Llewellyn H. Welsh- The Constitution of Acetylephedrine and Acetyl-psi-ephedrine

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128 LLEWELLYN. WELSH Vol. 69

The acetarnido compound (100 mg.) was dissolved in 1ml. of 8 AT ethanolic hydrogen chloride solution andallowed to remain a t room temperature for sixteen hours.After evaporation of the alcohol, concentrated hydrochloricacid (0.25 ml .) was added to the residue and the solutionevapora ted on a steam-ba th. The 2-amino-4-ethylthia-zole hydrochloride was recrystallized from a mixture of

ethanol and acetone; m. p. 185-187O.lOSummary

have been brominated and the resulting bromo-aminoketones have been to 2-amino-

The structures Of the brominationproducts of two P-aminoketones have been provedby independent syntheses of the 2-aminothiazolesderived from them. a ~ ~ ~ ~ o r o ~ ~ ~ p ~ p e r

piophenone has been synthesized from w-chloro-acetophenone by the Mannich reaction.

Several 6‘-t-aminoketones (“Xannich bases” 1 GLENOLDEN,ENNSYLVANIA RECEIVEDULY I, 1946

[CONTRIBUTIONFROM THE, u. s.FOODND DRUGADMINISTRATION,EDERALECURITY AGENCY]

The Constitution of Acetylephedrine and Acetyl-+ephedrine

BY LLEWELLYN. WELSH

,4cetyl-l-ephedrine was first prepared by Nagailby the action of acetyl chloride on an etherealsolution of 1-ephedrine (1-phenyl-2-methylamino-I-propanol), (I). He reported that the sub-stance formed a hydrate, melted a t 87’) and thathe was unable to obtain crystalline salts from acidsolutions of the compound. He represented it asan amide, or N-acetyl derivative of ephedrine.

Schmidt and CalliessZ prepared acetyl-d-*-ephedrine hydrochloride by refluxing acetic anhy-dride with d-*-ephedrine hydrochloride, (VI.HCl),or it s diastereoisomer, 1-ephedrine hydrochloride(I.HC1). On treatment with alkali the productyielded acetyl-&*-ephedrine which, without proof,was represented as an N-acetyl derivative.Later,3 Schmidt carried out a series of reactionswhich, according to his concepts, may be formu-lated in the following manner

hydrobromide instead of the compound repre-sented by structure XII . This fact would renderinconclusive Schmidt’s evidence for an N-acetylstructure.

Mitchell4 prepared acetyl-1-ephedrine andacetyl-&*-ephedrine by heating the correspond-ing alkaloids with one and one-half moles of aceticanhydride at 70” for ten minutes. From the +-ephedrine derivative he prepared the well definedhydrochloride, but efforts to prepare acetyl-l-ephedrine hydrochloride yielded a poorly definedproduct contaminated with the diastereoisomer.On treatment with nitrous acid the acetylatedalkaloids yielded nitrosoacetyl products of whichthe one derived from *-ephedrine was well de-fined, whereas that resulting from acetyl-l-ephedrine apparently consisted of a mixture ofdiastereoisomers. Mitchell considered the ready

formation of nitrosoacetvl com-P13r: pounds to be proof that the acetyl

derivatives have a replaceableamino hydrogen and that they and

HgO XI1 * an 0-acetvl structure. His inter-

V1.HC1--esH6CHBrCH(CH3)NHCH3,HBr4 CH3CO)zO

acetyl-d-’Ir-ephedrine < CsHjCHBrCH (CH3)S(CH3)COCH3 + HBr the derived from possess

Since XI]:, supposedly 1-bromo-1-phenyl-2-ace-tylmethylarninopropane, had no basic propertiesand yielded acetyl-&*-ephedrine by what wasinterpreted as replacement of bromine by hy-droxyl when treated with aqueous .silver nitrate,the N-acetyl structure (VII) was considered tobe proved, and the corresponding hydrochloridewas represented as an N-acetyl sal t (VIII) . Re-cently, however, Mitchell4 has submitted evi-dence that the product formed by the action ofacetic anhydride on XI is acetyl-d-+-ephedrine

(1) Ndgai, J . Pitarm. Svi. Japan, No . 127, 8:32 (1892). ‘ the

autho r is indebted to Dr. J. G. Yoshioka for the translation of a yur-

tion of this publication which does not appear to be indexed in th e

Western literature, although reference to i t and acetyl-l-ephedrine is

made in a review by Chen and K ao, J.Am. Pharm. Asso c . , 16, 25

(1926).

( 2 ) Schmidt a nd Calliess, .4rch. Phaum., 260, 15 4 (1912); see also

Calliess, Deut . Apolh. Z., 26, 677 (1910).

(3) Schmidt, ibid., 262, 111 (1914).

(4) Mitchell, J . C ‘ ~ W Z .Soc . , 1153 (1940).

pretation of the reactions is ex-pressed struc tural ly in t he following diagram.

It seemed possible that criteria simpler thanthose used by Schmidt3 and by L\Iitchel14 ould beemployed to differentiate between N-acetyl

(amide) and 0-acetyl (ester) structures. If acompound under consideration is a hydroxy-amide it should afford a practically neutral q u e -ous solution and should evince no titratable basic-ity under ordinary conditions. If i t is an amino-ester, however, i t should yield an alkaline solutionwhich, in the case of acetylephedririe and acetyl-*-ephedrine, would be expected to be susceptibleto quantitative titration with standard acid. I tseemed possible also tha t the relationship betweenacetylephedrine and acetyl-*-ephedrine on theone hand and the corresponding salts on theother might be that which exists between an N-acyl-/3-aminoalcohol and the salt of the isomeric

0-acyl-0-aminoalcohol. Although stable esters



Jan., 1947 CONSTITUTIONF ACETYLEPHEDRINEND -ACETYL-*-EPHEDRINE 129

(CH3CO)zO chloride is adhed thereimmediately precipitate

aminoalcohol HONO/ minoester in about 98$& yields rela-

CeHbCHOHCH(CH3)NHCHaA eHaCH(OCOCH3)CH(CH3)KHCHI

tively stable -crystallinecompounds having the

H C l

nitrosoaminoester aminoester hydrochloride of acetyl derivative andone mole of hydrogen

chloride. These hydrogen chloride adducts differsharply in properties from the salts of typicalaliphatic amines in that their aqueous solutionshave a strongly acid reaction and in that thecombined hydrogen chloride may be directly andquantitatively t itrated with alkali in the presenceof methyl red or phenolphthalein. The unal-tered original acetyl derivatives may be recoveredquantitatively by extraction methods after addingexcess alkali to aqueous solutions of the adducts.These facts make it obvious that acetylephedrineand acetyl-*-ephedrine have .an N-acetyl st ruc-

ture and not tha t of an aminoester.

CGHECH(OCOCH3)CH(CH,)N(SO)CH3 C~H~CH(OCOCHI)CH(CH~)NHCH~.HCIomposition O f one mole

may be formed from compounds in which anamino and a hydroxyl group are on adjacent car-bon atoms,5 it has been recognized for a numberof years that aminoesters having an aryl groupon the carbon atom bearing the acyloxy grouprearrange with extreme ease to form hydroxy-amides, and are stable only as salts. For ex-ample, when alkali is added to 1-phenyl-1-ben-zoyloxy-2-aminoethane hydrochloride an oil pre-cipitates which, although initially partly solublein acid, on crystallizing is found t o consist of anacid-insoluble hydroxyamide6

OH- The adducts are regarded as N-acetyl

/ cid-soluble aminoester they are converted into isomeric sub-

C6HSCH(OCOC6H,s)CH,SH,.HC1- C6H5CH(0C0CsH~)CH21 ;H21 hydrochlorides. On heating a t 110'

C6Ht,CHOHCH2SHCOCsHj

acid-insoluble hydroxyamide

1 -Phenyl - 1 -. benzoyloxy - 2 - aminopropanehydrochloride when treated with alkali yields 1-

phenyl-2-benzamido-l-propanol,7~8nd on heat-ing the hydroxyamide with concentrated hydro-chloric acid the benzoyl group undergoes an N-,0 hift to reform an ester hydro~h lor ide. ~

OH-

HC1CsHjCH(OCOC6Hj)CH(CH3)I;H1.HCl

*-C6HaCHOHCH(CH3)h"COC6Ha

The same N+O and O+N shifts of t he benzoylgroup have been observed in the N- and 0-

benzoyl derivatives of 1-(@-naphthyl)2-amino-e t h a n o l , C I ~ H ~ C H O H C H ~ N H ~ , ~nd reversiblemigration of acetyl also has been reported in aseries of l-aryl-2-(amino and hydroxy1amino)-1-propanol derivatives.'O

The investigation reported in the present paperwas undertaken in the light of the foregoing con-siderations.

Acetylephedrine and acetyl-*-ephedrine formaqueous solutions which are practically neutral,and by ordinary methods show no titratablebasicity." Ulhen the substances are dissolvedin benzene and an ethereal solution of hydrogen

( 5 ) Cope and Hancock, THIS OUXNAL, 66 , 1448 (1944); Fonr-

(6 ) Wolfheim,B e y . . 41, 1440 (1914).

(7) Kanao, J . Phavm . SOL. a p a n , 48, 1070 (1928); German ab-

(8 ) Hartung, Munch and Kester , THIS OURNAL,S4, 1526 (1932).

(9) Immediat a and Day, J . Org . Chem., 5, 512 (1940)

(IO) Bruckner and co-workers, Ann . , 518, 226 (1935); Avch .

Ph a vm . , 21S, 372 (1936); J . p v a k f . Chem. , 149, 287 (1935); 148, 117

(1937); 151, 17 (1938); von Fodor, Be r . , 1 6B , 1216 (1943).

(11) Th e formation of salt s from these substa nces, however, was

interpreted by Mitchell' as "direct neutralization."

neau, Bull. SOL . c h im . , 11, 141 (1944).

s tract, ibid., p. 145.

stances. N-Acetyl-d-*-ephedrine hy-drochloride (VIII ) thus gives a prac-tically quantitative yield of a product

(IX) of m. p. 179.5-1SlU, [CY]"D +98.6' (water),which is identical with the acetyl-&*-ephedrinehydrochloride prepared as described by Schmidtand Calliess.* It s aqueous solution shows a pHof 5 and cannot be directly titrated with alkali inthe presence of methyl red as can those of theN-acetyl hydrochlorides. However, on addition

of excess alkali and back-titra ting it is found t hatone mole of alkali has been consumed with thesimultaneous formation of one mole of N-acetyl-d-*-ephedrine (VII). These facts can be reconciledonly with an 0-acetyl structure for IX and anO+N acetyl migration according to the equation

RCH(OCORi)CH(Ri)SHRi.HC1 + S t O H+

aminoester hydrochloride

[RCH(OCORi)CH(Ri)SHRi]f SaCl f HOH

intermediate basic aminoesterI+CHOHCH(Ri)S(Ri)CORI

hydroxyamide

N-Acetyl-Z-ephedrine hydrochloride (111) whenheated yields a mixture of IX and 0-acetyl-I-ephedrine hydrochloride (IV) by virtue of ;t

Walden inversion occurring in the configurationabout the (number one) carbon atom adjacentthe benzene ring. This was demonstrated bythe isolation of IX to the extent of 59% of theproduct from I11 and by the isolation of 0-

acetyl-dl-ephedrine hydrochloride (dl IV), m. p.201-201.5° (dec.), to the extent of 2 3 % of theproduct from N-acetyl-&ephedrine hydrochlo-ride (d l 111). The use of a racemic substance t odemonstrate the presence of 0-acetylephedrinehydrochloride was necessary because, so far, allefforts to isolate crystalline I V have been un,



130 LLEWELLYN. WELSH Vol. 69

successfui. This compound appears to be muchmore solu'ble and difficultly crystallizable thanthe substances present in mixtures resulting fromreactions which obviously lead to its formation.Polarimetric examination of t he mixture of d-

ephedrine and d-*-ephedrine hydrochlorides ob-

tained af te r alkaline hydrolysis of the rearrange-ment product from N-acetyl-1-ephedrine hydro-chloride inldicated that the inversion amounted toabout Gi"%. 0-Acetyl-dl-ephedrine hydrochlo-ride, like the *-ephedrine analog, yields anaqueous solution of PH 5 which cannot be titrateddirectly with alkali in the presence of methyl red,bu t which in the presence of excess alkali con-sumes one mole of base while forming one mole ofK-acetyl-dl!-ephedrine (d l 11). It may be pre-pared in 50-7.370 yields by refluxing dl-ephedrinehydrochloride (d l I.HC1) with a mixture of acetylchloride arid acetic anhydride (5:l) or in about

yield by allowing a solution of dl I1 and hy-drogen chloride in !IOc) acetone to stand a t roomtemperature for six days during which an N-0

shift of acetyl occurs. Under the latter condi-tions 0-acetyl-d-@-ephedrine hydrochloride isformed from V I I . The formation of an N-acetyl hydrochloride as an intermediate precedingthe rearrangement undoubtedly occurs in eachcase.

A s stated previously, t he 0-acetyl salts cannotbe tit ra ted with alkali in the presence of methylred. Under the experimental conditions addi-tion of one drop of 0.1 N alkali to solutions ofthese substances yields solutions which are alka-line to this indicator (pH range cu. 4-8). In thecase of 0-acetyl-&*-ephedrine hydrochloride theyellow color gradually shifts toward the orangein the course of thirty minutes, whereas with thedl-ephedrine analog the yellow persists for amuch longer period of time. I n the presence ofphenolphthalein (pH range cu. 8-10) a consider-ably larger volume of alkali can be added to asolution of an 0-acetyl sal t before an alkalinereaction, a:; evidenced by a slowly fading pinkcolor, is pr'oduced. Addition of subsequent por-tions of alkali to a solution of 0-acetyl-&*-ephedrine :hydrochloride produces a pink colorwhich persists for about twenty seconds, and a

permanent end-point is reached only after oneequivalent has been added. A solution of 0-

acetyl-dl-ep hedrine hydrochloride gives with eachsubsequent increment of alkali a pink color whichdoes not ;fade completely until about fifteenminutes have elapsed. d permanent end-pointresults when one equivalent of alkali has beenadded.

These observations lead to the conclusion thatthe intermediate basic aminoester of the Q-ephe-drine configuration (X) rearranges much morerapidly to the hydroxyamide than does the onehaving the configuration of ephedrine (V), andth at the speed of rearrangement, in each case in-

creases as the pH is raised. If, instead of adding

- c v

alkali in portions until one equivalent is con-sumed, excess base is added at once, the rear-rangement of both diastereoisomers occurs prac-tically instantaneously.

Mitchell4 effected the hydrolysis of N-acetyl-l-ephedrine (11) and its diastereoisomer by diluteacid and alkali. Only d-*-ephedrine was isolableafter either treatment of the *-ephedrine deriva-tive, the yield being about 9770 in the presence ofacid and G5yOin an alkaline medium. Alkalinehydrolysis of N-acetyl-1-ephedrine gave only I-ephedrine in 78% yield, whereas acid hydrolysisprovided an S8yo yield of a mixture of hydro-chlorides which was separated "by the ordinarymethods" into approximately two parts of 1-ephedrine and one part of d-*-ephedrine hydro-chloride. His work was repeated in this Labora-tory bu t was carried out under quantitative con-ditions and was extended to include acid hy-drolysis of the 0-acety l hydrochlorides. Quan-tit ative yields of the 1-phenyl-2-methylamino-1-propanol having €he configuration of the originalmolecule were obtained in all cases except in theacid hydrolysis of N-acetyl-1-ephedrine. In thiscase inversion occurred a t the number one car-bon atom, and the product consisted of a mixtureof ephedrine and *-ephedrine hydrochlorides.Its optical rotation indicated a composition of(i1.770 of the lat ter and %.:<70 of the former.This was confirmed substantially by the separa-tion of the mixture into its components. Sep-aration was achieved by taking advantage of thewell-known difference in solubilities of the hy-drochlorides in chloroform and of the free basesin water: thus it was possible to separate thediastereoisomers in quantities totalling 96.2-9i.0yoof the original mixture. Of this percent-age d-*-ephedrine fractions totalled 6?&6570 and

those of 2-ephedrine amounted to 33-3770. Theratio of t he amounts of these substances is,therefore, almost the reverse of that reported byMtchell.* I t is of interest, however, th at i tcorresponds approximately to the 60% inversionindicated in the results of Emde12who studied theeffect of 2570 hydrochloric acid on ephedrine at100'. From a preparative point of view, theformation of *-ephedrine by acetylation and sub-sequent hydrolysis with dilute acid is simplerand more efficient than the classical methodwhich utilizes the action of strong hydrochloricacid on ephedrine. In the former method hy-drolysis may be carried out directly on the ace-tylation mixture, and more than SOcl, inversionis effected in little more than an hour, whereas inthe la tter method about sixty hours of heating in asealed tube is necessary to obtain approximatelythe same result.12

Since 0-acetylephedrine hydrochloride under-goes deacetylation without inversion in the pres-ence of dilute acid, inversion which occurs dur-ing acid hydrolysis of the N-acetyl derivative

(12) Emde, Hclv . C h im . Acto, 12, 377 (1929).



Jan., 19.4; CONSTITUTIONF XCETYLEPHEDRINEND XCETYI,-\~-EPIIEDRINE

I

I

+--

E---

0

0

26

ON

0

u,x2

c

0"x

0

Cf$

x

I

must do so during hydrolytic fission of the N-acetyl group or during an N+O shift of acetylprior to hydrolysis. Direct proof of the tran-sitory existence of 0-acetyl derivatives in thesystem would be difficult. However, indirectproof of the lat ter mechanism for the inversionmay be considered as furnished by the facts that

hydrolytic fission of the N-acetyl group would

occur a t a point relatively remote from the asym-metric atom involved, and that alkaline hydrolyticconditions, which could not in'volve an N+Oshift, cause no inversion. Kanao? has observed alike inversion during the N+O migration of acylradicals in derivatives of 1 phenyl-2-amino-l-propanol (norephedrine). Thus N-benzoylnor-

dl-ephedrine yielded 0-benzoylnor-&-*-ephedrine



132 LLEWELLYN . WELSH VOl. 69

hydrochloride, the only isolable product, onbeing heatt>dwith concentrated hydrochloric acid.The extent of inversion occurring during N-0acyl migrations in compounds of this type seemsto depend on the conditions, notably tempera-ture, which prevail during the acyl shift. In-crease in temperature favors inversion as ebi-denced by the results of Kanao in the norephed-rine series and by th e predominance of invertedmaterial in the product from the action of hotdilute acid on N-acetylephedrine. At lower tem-peratures less inversion takes place, since N-acetylephetlrine yields as much as 747, of 0-

acetyl hydrochloride of the same configurationby the action of hydrochloric acid at room tem-perature in 907, acetone. These results roughlyparallel those in which the hydroxyl group isesterified by acetyl which is provided by an ex-tramolecular sburce : acetylation of 1-ephedrinehydrochlorj de by boiling acetic anhydride2 yieldsas much as 58y0 of 0-acetyl-&@-ephedrine hy-drochloride, whereas under the considerablymilder conditions of refluxing with acetyl chlo-ride-acetic anhydride (5 :1) racemic ephedrinehydrochloride may furnish 737 , of uninverted 0-

acetyl salt. No inversion occurs during the re-verse (O-+N) migration of acetyl in the ephedrineand *-ephedrine derivatives even a t 100' :addition of alkali to boiling aqueous solutions of0-acetyl-dl-ephedrine hydrochloride and the cor-responding derivative of &@-ephedrine yieldedonly &ephedrine and d-\E.-ephedrine, espectively.Th e occurrence of inversion during an O+N acyl

migration in compounds of s tructures similar tothose described in this paper apparently has notbeen recorded in the literature.

It IS evident that the nitrosoacetyl derivativesprepared by Mitchell4 owe their formation to anN+O migration of acetyl which accompanied th enitrosation. Any inversion which may have oc-curred during this reaction, and the formation ofO-acetyl-d-'@-ephedrinehydrochloride in attemptsto prepare a hydrochloride from acetyl-1-ephedrineare interpreted t o be the result of such a migra-tion, and could hardly result from a simple re-action involving only the amino nitrogen.

Further study of the acyl migrations is in

progress.E~perirnental'~

Acetylation of Ephedrine and P-Ephedrine.-Twentzgrams of anhydrous l-ephedrine base was acetylated at 70by Mitchell's procedure4 with 20 cc. of acetic anhydride.The reaction mixture was dissolved in 25 0 cc. of water, 50g. of sodium bicarboqate was added in small portions, withstirring, an d the mixture allowed to stand, with occasionalstirring, until t he odor of t he anhydride had disappeared.Enough water was then added to dissolve the salts present,and the N-acetyl-lephedrine was extracted with chloro-form. After removal of chloroform, the residual oil slowlycrystallized when triturated with cold 30-65 O petroleumether. Th e yield of crude was about 95%. It was dis-solved in 40 cc. of warm benzene, and W cc. of 30-65'petroleum ether was added gradually, with stirring.

(13) Melting points are corrected.

Seeding an d scratching caused slow deposition of the com-pound in th e anhydrous form as the solution cooled to roomtemperature. The substance tends to crystallize ou t asaggregates of small prismatic forms, and too rapid coolingcauses it to be precipitated initially as an oil. When nomore material seemed to deposit, another 40-cc. portion ofpetroleum ether was added, the mixture was chilled for a

couple of hours, filtered, and the prec ipitate was washedwith petroleum ether. After drying several hours in vacuoover sulfuric acid it weighed 23.5 g. (93%), m. p. 85.5-86.5"; [CX ] ~"D % lo 50% ethanol, c = + 7 . 1 "(abs. ethanol, c = lo ) , -63 .2 ' (U. S. P. chloroform, c =

10). Mitchell4 has reported m. p. 87" [ C X ] ~ O D +7.0" (abs.ethanol).

N-Acetyldl-ephedrine was prepared in the same mannerand yield as the levo compound, and recrystallized by aqd -ing 50 cc. of petroleum ether to its solution in 50 cc. ofbenzene as described above. The white powder appearedas aggregates of plates under the microscope: m. p. 77-78.5".l5

Anal. Calcd. for CI~HI~NO~:, 6.76. Found: N,6.62.

Yields of crude N-acetyl-&*-ephedrine amounted toabout 90% of the theoretical. About 87 % recovery was

obtained on forcing it out of benzene solution by addingpetroleum ether (3 cc. of each solvent per gram of crude).The crystals consisted of small prismatic forms: m. p.103.5-104"; [CY]'~D 110. 4° (50% ethanol, c = 2 ) ,f113 .8" (abs. ethanol, c = 2), +121.8" (U. S. P. chloro-form, c = 2 ) . Values obtained by Mitchell4 are m. p . 103-1 0 4 O , [ c Y ] * ~ D$110.0" (abs. ethanol ). Sc>midt andCalliessa have reported a melting point of 101 .

N-Acetyl-dl-e-ephedrine was recrystallized from ben-zene-petroleum e ther in the manner described for theother N-acetyl compounds. It deposits slowly from super-saturated solutions as small prismatic forms, m. p. 76-77.5 ' This compound was prepared by Eberhardt'e byadding alkali to 0-acetyldl-*-ephedrine hydrochloride,bu t he was unable to induce it to crystallize.

Anal. Calcd.: N, 6.76. Found: N, 6.58.One per cent. aqueous solutions of each of the acety l

derivatives exhibited a pH of about 6.5, as did the dis-tilled water used in preparing the solutions.

Preparation of the N-Acetyl Hydrochlorides.-Fivegrams of N-acetyl derivative was dissolved in 60 cc. ofbenzene, and 15 cc. of a 2 .5 Nsolution of hydrogen chloridein absolute ether was added. The product from N-acetyl-l-ephedrine immediately precipitated in solid form, whereasthose from the racemic substance and from N-acetyl-&*-ephedrine precipitated as thick oils which completely crys-tallized after a few minutes of tri tura tion with a glass rod.After the mixture had stood a few minute$, any lumpswere crushed, the mixture was filtered with suction, andthe precipitate washed with benzene. The product wasfinely powdered under benzene, filtered and washed again.The filter cake was broken up and stirred frequently whilethe adherent benzene was allowed to evaporate duringexposure to the air. The powder was left over sulfuric acid

in a desiccator under diminished pressure (ca.40 mm.) fortwo hours. Yields amounted to 96-100% of the theoret-ical.

N-Acetyl-2-ephedrine hydrochloride, so prepared, was

(14) Tubes of 2-dm . length were used in all specific rota tion deter-

minations. The percentage of alcohol is expressed in per cent. by

vulume.

(15 ) Racem ic acetylephedrine and acetyl-*-ephedrine were first

prepared in this laboratory by the addition of alkali to the 0-

acetyl hydrochlorides. The ephedrine derivative so obtained melted

at 70-71°, whereas the *-ephedrine derivative began to melt at 6 3 O .

After standing one year in stoppered containers the substances

had melting poihts of 77-78.5" and 75-77.5', respec tively . Allsubsequent preparations of the compounds by this method and by

acetylation of the appropriate base yielded products showing the

higher melting point values. No explanation for the phenomenon is

offered, except t hat i t may be attributable to polymorphism.

(16)Bberhardt, Arch. P har m. , 268, 97 (1920).



Jan., 1947 CONSTITUTIONF ACETYLEPHEDRINEND ACETYL-*-EPHEDRINE 133

a white powder which, under the microscope (430 X),consisted of small prismatic forms. A capillary tube speci-men when placed in a melting point bath and heated at arate of 10" er minute to a temperature of loo" , and thenat a rate of one-half degree per minute melted a t 106-107".A similar specimen placed in a bath a t 100" and heated a t arate of 2 degrees per minute melted a t about 110 . The

[ P I 2 0 ~ as +5.6" (50% ethanol, c = 10) . Aqueous solu-tions of the substance, as well as those of the other N-acetyl salts, possess a free acidity which can be directlytit rated in the presence of phenolphthalein or methy l red.

Neut . equiv. Clalcd. for Cl2H17Pi02.HCl: 243.7. Found:neut. equiv., 242.

-4 .5131-g. specimen was dissolved in water, a slightexcess of 20% sodium hydroxide was added, and thesolution was quantitat ively extracted in a separatory, fun-nel with five 10-cc. portions of chloroform according to thetechnique commonly used in the assaying of pharmaceu-tical preparat ions. The filtered extract was evaporated todryness in a tared beaker which was then heated forty-fiveminutes at. 105" and cooled in a desiccator. The residualresin of N-acetyl-Z-ephedrine amounted to 0.4387 g. (1.006molecular proportions) . After being induced to crystallize,it melted a t 85-86'.

N-Acetyl-dl-ephedrine hydrochloride appeared underthe microscope as doubly refracting crystalline fragment:.Capillary tube specimens, when placed in a ba th a t 45 ,heated to 95' in four minutes, then heated a t a rate of >degree per minute, formed a partial melt a t about 100 .When further ra p i d l yp t e d , fusion progressed as the tem-perature rose to 175 : slow heating from this point re-sulted in a clear melt a t about 180".

i\'eut. equiu. Calcd.: 243.7. Found: neut. equiv., 243.

h'-Acetyl-d-*--ephedrine hydrochloride was seen underthe microscope as birefringent crystalline fragments.Specimens of the substance , contained in capillary tubes:when placed in a ba th a t 100" and heated a t a rat e of 5per minute, underwent some sintering as the temperaturerose to 175'. Heating at a ra te bf 1 per minute from th?point resulted in the occurrence of fusion at ca . 180 .Specimens, plunged into a bath at 130", in about fifteen

seconds formed at partially fused mass which resolidified.Specimens placed in a bat h a t 120" underwent no moreth an sintering or softening. The substance showed [a]*'D

+93:3" ( c = 2, ,50% C2H ,0H ). In absolute ethanol therota tion steadily decreased, probably a s a result of re-arrangement and deacetylation.

Neut. equiv. Calcd.: neut. equiv., 243.7. Found: 243.

By the same extraction procedure used on the N-acetyl-I-ephedrine salt, a 0.3028-g. specimen yielded 0.2581 g.(1.002 molecular proportions) of S-acetyl-d-*-ephedrineof m. p. 103-103.5".

0-Acetyl-&ephedrine Hydrochloride : A. From N-Acetvl-dl-ephedrine an d Hvdrochloric Acid-Acetone .-N-Aceiyl-dZ-e'phedrine (2.00 g.) was dissolved in 20 cc. ofacetone, 1.0 cc. of concentrated hydrochloric acid wasadded, a nd the container was stoppered and left a t roomtemperature. Presence of seed crystals a t this point did

not cause precipitation, bu t addit ion of seed after eighteenhours caused immediate growth of crystals. After six daysthe precipitate was filtered off, washed with acetone anddried. The yield of crystals melting at 200°, with foaming,was 1.76 g. (74.8%) and was quite reproducible. Recrys-tallization from 95% ethanol gave a 93% recovery ofmaterial in the form of rectangular platelets, m. p. 201-201.5" (dcc.). In melting point determinations the speci-men was placed in a bat h a t 195' and heated a t a ra te ofone degree per minute. The decomposition point was abouttwo degrees lower if the bath was at room temperature atthe star t of the determination. A 2% aqueous solutionhad a pH of 5.0.

A d . Calcd. for CI2Hl,NO2.HCI: C1, 14.55. Found:C1, 14.46.

The only crystalline material isolated in attempts toprepare the lephedrine derivative by this method was

lephedr ine hydrochloride. Occasionally a few crystals

formed shortly after adding the hydrochloric acid, butthese disappeared on standing, an d undoubtedly were theN-acetyl hydrochloride.

A 0.1320-g. sample was dissolved in 10 cc. of water andone drop of methyl red indicator was added. Addition ofone drop of 0.1 N sodium hydroxide caused the indicator toassume its yellow (alkaline) color which was unchanged for

a t least thirty minutes. Titration was attempted on asample of the above size in the presence of 2 drops of phenol-phthalein indicator. Alkali was added initially in 0.5-cc.portions. After addition of 1.5 cc. of 0.1 N base the solu-tion assumed a faint pink color which persisted for a num-ber of minutes. The alkali was subsequently added inapproximately one-cc. portions. Each addition produceda pink to red color which in fifteen minutes faded com-pletely. A red color which faded in ten to fifteen minutesto a permanent pink end-point was obtained afte r a totJ of5.49 cc. (1.013 molecular proportions) of alkali had beenadded.

A 0.2406-g. sample of the compound was dissolved in 5cc. of water, 20 cc. of 0.1 N sodium hydroxide was added,and the solution was backtitrated in the presence of methylred. The elapsed time between the sta rt of pipe tting thebase and the end of the tit ration was two minutes. Thealkali consumed amounted to 9.82 cc. (0.995 molecularproportion).

A 0.5000-g. sample was dissolved in 5 cc. of water, 1 cc.of 20% sodium hydroxide was added, and the mixture wasquantitatively extracted with six 10-cc. portions of chloro-form. The residue fr op the filtered chloroform extractswas heated in an oven a t 105" for one hour and cooled ina desiccator. The amorphous N-acetyld l-ephedr ineamounted to 0.4223 g. (0.993 molecular proportion).After being induced ,to crystallize by seeding and rubbingit melted a t 76-77.5 .B. By Heating N-AcetyldZ-ephedrine Hydrochloride.

-N-Acetyldl-ephedrine hydrochloride (5.00 9. ), con-tained in a small, loosely stoppered test-tube, was placedin an oven a t 110" and left for seventy minutes. The re-sulting hard mass, which had a slight odor of hydrogenchloride and acetic acid, was powdered and 4.88 g. wasdissolved in 20 cc. of boiling 95% ethanol. The solution

was cooled to room temperature, and allowed to sta nd onehour. The crystals were filtered off, washed with a littlecold ethanol, then with acetone and dried : 1.113 g.(22.8%), m. p. 200.5-201.5" (de c.) .

From Acetyl Chloride-Acetic Anhydride and dl-Ephedrine Hydrochloride.-Five grams of powdered d l -ephedrine hydrochloride, 50 cc. of acetyl chloride and 10cc. of acetic anhydride were refluxed together on the s teambath. As esterification proceeded the ephedrine salt be-came replaced by crystals of its acetyl derivative whichtended to remain dispersed throughout the solution whenboiling was inte rrup ted, whereas unacetylated materialcollected together as a denser solid phase a t the bo ttomof the flask. When no more ephedrine hydrochloride wasobserved (the time of reaction varied from five to six andone-half hours ), 25 cc. of the liquid was distilled off on thesteam-bath, the residual slurry was cooled and a mixture

of 15 cc. of acetone and30

cc. of ether was added. Thesuspension was cooled in ice, filtered, and the precipitatewashed with acetone and dried. The yield varied from 3.0to 4.4 g. (50-73%) of material melting at 201" (dec.) .The lowest yields were associated with the longest periodsof refluxing. Attempts to use acetyl chloride only as ace-tylating agent did not prove practical for the apparentreason that &-ephedrine hydrochloride is not sufficientlysoluble in the reagen t.

Efforts to prepare 0-acetyl-Z-ephedrine by this methodwere unsuccessful.

0-Acetgld-*-ephedrine Hydrochloride : A. From N-Acetyl-d-*-ephedrine and Hydrochloric Acid-Acetone.-N-Acetyl-d-"ephedrine (0.25 g.) was dissolved in 2 . 5 cc.of acetone and 0.13 cc. of concentrated hydrochloric acidwas added. In about one minute there began a depositionof crystals which grew to th ick, irregular , hexagonal plateshaving a decided tendency to twin. Within two hours

these had become markedly eroded. After five an d one-

C.



13.2 LLEWELLYN. WELSH \'d.59

half hours, during which erosion progressed, the liquidwas decanted off and seeded with 0-acetyl-&*-ephedrinehydrochloride. Sto ut six-sided prisms, also having atendency to twin, began to deposit. These were filteredoff af ter a short while, washed with acetone and dried:m. p . 178.5-181 O , not depressed when mixed with O-acetyl-&*-ephedrine hydrochloride prepared by other means, bu t

greatly depressed when mixed with d-"ephedrine hydro-chloride. In this experiment, the first precipitate was un -doubtedly the N-acetyl hydrochloride which dissolved oncontact with the mother liquor as the N-acetyl salt in solu-tion rearranged to the 0-acetyl salt. The method is of li ttlepreparative value since the la tter compound deacetylatesmuch more rapidly under the experimental conditions thandoes 0-acetyl-til-ephedrine hydrochloride. This was madeapparent by an experiment in which double quantities ofall the s.bove materials were used. After deposition of the0-acetyl salt had been initiated and the system had beenallowed to stand for eightcen hours, erosion of these crys-tals was noticed. After five days the qua nti ty of solid hadgreatly diminished, and the appearance of a thi rd crystal-line substance was observed. After one month the mixturewas filtered. The precipitate amounted to 0.33 g. (68%)of &*-ephedrine hydrochloride, m. p. and mixed m. p.183-181".

B. By Heat ing N-Acetyl-d-*-ephedrine Hydrochloride.--S-Acctyl-d-?€'-ephedrine hydrochloride (5.66 g.) washeated in the maimer described for the dl-ephedrine analog.The solid mass was recrystallized from 60 cc. of propanol-2.The yield was 5.01 g. (88.4%),17of rectangular parallele-p i p e d s , ? ~ ~1 . 5 2 5 , ~ ~1 . 5 3 4 , ~ ~1.573 (all *0.003),18m. p. 179.5-181", [ C Y ] * ~ D 98.6" (water, c = 2). Twoadditional recrystallizations failed to alter these constantssignificantly. A 2% aqueous solution showed a PH of 5 . 0 .Schmidt and Calliess* reported m. p. 176", [Q]~OD+96.8"(water), whereas the values obtained by Mitchellf arem. p. 187", [ c Y ] * ~ ' D 99.5" (water). The melting point ofthe compound varies somewhat with the rate of heating.Fairly reproducible results were obtained by placing capil-lary tube specimens in a bath preheated to 75', raising thetempera ture to 175' in five minutes, and then heating a t arate of one degree per minute. Melting points reported

in this paper for different batches of the substance weredetermined in this manner. Somewhat higher readingswere obtained if the ba th was preheated to 175". Fusionof t he specimen began a t about 176" if the temperatureof the bath was raised slowly from room temperature.

To explore the possibility that a few per cent. of 0 -

acetyl-1-ephedrine hydrochloride might be formed duringth e rearrangement as a result of inversion, a 0.2012-g.specimen of VI11 was heated as previously described. Theloss of weight as a result of heating was less th an 1 mg.The aqueous solution of the produc t consumed only 0.05cc. of 0.1 alkali on direct titration in the presence ofmethyl red, which shows that no more than a very smallamount of N-acetyl salt was present after the heating.Alkaline hydrolysis by the method described in a subse-quent section gave a quanti tative yield (2.168 g.) of d-";ephedrine hydrochloride, m. p. 183-184 , [ c y I z 1 ~ 4-61.0

(water, c=

1A). The melting point and rotation indi-cate that if any inversion occurred, its extent was quitesmall.

A 0.1354-g. sample was dissolved in 10 cc. of water an done drop of methyl red indicator was added. Addition of 1drop of 0.1 N sodium hydroxide produced a yellow color inthe solution. 1.n thirty minutes the color had definitelyshifted toward the neu tral, orange color of the indicator.A duplicate weight of substance was directly titrated inthe presence of 2 drops of phenolphthalein indicator.The 0.1 .T alkali was added in 1-cc. portions, and each offour such additions produced a transicnt pink color whichdisappeared almost a s soon as the flask was swirled. After

(17) The percentage recovery on recrystallization is in the same

range as those obtained from purified material an d indicates th e re -

action is practically qua ntita tive.

(18) Refra ctive indices by Wm . V. Eisenberg, Division of Micro-

biology, U.S. Food and Drug Administration.

____-_.

addition of the fifth portion a period of about tweuty sec-onds elapsed before disappearance of color. Alkali wasthen added in two-drop, and, finally, one-drop portions,with intervals of twenty seconds between additions. Apermanent pink end-point was obtained when 5.59 cc.(1.005 molecular proportions) of alkali had been added.The compound behaved in .the same manner as did 0 -

acetyldl-ephedrine hydrochloride on addition of excessalkali and backztitrating i n the presence of methyl red .A solution of 0.4512 g. of the substance in 5 cc. of water

was made alkaline and quantitatively extracted withchloroform. The residue of N-acetyl-d-*-ephedrine ob-tained amounted to 0.3847 g. (1 00 molecular propor tion),m. p. 102.5-103.5", [cy]% $120.5' (U . S. P. chloroform,c = 3 . 5 ) .C. By Heating N-Acetyl-Z-ephedrine Hydrochloride.-

N-Acetyl-Z-ephedri!e hydrochloride (5.00 g.) mas placedin an oven at 110 . After about forty minutes it hadcompletely liquefied, and af ter a n additional thir ty minutesthe melt had partl y resolidified. I t was digested with 50cc. of ho t benzene, cooled to room temperaturc, andallowed to stand fifteen minutes. The insoluble crystalswere filtered off, washed with benzene and dried. Thereresulted 2.58 g. (51.6%) of 0-acetyl-d-*-ephedrine hydro-chloride, ni. p. 175.5-177.5". Recrystallizatiotl from pro-

panol-2 yielded 2.26 g. of product melting a t 179-180.5".No well-defined crystalline material was obtained from thefiltrate from the benzene digestion.

To ascertain polarimetrically the cxtent of inversionwhich occurs during the rearrangement, a 0.5062-g. samplecontained in an open 50-cc. round-bottom flask was placedin an oven a t 110". The sample was cornplctely liquefiedafter twenty-five minutes, an d was kept a t 110' a n addi-tional eighty minutes. The product was subjected to thealkaline hydrolysis procedure described in a subsequentsection. The yield of mixed ephedrine and *-ephedrinehydrochlorides obtained from the ether extract was 0.4175g. (99.7%), [ a I z 0 D $29.7' (water, c = 3.8). The rota-tion corresponds to 66.7% d-*-ephedrine hydrochloride.In calculating the composition of t he mixture, values of+61.7" an d -34.5" were used for the d-*- and I-ephedrinehydrochlorides, respectively, and represent results obtained

in this laboratory from recrystallized materials.D. From Acetic Anhydride and I-Ephedrine Hydro-chloride.-I-Ephedrine hydrochloride (5.00 g.) was re-fluxed three hours with 50 cc. of acetic anhydride. Themixture was evaporated to a sirup on the stcam-bath in acurrent of air, and 30 cc. of acetone was added. Since de-position of crystals was slow, the mixture was left ty o daysin a refrigerator freezing unit. The crystals were washedwith acetone, then ether , and dried. The crop of productmelting a t 179.51 81 \as 2.32 g. A second crop of 1.18g., m. p. 177.5-179.5 , was obtained by adding moreether to the filtrate and washings. The total yieldamounted to 57.9%. Recrystallization from propanol-2yielded 3.17 g. (52.5%) of substance melting at 17 8. 3~180.5'. It gave no depression of rnclting point w hwmixed with the products obtained in A, B atid C. \\'henthe reaction was carried out on dl-ephedrine hydrochloridethe yield of racemic product ,I6 melting at 1613-170" wasabout 40%. Neither Schmidt a nd Calliess* nor I l b c r -hardt*G reported yields.

Acid Hydrolysis : A. N-Acetyl-[-ephedrine .-A mixtureof 5.00 g. of ?r'-acetyl-I-ephedrine and 100 cc. of 5%hydrochloric acid was refluxed one hour . The solution wasdistilled to apparent dryn5ss under a water-pump vacuum(bath temperature 5 06 0 , raised to 100" toFard end ofdistillation) a nd the rcsidue was dried a t 105 . Removalof water and acid a t a relatively low tempera ture was car-ried out in order to minimize any inversive or decomposingeffect which might be manifest under morc vigorous condi-tions as the acid concentration increascd during distilla-tion. The yield of mixed hydrochlorides was quanti tative(4.86 9.). The mixture began to melt a t 160", nd showed\a] 0 ~ 24.9" (water, c = 2 ) . This rotation correspondsto a composition of 61.7% of &?-ephedrine hydrochloridean d 38.3% of I-ephedrine hydrochloride. -4mixture pre-

pared to contain these percentages of pure hydrochlorides



Jan., 1947 CONSTITUTIONF ACETYLEPHEDRINEND ACETYL-*-EPHEDRINE 135

of ephedrine and *-ephedrine began to melt a t 161', andshowed [ c Y ] ~ ~ D25.0" under the same conditions. Thedried reaction product was refluxed with 120 cc. of U. S. P.chloroform for one-half hour, and the suspension wascooled to room temperature an d allowed to s tand one-halfhour. The crystals of I-ephedrine hydrochloride werefiltered off, washed with chloroform and dried: 1.128 g.

(23.20/0), m. p . 214-216". The residue obtained from thefiltrate and washings was dissolved in 10 cc. of water, 5cc. of 20% sodium hydroxide was added, and the mixturewas kept ai. 0" for one-half hour. The precipitate of d-*-ephedrine base was filtered off, washed with 20 cc. of ice-water and dried overnight over sulfuric acid: 2.366 g.(59.4%), in. p. 117.5-118.5'. The filtrate and washingswere quantitatively transferred to a separatory funnel,saturated with anhydrous sodium sulfate, and quantita.-tively extracted with five 20-cc. portions of chloroform. Aslight excess of ethereal hydrogen chloride was added to thefiltered extract, a.nd the suspension was evaporated todryness. The residue of hydrochlorides was treated asbefore with 10 cc. of chloroform, the suspension wasfiltered, and the ephedrine hydrochloride was washed withchloroform: 0.522 g. (10.7%), m. p. 21-1.5-216'. Theresidue from the chloroform filtrate was dissolved in 1.5cc. of water a nd filtered to remove a small amount of in-

soluble matter . The filtrate plus washings (volume 3.5cc.) was made alkaline with 0.5 cc. of 20% sodium hydrox-ide, and tht: crop Qf I-ephedrine was filtered off, washedwith cold water and dried: 0.096 g. (2.1%), m. p. 117-118". A third c rop of Z-ephedrine hydrochloride was ob-tained by benzene extraction of the filtrate (saturated withsodium sulfate) , addition of etherea l hydrogen chloride toth e extract, and digestion of t he mixed hydrochlori$es withchloroform. 0.050 g. (1.0%), m. p. 207.5-213.5 . Thecombined XP-ephedrine fractions showed [ C Y ] *OD $51.6"(abs. ethanol, c =: 5), and a neutralization equivalent of166.6 (calcd. 165.2!). A composite of the three I-ephedrinehydrochloride fractions gave [ C Y ] ~ O D -32.2' (water, c =

IO), EmdeIq reported [a] 7 ~ .53' for d-*-ephedrine inabsolute ethanol.

Hydrolysis was also carried out directly on reactionmixtures resulting from the acetylation of ephedrine base.

There was no appreciable difference between the resultsobtained from such mixtures and the results from thehydrolysis (o f purified material. In either case the totalrecoveries were 96.2-97 .0% of product consisting of 62.6-65.370 of d-*-ephedrine an d 34.7-37.4% l-ephedrine.Hydrolysis with 25% hydrochloric acid gave somewhatlower yields and 'was accompanied by the formation ofmaterial having a terpenoid odor.

B . 0-Acetyl-&-ephedrine Hydrochloride.-A solutionof 1.176 g. of the substance in 20 cc. of 5% hydrochloricacid was refluxed one hour and the liquid distilled off undera water-pump vacuum. The residue was dried at 105".The yield of &ephedrine hydzochloride was quantitative(0.978 g.), m. p. 187.5-189.5 . Digestion with 10 cc. ofchloroform resulted in a 1% loss of weight and raised themelting point to 188.5-190" (no depression on mixed m. p.) .C. N-Acetyl-d-*-ephedrine.-The hydrolysis mixture

from 0.5001 g. of substance a nd 10 cc. of acid was quant i-tatively transferred to a separatory funnel, the solution(volume now 30 cc.) was saturated with sodium sulfateand made alkaline with 8 cc. of 20y0 sodium hydroxide.The mixture was extracted quantitatively with six 25-cc.portions of ether , and the combined extracts were washedwith three '+-cc. portions of water. The water washings,af te r being combined, were shaken with 15 cc. of etherwhich was ihen added t o the main ether extract, and thewhole was filtered through cotton. A slight excess ofethereal hydrogen (chloridewas added and the mixture wasevaporated to dryness on the steam-bath in a current ofair. After drying a t 105' the residue of d-*-ephedrinehydrochloride weighed 0.4851 g. (99.7%), m. p. andmixed m. g . 183-184', [Cy]'OD +61.2" (water, c = 3) .D . 0-Acetyl-&*-ephedrine Hydrochloride.-The hy-

drolysis product from 0.5510 g. of material was subjected to-(19) Ernde, Helu . Ckim. A c t a , 14 , 365 (1929).

the procedure described in C. A quantitative yield(0.4562 9 . ) of &*-ephedrine hydrochloride was obta ined,m. p. and mixed m. p. 183-184', [ c ~ ] ~ ~ D61.5" (water,c = 3 ) .

Alkaline Hydrolysis: A. N-Acetyl-Z-e hedrine.-A0.5000-g. sample was dissolved in 1 cc. of 95& ethanol, 10cc. of 10% sodium hydroxide was added, an d the mixture

was refluxed four hours. The hydrolyzate was transferredto a separatory funnel by means of benzene and 10 cc. ofwater, and extracted quantitatively with six 20-cc. por-tions of benzene. The Z-ephedrine hydrochloride obtainedfrom the ext racts weighed0.4850 g. (99.7%), m. p. 217.5-218.5", [ c Y ] ~ ~ D34.8' (water, c = 4).

B. N-Acetyl-d-*-ephedrine.-Hydrolysis of 0.5000 g.as in A, and extraction of the *-ephedrine into ether in-stead of benzene, ultimately gave a quantitative yield(0.4,sSO g.) of &*-ephedrine hydrochloride, m. p. 187-184 , C Y ] ~ O D 4-61.9" (water, c = 3).

Rearrangement of 0-Acetyl Hydrochlorides at 100 ,--

Samples (0.50008 . )of 0-acetyld l-ephedrin e hydrochloridean d the &*-ephedrine analog were dissolved in a mixtureof 5 cc. of water and 1 cc. of 95% ethanol, and the solutionwas heated to boiling, under reflux. Five cc. of 20%sodium hydroxide was added dropwise through the con-denser, and refluxing was continued for four hours in orderto ensure complete deacetylation. The hydrolyzates wereworked up respectively as described in A an d B of the pre-ceding section. Th us was obtained 0.4115 g. (99.4%) ofdl-ephedrine hydrochloride, m. p. 188.5-189.5", and 0.4118g. (099.5%) of d-*-ephedrine hydrochloride, m. p . 1%-1 8 4 .

Summary

1. Acetylephedrine and acetyl-\E-ephedrinehave been shown to possess an N-acetyl (amide)structure. The acetyl-d- and -dl-*-ephedrine hy-drochlorides previously reported in the literatureare 0-acetyl (ester) hydrochlorides.

2 . Acetylephedrine and acetyl-*-ephedrineform, under suitable conditions, relatively stable

hydrogen chloride adducts (N-acetyl hydrochlo-rides) which, when heated, undergo an K-0shift of acetyl and rearrange to 0-acetyl hydro-chlorides. The rearrangement of the *-ephedrinederivative occurs without appreciable inversionat the carbon atom CY to the phenyl group, whereasthe product of the rearrangement of the ephedrineanalog is a mixture of diastereoisomers in whichthe *-ephedrine derivative predominates.

3. Treatment of N-acetyl-*-ephedrine andthe 0-acetyl hydrochlorides of ephedrine and +-ephedrine with boiling 5y0 hydrochloric acidyields only the aminoalcohol having the configura-tion of the original compound. NIAcetylephed-

rine yields a mixture of ephedrine and 9-ephedrine hydrochlorides in the approximateratio of 38:62. The inversion which occurs doesso during an N+O shift of acetyl prior to hy-drolysis, and does not result from the action ofthe acid on ephedrine.

Alkaline hydrolysis causes no inversion in anycase.

4. The extent of the inversion which accom-panies an N+O shift of acetyl in the ephedrineseries appears to increase with increasing tem-perature.

In the presence of alkali the 0-ace tyl hy-drochlorides rearrange quantitatively t o N-acetyl

compounds without change in configuration.

3 .



136 CHARLES D. ROBESONND JAMES G. B A X T E R Vol. AI )

The rearrangement undoubtedly takes place ephedrifie. The speed of rearrangement is af-through an intermediate 0-acetyl base, and is fected by the hydrogen ion concentration, and ismuch more rapid in the *-ephedrine derivative practically instantaneous a t a sufficiently high p H .

than in thie one having the configuration of WASHINGTON,. c. RECEIVEDUGUST 6, 1946

[COMMUNICATION NO. 1 FROM TH E LABORATORIESF DISTILLATIONRODUCTS, INC . ]

Neovitamin A’

BY CHARLES . ROBESONND JAMES G. BAXTER

It was previously reported t ha t a portion of thevitamin A in the unsaponifiable mat ter of fishliver oils could not be crystallized.2 This so-called “noricrystallizable vitamin A” has beenfurther studied and from it has been isolated incrystalline form a previously unrecognized geo-metric isomer of vitamin A, which we shall call

“neovitamin A.” Our work indicates that neo-vitamin A differs from vitamin A only in thespacial con.figuration about the double bondnearest the hydrdxyl group.

The new isomer constitutes about 35% of thetotal vitamin present in a number of the commonfish liver oils, so that its physical and chemicalproperties, and especially its biological potency,are of commercial as well as theoretical interest.This paper is concerned with these properties,with t.he method of isolation, and with the struc-ture of the newly recognized vitamin. A pre-liminary report on the work has already beenpublished.3

Isolation of Crystalline Neovitamin A.-Someof the preliminary steps in the isolation work havepreviously been de~cribed.~ he source materialwas shark liver oil. This was distilled in a cyclicmolecular still to concentrate t he neovitaminA andvitamin -4esters. The nonsaponifiable matter wasprepared from the concentrate and redistilled tofurthe r concentrate the two vitamins. The majoramount of the vitamin A was separated from thisdistillate by crystallization from ethyl formate a t- 0’.. After removal of solvent from the filtratean orange oil was obtained, from which substan-tially all the remaining vitamin A was removed byselective adsckption. Finally, the neovitamin A

concentrate was esterified with phenylazobenzoylchloride and the ester crystallized. This ester(m. p. 94-96’, Fig. 1) melted higher than the cor-responding vitamin 9 ster (m.p. 79-SO’, Fig. 2).

Saponification of the ester yielded neovitamin Aas an oil which crystallized from a solution inethyl formake a t -35’ as pale yellow needles(m. p. 6S--6Oo). The crystals (Fig. 3 ) weremarkedly different in appearance than the yellow

(1) Presented in part at the Atlantic City Meeting of the American

(2) J, G . Baxter, P. L. Harris, K . C. D. Hickman and C. D. Robe-

(3 ) C . D. Robeson and J. G. Baxter, Nn f u v e , 155, 300 (1945).

(4 ) J . G. Baxter and C . D. Robeson. THIS OURNAL, 64, 2411

Chemical Society, Atlantic City, New Jersey, April 1 1 , 1946.

son, J . B i o l . Chem. , 141,991 (1941).

(1942).

prisms of vitamin A (m. p. 62-64’, Fig. 4) and amixed melting point determination showed adepression.

The crystalline anthraquinone /3-carboxylateesters of neovitamin A and vitamin A were pre-pared and found to differ. The neo ester was red(m . p. 134-136’) while the vitamin X erivative

was yellow (m. p. 121-122’). Hamano” andMead6 obtained red crystals (m. p. 118’) andyellow crystals (m. p. 123-124’) which they con-sidered to be polymorphic forms of the samecompound. It now seems probable that theirred crystals, which melted 16-18’ lower than ours,were a mixture of the neovitamin A and vitamin Aesters, while their yellow crystals were purevitamin A anthraquinonecarboxylate.

Physical and Chemical Properties of NeovitaminA

Ultraviolet Absorption Spectrum.-Neovita-min A has an absorption curve similar in shape to

that of vitamin A bu t the position of the maximum(32smp) is slightly different from that of vitamin

A (324-5 mp, Fig. 6).(328 mp) = 1646 for neovitamin iZ was found (5preparations).’

Infrared Spectrum.-The infrared transmis-sion spectrum of neovitamin A is compared withthat of vitamin A in Fig. 6. The curves arealmost identical, with slight differences occurringin the position of the bands at 9.25 and 8.00microns.8

Atmospheric Oxidation.-Neovitamin A wasslightly more resistant to atmospheric oxidationthan vitamin A when dissolved in refined cot-

tonseed oil at a concentration of 20,000 U. s. P.units per gram. The palmitic esters of the twocompounds were equally stable in refined cotton-seed oil a t a concentration of 90,000 units pergram. These conclusions were based on data ob-tained by uniformly exposing the oil solutions toair a t 55’ in an oven. A rocking device and glassrocker tubes provided, respectively, the agitation

An average value of

(5 ) S . Hamano, Sci . Pa p e rs In s t . Ph y s . Chcm . Reseavch T o k y o , 32,

( 6 ) T. H. Mead, Biochem. J . , 33, 589 (1939).

(7) Mr. G.Wait and assistants of this Laboratory made the meas-

urements using a Beckman spectrophotometer.

(8) Th e infrared transmission spectra were obtained by Dr. S. F.

Kapff of th is Laborato ry, using a Perkin-Elmer infrared spectrome-

ter, Model 12-A.

44 (1937).

Documents

Llewellyn H. Welsh- The Constitution of Acetylephedrine and Acetyl-psi-ephedrine