oxazole derivatives and analogs

MIYADERA, et al.

520 Journal of Medicinal Chemistry, 1971, Vol. 14, No. 6

Anxiolytic Sedatives. 1. Synthesis and Pharmacology of Benzo[6,7]-1,4-diazepino[5,4-b]oxazole Derivatives and Analogs TETSUO A I I Y A D E R A , ATSUSUKE 'rEHAD.4, >IITbUNOBU I?UKUSAGA, Y O I C H I IRA, et nl.

AXXIOLYTIC SEDATIVISS. 1

Journal of Medicinal Chemistry, 1971, Vol. 14, No. 6 525

W

v

K!

m

A

A

A A

526 Journal of Medicinal Chemistry, 1971, Vol. 14, Y o . 6 Synthesis ofBenzo [6,7]-1 ,I-diazepino [5,4-b]oxazole'Derivatives and Their Analogs ( I X ) from 2-Aminobenzophenone Derivatives (X)via Oily Condensation Products or Schiff Bases (XI). .\ iiiixt of S 11 inole) :uid alkaiiolarniiie (4-6 mole.*j a.:i-. he:it ed :it 170-2000" for about 4 hr, arid the excess :ilkniiolaiiiiiie ~v:tc. theii reinoved slowly iriider reduced pressure. The re-idue w:ia tli,epd f r u r i i t he :tq Inycr, tlrietl (NazSOr mid then coiicd iuider rediiced prwhurv, l'hr re-idire tct fri)ni EtOII t o give t h e desired prudirvt. 111 thi:ti possit)le to uue it11 aiihyd iiiorg base hiicnh :i; XaL'O:,, IirCOr, or XalTCO3, or a i 1 urg tertiary uiiiiie, for es:iiiiple, p i r i j h i e , yiiiiioliiie, or l';tJV i i i pl:iee of riyridiiie. Isolation, Structure Determination and Isomerization of the 111 ( J f IStl : l l l ( ~ IsIJ fl'iJlll Trans Isomers (IXa and I X b b I k c 70''; aq Et011 gave the tr:iii> isoilier iieedles with i i i i eloiignted (' mi.. The cell coii;ts of 1x1) were ($ale4t)). OY N'ei3se;iI)erg photvgmph.: t 11 he 13.S9 .I)and 6 -= 102". The c ,stern aiid the *pace gri~iipis lved by 1 he lie:tvy-:itoin rnelIiod with Siiii'i weighting scheiiic." The p;irniiieter. were refined by block dittgoii:il le:i>t-s(liiiircprocedure. After S yyclea of t1ie.e refiiienieiit,, the I/ fact t)r rearheti 12.3'!( which worild I Jsiilficierit ~ t o di>ciiq:- the c,heiiiicd striictiiLe. The ce!lccuiists crf 1x2 were e.:lirn:ited t o tJc ( i -= c = 33.536 afid 8 = 1020>wl1o.e vdlren ,tal dimeiiqioii- were i s i ) i i i i ~ r p l i i ~ti i ~ The refiectioii iiitenitieh of tloth ch other. Therefore, it is ( ' l J l i ( ' ~ i i d the mol eoiifigiii~atii~ii. of IXn :iiid IXt) iire ideiit The 11inr -pectriiiii of the ti,nii-. isoilier (Jf -30" ahowed a doublet at 1.38 ppiii ( 3 11, J = ('€I3,aii d B type qriartet a t 3.40 arid 3.56 ppin ahsigiied t o ( ' I f 2 Iietweeii the XIl(,'==O niid the 3' i i i the 4 p ~ ~ h i t i o i two i, ti,iplet- at 2.53 aiitl 3,3!J ppiii ( 2 11, .I = h.5 c.orre,qmiidiiig to the C H , of the osazolidiiie riiig, i~ iiiiiltiplct :it 4.0-4.60 plim aiigiiahle t o the C:H :rtljaceiit t u the 0 atom2 :I '3s pprn 1s 11) drie to the I1 ~ i the i 2 : I ~ I J I I Iriiig,, a t X.36 ppiri. Ilowever, :I dorrblet of low iiiteii-it? of the cis isomer appeared :it 1.25 p p r i i 1.l = ti.5 w i i i i i i at room teiiip :itid the propwtioii of the ?is ihoiiier iiicrewed kly degrees ruitil aii eqiiil mist of the irxlis arid ciz isonier. (iieiirly 3 : 2, respectively) i i i C1)Cl0wii> reaclied. Alkylation of KH at the 7 Position of Henzo[6,7]-1,4-diazepino[5,4-(J]oxazole Derivative and Its Analog (IX).---The cwnpd 1s ( 1 iiiole) wtt- iiiixed wit11 S a O l I e ( 1 .2 mole-) i l i AIeOlI :it i'oorn temp iiiid then JIeOIl way evnpd uiider reduced prehsrire below 40". To the reiidunl oil wah :tdded 5 1. of I)JIF, arid the niisl was stirred for 2 h r at I ' O O I I ~ temp, The re~riltiiig.\leOIi w a s itgain evapd iiiitiei, retliiced preqsiire :it i i low teiiip :ind t h e i i alkylating Ligeiit ( 2 - 3 iiiole.:) WI. added t o the ahove mist with Ytirriiig iiiider ice-lTsC) cwliiig. --iftei. stmidirig overiiight, the d v e i i t ivay removed. The rmidiie \ v : L ~dis.*i~Ivedi i i CIlLli, wa>hedw i t h J J 2 0 , arid dried f S i i p S 0 4 i ,u i i d the holveril \va< ev:ipd. The residiial solid wva.: recnrpsttl from Et011 t o give the protfric.1 iTable I11 1, .\j

.-rl P

d

-

c 1

i

.

-

-?

0

p: c

.-

e c

4

'i;

c

cz

Acknowledgments.---iVc \\ ish to express our gratitudr> t o Dr. C;. Sunagawa, Director of these I,aboratories, and t o I h . Ti. Tariahe, Ai t m t Director, for their ellcouragemerit and discussion. JTe arc :tlso indebted s 11. T:il;ern:isa for their H. I < u ~ ~ - a for n o t h e mea-

1:

10.

IC

2

liods a n d tile I'liase Problein i n S - r a ? ItoiJertsori, a n d .I. c. s w . k m * r 1 . Ed.,

,