Catalytic hydrogenolysis of benzylmethylamino analogs of methadone

Catalytic hydrogenolysis of benzylmethylamino analogs of methadone and .alpha.-methadol. Alan F. Casy, M. M. A. Hassan,. J. Med. Chem. , 1969, 12 (2),...
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T.luI,I; 11 Reaction

,---.imineNO.

~

g

(:yanoguanidine, g

1120, ml

IlC1, ml

EtOII, ml

I I1 I11 IV 4

22.3 17.0 20.0 50 4.0 0.9 1.2 11.6 9.2 9.2 5.0 1.7 2.0 ti llihydrochloride. * Code nuniber T 1214.

time, min

from 3.0 mg/kg for YIII to 112 mg/kg for VI, XI, and XI1 (Table I). Antimalarial Activity."-Three compounds showed :tntimalarial activity: VI, X, and XII. Compound XI1 was the most active but shoned a slight toxicity :It the active doses, lobs of weight a t 1GO mg'lig, LD80 = 320 mg/lig; VI was less active but no signs of toxicity were detected. The therapeutic dose is probably higher than 1000 mg/kg; X was less active but more toxic than VI; the results are collected in Table I. Experimental Section .411 analytical data of the new compounds were in agreement with the calculated ones for the expected structures. I r abzorption bands were also as expected. Biguanides V-1-111 (Table 11) were obtained as follows. The amines I-IV were mixed with HC1, solvent, and cyanoguanidine and refluxed; the resulting hydrochlorides were recrystallized (V)or converted into the bases (VI-VIII). Amidinoureas IX-XI1 were obtained from biguanides on heating in dilute HC1 (Table 111).

TABLE I11 -13iguanidNo. g V 2.0 VI 1 . VI1 2.5 VI11 3.0

loL& Reaction HC1, time, ml min 8 30 0 4 10 5 15 30 2.5

Dihydrochlorjde. iiumber T 1213. a

7----Product----Yield-

KO.

g

'lo

RIP, OC

IS Y XI XIIe

1.5 0.6 1.25 1.0

75

246-24ia 172-173 220-221b 221-223

* Dihydrochloride

60 50 33

Recrystn solvent

HrO Dil R I e C O

EtOH Dilpyridine

monohydrate.

c

Code

Oxidation of VI11 and XI1.-To 3.3 g of VI11 in 10 ml of ScOI1, 8.0 g of 20' ;AcO2H was added during 10 min; the temperature rose to 6 0-70"; a f k r 2 hr the solvent was evaporated in uacuo, the mixt,ure was made alkaline, and t,he resulting product was recrystallized from dilute AIerCO yielding 2.7 g (75%) of VI, mp 183184'. Similarly, 3.3 g of XI1 in 16 ml of AcOH gave 2.3 g (6575) of X, mp 172-173'. Toxicity.ll--Bcute toxicity on oral administration was tested with Swiss male albino mice in groups of ten animals. The compounds were administered by stomach tube in a 5% suspeiision of aqueous gum arabic a t 0.8 mg/20 g of body weight. The LI):," was calculat'ed graphically according to Litchfield and Wilcoxon by the modification of Itoth. The animals were observed for 10 days. Acute t'oxicity on intraperitoneal admiuistration was investigated with compounds suspended in 45% Tween 80. The doses were 0.2 m1/20 g of body weight, (Table I). Antimalarial Activity.12-Tests were carried out using an old laboratory strain (strain N ) of P l a s m o d i u m berghei berghei. Mice were inoculated intravenously withca. 10: parasitized rbc on day 1. They were dosed orally with drugs in 10% (v/v)methylcellulose on days 1 4 . Blood films were taken on fifth day. The percentage of red blood cells containing parasites was counted and compared with that of untreated control mice. Five mice were used for each dose. The relative parasitemia was calculated as a percentage of the controls (Table I ) . (12) Tests were carried out at t h e S a t i o n a l Institute for Aledical €roLi,,ct Y-Yieldv8.9

\-I"~",'J YII YIII

57.5 ,57,0 68.0 68..5

2.5.0 1, 0 .5.S .i.O

RIP,

Recrystn solvent

OC:

HnO Dil AIe2C0 DAIS0 EtOH

2,58-260(' 183-184 206-207 232-23.5

Acknowledgments.-We wish to express our gratitude t o Dr. L. J. Bruce-Chnatt and Dr. J. Haworth of the World Health Organization for their kind interest in our research and aiding us with supplies of instruments and materials. We are greatly indebted to Dr. 1;. Han king, Kational Institute of lledical Research, London, for offering us facilities to carry the antimalarial tests, to *\Irs. T. Boleshv-ska for assistance in the synthetic work, and to A h , R. 0. Folwell for help with antimalarial tests.

Catalytic Hpdrogenolysis of Benzylniethylamino Analogs of Methadone and a-hlethadol -4.F. Casv

ASD

11. AI. A. H a s s . i ~

Faculty o j Pharmacy and Pharmaceutical Sciences, University of Alberta, E d m o n t o n , dlberta Received September 23, 1968

The great majority of analgetics with morphine-like effects are tertiary amines.',* Among the few examples of active secondary amines that have been reported are the S-methylamino analogs of methadol and acetylmethadol,3 normorphine,2 and certain 6,14-end0ethenotetrahydrothebaines.~Interest in analgetics with secondary amino functions has been aroused as a result of a hypothesis implicating such bases as intermediates in the mediation of analgesia.2J 3-11et hylamino-1 ,1-diphenylpropylamines (1) (It is an oxygenated function) have proved difficult to synthesize from corresponding S-dimethylamino analogs. Thus, treatment of methadone (2a) and amethadol (2b) with B r C S yields the cyclic products 3 and 4, respectively, rather than the S-cyanomethyl derivatives, potentially capable of liydrolysis to the Ph

MeiNCHMeCH,CPh2R

I

2a,R = COEt b,R = CHOHEt

Me ,NCHCHCCR \

I1

I / PhI

C,

R = CH(OC0Me)Et

1

Ph

Ph

3

4

(1) G. deStevens. Ed.. Analgetics, Academic Press, New York, N. Y., 1965. (2) A. H. Beckett and A. F. Casy, Proor. Jfed. Chem., 2, 43 (1962); 4 , 171 (1965). ( 3 ) N. B. Eddy, Cliem. Ind. (London), 1462 (1989). (4) K. W.Bentley and D. G. Hardy, J . Amer. Chem. Soc., 89, 3281 (1967). ( 5 ) A. H. Beckett, A . F. Casy, and N. J. Harper, J . Pharm. Phurmacol., 8. 874 (19.56).

tlesired mmnclary : m i i ~ i e s . ~ T t ~h e S-methylamino derivative of a-acetylmethadol (2c) hay however, heen reported in the patent literaturel6 being prepared hj, catalytic hydrogeriolysis of the S-benzylmethyl amino analog 5c. I n a further investigation of thih route t h r PhCHINCHMeCH,CPh,R

I

Me 5a, R = COEt b, R = CHOHEt c, R = CH(OC0Me)Et PhCH,NCHMeCH,CPh,CN

I

Me 6 PhCH,NCH,CHMeCPh,COEt

I

Me 7

S-bcnzylmethylaniino ethyl hetoric 5a (prepared from the cyanide 6) \va subjected to catalytic hydrogenolyy i q in the expecta on of obtaining the S-methylamino aiialogs of methadone and/or a-methadol. Formation of the methadol l l b \va> indicated initially berausr 2 moIes of Hz were absorbed in the reaction. The product, however, was proved to be the pyrrolidine derivative 8 from ir (absence of v01I and v?;H bandi n the spectrum of the base) and pmr characteristic. [the X‘-;\Ie pmr signal \viis :I hiriglet in the base :ind a doublet ( J = .i Hz) i n the salt ( d v e n t , C‘DCl?) r:rther than the doublet (base) and triplet (sdt) expected tor l l b , while the sec-3Ie-Et .ign:il \va\ complex arid did not resemble that of acyclic methadoli] and from microanalytical datu. Iri further confirmation, :I simple of 8 prepared unambiguously by reduction of the A’-pyrroline 991*owas identical with the product ticrivcd from 5a. L>ebeiixylation of the isomeric l\(~totic~ 7 .imil:dy gave a cyclic product 10; this provcd Ph

Ph

Me

Me 8

9

I

CX 12

l l b is mentioned i i i the patent in r e f s hut without evidence of structure. Evidence for the hecoiid mechanism T from an experiment in which the catalytic hydrogenation of the l~erizylnietliylamirio kctone 7 n-ainterrupted after the uptake of 1 mole of Hj. (-11reacted lxtoiic \v:i> recovered together with :t hasic. oil which had :HI ir 5pectruni characteristic of thc A’-pyrroline 9, i l l pnrticulur, :L *trong h i d a t 1 6 3 em-‘ assigned to C=S stretching. It rapidly drveloped :i red color. behavior also cliaracteristic of 9. The saturiitetl cyclic product 8 lacked significant :inalgetic pi*opertic,+ a 3 ertabliqhed by its high E11 )I) value (Xi nig lig) I I I the mice hot-plate test. Th:inli\ are due t o Dr. ELerettc I,. >\hyof the S:~tioiial Institutei of Hcaltli, B c t h c d i , A\ld.,for arrnnging thitest. The cyclic product 9 ha\ been hhoivii to tw :I m t j o r metabolite of methadone in rats :ind in :ind it almost cert airily results from the S-demethylatrd ketone l l a . S-Demethylntion of methadol :uid i t + acetate ih equally likely hut unchtinged nor productrather thurl ryclized form, are probably metabolitein these cases since this \veri; has established the st:]bility of dipheriylpropylaniiries with secoiidary aniiiio arid hydroxyl functions. lictabolites of this nature may well play a role in the mediation of thc :tn:tlgetir effects of the parent dimethylamino compounds (6. i d 1 1 ) i i i vicv of thcii. -igriific:int :iiialgetic I)ropcrtic>

Mel& I

Me

10

inore difficult to characterize because ~i 5olid base could not be obtained nnd the HCl salt crystallized n i i h 1 mole of water. Its identity was established, hon.ever, through ir (abmlce of V O H and Y N ~ Iin free

March 19ti9

339

XOTES

Experimental Section When analyses are indicat,ed, analytical results obtained for those elements were within f 0 . 4 7 , of the theoretical values. Catalytic Hydrogenation of 6-Benzylmethylamino-4,4-diphenylheptan-3-one and Its 5-Methylhexan-3-one Isomer.--& mixture of the amino ketone 5a'* (20 g), 4 S €IC1 (20 ml), 1070 Pd-C (2.5 g), and EtOH (400 ml) was shaken with H Zat room temperature and pressure until gas uptake ceased. The filtered product was evaporated and the residual salt (11 g) gave the pyrrolidine base 8: bp 128-132" (0.5 mm) (8 g); mp 56-38' from EtOH; N-Ale pmr characteristics in CDC13 (Hz from TAIS), base 147 (singlet), HC1 176 (doublet J = 5 Hz). Anal. (CZOHW N ) C, H, N. The same product, mp and mmp 36-58', was obtained by shaking a mixture of the freshly distilled base (2.5 g) from 2ethyl-4-methyl-3,3-diphenyl-A'-pyrroline hydriodide S,s.10 10% Pd-C (0.2 g), and EtOH (70 ml) with H2 at 60". The hydriodide 9 resisted hydrogenation under these conditions. The same rediiction procedure applied to the benzylmethylamino ketone 712 gave the 4-methylpyrrolidine isomer 10 as a hydrochloride monohydrate, mp 226-227" from EtOH-EtZO. Anal. (c&26C l S . H z 0 ) C, H, N. Debenzylation of 6-Benzylmethylamino-4,4-diphenylheptan3-oL-The benzylmethylaminomethadol 5b ( 0 1 isomer) was obtained as a hydrochloride, mp 188-190" ( l i t 8 178-179') from EtCO-EtsO, by treating the ketone 5a with LAH. Anal. (C27H34C1SO)C, H, N. A mixture of the free base 5b (6 g), 4 AVHC1 ( 6 ml), 10% Pd-C (1 g), and EtOH (120 ml) was shaken with H2 and processed as described for the reduction of 58. The sec-amine reaction product l l b was isolated as a hydrochloride (3 9 ) : mp 183-185" from EtOH-EtzO; N-Me pmr characteristics of HC1 (Hz from TJIS), 135 (triplet J = 5 ) in DMSO-&, 143 (triplet J = 5 ) in CDC1,. The salt had a sharp ir absorption a t 3400 cm-I ( Y O = ) and the base at 3280 cm-' superimposed upon a broad shoulder between 3500 and 3100 cm-I typical of methadols ( P O = and Y K H ) . -4nal. (CzoH&l?r'O)

la, X = H b, X=C1

2a.X=H

b. X = C1 CH,

3a, X = H

b, X = C1

C, H, K. Hydrolysis of ~~3-Acetoxy-6-cyanomethylamino-4.4-diphenylheptane.--h mixture of the N-cyanomethyl derivat,ive 12 (15 g)' and 6% HC1 in HzO (300 ml) was heated under reflux for 12 hr, cooled, and extracted (EtaO) to remove nonbasic products. The base (3.5 g) recovered from the aqueous phase as usual was treated with HBr-EtOH to give the sec-amine l l b hydrobromide, mp 206-207" from EtOH-EtzO. Anal. (CzoHZ8BrXO) C, H, N. The melting point of this salt was undepressed by the hydrobromide of the sec-amine derived from 5b. Pmr spectra were recorded on a Varian A4-60 spectromeler with CDCL or DMSO-& as solvents and ThIS as standard. (12)

W.Wilson, J . Chem. Soc.,

4a,X=H b. X = C1

aq NaOH

Me,CO

5

3524 (1952).

Synthesis of Some Lreidodihydrofurans and Related Pyrimidones as Potential Antimalarials'J G

E. CAMPAIGXE, R. L. ELLIS,AI. BRADFORD, AND J. Ho Chemistry Laboratories of Indiana Universaty, Bloomington, Indiana 4r40l Received August 13, 1968

Extensive studies have been carried out in these laboratories concerning sulfuric acid cyclizations of ylidenemalonitriles derived from aryl- and alkyl- subst'ituted aromatic k e t o ~ i e s ~leading -~ t o the forma(1) Contribution No. 1640 from t h e Chemistry Laboratories of Indiana. Gniversit y. (2) Taken in part from t h e thesis of R. L. E. submitted t o t h e Graduate School of Indiana University in partial fulfillment of t h e requirements for t h e Pi1.D. degree, M a y 1967, ( 3 ) E. Campaigne and G. F. Bulllenko, .I. Oro. Chem., 26, 4703 (1061). ( 4 ) E. Campairne, G. F. Rull~enko,J\-. E. lireiylil>aum,and 11. R . Mauldi n r , i t ~ f d . ,27, 4-128 (lY62). ( 5 ) E. Campaigne, D. R. Xlaulding, and I\-. L. Roelofs, ibid., 29, 1543 (1964). (6) E. Campaigne a n d I\-.L. Roelofs, ibid., 30, 396 (1966).

a,X=Y=H b, X=H;Y =C1 C, X = H; Y =OCH3 d,X=H;Y=CH3 e. X=H;Y=NO,

f , X = C1; Y = H g, = Y = c1 h, X = C1;Y = OCH3 i, X = C1; Y =CH3 j, X = C1; Y = NO,

x

tion of both iridenone arid indanorie derivatives. Cyclization, however, of certain alkyl-substituted ylidenemalorionitriles in polyphosphoric acid (PPA) leads to the formation of b u t y r o l a c t ~ n e s which ~~~ contain functional groups susceptible to metathesis. For example, cyclization of a-cyano-p-isopropylcinnamonitrile (la) in hot PPA produces the lactone 2a (see Chart I). It was eiiviioned that 2a offered ( 7 ) E. Camyaigne and R . L. Ellis, Chem. Commun., 1-11 (1066). (8) E. Campaigne and R . L. Ellis, J . Oro. Chem., 32, 2372 (1967).