NO\-. 30, 195s
*bVIDES O F
d-a-xf ETHYLPHENETHYLAMINE
6065
u.s. VITAMIN CORPORATIOX] Analeptic Amides of d-a-Methylphenethylamine
[COYTRIBCTIOY
FROM THE
RESEARCH LABORATORIES O F THE
BY SEYMOUR L. SHAPIRO, IRAM. ROSEAND LOUISFREEDMAN RECEIVED JUSE 16, 1988 A series of amides of d-a-methylphenethylamine (I) have been synthesized and examined for excitant activity. Such activity has been found in the formamide and with selected a-oxyacylating groups. The structural parameters t o which activity is confined are discussed, and a molecular model of the active form of t h e products proposed.
The noted cardinvascular side effects' of d- and amide were obtainable.8 The compound (Table dl-a-methylphenethylamine have detracted from I, compound 3) also was prepared readily using the wider clinical application of these compounds acetyl chloride. in a variety of therapeutic indications. The aminolysis of the a-hydroxy esters such as With the premise that relatively small quantities ethyl glycolate, ethyl lactate and ethyl a-hydroxyof free d-a-methylphenethylamine (I) are required isobutyrate proceeded readily. Here, reactivity for pharmacologic r e s p o n ~ e ,we ~ . ~have investigated was probably increased as a result of forms such the effect of acyl derivatives of I in the search for as those postulated by Ratchford.g active structures which might be free of the noted An asymmetric a-carbon atom in the acylating cardiovascular side effects of the parent amine. moiety reflected the possibility of isolation of the Since activity is associated largely with d-a- dd- and dl-forms of the resultant amides. Such methylphenethylamine, our explorations were separation was effected in selected instances (Table largely limited to derivatives of this substance. 11, compounds 59, 60 and 66, 67) by fractional A broad program of synthesis was undertaken crystallization procedures. and the compounds prepared are described in The aminolysis reaction with benzilic acid proTables 1-111. In selected instances] parallel series ceeded with difficulty and yielded the benzilic of dL-and I-, as well as d-derivatives were studied. acid salt of the amine, and from the breakdown prodAs the work progressed, i t became evident t h a t uct] benzophenone,'O a 34y0 yield of N-a-methylactivity was substantially confined to selected phenethylbenzhydrylimine. Reaction with methyl structures containing an a-oxy function on the benzilate" (as above) afforded only the benzilic acid acylating group and these were explored in more salt of d- a-methylphenethylamine. detail. The corresponding a-chlorodiphenylacetamide The role of the acylating groups containing an (Table I, compound 34) was prepared readily from o-oxy function was explored with the sympathomia-chlorodiphenylacetyl chloride, but hydrolysis12 metic amines, d-N-methyl-a-methylphenethyland isolation of the desired benzilamide was unamine (Table 11, compounds 41, 5 3 ) and phenyl- successful. propanolamine (Table I I I ) , to establish whether The aminolysis with dibasic esters was effected desirable modification of the properties of these readily in most instances. With the malonates, substances would also be obtained. The synthesis of the compounds followed es- the required bisamide was obtained using diethyl tablished procedures and the acylating component malonate and diethyl ethyl malonate. With diused, reflected in general, its commercial accessi- ethyl phenylmalonate, no reaction was noted,13 bility, and this was varied as esters, acid chlorides, and upon addition of sodium methoxide as a basic catalyst, the reactant ester suffered decarbethoxylfree acids, lactides and lactones. Although a-methylphenethylamine is a struc- ation l 4and N-d-a-methylphenethylphenylacetamide turally hindered amine, no complication occurred (Table I, compound 31) and bis-N,N'-d-a-methylin the aminolysis of ethyl formate5 though the phenethylurea were obtained. Under similar conhigher boiling ethylene diformate6 was more con- ditions, diethyl ethylphenylmalonate afforded the urea and N-d-a-methylphenylethyl-a-phenylbutyrvenient and afforded a cleaner product. By contrast, under parallel conditions, the hin- amide (Table I, compound 3 2 ) . The noted decarbethoxylation of the substituted dered a-methylphenethylamine failed to react with ethyl acetate' although under forcing condi- malonate esters14 when treated with alkoxide to tions under pressure, excellent yields of the acet- give the phenyl acetate and ethyl carbonate followed by reaction with I, would account for the (1) (a) L. S. Goodman and A. Gilman, "The Pharmacological Basis product isolated. The amine I, however, yielded
of Therapeutics," 2nd ed., T h e Macmillan Co., New York, N. Y., 1955, p. 516; (b) K. Soehring and G . Ergenzinger, Arzneimitlel-Forsch., 6 , 478 (1955). ( 2 ) S. L. Shapiro and L. Freedman, A r c h . i n t e r n . p h a r m a c o d y n a m i e , 112, 419 (1957). ( 3 ) J. Axelrod, J. Pharmacal. E x p . Therap., 110, 315 (1954). (4) For specific reaction r a t e constants for sympathomimetic amines with methyl acetate, see S. L. Jung, J. G. Miller and A. R. D a y , THIS J O U R N A L , 7 6 , 4604 (1953). ( 5 ) W. H. Watanabe a n d L. R. DeFonso, ibid., 78, 4542 (1956). (0) S. L. Shapiro, V. 8 . Parrino, K. Geiger, S. Kobrin and L. Freedman, ibid., 79, 5064 (19571. (7) Failure of aminolysis of ethyl acetate b y t-butylamine is noted: W. P. Ratchford a n d C. H. Fisher, J . Org. C h e w . , 15, 317 (1950); see ref. 4.
(8) For enhancement of t h e r a t e of another sterically unfavorable reaction through t h e use of forcing conditions, see I. S. Bengelsdorf, THISJOURNAL, 80, 1442 (1958). (9) W. P. Ratchford, J. Org. Chem., 15, 326 (1950). (10) H. H. Wasserman, H. W. Ackerman, H. H. Wotiz and T. Liu, THISJ O U R N A L , 77, 973 (1955). (11) A. Rahman and M. 0. Farooq, N a t u * ~ i s s e n s c h a J t e n . 41, 1 (1954). (12) Possible complicating side products may he 2,2'-oxyhis-(nphenylphenylacetamides) similar t o t h e bisamides reported b y A. H. Schlesinger a n d E. J. Prill, THISJOURNAL, 78, 6123 (1956). (13) S. B. Speck, ibid., 74, 2876 (1952). (14) V. H. Wallingford, A. H. Homeyer and D. M. Jones, ibid., 63. 2056 (1941).
SEI-BIOUR
L. SHAPIRO,
IRA
d Compound
1' 2Q " 1 3 1 h (1 1
5%
6 7" 2 8 9 10 11 12"2 13 14"* 15 16"2 17"2 18 19 20 21 22 23 24 25 26 27 28l 29" 30 31 32 33 81
K
H H CHr CH3ClCHr BrCH2BrCHlC12CHC&cClZFCClFZC ClFJCF3CFdCCF3CF2CFaCF2CF~CF~CFISCCH2CH,CHRrClCHaCHr HOCH~CHZO-~ HOCHzCHCHtOOCHHOOCCHzCHzC?HdOCH2CH?2-H OCoH4~ ~ ~ ~ 0 C4H4S--h 3-C0H6 S-'" I-C,H,S-'" CoHbCHaC6H5CH(CzH,)CIHaOCH=CH(CeHdLCHCl-
\ I 11 , " C , bsc h P (mm)
49-50 104 (0 08) 123-125 93-94 49-50" 102-114 (0 03) 114-128 (0 1) 82-8GC6 73-75 92-93c'
79-80'' 79-8 1' I 79-81C1 82-8403: C, 67.3; H , 7.5; S , 6.5. Found: C , 66.5; H , i.3; S,6.8. The analytical figure indicates two moles of d-a-methylphenethj-lamine reacting with one mole c?f glucuronolactone with elimination of one mole of water. The compound was not further investigated. Hydroxyethyl Urethan of d-a-Methylphenethylamine (Table I, Compound 21).--.1 mixture of 6.75 g. (0.05 mole) o f d-a-ineth?-lphenethylaniine and 4.8 g. (1070 excess) o f ethylene carbonate was heated at 60' for 24 hr. and then a t i).2 inin. and 100" for 1.5 hr. On distillation of the residue there wvas obtained 68''; yield of product, b . p . 144-149' a t 11.2 111171. Coinp~iuritl22, Table 1 \v:ti siinihrly prepared. -.
~~~
.
(30) T h e compound has been described herein in view of the y h a r m a c o l o g i c d acti\.ity i t s i m l , r t e d (31) T h e authors a p p r c c l r t c t h c hainl,Ic of gluciirt,tiiililct~,oclira \ i < l e d b y - 13r 11 \I. Iiathmann. Ccxn P r o d u c t s Refining Co., S e a Y ( i r k . ?-. T.
Nov. 20, 1958
AMIDESOF
d-(U-METHYLPHENETHYLAMII\'E
T h e Diastereoisomers of N-(d-a-Methylphenethy1)-amethoxyphenylacetamide (Table 11, Compounds 66 and 67) .-When 8.3 g: (0.05 mole) of dl-a-methoxyphenylacetic acid a n d 6.76 g. (0.05 mole) of d-a-methylphenethylamine in 100 ml. of xylene were treated as above, 0.9 ml. of water was collected in 15 hr. After the removal of the xylene, the residue of 12.5 g. crystallized on cooling. T h e solid was dissolved in 100 ml. of boiling hexane and five 20-1111. portions of hexane added as the solution cooled. On standing for 4 hr., 5.9 g. (m.p. 50-68") separated, called fraction I. T h e filtrate stored a t 10" for 72 hr. afforded 4.0 g. (m.p. 58-60'), called fraction 11. Fraction I was dissolved in 150 ml. of boiling hexane and after standing 4 hr., 2.3 g. (compound 66), m.p. 70-76", was obtained, CYD (CHCla) -24.6". Fraction I1 was dissolved in 100 ml. of hexane. On standing for several hours, the hard needles of compound 66 formed. These mere separated and on standing for 20 hr., 1.8 g. of fluffv needles of comDound 67 was obtained, m.D. 55-56", LYD (CHC13) -55.1O.T h e Diastereoisomers of N-id-a-MethvlDhenethvli-aphenoxypropionamide (Table 11, Compound; 59 a n d 60). A solution of 9.23 g. (0.05 mole) of dl-a-phenoxypropionyl chloride in 25 ml. of benzene was added to a stirred cooled solution of 13.85 g. (0.015 mole) of d-a-methylphenethylamine in 75 ml. of benzene a t 15". T h e stirred suspension was allowed t o warm t o room temperature over 30 minutes. T h e amine hydrochloride was separated and the benzene solution was washed with dilute hydrochloric acid, water, dilute sodium hydroxide and finally water. Upon removal of the benzene, there was obtained 13.1 g. (92Yc) of the mixture of isomers, m.p. 80-110'. Compound 59, Table 11.-The crude mixture was stirred with 1 liter of hexane a t room teniperature and filtered. The insoluble material, 4 g. melting about 123", was recrystallized from a mixture of 110 ml. of hexane and 20 ml. of eth) 1 acetate, yielding 3.2 g. j22yLL)of needles, m.p. 124-125.5". Compound 60, Table 11.-To the filtrate above, hexane was added to a total volume of 1.5 liters and a small additional crude crop of compound 59 was separated a n d discarded. On cooling a t 10" for 48 hr., a n additional 0.6 g . of mixed product, m.p. 87-94', was obtained and discarded. T h e filtrate was concentrated to 250 ml., carbon added and the solution filtered. After several hours, the formed crystals of compound 60 were separated, washed with hexane and dried; yield 4.0 g. (28761, m.p. 97-98'. Reaction of d-a-Methylphenethylamine with Diethyl Phenylmalonate in the Presence of Sodium Methoxide .--A mixture of 11.8g. (0.05 mole) of diethyl phenylmalonate, 20 ml. (excess) of d-a-methylphenethylamine and 1.0 g. of sodium methoxide was heated under reflux. After 1.25 hr. the formed ethanol was removed (4.0 ml.). \Vhen cool, the solid residue was triturated successively with 1 -V hydrochloric acid, water and hexane, yielding 20.2 g. of a mixture of products, m.p. 8G90". Isolation of N,N'-Bis-(d-a-methylphenethy1)-urea.--A solution of 2.0 E. of the above material in 15 ml. of hot ethanol (charcoal) was filtered, diluted with water (5.0 ml.) till just cloudy, and seeded. After standing overnight, the crkstals which had formed were filtered, washed with 5 0 7 ethanol and dried over phosphoru2 pentoxide a t 80" giving 0.53 g. of the urea, m.p. 147-151 . h mixed m.p. with a n authentic sample of the urea (m.p. 149-151') was 148-151'. Anal. Calcd. for C ~ S H Z ~ S ? C, O : 77.0; H, 8.2; N,9.5. Found: C, 77.6; H , 8.0; N, 9.7. Isolation of N- (d-a-Methylphenethy1)-phenylacetamide .T h e product mixture, 2.0 g., was extracted with 100 ml. of boiling hexane. On coooling, the filtrate deposited 0.42 g . of a mixture, m.p. 88-91 . l f t e r several recrystallizations from hexane, most of the urea wau removed and the m.p. of the needles (0.12 9.) was raised to 89-96". The mixed melting point with authentic amide (Table I , compound 31) wa? 92-98'. N,N'-Bis-(d-a-methylphenethy1)-urea.--B solution of 8.0 g. (0.059 mole) of d-a-methylphenethylamine, 2.0 g. (0.033 mole) of urea and 10.0 g. of glacial acetic acid was heated in a n oil-bath until 4.0 ml. of acetic acid distilled 0 ~ t . 3 2 T h e cool, still liquid residue was diluted with 70 ml. of methanol and 30 ml. of water was added to the cloud Doint. T h e product Crystallized and was separated, 0.76' g. (8.5%), m . p . 149-151'. (32) R. H. Wiley, P. Beasley and L . H. Knabeschuh, THISJ O U R XAL.
7 6 , 311 (1954).
607 1
Reaction of d-0-Methylphexiethylaminewith Diethyl Ethylphenylmalonate in the Presence of Sodium Methoxide.-A solution of 13.2 g. (0.05 mole) nf diethyl ethylphenylmalonate and 20 ml. (excess) of d-a-methylphenethylamine heated under reflux showed no reaction, with the internal temperature remaining a t 214' for 2 hr. Upon addition of 1.1 g. of sodium methoxide, the internal temperature fell to 116' after 2 hr. under reflux. Distillation a t atmospheric pressure up t o 190" yielded 3.7 ml. of formed alcohol. Upon additional heating under reflux, the internal temperature fell from 185 t o 173" after 3.5 hr. IVhen cool, thesolid residue was washed successively with 1 N hydrochloric acid, water and hexane t o give 19.8 g. of a mixture of products which was dissolved (charcoal) in a mixture of 700 ml. of heptane a n d 65 ml. of ethyl acetate, and filtered. On standing 5 hr., 6.1 g. (41%) of N,I\;'-bis-(d-a-methyl-@-phenethy1)-urea, m.p. 148-149", was obtained. Upon recrystallization (ethyl acetate), the m.p. was 151-152'. A mixed melting point with a n authentic sample of the urea (m.p. 149-151') was 150-151". Anal. Calcd. for C I ~ H ? ~ K ; ~C,O 77.0; : H, 8.2; N, 9.5. Found: C , 77.0; H,7.9; hT,9.1. T h e heptane mother liquor, stored a t lo", gave 6.62 g. (4770) of material, m.p. 80-85", still containing some of the urea. Recrystallization (hexane-ethyl acetate) gave 4.3 g. of N-(d-a-methylphenethy1)-a-phenylbutyramide,m.p. 8990". A mixed melting point with authentic material (Table I, Compound 32) was 89-90'. Anal. Calcd. for C I ~ H ~ ~ NC, O :81.1; H , 8.2; N, 5.0. Found: C, 81.5; H , 8 . 1 ; iY,4.8. N-(dl-a-Methyl-p-hydroxyphenethy1)-lactamide (Table 111, Compound 5).-.4 mixture of 7.2 g. (0.05 mole) of lactide and 17.5 g. (0.16 mole) of phenylpropanolamine was heated a t 140' for 4 hr. IVhen cool, 50 ml. of water was added, the solution acidified with hydrochloric acid and the product extracted with nine 100-ml. portions of ether. After removal of the ether, the residue was distilled in vacuo yielding 12.5 g. (56%) of amide, b.p. 180-186" a t 0.1 mm.
N- (dl-a-Methyl-@-hydroxyphenethyl)-a-ethoxypropionamide (Table 111, Compound 7).--A solution of 8.0 g. (0.053 mole) of phenylpropanolamine and 7.32 g. (0.050 mole) of ethyl a-ethoxypropionate was heated under reflux t o a constant internal temperature and the formed ethanol then was distilled out until the internal reaction temperature reached 180'. The reflux step was repeated. T h e residue, after cooling, was dissolved in ether and the solution washed with dilute hydrochloric acid. On removal of the ether, the residue was dried by boiling with benzene, the benzene removed on the steam-bath and the residue distilled. There was obtained 6.8 g. (547,) of amide, b.p. 146-154" a t 0.05 mm . Compounds 1, 2 and 4 in Table I11 were prepared in a s'milar manner.
N-(dZ-a-Methyl-p-hydroxyphenethyl)-a-benzyloxyproiionamide (Table 111, Compound lO).--iZ solution of 7.8 g. (1.0393 mole) of dZ-a-benzyloxypropionyl chloride in 25 ml. : f acetonitrile was added dropwise over 30 minutes with :irring to a solution of 12.48 g. (0.0825 mole) of phenylproI molamine in 500 ml. of acetonitrile while maintaining the .eaction temperature below 25'. Stirring was continued 'or 30 minutes after addition was complete, the phenylprolanolamine hydrochloride was separated and the acetonitrile removed from the filtrate in vacuo. The residue was dissolved in 300 ml. of benzene and 100 ml. of 0.5 N hydrochloric acid. T h e benzene layer was washed with water, dilute sodium hydroxide solution, water, and then the benzene was evaporated on the steam-bath. The residue on distillation yielded 9.17 g. (74%) of product boiling a t 187189' a t 0.03 mm. Compounds 3, 6, 8, 9 a n d 11 in Table 111 were prepared in a similar manner.
Acknowledgment.-The authors are indebted to Dr. G. Ungar and his staff for the pharmacological results herein reported, to V. Parrino and E. Rogow for the synthesis of compounds 6-18 and K. Geiger for the synthesis of compound 38 of Table I, and especially to E. Roskin for his technical assistance. YONKERS 1, S. Y .
