Sept., 1946 ml. of water. An excess (15.2 ml.) of thioglycolic acid6 was added and the mixture was heated t o 100" with rapid stirring. When the solution became almost clear, it )vas filtered rapidly while very hot. The filtrate was allowed t o cool, and a copious crystalline precipitate formed irnmedktely. The precipitate was filtered off and washed with three portions of 50 ml. of cold water. It was then dried to constant weight a t 40" and then in a vacuum dr+catot-; yield was 18.8 g., 987; ; in. p., 158 162". Anal. Calcd. for C ~ I H I ~ O J ' & ~ SN, ; 3.71; As, 19.85; neut. eq., 184.5. Found: K,3 . 6 3 ; As, 19.75; neut. eq., 185.7. The acid (11) is insoluble in cold water but soluble in water above 90". It is sparingly soluble in cold ethanol and methanol, and very soluble in these solvents when warm. It. is insoluble in warm isopropyl ether. The acid ,]issociation constant is pKs = 4, which is similar t o that of thioglycolic acid. A potentiometric titration of the acid showed that the disodium salt is stoichiometrically formed in solution a t PH 7-8. For therapeutic purposes I1 is used in the form of an aaueous solution ureuared bv dissolving the acid in sufficient 0.2 N sodium hkdroxide to yield asolution of PH 7. .125% solution, formed in this way and sterilized by filtration, is stable in sealed amber ampules a t room temperat ure for a t least six months. In practice it has been useful i o include, for each liter of solution, 72 ml. of M/15 Va,HP04 and 41.1 ml. KHlPOh t o maintain the PH value. Both unbuffered and buffered solutions have been used successfully for iitravenous therapy in dogs.
-
( 5 ) Attention must be given t o the purity of HSCHd2OOH. It should be water-white, spec. grav. 1.32, and distilled a t 105-109' tinder 13-10 mm pressure. The acid used in this Laboratory was purchased according: to these specifications from Wallace Laboratories, Xew Brunswick, Piew Jersey.
DEPARTMENT OF PARASITOLOGY OF HYGIENE AND PUBLIC HEALTH SCHOOL JOHNS HOPKINS~JNIVERSITY RECEIVED APRIL 23, 1946 ~ 3 A L T I R I O K D ,>I.\l?TI,AND
NOTES
1865
was heated gently over a micro burner until the evolution of hydrogen chloride ceased. This usually required from three to five minutes. The molten mass was then poured into 20 c c . of a ZOq0 solution of alcohol to which cracked ice had been added. Some of the compounds solidified instantly and those that came down as oils changed to solids in a few minutes without further manipulation. All of the esters can be recrystallized from 95% alcohol, but 50y0 alcohol is a hrtter recrystallizing solvent for the esters obtained from inethyl and butyl carbitols. Otic i ecrystallization is frequently enough to give a pure compound, but two may be needed. The esters precipitate in granular form, with the exception of the isopropyl cellosolve derivative which comes down in the form of fine needles. The melting points were taken with Anschutz thermometers, but are not corrected.
TABLLC I ESTERS O F 3,4,5-TRIODCIBEXZOIC 9 C I D Cellosolve or carbitol used Methyl cellosolve Cellosolve Isopropyl cellosolve Butyl cellosolve Phenyl cellosolve Benzyl cellosolve Methyl carhitol Ethyl carbitol Butyl carbitol
M. p.. Yield, Formula OC. % 152.0-152.3 54.2 CioH90aI3 1 2 7 . 7 - 1 2 8 . 2 7 4 . 3 CiiHiiOiTa
Iodine, % Calcd. Found 68.26 6 8 . 4 7 6 6 . 2 8 07.11
79.5- 8 0 . 0 85.0- E5.5 144.9-145.3 103.5-104 .O 82.0- 82.5 75.5- 7 6 . 5 53.8- 5 4 . 5
04.99 65.45 63.46 63.93 6 1 . 4 1 61.60 60.06 60.61 6 3 . 2 6 63.25 61. E l 6 2 . 2 0 69.11 58.99
DEPT. OF CHEMISTRY BOSTONCOLLEGE HEIGHTS UNIVERSITY CHESTNUT HILL,MASS.
47.7 37.1 71.7 65.6 39.7 42.0 37.1
C12HI303Ia C13H1503I3 CisHtiOaIs CisHaOaIa Ci1Hi303Ia CiaHisOaIa CisH190313
RECEIVED JUNE 26,1946
Catalytic Acetylation of Steroid Compounds BY BRADLEY \ \
,
7 A~ N D~ ERWIN ~ ~ SCHWENK ~ ~ ~
Based on the work of Conant and Bramann,' we have found that acetylations may be carried BY DAVIDC. Q'DONNELL AND RICHARD J. C A R E Y ~ ~ * out rapidly a t room temperature if a trace of anhydrous perchloric acid is used to catalyze the reMany derivatives of the alcohol-ethers of the action. cellosolve and carbitol type have been prepared by gram of the substaiicc to be acetylated various ~iiethotis,~ but these have not usually been is Procedure.~---Oiic added to a mixture of 10 cc. of glacial acetic acid and 3 easily obtained solids of characteristic melting cc. of acetic anhydride. The mixture is cooled to 18" points. We have therefore now prepared nine and 0.1 cc. of 5 N anhydrous pef;chloric acid added. The esters of these alcohol-ethers with 3,4,S-triiodo- temperature is kept below 35 with external cooling. After standing for thirty minutes, the reaction mixture is benzoic acid. The alcohol-ethers were gener- cooled to 18" and sufficient ice added to destroy the excess ously supplied by the Carbide and Carbon acetic anhydride. The reaction mixture is worked up by Chemical Corporation and were simply frac- pouring into water and filtering the precipitate. This procedure has been used successfully on a great tionated except for the methyl and ethyl carbivariety of bile acids and their derivatives. The yields are tols which were purified by the method of Seikel.4 excellent and the physical constants are in agreement with The acid chloride of the 3,4,5-triiodobenzoic acid those in the literature. When the diphenyl carbinols enwas prepared by the method of Klemme and countered in the Barbier-\.Vieland* degradation of the sideHunter6 and proved to be quite stable, a sample chain of 3,12-dihydroxycholanic and similar acids are acetylated by this method, the 3,12-diacetoxydiphenylof i t kept in a stoppered vial melting unchanged ethylenes are obtained; water splitting takes place even after t w o years. under the mild conditions of this reaction.
Solid Esters of Cellosolves and Carbitols
Procedure.-T'o 1 g. of the acid chloride in a 10-cm. testtube 0.5 cc'. of the alcohol-ether was added and the mixture (1) Taken for the most part from a thesis submitted by Richard J. Carey in partial fulfilment for the M.S. degree. ( 2 ) Presetit itddrc':~:Compo Shoe Machinery Cixpciration, Boston, Mass. (3) Mason nnrl Manning, '1111s JOURNAL, 62, 1635-1640, 31363139 (1940). (4) Seikel, I n d . E.ng. Chem., Anal. E d . , 13, 388-389 (1941). ( 5 ) Klemme and Hunter, J . Org. Chcm., 5, 508-511 (1940).
In the course of this work, three cases of polymorphism were encountered. 3(a)-12(P)-Diacetoxy-nor-cholanicacid and 3(a)-12(~)-diacetoxy-bis-nor-cholanicacid may be obtained in high melting forms by recrystallization from ether-petroleum ether and in low melting forms by salting out the ammonium salts and regenerating the free acids.
(1) Conant and Rramann, T i m JOURNAL, 60, 2305 (192s). (2) (a) Barbier and Locquin, Compl. rexd., 166, 1433 (1933); (b) Wieland. Schlichting and Jacobi, 2. physiol. Chem., 161, 80 (1926).
In each case the mixture of the two forms melted at the melting point of the higher melting form. 3(a)-12(~)-Diacetoxy-ter-nor-diphen'ylethyleneprepared by this method had a melting point of 127-120°, while the reported melting point was 158-160°.3 The high negative rotation ( - 138' in chloroform) left no doubt that it was the desired substance. 3(a)-12(~)-Diacetoxy-nor-cholanicacid,4 high melting form, 209-210 ; low melting form, 164-66 '. Anal. Calcd. for C27H4208: C, 70.1; H , 9.2. Found: high melting form, C, 69.9: H, 9.4; low melting form, C, 69.6; H,9.5. 3 (a)-12(8)-diacetoxy-bis-nor-cholanicacid, high melting form, 167.8"; low melting form, 99.5-100'. .4nal. Calcti. for C ~ O H ~ OC, O 69.6; ~: H, 9.0. Found: high melting form, C. 69.4; H, 9.2; low melting form, C, iiR.2; H, 8.9. Two new compounds were prepared, the above 3(01112(13)-diaeetoxy-his-nu~-cholaiiic acid and ethyl 3(aiacetoxy-12-ketocholanate (m. p. 123-12-1'). Anal. Calcd. for C ~ ~ J H C, ~ ~73.0; O ~ : H, 9.6. Found: C, 73.0; H, 9.9. (3) Hoehn and Mason, THISJOURNAL, 60, 1493 (1938). (4) Brink, Clark and Wallis, J . B i d . Ckem., 162,701 (1946), found a melting point ai' 205-6'.
CORPORATION BLOOMFIELD, >JEW JERSEY
SCHERIXG
RECEIVED MARCH9,1946
The Catalytic Reduction of a-Nitrostilbenes to cy, 6-Diphenyle t hylamine s BY &'ARREN D. MCPHEE,ERNSTs. E:N. 17. JOSEPH SALVADOR
J K . , l AND
In a recent publication2from these Laboratories TABLEI SUBSTITUTED a-XITROSTILBENES, Ar-CH=C ( NO)2-C6H6 Reaction temp., Y$ld,
Substituent
2'-Methosy 2'-Benzyloxp 4'-Methoxy 4'-Benzyloxy 3 '-R.1 ethoxy4 'benzyloxy Knoevenagel in. p. 151.
'C.
Z
31.p..
3 3 22 22
YS 71
117.5-119 131-132 152-153" 113-174.5
ti4
(i1
OC.
N, %
Calcd.
Found
5.49 4.23
1.56
4.23
4.74
5.75
22 19 132-132.5 3.88 3.83 and Walter [Ber.,37,4502 11904)j report
SU8STITUTED
a,S- I~IPHI:NYLETHYLAMINE
Substituted @-phenyl
Keduction time, hr.
catalytic reduction of a-nitrostilhenes to clip11envlethylamines. Ar-cH=c-c~,H~
---f
I
cy,@-
Ar-CH2-CH-C6H6
I
NO2
Z"
Subsequent to our previous work we have found that a-nitrostilbenes may be conveniently reduced in methanol in the presence of a readily prepared palladium-on-charcoal catalyst. The amines are easily isolated as their hydrochlorides in a state of purity. In one instance, a-nitro-4'methoxystilbene gave rise t o a small amount of the corresponding oxime when the hydrogen uptake was less than theoretical. The diphenylethylamine hydrochlorides described herein are being studied pharmacologically by Dr. T. J. Becker and his associates in these Laboratories. Experimental' Substituted a-nitrostilbenes were prepared by condensing a substituted benzaldehyde with an equivalent of phenyliiitromethane in the presence of methanolic methylamine, either a t room temperature (22') or in the re,rigerator (3 "). Analytical samples were recrystallized From alcohol. The following experiment is typical: a-nitro-2'-methoxystilbene was prepared by shaking 6.85 g. (0.05 mole) of phenylnitromethane, 6.80 g. (0.05 mole) of o-methoxybenzaldehyde and 2.5 cc. of methanolic methylamine (10 g. of methylamine in 70 cc. of methanol) until solution occurred. The solution was placed in the refrigerator for fifteen hours. The resultant bright yellow crystals were admixed with ether t o dissolve the oily impurities, filtered and dried in the air. This material (10.8 g.) was pure enough for reduction, melting at 113-115". Recrystallization from alcohol gave yellow needles of m. p 117.5-119'. The same reaction carried out a t room temperature gave approximately the same yield of material of equal purity. Substituted a,j3-diphenylethylamine hydrochlorides were prepared by the following general method: 10 g of the substituted nitrostilbene was dissolved in 150 cc. of boiling methanol. One gram of Darco G-60 and 0.2 g. of palladium chloride were added and the hot mixture was hydrogenated immediately at 55' and 50-60 lb. initial pressure. Reductions were generally complete in one t o three hours. The catalyst was then removed by filtration and 10 cc. of saturated ethereal hydrogen chloride was added t o the cooled filtrate. The resulting solution was evaporated t o dryness in vucuu and white crystals formed immediately. 'These were washed with acetone and recrystallized.
TABLE I1 I
