RESOLUTION OF EXTERNALLY COMPENSATED PAVINE, ETC, 2207CCXXIX.-T/ze Resolution of Externnlly CompensatedPavine and a- B? -0 rnocarnphor-r-sulp ho ?a ic A cid.By WILLIAM JACKSON POPE and CHARLES STANLEY GIBSON.PYMAN has recently demonstrated the probability (Trans., 1909,95, 1610) that the tetrahydropapaverine ” described by Gold-schmiedt (Morzutsh., 1886, 7,485; 1898, 19, 324) is the 1 : 2-dihydro-papaverine; some little uncertainty still remains as to theconstitution of Goldschmiedt’s base, and Pyman and Reynolds (thisvol., p. 1320) consequently prefer to call the substance pavine. Thepresence of an asymmetric carbon atom in the molecule of “tetra,-hydropapaverine,” or pavine, was demonstrated by the resolutionof the ba-se into its optically active components (Pope and Peachey,Trans., 1898, 73, 893), but in view of the interest which nowattaches to pavine it seemed desirable to apply to its resolution themethods which have been developed since that date.Preparation.of Ext ern&& Compensated Pavine.The method of reducing papaverine described by Pyman yieldsthe true tetrahydropapaverine as the chief product ; the followingprocess furnishes good yields of pavine. Papaverine (35 grams),hydrochloric acid (480 c.c.), and water (800 c.c.) are heated togetherunder reflux, powdered tin (95 grams) being added in smallportdons ; the tin becomes completely dissolved after about twentyhours’ boiling, and, on coding, a white, crystalline double saltseparates. The latter is crystallised once from boiling water, andfreed from tin by precipitation with hydrogen sulphide in boilingaqueous solution ; the filtered solution, on evaporation, yields pavinehydrochloride, which is purified by crystallisation from hot water.About onsquarter of the papaverine used is thus obtained aspavine, whilst the mother liquors contain both the latter base andtetrahydropapaverine.This considerable yield of pavine is ofinterest in connexion with the suggestion, made and rejected byPyman and Reynolds (loc. cit.), that this base is formed from someimpurity present in the papaverine used.Resolution of Externally Compensated Pavine.The resolution of pavine into its optically active components, bycrystallising the externally compensated base with one equivalentof d-bromocamphor-n-sulphonic acid, as described by Pope andPeachey, proceeds slowly, because the sparingly soluble crystallinesalt of the laevo-component and the resinous salt of the dextro2208 POPE AND GIBSON: THE RESOLUTION OFcomponent separate together ; the former salt is with difficultypurified from the latter by crystallisation.The following appli-cation of Pope and Peachey's method (Trans., 1899, 75, 1066)leads to a more satisfactory resolution of the base into its opticallyactive components.Externally compensated pavine hydrochloride is treated withone-half an equivalent proportion of ammonium d-a-bromocamphor-n-sulphonate in hot aqueous solution ; on cooling, I-pavine d-a-bromo-camphor-n-sulphonate separates in long needles not contaminatedby the resinous salt of the d-base.That the salt ZBdAthus obtained contained none of the salt dBdA was shown bytreating it, without recrystallisation, with ammonia, and deter-mining the specific rotatory power of the liberated base; in an8 per cent. chloroform solution the value [a],, - 152*0° was obtained,which agrees well with the more accurately determined constantgiven below. It is clear that the resolution proceeds in accordancewith the first type distinguished by Pope and Read (this vol.,p. 989).Although the separation of a pure I-pavine salt is rendered easyby the above method, yet the yield is not large, because on workingin concentrated solutions, or on concentrating the mother liquors,hydrochloride of the base crystallises together with the salt ZBdA;the following modification of the original pocess, which is applicablein other cases, was therefore adopted.The salts formed by pavinewith inorganic acids are in general sparingly soluble in water, butPope and Peachey found that the d-camphor-B-sulphonates of thebase are readily soluble in water (Trans., 1898, 73, 902); theexternally compensated pavine was therefore dissolved in one equi-valent proportion of d-camphor-P-sulphonic acid, and to the solutionwas added half an equivalent of ammonium d-a-bromocamphor-n-sulphonate, water being used as the solvent, and the solutionbeing kept as concentrated as conveniently possible. Of the numberof salts which might be formed in the mixed solution, Lpavined-a-bromocamphor-n-sulphonate is the least soluble, and, as onlysufficient ammonium salt was added fo allow of the formation ofthis salt, it was to be expected that practically the whole of theE-pavine would separate as the pure salt.In accordance with thisanticipation, the solution, prepared as described above, depositedalmost all of the I-pavine as the sparingly soluble d-a-bromocamphor-r-sulphonate, and the deposit'ed salt, after once recrystallising fromboiling aqueous alcohol, has the properties previously ascribed t o it.After the I-pavine d-a-bromocamphor-n-sulphonate has beenobtained in a pure state, the residual base-consisting almost entirelyof d-pavineis precipitated from the mother liquors by addition oEXTERNALLY COMPENSATED PAVINE, ETC.2209ammonia, and its actual content of d-pavine determined from itsrotatory power in chloroform solution; the base is then dissolvedin the requisite amount of d-camphor-P-sulphonic acid solution, andammonium Z-a-bromocamphor-?r-sulphonate added in just sufficientquantity to precipitate all the d-pavine as the salt dBZA, which,being enant.iomorphously related to the crystalline. salt ZBdA dealtwith above, exhibits ordinary physical properties identical with thoseof the latter.d-Pa& e l-a-Bromocamphor-?r-sulphonat e,C,,H,304N,C,oH,40Br* SO,H.This new salt separates immediately in long, colourless needleswhen the above operation is performed; after cooling, the salt iscollected and recrystallised from boiling aqueous alcohol.Thesubstance decomposes at 290-300°, and gave the following r e d t son analysis:0.0933 gave 0.1888 CO, and 0-0482 H,O. C=55-19; H=5-78.C3,H3,08NBrs requires c = 55.19 ; = 5-87 per cent.d- and l-Pavine.These substances separate on cooling a, hot dilute alcoholic solu-tion of the corresponding bromocamphorsulphonates after additionof ammonia; after recrystallisation from benzene, the bases meltedat 224O. The following determinations of rotatory power were madewith the recrystallised substances after drying at llOo :1- Pavine.0'1983 gram, made up to 20 C.C. withNa(o line). Hg(ye11ow). Hg(green).Chloroform, in a 2-dcm. tube a t 23":u -2.990" -3.119" -3.500"[u] - 150'8 - 157'3 - 176.50,7316 gram, made up to 20 C.C. withchloroform, in a l-dcm.tube at 22":u -5'445" -5T30" -6-500"[a] - 148'8 - 156'6 - 177.7d -Pa vine.0.1970 gram, made up to 20 C.C. withchloroform, in a 2-dcm. tube at 23":N;~(D line). Hg(ye1low). Hg(green).a +2'960" +3*093" +3*470"[u] + 150.3 + 157.0 + 176.1chloroform, in a l-dcm. tube at 22":a +5'241" +5-520" +6*250"0'7033 gram, made up to 20 C.C. with[a] + 149'0 + 157.0 + 177.7The values obtained under similar conditions for the twoenantiomorphously related bases are in good agreement, and areslightly higher than those previously recorded ; the specific rotatorypower diminishes slowly with increasing concentration, and thenumbers afford some indication that the rotatory dispersion isdependent on the concentration of the solution22 10 RESOLUTION OF EXTERNALT,Y COMPENSATED PAVINE, ETC.dl-Pavine dl-a-Bromocamphor-n-suZphonat e,2C20H2,0,N,2C,oH1,0Br*S0,H,H,0.In view of the sparing solubility of the two crystalline salts dealtwith above, nam:ly, ZBdA and dBZA, and of the fact that the saltsdBdA and ZBZA are resinous and also sparingly soluble, it seemeddesirable t o examine the salt formed by externally compensatedpavine with the externally compensated a-bromocamphor-7r-sulphonicacid. This substance was easily prepared by dissolving dl-pavinein an aqueous solution of the requisite amount of &-a-bromo-camphor-n-sulphonic acid, and evaporating to a gummy consistency ;the residue crystallises on keeping, and after several recrys-tallisations from strong alcohol the salt is obtained in radiate clustersof soft, white, silky needles.The salt is optically inactive inaqueous solution, and the following analyses were made on theair-dried material :0.1111 gave 0.2204 CO, and 0.0595 H20.0.3233, heated at l l O o for three hours, lost 0.0044.C=54.11; H=5*97.H,O=1*35.C,oH76016N2Br2S2,H20 requires C = 54.44 ; H = 5-94 ;H20 = 1-36 per cent.This fully racemic salt thus differs from the active ones previouslydescribed, which crystallise without water, in containing water ofcrystallisation; it is a h very soluble in water, and melts withoutblackening at 248-250°, whilst the active salts are sparingly solubleand decompose at 290--3OOO.The Resolution of Externally Compensat ed a-Bromocamphor-a-szclphonic A cid.The ease with which the resolution of externally compensatedpavine can be effected with the aid of d- and Z-a-bromocamphor-7r-sulphonic acid suggests that the optically active bases could beused in effecting the resolution of the externally compensated acidin accordance with the method of Pope and Peachey.With this object, an aqueous solution was prepared containingd-pavine (one equivalent), ammonia (one equivalent), and dZ-a-bromo-camphor-n-sulphonic acid ; a clear solution is obtained on boilingwith addition of a little alcohol, and, on cooling, the greater partof the alkaloid separates as the crystalline d-pavine I-a-bromo-camphor-n-sulphonate.After recrystallisation from water, thelatter salt was treated with ammonia, and the resulting ammoniumI-a-bromocamphor-n-sulphonate separated by crystallisation ; 0-1080gram 09 this ammonium salt, made up t o 20 C.C. with water, gaveaD - 0.915O in a 2-dcm. tube at 22O, whence [aID - 84.7O. The lattePOPE AND GIBSON: ROTATORY POWERS, ETC. 2211value is identical with that observed with ammonium I-a-bromo-camphor-?r-suIphonate prepared from I-camphor, so that theresolution of the externally compensated acid has been effected.The mother liquors from which the d-pavine salt had beenseparated were next treated with ammonia, filtered, and evaporateduntil crystallisation occurred ; on recrystallising the residue fromaqueous alcohol, pure ammonium &a-bromocamphor-n-sulphonatewas obtained. 0.1082 gram, made up to 20 C.C. with water, gavea, +0*915O in a 2-dcm. tube at 22O, whence [a], +84*6*, whichis the value ordinarily assigned to pure ammonium d-a-brorno-camphor-n-sulphonate.THE CHEMICAL LARORATOKY,UNIYERSITY OF CANBILIDGE