HYPOPHOSPHOROUS ACID PREPARATION OF ARSPHENAMINE


HYPOPHOSPHOROUS ACID PREPARATION OF ARSPHENAMINE. (3,31-DIAMINO-4,41-DIHYDROXY-ARSENO-BENZENE DIHYDROCHLORIDE.)1...
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MTRIUUTlON

WALTER G. ~

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PROBK TNB DBPARTIVIE:NT OF [email protected], WARVAKD

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Received September 16, 1920.

Tn the course of our work it was foilad f.hat the reduction of 3-amino-4~udrdroxy-phenyl-axsonicacid by hypophosphorous acid consistently gives arsphenamine of low toxicity. The amino acid was secured rimst readily by reducing 5-nitro-4-hydroxy-171-lenyr-arsonic acid with sodium hydroswlPkc and then purified by precipitation from a hydrocQiloricacid solut i o ~ with ~ sodium acetate. Instead of isolating the arsphenamine h e after the reduction of the amino acid, as done by Fargher and Pyman, the reduced solution was poured into hydrochloric acid, thereby precipitating the arseplienamine as the dihydrocliloride, which, although di5cultly soluble in cold water, conforms to the qualitative -tests for arspbeszi,mi.neoutlined in the Public Health report^.^ I t has been found that by oxidizing toxic arsphenamine to the 3-amino~~-laydroxy-pheny~.-arson~c acid a d then reducing this intermediate w2t.b ~ ~ y ~ ~ ~ acid ~ tirsphenamine ~ ~ s ~ ~of hiowo "toxicity r ~ ~wasu obtained. ~ Fwgher’s4 modification of Leliniann’s metlmd was iised in the. arsenic ~ ~ ~ ~ ~ and ~ ~the~ toxicity ~ i ~of tthei products o n ~ was , determined by in.~~~~~~0~~ injection. into albino rats according to the standard method a,dopted by the U. S. Public Mealth Service. t 1 1.heamino acid was synthesized by 4. different methods, and the arsphena.snine secured from it was, in .ch case, of low toxicity.

~~~~~~i~~ of Ar~phenamine.~--rhirty-fi.~eg. of arsphenamine is dim$ved in 360 cc. of water, 40 cc. of I O i W sodium hydroxide solution i s a,d$ed, and then hjrdrogen peroxide (3%) slovvly-. The reaction is quite excthermic, and the solution becomes dark brown. After a while, a precipitate forms -vvh.ich i s redissolved by adding a little YO N sodium lay-This is the first of a series ol studies on the properties contributing t o the toxicity of arsphenamine being mzde under a grant from ?lie Iaterdepai-tnierital Social Hygiene Board to the Harvard MedicaI School; the work i s imder the general direetiun of Dr. Reid Hunt, who is also rcspomsibie for the biological tests reported in t h i s pa.pc,r. The experimental work reported ’sere was largely completed before the publication of the paper by Fargher and Pyman, J . Chem. Soc., 1.17, 370 (1920). Fargher, ibid., 115, 982 (1919). Myers and I)u &fez, Public flealth jPeports, 33! rooq (1918).

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’This method i s suggested by Ehrlich and Bertheim, Ber., 4s3 736 details were not given.

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PREPARATION OF ARSPHGNAMINE.

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ide solution. More hydrogen peroxide is now added until the preate reappears. This alternate addition of the sodium hydroxide and hydrogen peroxide is continued until a precipitate no longer appears when the oxidizing agent is added. The total quantity of hydrogen peroxide used is about 310 cc., and 14 cc. of IO N sodium hydroxide was added to redissolve the precipitates. The solution is acidified with glacial acetic acid (39 cc.); if a mineral acid is used care must be taken to reach the point when the solution is acid to litmus, but not to congo red, as the aminohydroxy-arsonic acid is soluble in an excess of mineral acid. Yields, 60y0 of brown solid. Purification of Crude 3-Amino-4-hydroxy-phenyl-arsonic Acid.--en g. of the crude acid is dissolved in IOO cc. oi water plus 8 cc. of hydrochloric acid ( I . IS), super-filtchar' is added and the solution agitated for r g minutes a t room temperature. Heating was found to hinder the decolorization. After filtering, 2 0 7 ~ sodium acetate solution (about go cc.) is added to the colorless or light yellow filtrate until the latter is no longer acid to congo red. White or slightly pink, minute plates crystallize, and after thorough cooling, they are filtered off and air-dried. The yield is 78%. Subs., 0.1ggg: 34.91 cc. of 0.04889 A7 Na&03 solution. Calc. for CsH804NAs: As, 32.17. Found: 31.99.

Preparation of Arsphenamine.-Twenty-three g. of purified 3-amino4-hydroxy-phenyl-arsonic acid is dissolved in 736 cc. of water plus 138 cc. of jo% hypophosphorous acid plus I I . 5 cc. of 3% potassium iodide solution. The mixture is heated gradually to 5 j O and maintained at j560' €or yo minutes. The deep yellow solution is cooled to IO' and poured with vigorous stirring into 1640 cc. of I : I hydrochloric acid which has been previously cooled to 2 The precipitate is filtered and washed with 100 cc. of cold I : x hydrochloric acid and dried in thin layers i n vamo over flake sodium hydroxide. Yield, 98.370 of light yellow powder of high specific gravity. Subs., 0.2007: 13.38 cc. of 0.1280 N Na2S203. A S 32.82. ~ . H Z OCalc : for zHzO: As, 31.58. Found: Calc. €or C ~ ~ H ~ ~ O ~ N ~ C I ~ As, 3K.99.

The product is yellow, dissolves readily in warm water, and its aqueous solution is clear bright yellow. With cold water it forms a jelly. The material was found to be free from inorganic arsenic and sulfur and conformed to the qualitative tests for arsphenamine. Arsenic Content.-The average of the analyses of 25 samples prepared by hydrosulfite reduction2 and Kobex's3 conversion of the base into A high grade of decolorizing carbon prepared by the Industrial Chemical Co.,

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Ehrlich and Bertheim, Eoc. cit. Tms JOURNAL, 41,442 (rgrg).

dihydrochloride shows 3 1 , 3 0 7 ~of arsenic, while the average of the analyses of 10samples prepared by ~ i y p o ~ ? h o s pacid h ~ reduction ~ ~ ~ s followed b y hy di-ochloric acid precipitation of the d ~ ~ i y ~ ~ r ~showed ) ~ ~ ~3 I l ,oo% o i ~ ~ ~ e of arseiiic. 'I'heoretical'ly , arsphenamine with 2 niolecrales of water of cry-5taP~izai.imshould contain 3 I .58%, of a.resnie. ~ ~ ~ average i tolerated ~ dose ~ OC ~44 samples ~ prepared ~ ~ by ~ h y ~ ~ reduction o s ~ and ~ methyl ~ ~ akohol-etl~er~ ~ ~ or Mdber's method of coxaversion oC the base into the dihydrochloride is 100 mg./kg. bodyweight, and the doses ranged from below 60 to r4o mg./icg. 'Phe average tolerated d o x of xo sainples prepared by the method ozltiined above i s 140 mg./k.g. and ranged from 1 2 0 to 160 mg./lig. ~~o~~~~ of Toxic Arspli~namiiie.---Four samples of arsphenamine h would not pass the present U. S. P. II.SS2requirements were oxidized to the amino-hydroxyphenyl-arsonic acid which, after purification, wa.s reduced to arsphenamine with hypophosphorous acid and precipitated by pouring into I : I hydrochloric acid. Tolerated dose of original.

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