RELATION BETWEEN CHEMICAL CONSTITUTION ETC. 167 XVIII .-Relation between Chemical Constitution and Physiological Action in Certain Substituted Aminoalkyl Esters. Part 11. By FRANK LEE PYMAN. SOME years ago (T.) 1908 93 1793) the author described the pre-paration and physiological properties of a number of aininoalkyl esters and subsequently with Jowett (Proc. Seuenth Iiiterilat. C'o~y. A4ppl. Chern. 1909) discussed the relation between chemical consti-tution and physiological action in these and other similar com-pounds. A number of substances which were prepared about that, time have not yet been described and the present paper is written with the object of putting their chemical and physiological proper-ties on record. The physiological tests ware carried out during 1908-1910 a t the Wellcome Physiological Research Laboratories by Dr.H. H. Dale F.R.S. and Mr. C. T. Symons to whom the author desires t o tender his best thanks. It had previously been shown that replacement of the benzoyI by the phenylacetyl group leads in the case of cocaine to a substanc 168 PYMAN RELATION BETWEEN CHEMICAL CONSTITUTION devoid of local anzesthetic properties (compare S. Friinkel “ Die Arzneimittel-Synthese,” 1912 p. 349) but in tlie case of a-eucaine to a substance having local anzesthetic properties (Vinci Vircli. Arch. 1898 154 549). With the object of testing the effect of a similar substitution in the local anzesthetics ethyl paminobenzoate (‘ anzesthesine ’) and P-diethylaminoethyl paminobenzoate (‘ novo-caine ’) the two substances ethyl paminophenylacetate and P-di-ethylaminoethyl p-arnitiopl~eiiyl~tcrtccte were prepared.The first was tested in the farm of a 5 per cent. solution in olive oil and the second in the form of a 5 per cent. aqueous solution of the hydr-iodide ; neither showed any local anmthetic propesty. It had been found (T. 1908 93 1794) that the salts of aminoalkyl esters of the general forinula R*CH,*CH( O*COPh)*CH,*O COPh (R = NMe, NEt, NC,H,,) were possessed of very considerable local anaesthetic action but were distinctly toxic and irritant and also acid in reaction. A substance of a modified type was now pre-pared in which one of the berizoyl groups was replaced by a phenyl group. First ~-dietILyltcrni~~o-Pf-i~herio,r~~isoyl.opyl cilcohol was ob-tained by the interaction of plieiiyl glycido ether and diethylamine, Another line of work was suggested by earlier results.PhO*CHI,*CH-CH + NHEt = PhO*CH,* CH(OH)*CH,.NEt,, \/ 0 a nietliod which had previously beeii euiployed fos the preparation of fi-arnino-/Y-o-tolyloxyisopropyl alcohol from ammonia and o-tolyl glycide ether by Boyd and Knowltoii (T. 1909 95 1803; compare also Boyd T. 1910 97 1791) and from this tlie beti;oyl derivative was prepared but aqueous solutioiis of its salts were so strongly acid t h a t they could not be tested satisfactorily for local anzesthetic properties. The hydrochloside of the amino-alcohol itself however, produced a distinct degree of local anaesthesia when tested in 5 per cent. aqueous solution. Fourneau (b. Plictrtrz. C’Iiinz.[vii] 1910 1, 55 97) has also prepared a number of amino-alcohols of this type, and sta,tes t h a t they have remarkable antipiretic and analgesic properties. A n aminoalkyl ester of a different type 8-beiizuyloxy-l-nicthyl-1 2 ; 3 :$-tetmli~/nrotyztitiu7;t~(? was prepared by benzoylating the parent compound; it gave a hydrocliloride so strongly acid t h a t it could not be tested physiologically. An attempt was then made t o prepare the corresponding paminobenzoyl derivative. F o r this purpose 8-p-~iitrobe~~zoylo~x:?/-~l-rrictl~l-l 2 ; 3 4-teti.ccliydl.ozuinolilze was first made but suffered hydrolysis so readily that the work was disc on tinued . I n connexion with this investigation it appeared t o be of interes AND PHYSIOLOGICAI; ACTION ETC. PART 11.169 to test p-Q.minobenzoy~pphenetidine a substituted amide of paminobenzoic acid. This substance is almost insoluble in water, and when introduced in powder into the conjunctival sac caused no local anmthesia, EXPERIMENTAL. E thy1 p-A minopheaylncetn t e. This ester had been prepared previously by Salkowski (Ber. 1895, 28 1917) by the action of boiling alcohol on the hydrochloride of paminophenylacetic acid ; he gives the melting point as 49.5O. The material required for the present investigation was obtained by the reduction of ethyl p-nitrophenylacetate by means of iron filings and dilute acetic acid. When dissolved in hot water and cooled with ice i t separated in nearly colourless glistening microscopic plates which melted a t 51° (corr.). (Found C=67.1; H = 7 * 2 ; N=7.9.Calc. C=67*0; H = 7 * 3 ; N=7*8 per cent.) P-Diet7~ylnmiizoethyl p-ivitrophe?zylacetate, N0,-C,H,*CH2*C0,*CH,*CH,-NEt2. The p-nitrophenylacetyl chloride required for the preparation of this ester was made by the action of phosphorus pentachloride on p-nitrophenylacetic acid. Its preparation has since been described by Wedekind (dniinZen 1911 378 288) who gives the melting point as 47O. The material used in the present investigation crystal-lised from light petroleum in very pale yellow thin serrated plates which melted a t 48O (corr.). (Found C=47.8; H=3*2. Calc., C = 48.1 ; H = 3.0.) Ten gram; of B-diethylaminoethyl alcohol were converted into the hydrochloride dried powdered and mixed with 20 grams of p-nitrophenylacetyl chloride.The mixture was heated for one hour in the water-bath dissolved in water and extracted with ether t o remove non-basic matter. The aqueous solution was basified with sodium carbonate and extracted with ether which removed 13.8 grams or brown oil. This was mixed with absolute.alcoholic hydrogen chloride when 10.9 grams of B-diethylaminoethyl p-nitro-phenylacetate hydrochloride melting a t lOSo separated. The hydrochZoride crystallises from absolute alcohol in prisms which melt a t 1 1 1 O (corr.) and are anhydrous. Found C = 53.5 ; H = 6.8 ; C1= 11.3. C,,H,,O,N,,HCl (316.7) requires C = 53-1 ; H = 6.7 ; Cl=11*2 per cent. The hydrobromide crystallises from ethyl acetate in very pale yellow prismatic needles which melt at 122-124O (corr.) and are VOL.CXI. 170 PYMAN RELATION BETWZEN CHEMICAL CONSTITUTION anhydrous. ingly so in alcohol or ethyl acetate. It is somewhat sparingly soluble in water and spar-Found C= 46.9 ; H = 5.9 ; Br = 22.2. C,,H,,O,K;,,HBr (361.2) requires C = 46.5 ; H = 5.9 ; Br = 22-1 per cent. P-Dieth ylu min oet hyl p-A minophe?hylacetat e , NH,*C,H,*CH,*C02*CH,*CH2*NEt,. Twenty grams of /3-diethylaminoethyl pnitrophenylacetate hydro-chloride 200 C.C. of water 5 C.C. of glacial acetic acid and 20 grams of iron filings were mixed ar,d warmed on the water-bath for two hours with frequent shaking. After filtering making aIkaline with sodium carbonate and extracting with chloroform 2'4 grams of a brown oil were obtained which gave 2.2 grams of the crystalline hydriodide. The hydriodide crystallises from absolute alcohol in f ern-like plates which melt a t 155-157O (corr.) and are anhydrous.It is soluble1 in water to the1 extent of about 4 per cent. at 25O and 10 per cent. a t 35O giving a neutral solution; it is sparingly soluble in alcohol. C,,H2,0,N,,HC1,(378.2) requires C = 44.5 ; H = 6.1 ; I = 33.6 per cent. The poor yield was due to hydrolysis of the ester. Found C = 44.9 ; H = 6.0 ; I = 33.4. P-Dietkylanzino-St-l~he12oxyisoy~~opyl A Icokol, PhO * CH,*CH (OH) =CH,.NEt,. Fifteen grams of phenyl glycide ether and 8.0 grams of diethyl-amine were heated in a sealed tube for five hours a t l l O o . The resulting oil was dissolved in ether washed with water and ex-tracted with dilute hydlrochloric acid. The acid extract was basified with sodium hydroxide and extracted with ether.The ether residue amounted to 21.5 grams of oil which distilled completely a t 178-179O under a pressure no6 accurately recorded but probably in the neighbourhood of 30 mm. The distilled base was converted into the hydrochloride which is very readily soluble in water or alcohol but can be crystallised from ethyl acetate. It melts a t 90-92O. C,,H,,O,N,HCl (259.7) requires C = 60.1 ; H = 8.5 ; C1= 13.7 per cent. Found C=60*2; H = 8 * 7 ; C1=13*8. &Diet hylamirzo-P'-phenoxyisolvroinyl Bemoa t e , PhO*CH,-CH( O*CO-Ph)*CH,*NEt,. Ten grams of /3-diethylainino-~'-plieiioxyisopropyl alcohol regen-erated from the pure liydrocliloride were beiizoyIated by th AND PHYSIOLOGICAL ACTION ETU. PART II. 171 Scliotteii-Baumann method yielding about 13 grams of crude base.This was converted into the riitrccte which is very sparingly soluble in water and was purified by recrystallisation from ethyl acetate. The pure salt melted a t 100-103°. Found C = 61.4 ; H = 6.8. C,H,,O,N,HNO (390.3) requires C= 61.5 ; H = 6.7 per cent. The base regenerated from the pure nitrate did not crystallise but a number of crystalline salts were prepared from it. The hydrocldom'de which is easily soluble in water giving a n acid solution melts a t 107-109°. Found C = 66.1 ; H = 7.3 ; C1= 9.9. C,,H,,O,N,HCl (363.8) requires C = 66.0 ; H = 7.2 ; Cl= 9-7 per cent. The hydrobromide melts a t 114-115O after crystallisation from benzene and dissolves in about. 70 parts of cold water. Foulzd C = 58.4 ; H = 6.5.C,,H,,O,N,HBr (408.2) requires C = 58.8 ; H = 6.4 per cent. The hydrz*odide melts a t 112-113O after crystallisation from The Izydrogen oxnlate melts a t 112-114O after crystallisation Found C = 63.3 ; H = 6.6. C,oH,50,N,C,H,0 (41 7.3) requires C = 63.3 ; H = 6.5 per cent. benzene; it is almost insoluble in water. from ethyl acetate. 8-13enzo?/lo~y-l-?nethyl-l 2 3 4-tetrahyclropziir~oline. Ten grams of 8-hydroxy-1-methyl-1 2 3 4-tetrahydroquinoline were benzoylated by the Schotten-Baumann method and t h e pro-duct was extracted with ether. It was removed from the ether by dilute hydrochloric acid regenerated by sodium carbonate and again extracted with ether. The ethereal residue amounting to 12 grams was converted into the hydrochloride which was crystal-lised from absolute alcohol yielding 8.7.grams melting a t 1 8 8 O .The base crystallised when liberated from the pure hydrochloride and melted a t 58-59O after crystallisation from light petroleum. Found C = 76.7 ; H = 6.4. The hydrochloride prepared flrom the pure base still melted at C,,H,,O,N (267.2) requires C = 76.4 ; H = 6.4 per cent. 1 8 8 O . Its aqueous solution was strongly acid. 8-p-Nitrob enzoyloxy-1-methyl-1 2 3 4-tetra~~dropzcinolilze. Ten grams of 8-hydroxy-1-methyl-1 2 3 4-tetrahydroquinoline were1 dissolved in 160 C.C. of 10 per cent. aqueous sodium hydroxide and well shaken with 30 grams of pnitrobenzoyl chloride dissolved I 172 MYERS BORIC ANHYDRIDE AND ITS HYDRATES. in chloroform the mixture being kept cold.A quantity of sodium pnitrobenzoate separated and was rem,oved by filtration. The chloroform Iayer of the filtrate was dried distilled to remove the solvent and the residue was crystallised from acetone when 3.0 grams of the above compound were isolated in a pure state, melting a t 127-128O. Found C=65.8; H=5*2. C,,H,,04Nz (312.2) requires C = 65.4 ; H = 5.2 per cent. This compound readily undergoes hydrolysis when boiled with alcohol with the formation of 8-hydroxy-1-methyl-1 2 3 4-tetra-hydroquinoline p-nitrobenzoic acid and ethyl pnitrobenzoate. p-NitrobenaoyZ-p-;xrhenet~ine NO,*C,H,*CO*NH*C,H,*OEt. Twenty-five grams of pnitrobenzoyl chloride were melted and poured on 18 grams of freshly distilled p-phenetidine. A vigorous reaction took place hydrogen chloride being evolved and a yellow Bolid melting a t 170-185O resulte'd. After crystallisation from dilute alcohol it formed matt'ed yellow needles which melted a t 186-1 87'. p-4 mino b eiaaoyZ-p-phe~zetidi.lze NH,. C,H,* CO *NH*C,H,*OEt. This substance was prepared by the reduction of p-nitrobenzoyl-pphenetidine with iron and hydrochloric acid in alcoholic solution. It crystallises from alcohol in colourless needles which melt a t 157-158O. It is almost insoluble in boiling water sparingly so in cold alcohol but readily so in hot alcohol. Found C = 70.5 ; H = 6.3. THE WELLCONE CHEMICAL WORKS, C,,H,,O,N (256.2) requires C = 70.3 ; H = 6.3 per cent. DARTFORD KENT. [Received February 27th 1917.