NOTES
Sept., 1949 and corresponded to one mole of hydrogen. The alkaline solution was filtered to remove the nickel catalyst, diluted to 500 cc. with 25% sodium hydroxide solution. TOthis solution there was added 50 cc. of dimethyl sulfate and the methylation was carried out as usual. The alkaline solution was then extracted with two 100-cc. portions of ether and the combined ether extracts washed and dried. After removing the ether, the residue was distilled; yiel: 12.7 g. (72y0),b. p. 135-139' (1 mm.), m. p. 75-77 The semicarbazone, prepared in the usual manner, melted at 235.5-236.5 O after recrystallization from aqueous alcohol. Anal. Calcd. for CI2Hl5O2N3: N, 18.01. Found:
.
N, 18.06.
3247
2-amino-6-methylquinoxaline, prepared by a method which could yield only one isomer, to have m. p. 181-182', and 2-amino-7-methylquinoxaline, prepared in a similar manner to have m. p. 178180'. A mixture of the two in approximately equal proportions had m. p. 172-174'. It is well known that mixtures of isomers in the quinoxaline series are very difficult to separate. 2-Chloro-5(or 8)-methylquinoxaline, m. p. 9293', of Table 11' is identified as 2-chloro-5-methylquinoxaline which wea have synthesized rationally (m. p. 95') and converted to 2-amino-5-methylquinoxaline (m. p. 201-2'). 2-Amino-5(or 8)methylquinoxaline (m. p. 202-3') of Table 111' is therefore the 5-methyl isomer. (The isomeric 2amino-8-methylquinoxaline we find to melt a t 129'). The corresponding N4-acetylsulfanilamide, m. p. 228-229', and the N1-sulfanilamide, m. p. 205-206' (Tables IV and V') accordingly have the methyl groups in the 5-positions.
Reduction with Platinum Oxide Catalyst.-To 16.0 g. (0.1 mole) of 1,6-dihydroxynaphthalenein 150 cc. of acetic , acid, there was added 200 mg. of Adams platinum oxide catalyst. The hydrogenation was carried out as described for the nickel catalyst and a t the end of approximately three hours one mole of hydrogen had been absorbed. After filtering the platinum catalyst, the acetic acid was removed in vacuo and the residue dissolved in 300 cc. of 10% sodium hydroxide. Methylation of the crude hydroxy tetralone and isolation of the methylated product was carried out as described above. In this case, distillaTHEWELLCOME LABORATORIES OF TROPICAL MEDICINE tion yielded 6.8 g. of a pale yellow liquid, b. p. 130-144' (1 mm.) from which no crystalline material could be iso- LONDON,N. W. 1, ENGLANDRECEIVED APRIL26, 1949 lated. One gram of the distilled product was treated with semicarbazide hydrochloride and 0.16 g. of semicarbazone was isolated. The semicarbazone, after recrystallization [CONTRIBUTION FROM THE EASTERN REGIONAL RESEARCH from aqueous alcohol, melted a t 230-232' and showed no LABORATORY,' PHILADELPHIA 18,PENNSYLVANIA] depression on admixture with the product obtained by the nickel catalyst reduction. We are continuing our studies of this reduction procedure in order t o establish the nature 2-(2-Chloroethoxy)-ethyl Acetate and 2-Chloroethyl Vinyl Ether of the non-ketonic material. CHEMICAL RESEARCH DIVISION BY C. E. REHBERG SCHERING CORPORATION RECEIVED JUNE 22, 1949 BLOOMFIELD, NEWJERSEY Dioxane is the principal impurity in the crude 2-
chloroethyl vinyl ether prepared by the method of Cretcher.2 Cretcher considered that the two Sulfanilamido-quinoxalines formed an azeotrope which boiled a t 107'. This azeotrope appeared remarkable in that its boiling BY BERTIEC. PLATTAND THOMASM. SHARP point was between those of the two components of A paper b y Wolf, Pfister, Beutel, Wilson, Rob- the azeotropic mixture. inson and Stevens' has appeared almost simultaI n the work reported here, chloroethyl vinyl neously with one by us2 on sulfonamides derived ether was prepared in 6001, yield by Cretcher's from substituted quinoxalines. It is possible b y method. When the crude product was distilled inspection of the melting points quoted by Wolf,' through a column having 60 theoretical plates, diet at., to identify some of the compounds which oxane was obtained a t 101-102', a mixture of diwere not fully identified by them. oxane and ether a t 102-108', and finally, pure I n Table 111' two 2-amino-6(or 7)methylquin- ether at 108'. Since both pure dioxane and pure oxalines are described (a) m. p. 178-180' and (b) ether were distilled from the mixture, it is evident rn. p. 171-173'. The former must be 2-amino-6- that no azeotrope was formed. methylquinoxaline since i t was prepared from 2The ether was also distilled a t reduced pressure chloro-6-methyl-quinoxaline identified by Platt3 (120 mm.). Dioxane distilled a t 52-53', and chlob y an unambiguous synthesis of 2-hydroxy-6- roethyl vinyl ether a t 59' ; a mixture of variable methylquinoxaline from 4-nitro-m-tolylglycine composition was obtained between the pure comand conversion to the corresponding chloro and ponents. amino derivatives. ,The compound (b) m. p. 171The following properties were observed with 173' appears t o be a mixture of 2-amino-6-methyl chloroethyl vinyl ether3: b. p., 108', 59' (120 and 2-amino-7-methylquinoxalinessince it was mm.); T Z ~ O D 1.4378; d2041.0475. prepared from an impure 2-chloro-7-methylquin(2-Ch1oroethoxy)-ethyl Acetate.-An effort oxaline m. p. 56-57'. Pure 2-chloro-7-methyl- was made t o produce chloroethyl vinyl ether by quinoxaline has rn. p. 76' (Platt3). Platta found (1) One of the laboratories of the Bureau of Agricultural and In(1) Wolf, Pfister, Beutel, Wilson, Robinson and Stevens, THIS JOURNAL, 71, 6 (1949). (2) J . Chcm. Soc., 2129 (1948). (3) Platt, ibid., 1310 (1948). This was recognized by Wolf, el ol., but by an unfortunate miaprint they say ambiguous instead of unambiguous.
dustrial Chemistry, Agricultural Research Administration, United States Department of Agriculture. Article not copyrighted. (2) Cretcher, Koch and Pittenger, THIS JOURNAL, 47, 1173 (1925). (3) Cretcher reported b. p., 109O (740 mm.); d% 1.0525; W . Cbalmers reported b. p. 1OSo, %SOD 1.4362; d2% 1.044 (Can. Je Ruruorch, 7, 464 (1932)).
NOTES
3348
the pyrolysis of 2-(2-~hloroethoxy)-ethyl acetate. Since the latter is a new compound, its preparation and pyrolysis are described. Diglycol chlorohydrin was acetylated with acetic anhydride, and the product (94% yield) was purified by distillation: b. p. 80" (1 mm.); dZo41.1546; n Z 0 D1.4398. Found : M 2 ' 38.02; ~ C, 43.3 ; H, 6.8. Calcd. : d P o D 38.07; c, 43.3; H, 6.7. Pyrolysis over Pyrex glass a t 500 and 550' (contact time, 8 sec.) decomposed 32 and 83%, respectively, of the ester but produced little if any chloroethyl vinyl ether. Most of the products were gases. PHI1,ADELPIiIA 18, PA.
RECEIVED MARCH11, 1949
Vol. 71
The ethers were prepared by previously described methods l s 2 from 2-chlorotriazines already described.a The compounds were tested b y Dr. Graham Chen and Mr. Charles Ensor of our laboratories by the histamine-aerosol technique of Dr. E. R. Loew.2 The physical properties and effective antihistaminic values are recorded in the accompanying table. (3) Pearlman and Banks, ibid., 70, 3726 (1948).
RESEARCH LABORATORIES PARKE,DAVISAXD Co. 32, MICH. DETROIT
RECEIVED MAP 19, 1949
.-.
Alkoxy-s-triazines.
Synthesis of
I11
BY WILLIAMM. PEARLMAN, JACQUELINE DOWNS MITULSKI AND
C. K. BANKS
I n the search for antihistaminic compounds of the triazinyl ether type the alkyl 2,4-diamino-6-s-
3-Carbomethoxy-3-methylcyclopentanone
BYJOHN D. ROBERTS, A. K. JEYDEL
AKD
ROSEARMSTRONG
Ruzicka' has reported the preparation of 3-carbethoxy-3-methylcyclopentanone (I) through sev-
TABLE I (Ki) (Rz)N-C=K-C--n'(R3) 11
ALKOXY-S-TRIAZINES
S=C-N
II11
(RJ
I
O--Rs
--
Analyses,) %------Carbon Hydrogen Calcd. Found Calcd. Found
Kecrystallization Yield, % solventa
A. H.0 value (effective dose, mdkg.1
M. p . , "C. 181-183 48.7 7.4 25 48.7 7.7 30 Ch 7.7 7.3 170-172 50 48.7 48.7 B 30 12.5 6.7 42.6 42.8 170-171 Hz0-E 6.6 79 7.2 7.2 175-177 12.5 45.9 16.1 68 Hz0-P 8.5 166-168 75 53.3 53.7 8.5 >50 H20-E 7.5 12.5 232-234 54.0 54.2 7.7 64 H,O-MC 2 11-2 13 4.9 55.3 55.5 5.1 64 >25 H20-D 12.5 7.3 171-173 45.9 46.1 7.2 61 Hz0-E 7.2 25 45.9 46.2 7.2 156-158 88 B 173-175 25 7.7 7.6 48.7 48.6 801 B 8.4 M 57.3 57.6 8.4 >25 154 75f 8.2 103-105 8.5 >25 53.3 53.4 55 HzO-E 8.7 8.9 .. 55.2 54.8 46 92-95 Hz0-E 8.1 8.2 51.2 44 51.2 >25 116-1 18 Hz0-E 8.4 53.5 8.5 .. 53.3 82-84 88 Hz0-E 6.1 50 56.7 56.7 6.2 83 194-196 d. Hz0-EC All compounds were colorless: B = benzene, Ch = chloroform, D = dioxane, E = ethanol, E C = Ethyl Cellosolve, Analyses by our Microanalytical Department under the M = methanol, MC = Methyl Cellosolve, P = propanol. See ref. 2. 3-Methylbutyl. e 2-Methylbutyl. Prepared by direction of Messrs. A. W. Spang and C. E. Childs. Mr. John Controulis. 0 Hydroxyethyl.
triazinyl ethers were found to have a peak of activity a t the n-propyl compound.' A subsequent investigation of the methyl and butyl ethers of thirty substituted-aminotriazines disclosed no regular progression of activity as was noted in the first series.z Subsequently, an examination of the previously determined antihistaminic activities indicated that certain miscellaneous alkyl ethers should be prepared to determine if any products of appreciable activity had been overlooked. (1) Controulis and Banks, Txxs JOURNAL, 61, 1940 (1946). (2) Pearlman and Banks, ibid., T I , 1128 (lQ4Q),
era1 steps from ethyl levulinate. In the present investigation, a shorter synfhesis of the corresponding methyl ester (11) was achieved from the adduct of butadiene with methyl methacrylate by the following route.
RCHa CH
CH I
+
I
C-CO2CHa
/I aCHzCHz
180"
__j
a%
(1) Ruzicka, Bcr., 00, 1882 (lQl7).
