1064 Journul of Jledicinal Chetnzstrg, 1970, 1'01. 1.3, ,Yo. h'
Azamorphinan and Related Conipounds. 111. Syntheses of 3-Hydroxy-~Y-substitu ted -9-azainorphinans'
\Ye had reported the syntheses of several t ! p r of imhenzomorphans (I-V)4 and 3-hydrox?;-llr-meth~~l(VI) la arid 3-methoxy-N-alkyl-9-asamorphinanr (VIIX1I),li)prepared in order t>oobtain drugs acting on tho CSS, and i w found VI t40have a strong analgetic iictivit).. l u t'his paper, we wish to report, the demethylat ion of' :~-iiiethoxy-N-substituted-9-~~zamorphiii~~is imd the introduction of several kinds of S-substituents iii :l-hydroxy-Y-azamorphiiiari (XXVI), in a search for more txffective analgetic ageiit,s t,hari VI. We also r(1port an alternative synt hesis of 3-hydroxj.-;C'-phrrie bh).l9-azamorphinan (XXII) which compound s h o w :I strong analgetic :tctivit,y and no suppression of withdrawal sympt'oms in monkeys physically dependent o i i morphirw. Demethylation of VI1 and X \vas carried out. with 4'775 HBr in AcOH or wit'h pyridine'HC1 by fusion t o give t'he corresponding 3-hydroxy compounds Vila t ~ n d XXII, respect'ivel!: Introduction of S-alkyl groups was examined t)>preparing :+hydroxy-Y-azamorphinan (XXVI) from VIII, acylating and reducing as shown on Scheme I t,o give XX, XXI, and XXII. The structures of thr S,( )-diacyI and S-alkyl compounds were identified h!. spectroscopic methods arid microanalyses. On the ot hcr hand, nionohenzoylation of X X V I with HzC1, t'ollowt~clby rtduct,ion, gavr t,hfxt,arget compound XX, hut thv yield in this method was infc.rior t o the method ~ i t rt hv S,O-di:tcyI compouiid. .is :(-hydroxy-,~-pheriethyl-~-a~~~morphiIiaii (xxlli ri~i.t&tl the most rffectivr analgetic activity iri this igated u simple synthesis uf this com.thox\phenyl)cycloliexaIionr (XIVa)*" u w t r e i i t d with eth>.l hromoucetate and the resulting y-kc~tocarboxylic acid (XVa) was converted into thrb oct:~hydrocinnolinederivative XVIa by refluxing with j)hi.Iit.t'h?-lhydrazinefi in :by EtOH. XVIa was identifiwl t)), ir spectrum; reduction with IAH gave t,he dccah?..dt.ociririoliiit~derivativ(1 Xi-11:~: which was s u b ( I 1 ia, I'arI I : 'r. Kaineiani, I0 ml of C€TC1, was added 1.3 g o f 13xCl in the presence of 0.4 g of NaOH aiid 100 nil of 1 1 2 0 :it roiiin k r n p with stirring. -After stirriiig f o r a further 1 hi,, t h t . oi,g:iiiic, layer was sepd atid washed ( loc); aq NaOH a i d I l d ) ) , t i r i c d (K2C0,), mid evapd t o leave crystals after tritiiraiioti with hexaiie. The conipd was recrystd froin i-PrOII to give 0.76 g (41.0(,;i) of X S I I I as cdorless primis: mp 180--lX%o: ii, vi"" VII-' 1725 and 1640 (CEO). ; I d . (CIY!~H~~N C,~ 11, O ~N ) ,. 3-Cyclopropionyloxy-S-eyclopropionyl-9-azamorphinan (XXIV).--A .jy6aq S a O H solii (50 ml) was added lzoa si~spe~isioii of 2.4 g of S S V I iii 100 ml of Et,O aiid tmhent o this mixtiire was added wit~hshaking 2.0 g of cyclopropionyl chloride. After shaking for 1 hr, the organic layer was sepd aiid washed ( IO', i, aq NaOH mid I-120). The dried (KZCO3)solveiit was removcd by distil t o give ail aniorphous powder, which was recrystd f r o m i-PrOH t,o afford 1.4 g (37.6(;i) of S X I V as coloi~les~ prisni.: nip 375~-177'; ir :::Y mrl, 174.5 and 1640 tC-01. 3-Phenacetyloxy-1~-phenacetyl-9-azamorphinan 1 X X V ). I'heii:ic.eiyl chloride ( t i g) w:ts :iclded t o :L ~iiS~lt?llhi(Jll( i f 1.): g
(Jf SXVI
,,ILL
of XXVI i n 200 ml of Et20 aiid 300 nil of 5 shaking a t room temp, and the shaking wa furt,her 1 hr. The organic layer was sepd, washed (10% aq NaOH aiid H,O), dried (&C03), and evapd to leave 2.6 g (8X.1%) of XXV as a colorless oil: ir cm-l, 17.55 and 1645 (C=O). 3-Hydro~y-,~~-benzyl-S-azamorphinan (XX).-A suspension of 0.3 g of X X I I I and 1.0 g of LAH in 100 ml of dry dioxane was refllixed for 6 hr and then the excess of LAH was decompd with H2O. The organic layer was collect,ed by decantation, dried (?\Igso4), and evapd to leave a solid, aiter trituration with hexane, n-hich was recryst,d from PhH-hexme to give 0.25 g (67.6%) of YX a:, colorless needles, mp 124-125'. XX.HC1 was recrystd from EtOH to afford colorless needles: mp 245" dec; ir v::: cm-', 3200 (OH); nmr 6 (in CF&OO.H), 4.68 (2 H,s, XCH2CeH:,). d n d . (?2H?iClN20),C, H, N. 3-Hydroxy-S-cyclopropylmethyl-9-a~~amorphinan IXXI).-A siispetisioti of 1.3 g of XXIV and 1 g of LAH iri XU ml of dry T H F was refluxed for 7 hr, and the excess of LAH was decompd with H 2 0 . The orgaiiic layer was collected by decantation, dried (MgSO,), aitd evapd t,o leave :L yellow oil, which was solidified 1111 trituratiott with Et20 aii(i recrystd from EtOIIEt,& t.o atf'ord 0.S g (7S.451) of X X I as colorless prisms: mp
v z
172-174"; ir Y:,": uii-l, 273-9200 (S+H);rimr 6 (in CDC1,) 4.07 ( 2 H, s, ArCHaN), 8.26 (1 H, broad s, OH). Anal. (Cl9HZ6ON?) C, H, Y. 3-Hydroxy-,Y-phenethyl-S-azamorphinan(XXII).-A siispeiision of 2.6 g of XXV aiid 3.0 g of LA4Hill 200 nil of dry dioxane was refluxed for 6 hr and t,he excess LAH was decompd with H20. The organic layer was separated by decalitation, dried (hIgSOd), atid evapd to leave a colorless oil, which wa:, solidified by trit>iirationwith Eteo and then recryhtd from Et,OH to give 1.03 g (50.0%) of X X I I as colorless primis, mp 17&180". This sample was identical with a standard sample in all aspects.
Acknowledgment.-We thank Pre4dent A. Yanagisawa and Director 0. Taliagi of the Grelari Pharmaceutical Co. Ltd. for their encouragement. We also thank Miss A. Iiawaltami and Miss C. I'oshida for microanalyses, A h . S. Hayashida and 11r. 0. Koyama for technical assistance. We are also grateful to Dr. I
