1236
WALTERF. HOLCOMB AND CLIFFS.HAMILTON
[CWrRIBUTION FROM T H E PARKE, DAVIS& CO. RESEARCH LABORATORIES AND THE AVERY1.ABORA.TORY OF THE UNIVERSITY OF NEBRASKA ]
VOl. 61 017
CHEMISTRY
Arsenated Phenoxybutanols BY WALTER F. HOLCOMB AND CLIFFS.HAMILTON 4-@-Hydroxyethoxyphenylarsonic acid, 4-y- talline form by reduction of the arsonic acid with hydroxypropoxyphenylarsonic acid,l and 4-p- sulfurous acid in the presence of hydriodic acid. hydroxypropoxyphenylarsonic acid2 have been Experimental prepared by condensing 4-hydroxyphenylarsonic 4-p-Methyl-~-hydroxypropoxyphenylarsonic Acid and acid with the appropriate chlorohydrin. Since a cooled solution of 65 g. of 4its Sodium Salt.-To the arsenical containing the secondary hydroxy hydroxyphenylarsonic acid in 225 cc. of 4 N sodium hygroup was found to be more effective against T. droxide was added 65 g. of isobutylene oxide. The mixequiperdurn3 than that with the primary hydroxyl ture was placed in two small pressure bottles and heated it was thought that an analog containing a ter- t o 80" for twelve hours with occasional shaking. It was tiary hydroxyl group would be interesting. In the diluted to 3 volumes, charcoaled, filtered, cooled, and the arsonic acid precipitated by making the solution just acid present investigation 4-P-methyl-P-hydroxypro- to congo red paper with concentrated hydrochloric acid. poxyphenylarsonic acid and a number of its deThe acid was dissolved in sufficient 2 N sodium hydroxrivatives were prepared. ide t o yield a solution neutral to litmus paper. This Condensation of isobutylene chlorohydrin4 with solution was filtered into cold absolute ethanol, whereupon 4-hydroxyphenylarsonic acid in alkaline solution the monosodium salt separated. 3 - Nitro - 4 - p - methyl - @ - hydroxypropoxyphenylargave only traces of the arsenated phenoxyalkanol. sonic Acid.-4-@-Methyl-~-hydroxypropoxyphenylarsonic However, when isobutylene oxide6 was used and acid (10.5 9.) was added gradually t o a solution of 20 cc. the reaction carried out in a pressure bottle in of nitric acid (sp. gr. 1.50) and 4 cc. of concd. sulfuric 4 N sodium hydroxide, excellent yields were ob- acid a t 0". After all the arsonic acid was added (about fifteen minutes) it was stirred a t 0 'for one hour. The prodtained. uct was precipitated by pouring into one liter of ice water. 4 - p - Methyl - P- hydroxypropoxyphenylarsonic 3 - Amino - 4 - p - methyl - p - hydroxypropoxyphenylacid was nitrated in a manner similar to that of arsonic Acid. 1. Ferrous Hydroxide Method.-To a susthe analogous ethyl and propyl compounds but pension of 27 g. of ferrous chloride (FeC12.4H20)in 40 cc. the reaction was effected so much more readily of water and 33 cc. of 10 N sodium hydroxide at 20" was that one hour a t 0' was sufficient to obtain the added a solution of 6.5 g. of 3-nitro-4-@-methyl-@-hydroxypropoxyphenylarsonic acid in 20 cc. of 1 N sodium hymono nitro derivative. 3-Nitro-4-P-methyl-P- droxide. The mixture was stirred for one-half hour, filhydroxypropoxyphenylarsonic acid was isolated tered, the residue extracted with 20 cc. of 2% sodium hydirectly from the diluted acid solution. Sweet droxide, and the combined filtrates made just neutral and Hamilton6 found that on nitration of the pri- t o congo red paper. The solution was warmed with a little mary phenoxy-alkanols the nitro derivatives were activated charcoal and filtered. The colorless filtrate was concentrated in vacuo to a saturated salt solution obtained from the nitration mixture only as the whereupon the amine crystallized out. nitrate esters which were subsequently hydrolyzed 2. Catalytic Method.-3-Nitro-4- @-methyl-p-hydroxyin 3 N hydrochloric acid. -It appears, therefore, propoxyphenylarsonic acid (20 g,) was dissolved in 240 that the isobutylene oxide has split in the normal cc. of 0.5 N sodium hydroxide and the solution placed in manner to give the tertiary alcohol, whose inor- the reduction container with about 5 g. of Raney catalyst. After the air was expelled from the apparatus the hydroganic ester would of course be easily hydrolyzed. gen pressure was set a t 60 lb. (4 atm.) and the mixture Reduction of 3-nitr0-4-P-methyl-P-hydroxy-was agitated for two hours. The solution of the reduced propoxyphenylarsonic acid by means of alkaline product was charcoaled and filtered free of catalyst. ferrous hydroxide gave the corresponding amine I t was made just neutral to congo red paper with hydrobut better yields were obtained by catalytic re- chloric acid and the neutral solution concd. in oacuo to 100 cc. The crystalline amine was filtered off and a n adduction in alkaline solution using Raney nickel ditional yield obtained by concentrating the filtrate to 50 cc. catalyst. The arsine oxide was obtained in crys3 - Amino - 4 - p - methyl - p - hydroxypropoxyphenyl(1) Sweet and Hamilton, THISJOURNAL, 66, 2409 (1934). (2) Stevinson and Hamilton, ibid., 17, 1600 (1935). (3) Kuhs and Tatum, J . Phnrmacol., 61, 451 (1937). (4) Michael and Leighton, B e y . , 39, 2157 (1906). (5) Obtained from Shell Chem. Co., San Francisco, California. (6) Sweet and Hamilton, THIS JOURNAL, 66, 2409 (1934).
arsine Oxide.-A solution of 6 g. of 3-amino-4-@-methyl8-hydroxypropoxyphenylarsonic acid in 30 cc. of water and 15 cc. of concd. hydrochloric acid was cooled t o 10" and 0.8 g. of potassitlm iodide added. Into this solution was passed 2 g. of sulfur dioxide gas. After cooling t o 10
May, 19339
STRUCTURE OF VITAMIN
1237
Be
TABLE I Micro assays by C. S. Chamberlain, Research Laboratories, Parke, Davis & Co. Macro assays by the method of Cislak and Hamilton, THIS JOURNAL, 52, 632 (1930). As analyses, % Name
Crystal form
1 4-~-Methyl-~-hydroxypropoxyphenylarsonic Blunt needles” acid 2 Sodium salt of 1 3 3-Nitro-4-p-methyl-p-hydroxyHexagonal plates“ propoxyphenylarsonic acid Rectangular 4 3-Amino-4-p-methyl-p-hydroxyprismsb propoxyphenylarsonic acid
M. p., ‘C.
Calcd.
Found
189-192 > 325
25.83 25.68 24.05 23.90
210-215
22.38 22.30
150-155
24.55 24.40’
123- 124
25.9
13,5-140
31.30 31.50
5 3-Amino-4-p-methyl-p-hydroxyIrregular bars” Yellow amorphous powder Yellow amorphous powder
propoxyphenylarsine oxide
6 4,4’-Di-p-methyl-@-hydroxypropoxyarsenobenzene
7 3,3’-Diarnino-4,4’di-@-methyl-bhydroxypropoxyarsenobenzene
29.4
12.5-130
’By recrystallization from water. With one n~oleculeof water of crystallization, m. p. 65-7:J0. Micro arsenic. N % calcd. 4.58, found 4.45.
25.7d
29.15
Micro Dumas for
again 75 cc. of 6% ammonium hydroxide solution was added. The neutral solution was cooled to 0 ’, made slightly alkaline for fifteen minutes, then made neutral to litmus paper with acetic acid. I t was then charcoaled, filtered, and cooled for three days before crystallization was complete. 4,4’ Di p methyl p hydroxypropoxyarsenobenzene
with isobutylene oxide to form 4-0-methyl-P-hydroxypropoxyphenylarsonic acid and this was reduced to the corresponding arseno derivative with hypophosphorous acid. 3-Nitro-4- /3-methyl- fl-hydroxypropoxyphenyl- - and 3,3’-Diamino-4,4’-di-p-methyl-p-hydroxypropoxy- arsonic acid was obtained directly from the niarsenobenzene.-To 100 cc. of hot water was added 4 g. tration of 4-/3-methyl-/3-hydroxypropoxyphenylof 4-@-methyl-~-hydroxypropoxyphenylarsonic acid and arsonic acid. 25 cc. of 50% hypophosphorous acid. The solution was 3 - Amino-4-/3-methyl-/3-hydroxypropoxyphenylboiled for one-half hour and the pale yellow amorphous solid which separated was filtered off, washed well with arsonic acid was obtained by reduction of the water, and finally with a little ethanol. The correspondcorresponding nitro derivative with ferrous hying 3,3’-diamino-arseno derivative was obtained in a simi- droxide and catalytically with Raney nickel lar manner except that the reaction mixture was neutralcatalyst. The corresponding arsine oxide and ized with sodium hydroxide before the arseno separated. arseno derivatives of this amino arsenical were Summary also prepared. 4Hydroxyphenylarsonic acid was condensed DETROIT, MICH. RECEIVED FEBRUARY 3 , 1939
-
[CONTRIBUTION PROM
THE
RESEARCH LABORATORIES OF MERCK & Co., INC.]
The Structure of Vitamin B,. BY
ERICT. STILLER, JOHN
I
c. KERESZTESY AND JOSEPH R.STEVENS
Since the reports by Keresztesy and Stevens1i2 worker^^-^ have announced the results of researches from this Laboratory on the isolation and charac- which led to the same structure for the vitamin. terization of crystalline vitamin Be, further reOther worker^^-^ have confirmed the original search work has been carried out with the object findings of Keresztesy and Stevens.lS2 of determining the chemical constitution of this (3) Kuhn and Wendt, B ~ ? .72, , 305. 311 (1939). (4) Kuhn, Andersag, Westphal and Wendt, i b i d . , 71,309 (1939). vitamin. This objective was reached and we now ( 5 ) Kuhn, Wendt and Westphal, ibid., 72, 310 (1939). wish to record the evidence which led us to the StrUC(13) Leukovsky. J . ~ $ 0 1 them.. . 124. 125 .. Science.. 87.. 169 (1938): . ture of vitamin Be. Recently, Kuhn and his co- (1938). I
(1) Keresztesy and Stevens, Proc. Ezptl. B i d . Mcd., SS, 64 (1938).
( 2 ) Keresztesy and Stevens, THIS JOURNAL, 60, 1267 (1938).
,
(7) Kuhn and Wendt, Bcr., 71, 780, 1118 (1938). (8) Ichibe and Michi, Sci. Papers Inst. Phys. Chem. Research, 34, 623, 1014 (1938). (9) Gyargy, THIS JOURNAL, 60, 983 (1938).
