colorless needles were obtained, melting above 3 0 0 ~ . Found: N, 16.93. Calculated for C,,H,O,N,: E,16.8. a-Methyl-~-phenyl-~-nztro-~-quinazolone-6-carboxylzc Acid.-4-Nitroacetanthranil-5carboxylic acid was boiled with a slight excess of aniline, the solution allowed to cool, dilute acetic acid added, and the precipitated quinazolone filtered out. Crystallized from alcohol, i t forms beautiful, yellow prisms, m. p. 315O (uncorr.). Found: N, 13.41. Calculated for C,,H,,O,N,: N, 13.4. 4,6-Diketotetrahydro-1,3,7,9 - naphthotetrazine (4~5-Dihydroxy- 1,3,7,9 - naphthotetra-
zine),
I1
0
/I
0
I
OH
I
OH
-Diethyl 4,6-diamino-m-phthalate was heated with excess of formamide for seven hours at zo0-10~in a sealed tube. The crude crystalline product from the tube was dissolved in dilute potassium hydroxide solution, the solution boiled to expel all ammonia, filtered, the filtrate precipitated by carbon dioxide, the precipitate washed, redissolved in potassium hydroxide solution, and reprecipitated by carbon dioxide. Yield nearly theoretical. Found: N, 26.11. Calculated for C,,H,O,N,: N , 26.17. Reddish yellow powder, melting above 310°, insoluble in water or the usual neutral organic solvents. I n solutions of the caustic alkalies, i t dissolves readily, and is reprecipitated by acetic acid or carbon dioxide. ~,8-DimethyZ-4,6-diketotetrahydro-1,3,7,9 - naphthotetrazine (2,8-Dimethyl-4,6 - dihydroxy-1,3,7,9-naphthotetrazine),
-Ethyl 4,6-diacetamino-m-phthalatewas heated with excess of alcoholic ammonia for five hours at zooo in a sealed tube. The solid material which separated in the tube was purified by solution in dilute potassium hydroxide solution, filtering, and reprecipitating with acetic acid. The precipitate was washed with hot water, redissolved in potassium hydroxide solution and precipitated with carbon dioxide. Dried to constant weight a t I I O O and analyzed, the result was as follows: Found: N, 23.3. Calculated for C,,H,,O,N,: N, 23.1.
1076
ORGANIC AND BIOLOGICAL.
Pale yellow, amorphous powder, melting above 3 1 0 ~ ;insoluble in water, alcohol, ether, benzene or chloroform. The yield by the above method was poor. The same substance TKLS obtained, in acetanthranil (of the diaminophthalic nearly theoretical yield, by boiling the acid) with dilute ammonium hydroxide wiution. The antliranil dissolved a t first, and the naphthotetrazine snon separated from the boiling solution. I t was purified a $ above. Found: c', ;~L(JS: I f , 1 . 2 4 ; \ , 2 2 . 0 . C'dculatetl for C;!HloO:,X,: C', 5(1 5 ; t-1. ~ C I ( ] ;
s, 2 3 . 1 . 2,,;,7,3 7 ' i ~ t , ~ ~ ~ ~ ~ c f ~ ~ / - . ~ , 6 - r l iI k, ,~i ,t;~' ,/yi-~' ltu~pihlt/i 1~ ~o t, ~d~r ),i,~i ~ ; ~ ~ ,
-The bis-ncetanthranil was heated with excess of 33 per cent. aqueous niethylaniine solution, The anthranil gradually dissolved and after a few minutes' boiling the naphthotetrazine separated from the boiling solution in colorless crystals, which were washed with hot water and recrystallized froin alcohol. Found: N, 20.9. Calculated for C,4Hl,02K4:N,no.;4. Long, colorless needles (from alcohol), melting above 3;o0 ; insoluble in water, benzene, ether or chloroform, moderately soluble in alcohol. 2,6-uimcthyl-3,7-tli-,I-pi'op41 - 4,6 - dikctot y d I u - 1,3,7,9- riaphthotctraziuLe. --The bis-acetanthranil was added to a cold dilute aqueous solution of propylamine and the temperature gradually raised to boiling. l'he anthranil dissolved and the naphthotetrazine soon separated froin the boiling solution ns a flocculent precipitate. l t was purified by crystallization from dilute alcohol. Found: N , I 7 . O j . Calculated for C,,H,,O,N,: K, I 7 . 1 . Small, glistening needles, softening somewhat a t about I S O O , and melting a t 2 o 0 (uncorr.) ; insoluble in ulster, benzene, ether or chloroforni, but quite readily solulde in alcohol. z,B-Dirnethyl-3,7-diphen).l-4,6 - diRetotctralzydro - 1,3,7,9 - naphthotctraziiie. -- Aniline was without apparent action upon ethyl 4,6-diacetamino-m-phthalate when the two were heated together for two hours a t zooo in a sealed tube. B u t when the bis-acetanthranil was boiled for I j minutes with excess of aniline, mlorless needles separated from the solution on cooling. They were xashed ivith acetic acid, then with water, recrystallized from alcohol, and analyzed. Found: S , 14.0. Calculated for C,,H,,O,N,: 5 , 14.21. The compound crystallizes from alcohol in minute, colorless needles, ni. p. 3 1 5 ~in; soluble in water, acetic acid, ether, ligroin or benzene. ~,8-Uimethyl-3,~-di-~-napilthyl-4,6-d~ketot~tra~iydro-1,.~,7,y-naphtitotetruziiie. --IVhen the bis-acetanthrznil and ,3-naphtliylamine were heated together, the mixture liquefied and considerable frothing occurred [presumably from the water separated in the reaction), After the cessation of the frothing, the mass solidified. IVhen cold i t was pulverized, extracted repeatedly with hot, dilute hydrochloric acid (to remove unchanged naphthylamine), washed with water, and the grayish amorphous residue crystallized from alcohol. Grayish, fluorescent needles resulted, which xere washed with alcohol, dried a t I I O O , and analyzed. Found: N , 11.3. Calculated for C,,H,,O,S,: S , 1 1 . 2 4 . I t melts a t 3 0 4 ~(uncorr.), and is apparently insoluble in water, benzene, ether ur chloroform. I n alcohol, i t dissolves sparingly, the solution being distinctly fluorescent. ~,8-Dintethyl-g,7-iLiclrni,io.4,6-dikcto!etral~ydl.o- 1,3,7,9 - mphthotetrazine. - 'She his~
RESEARCHES ON OUINAZOLINES.
I077
acetanthranil was added to a n aqueous solution of slightly more than two molecules of hydrazine hydrate and the mixture heated to boiling. The anthranil gradually dissolved, and the naphthotetrazine soon separated from the boiling solution in beautiful, yellow, nacreous scales, yhich were washed with water, dried a t I I O O and analyzed. Found: N, 31.15. Calculated for C,,H,,O,N,: N, 30.9. The substance appears to be insoluble in water or benzene, but dissolves sparingly in alcohol. I t is soluble in hot concentrated hydrochloric acid and separates as the hydrochloride on cooling. With acetic anhydride, two acetyl groups are introduced. I t undergoes the Biilow condensation' with diacetosuccinic ester. II'hen its solution in dilute hydrochloric acid is treated with sodium nitrite, the amino groups are genersly replaced by hydrogens; but if, after the addition of the nitrite, the solution be pourled immediately into an alkaline solution of a- or /3-naphthol, a deep red dye is formed. If the hydrochloric acid solution of the diaminonaphthotetrazine is allowed to stand for many seconds after the addition of the nitrite, no dye is formed on adding i t to the alkaline naphthol solution. Hydrochloride.-Colorless prisms, melting with decomposition a b w e 360° ; readily soluble in cold water. Addition of sodium carbonate to the aqueous solution precipitates the free diaminonaphthotetrazine. ~,8-Dimetlzyl-~,~-diacetamino-~,6-diketotetrahydro-1,~,~,~-naphthotetrazine was prepared from the above diamine and excess of acetic anhydride. The crystals which separated on concentrating the acetic anhydride solution were washed free from anhydride by carbon tetrachloride and recrystallized from alcohol. Found: N, 23.9. Calculated for C,,H,,O,N,: N, 23.6. Small, colorless needles (from alcohol), melting above 3 6 0 ~ ;practically insolub!e in water, benzene, ether or chloroform, moderately soluble in alcohol. Boiling with acetic anhydride does not further acetylate the compound. ~,8-Dimethy~-~,~-dianilino-~,6-diketotetrahydro-r,~,~,~-na~hthotetrazi~,
-Phenylhydrazine reacted readily with the bis-acetanthranil even in the cold, a The reaction was completed by warming the mixture for a short time. On cooling, a granular solid separated. Alcohol was added, the temperature raised to boiling, and the hot mixture filtered. The insoluble material was thoroughly washed with boiling alcohol, leaving a colorless, granular solid, which gave the following figure on analysis: Found: N, 20.05. Calculated for C,,H,,O,N,: N, 19.81. The pure substance melts above 320° and is essentially insoluble in alcohol. a,8-Dim~tltyl-~,~-dibenzalamino-~,6-diketotetrahydro-1,~,~,~-na~hthotetrazine, CH3.F : S.CH, C,H,CH: N.N.CO
C0.N.N: CH.C,H,
-The diaminonaphthotetrazine was boiled for a few minutes with excess of benzaldehyde. Solution occurred, with evolution of steam, and on cooling a granular, yellow solid was obtained. This was washed repeatedly with boiling alcohol, to remove all benzaldehyde and benzoic acid, and then dried and analyzed. Found: S , 18.9. Calculated for C,,H,,O,N,: N, 18.7. I t melts above 350°, and is practically insoluble in the ordinary neutral organic solvents. It can be dissolved, however, in hot benzaldehyde, and crystallizes from this solution in granular form. Cit. Compare Rogert and Gortner,
LOC.
THISJOURNAL,
31, 943 (1909).
I078
ORGANIC AqXD BIOLOGICAL.
a,8-Dimethyl-3,7-di(a,g-dimeth~l-g,~-ificcirheti2o~~~Pyrrole) -1,6-diketotetraiiydro-r ,3,7,o-itabhthotetuazinc. CH,C : S ? . Ci CH, H,C,OCO.C: Cf CH,) C ( C H , ) : C.COOC,H, I
'
i
H5C,0C0.C: C ( C H , )
C ( C H I ) . C COOC,H;
--The diarninonaphthotetrazine was boiled for an hour with a glacial acetic acid solution of the calculated amount of ethyl diacetosuccinare. On concentrating. sorue unchanged nap1itl.iotetrazine separated. 'I'his was renir>ved and the mother liquor diluicd with watcr, X white, aniurlilious precipitate :~ppearwl, On boiling the solution, tl;c ])recipitate dissolved and, on cooling, minute, colorless prisms or needles crystallized out. 1-\ second crop of crystals was obtained by further dilution of the mother liquor. 'I'lie crude product \vas recrystallized from alcohol, dried and analyzed. Found: 8 ,12.1. Calculated for C,,H,,O,, 1 he piire compound melts a t 2 6 8 . 2 O (corr,). ~ , ~ - U i p l z e t ~ y l - ~ , ~ , 6 , S - f e t ~ a k e t o - o c t ~ ~ i ~ ~ d r o - ~ , ~ , ~(3,7 , ~ - n- ~Ilipheiiyl ~ ~ h t l i o- t2,s' eiua~zti~ d z l i y d v o x y - ~ , 6 - d ~ k e t o t e t r a l i ~ ~ d ~ o - r , ~ , ~ , ~ - n a p l ~ t,i i o t e t r a z ~ ~ z c ) ,%
-1Vhen diethyl ~,6-dipheny1uramino-r,t-phthnialatewas boiled with aniline, no cliange was evident. Rut wlien the two a e r e heated together in a sealed tube for six hours a t 21,jO, a reaction occurred accompanied by considerable deconiposition. The crude product was boiled with glacial acetic acid, the solution filtered, and on cooling large, brownish-green crystals were obtained. These were washed with glacial acetic acid, then with water, dissolved in dilute potassium hydroxide solution and reprecipitated by carbon dioxide. Found: X, 14.0;. Calculated for C,,H,,O,?;,: ? 14.0;. i, The pure compound is colorless and amorphous, melts above 3ooo, is apparently insoluble in xater, alcohol or benzene, but. dissolves in glacial acetic :Lcid. O R G A A I CL A I ~ O R A T OJuiir, R Y , 190y.
[FROM THF,
L.IBORATORY
O F PHYS1OLOGIC.U.
CHEMISTRY, DEPAXThIENT OF !,NI>IAL
HCSB.~NDRP, ~ N I V E R S I T YOG
ILLINOIS.]
THE DETERMINATION O F UREA IN URINE. NUTRITION INVESTIGATIONS, PUBLICATION NO. 26. B Y F. U'. GILL, F. G. ALLISOX, A N D €1. S . GRINDLEY. R e c e i v e d J n l y 6, 1909.
The method of Folin' for the determination of urea in urine has been very generally used since it was first described. I t has been conclusively proven repeatedly that Folin's method gives quite uniforni resiilts when properly carried out with due regard to all details. On the other liand, the method requires very careful work, and it is long and tedious, requiring close attention continuously. The difficulties attending the accurate determination of urea in tirines by the 1;olin method have been espe2 . physiol. Chem., 32, 504 ( I q " j ; Physiol., 13, 45 (1905).
36, 333 ( 1 9 0 2 ) ; 37, 548 (1903);Amer. J u w .
