New Compounds. Some Mono- and Disubstituted Guanidines

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NEWCOMPOUNDS

Sept., 1942

cator over sulfuric acid the compound melted a t 276-278" (uncor.). Anal. Calcd. for CZZHI~SSOSN~: N, 9.96; S, 17.09. Found: N, 9.54; S, 16.85. CHEMO-MEDICAL RESEARCH INSTITUTE GEORGETOWN UNIVERSITY FILADELPO IRREVERRE M. X. SULLIVAN WASHINGTON, D. C. RECEIVED JUNE 25, 1942

2331

--C

Formula

NO.

CilHioONsClz C12H210NSClz ClsH2sONaC12 C1sHzrONsClz CizHilONsClz CISH~~O~ C~sHz602NzCIz

I I1 I11 IV V VI VI1

47.12 48.96 50.63 53.56 48.96 N 51.12 ~C~ 63.39

--

Analyses,

% '

H

C

H

6.84 7.20 7.52 8.13 7.20 ~7 . 7 3 7.77

47.38 48.67 50.67 53.45 49.05 51.27 53.02

6.61 7.27 7.80 8.04 7.51 7.75 7.62

Calcd.

Found

BURROUGHS WELLCOME & Co., U. S. A. RICHARD BALTZLY EXPERIMENTAL RESEARCH LABORATORIES WALTERS. IDE TUCKAHOE, NEWYORK JOHANNES S. BUCK Dimethylamine reacted with p-nitro-p-bromopropionRECEIVED MAY18, 1942 anilide t o form p-nitro-8-dimethylaminopropionanaide, m. p. of the hydrochloride, 200-20l0. A portion of this was transformed into the methochloride and both subSome New Quaternary Salts stances were reduced catalytically in alcohol containing Methylaniline and octadecyl iodide reacted to yield hydrogen chloride to give, respectively, p-amino-p-dimethylaminopropionanilide dihydrochloride (I), colorless methyloctadecylaniline, a yellow oil, b. p. (3 mm.), 234". felted needles, m. p. 218-219 ', and p-amino-p-dimethyl- This was treated in benzene solution with methyl iodide aminopropionanilide methochloride hydrochloride (11), forming octadecylphenyldimethylammonium iodide which crystallized in leaflets from ethyl acetate. hygroscopic crystals, m. p. 211-212". Cyclohexylethylamine (prepared from cyclohexylacetic N,N-Diethylethylenediamine,' prepared by the reduction (sodium and alcohol) of diethylglycine nitrile, reacted acid by the sequence: acid --j acid chloride -+amide -+ with p-nitrobenzoyl chloride, forming @- [p-nitrobenzoyl- nitrile +amine) was methylated by the Clarke-Eschweiler amidoethyl] -diethylamine hydrochloride, colorless needles method. The resulting tertiary amine reacted with benzyl melting a t 164-5". This substance and its ethochloride chloride in ether to give cyclohexylethylbenzyIdimethy1were reduced catalytically in alcoholic hydrogen chloride to ammonium chloride. Benzyl-@-bromoethyldimethylammonium bromide was @- [p-aminobenzoylamidoethyl]-diethylamine dihydrochloride (111), m. p. 176.5-178", and t o p-[p-aminobenzoyl- prepared from benzyldimethylamine and ethylene broamidoethyll-triethylammonium chloride, hydrochloride mide. Triethylamine and a-menaphthyl chloride (a-naphthyl(IV), which forms stubby prisms melting a t 228". Reduction of p-dimethylaminopropionitrile gave y- methyl chloride) yielded a-menaphthyltriethylammonium dimethylaminopropylamine, m. p. of the dihydrochloride, chloride. Data on these substances are presented in the 182-184' The base reacted with p-nitrobenzoyl chloride subjoined table.

Some Diamino Peptides

c

Formula

M .p., o c .

Composition

C

(n-C1&~,7)CeHSNMeJ (C6HnCHZCHZ) ( CsHsCHz)NMezC1 (CBHSCHZ) (BrCHzCH2)NMezBr (a-CioH7CH2)NEtaCl

93-94 906 dec. 174 197 dec.

CzsHasNI Ci7HzeNCI C11H11NBr2 CirH24NCl

82.25 72.44 40.87 73.49

to form y-[p-nitrobenzoylamidopropyl]-dimethylamine hydrochloride, m. p. 190-192". This was reduced catalytically in alcoholic hydrogen chloride solution to y-[paminobenzoylamidopropyl] -dimethylamine dihydrochloride (V), m. p. 184185". Reduction of the p-nitrophenylurethan of @-hydroxyethyltriethylammonium chloride yielded 6- [p-aminophenylcarbamatoethyl]-triethylammonium chloride, hydrochloride (VI), which forms irregular prisms melting a t 138139 '. By the reduction of @- [p-nitrobenzoyloxyethyl] -triethylammonium chloride, there was obtained @- [p-aminobenzoyloxyethyll-triethylammonium chloride, hydrochloride (VII), m. p. 214-215". This has been reported2 previously, but the synthesis used was not free from ambiguity. The salts described here were crystallized from absolute alcohol or from alcohol-ethyl acetate mixtures. The analytical data are in the table. (1) Ristenpart. Rer., as, 2526 (1896). (2) Einhorn and lThlfelder,A n n . , 871, 138 (1909).

Calcd.

Analyses, % '

Found

H

C

9 . BS 10.02 5.31 8.71

62.12 7 2 . 13 40.91 3 41

n 9.69 10.16 5.61 8.82

BURROUGHS WELLCOME & Co., U. S. A. EXPERIMENTAL RESEARCH LABORATORIES TUCKAHOE, NEWYORK RICHARDBALTZLY CLAYTON W. FERRY JOHANNES S. BUCK RECEIVED MAY18, 1942

Some Mono- and Disubstituted Guanidines The guanidines here described were all prepared by conventional methods. The S-methyl-isothiourea sulfate method (generally applicable with amines of moderate strength and water solubility) wyas used to prepare the five following : 6- [N-morpholinoethyl]-guanidinesulfate (from aminoethylmorpholine), @,p-diethoxyethylguanidine sulfate (from amino acetal), N,N-dicyclohexylguanidinesulfate (from dicyclohexylamine), N-benzyl-N-methylguanidine sulfate (from benzylmethylamine) and 6-phenoxybutylguanidine sulfate (from 6-phenoxybutylamine prepared by reduction of y-phenoxybutyronitrile) . In all these cases the salt was isolated by evaporation of the reaction mixture

2282

i T 0 l .ti4

N E W COMPOUNDS

and crystallized from mixtures of polar and non-polar solvents. Diethoxyethylguanidine sulfate crystallized best from n-butanol-ethyl acetate. The others were crystallized from alcohol-ether. N-Benzyl-N-a-naphthylguanidineHydrochloride.Benzyl-a-naphthylamine was refluxed in amyl alcohol with 1 mol of cyanamide and 1.2 mols of hydrogen chloride. On cooling, ether was added and the hydrochlorides separated as a purple sirup. Attempts to crystallize having failed, the mixture was dissolved in water and ammonia added. Some unreacted benzylnaphthylamine separated together with most of the color. The aqueous layer was then basified with sodium hydroxide and the precipitated guanidine taken into ether. After drying over potassium cwboiiate, alcoholic hydrogen chloride was added. The \alt was recrystallized from alcohol-ether mixtures. N,N'-Dihomoanisylguaddine Hydrochloride.--To a

R

s

T

CHI CsHbCH:! p-ClCeHICH? P-ClCeH4CHg p-BrCeH&H:: 'lK. DCl.

c1 H H C1

I c1

C1

c1

c1 C1

M. p . .

3c

152 122-123 166--166.5 160 1 5 6 . 5 157

Some Quaternary Salts from pDimethylamino-8'cymoxydiethyl Ether . .

A concentrated aqueous solution of sodium thymolate or sodium $-chlorothymolate was heated under reflux with B$'-dichlorodiethyl ether. After separation of the aqueous layer, unreacted dichlorodiethyl ether was removed in UQCUO,and the residue was heated for seven hours at 145" ( p = ca. 150 lb.) in a glass-lined bomb with 331, methanolic dimethylamine. After removal of volatile materials on the steam-bath under diminished pressure, the residual tertiary amines were partially purified by solution in acid and extraction with ether; on liberation with alkali, they were obtained as oils which could not be distilled in vucuo. but were converted directly into quaternary salts by warming on the steam-bath with the appropriate halides. The salts crystallized from acetone or alcohol on addition of ether

Cnlcd.

51. p . ,

c 16.20 3.91" 61.85 60.12

6.62 9.05* 7.80 7.00 6.38

I

Fou11d

.54.95

BURROUGHSWELLCOMB AND eo., U. ~

--.

--Analyses, yo-

Ii

Ci7Hz80sNClI 46.19 C23Hsa02NCl 3 58" C ~ ~ H Z ~ O Z N C 64.7'6 ~? 59.92 C2aHss02NCls CaHs20?NC12Br 54. A4

solution of 2 mols of homoanisylamine in absolute ether was added, with shaking and ice-cooling, a solution of 1 mol of cyanogen bromide in ether. -4fter standing onehalf hour the ether was evaporated by a stream of dry air, a little absolute alcohol added to homogenize the mixture and the whole was heated three hours in an oil-bath at 150". The material was then dissolved in water, the base liberated with alkali, and extracted with ether. Chi drying over potassium carbonate a crystalline solid appeared on the ;arface of the drying agent, 'rile ether Lyas decanted off, the solid dissolved in chloroform and transformeci illto the hydrochloride by alcoholic hydrogen chloride. I t was recrystallized from alcohol-ether, fornling lustrous plates, N-Methyl-N'-a-naphthylguanide.-Methylanline and cr-ilaphthylisothiocyanatc yielded N,N'-methylIlaphthyl. thiourea, hlethylation with methyl sulfate gave the sIllethyl derivative which lvas desulfurized in the usual manner with lead oxide and ammonia. Data on these compounds are presented in the taillr. Substance

c

Formula

FI

6.42 9.211 7.80 7.01 6 , 35

s. A.

~ LABoRAToRIEs ~CLAYTON W.~FERRY

~

ALAN E. ARDIS JOHANNES s. BUCK RECEIVED MAY 18, 1942

N,N-Dimethylethylenediamineand Some Derivatives 'The readily available dimethyl glycine nitrile' can be reduced by sodium and absolute alcohol to give N , K tiimethylethylenediamine. This is a colorless liquid boiling, when anhydrous, a t 107". As its dehydration is difficult and its dihydrochloride (melting around 160") is also hygroscopic, it is better characterized through a derivative. The following compounds were prepared as outlined, nitro derivatives being reduced with Adams catalyst in alcoholic solution containing hydrogen chloride. .