Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~ HA143/55/56
Cyclitol derivatives having the Eorrnula
Cll -CH -CII -N~
2)n
0-~ O--Y
wherein Y is hydrogen or alkanoyl, t~le group -NXX' is a
heterocyclic nitrogen con-taining yroup, and n is 0, 1 or 2
are encompassed by the disclosure of United Statcs patcnt
3,894,031, issued July 8, 1975. Among the heterocycli.c
groups disclosed are pipera~ino, (lower alkyl)piperazino,
di(lower alkyl)piperazino, (lower alko~y)piperazino, (hydroxy-
lower alkyl)piperazino, (alkanoyloxy-lower alkyl)piperclzino,
(hydroxy-lower alkoxy-lower alkyl)piperazino, an-l tcarbo-
lower alkoxy)piperazino. The treatment of hypertension is
one of the utilities for the compounds disclosod by t~,e patent.
~uryer, ~ledicinal Chemistry, third edition tpclrt II),
John Wiley & Sons, Inc.! New York, 1970, chapter 39, "~nti-
hypertensive Agents", pgs. 1019-1064 disclo~es various classcs
of antihypertensive agents. ~,mong the classcs of compounds
20 disclosed are veratrum alkaloids, the hypotensive activity of
which may be largely attribu-table to the acylation of sevcral
hydroxyl functions of an alkamine. Other classes o~ anti.-
hypertensive agents disclosed by Burger include pherlo~y-
~i- propanolamines and phenethanolamines.
'
Compounds having the formula
Cl-'2-C~i--CE~2-R2
ORl OI~ll OR
~ ~ 6
( ~ ~Cll
- 1 $
.
- HA143/55/56
and the pharmaceutically acceptable salts thereof, have
hypotensive activity. In formula I, and throughout the
specification, the symbols are as defined below.
n is 0, 1 or 2;
Rl is alkanoyl (acetyl is preferred);
R2 iS
(i) -N N-R7 ~
( i i )
~.
(iii) ~ '
'
(iv) ~ CH=CH~)
; ~ , .. ;.
:;
.. . .
(v ) ~
.'.,
(vi) ~ , or
,
.~- ' (vii )
~ N==
: ~ N~
~..
,~
. ~ -2-
~;5 ~ 7 HA143/55/56
(viii) N ~ ~ R3
t
(ix)
~4
-N
',
(xi~ ~} (CE12)m-R5
(xii) O H or
,~ ,
(xiii.)
i
.,~ .
. .
R3 is alkyl of 1 to 4 carbon atoms;
~: R4 is cyano or hydroxy;
`:: R5 is hydroxy or alkanoyloxy (acetyloxy is pre~erred);
R6 is hydrogen or alkanoyl (acetyl is preferred)
~ ~ .
: ~'
,X
~33~,7 HA143/55/56
~ is arylorpyridinyl;and m is 2, 3, or ~.
The terrns "alkanoyl" and "alkanoyloY~y'i, as used
throur;~,ollt the .spec ~ication, refer to groups having the
formu]a Y-C- and Y-C-O- respectively, wherein Y ls alkyl
having 1 to 6 carbon ator.s (i.e., groups having 2 to 7
car~,on atoms).
The com~.ounds of this invention wherein R6 is
hydro~en can be prepared by reacting an oxirane compound
having the formula
II O
CH 2 -CH-CI12
~H2)n
or~l ORl
with a compound having the formula
III
; R2 H-
Reaction conditions are not critical, but the reaction proceeds
more rapidly when carried out with heating in an organic solvent,
or mixture of organic solvents, e.g., a lower alkanol such as
ethanol, or an aromatic hydrocarbon such as benzene in combin-
ation with a lower alkanol. Those compounds of ormula I wherein
R6 is alkanoyl can },e prepared from the corresponding cornpound
wherein R6 is hydrogen using conven-tional acylation techniclues.
The oxirane compounds of formula II are readily ohtained
from a corresponding compound having the formula
~ 3~ Y HAl43/S5/56
IV
ORl CH2-CH2-CH2-~ (alkYl)2
~,
~ (~H2)n
ORl ORl
; Compounds of formula IV are known; see, for example, Unitcd
; States patent 3,894,031, issued July 8, 1915. Oxidation of a
compound of formula IV yields the corxesponding N-oxide having
the formula
V
Cl~2-cH2-c~l2-N(alkyl)2
. ORl Rl¦
~ CH2)n
~ ORl 1
, Exemplary of oxidizing agents which may be used are the peracids,
?
e.~., m~chloroperbenzoic acid.
Vacuum pyrolysis of an N-oxide of formula V yields an
.,! ~ ~ ,
olefin having the formula
~ "I
;~ 20
; ~ CE~2-C~=C~2
; 0~0~
CH2)n
ORl ORl - ~:
~Oxidation of an olefin of formula VI yields the corresponding
oxirane compound of formula II. Exemplary of oxidizin~ agen~s
which may be used are the peracids, e.~., m-chloroperhenzoic acid.
The oxirane compounds o formula II and the olefins of
formula ~I are novel intermediates which are useful in the
preparation of the compounds of formula I, and as such, con
30 stitute an integral part of this invention.
HA143/55/56
v~7
The compounds of formula I can be converted to their
pharmaceutically acceptable acid-addition salts with hoth
organic and inorganic acids using methods well known in the
art. ~xemplary salts are hydrohalides (e.g., hydrochloride
and hydrobromide), nitrate, phosphate, borate, acetate, tar-
trate, methanesulfonate, benzenesulfonate, toluenesulfonate
and the like.
Formula I includes all stereoisomers and mixtures
thereof. Particular stereoisomers are prepared hy utilizing
as the starting material the compound of formula IV ~!ith
the correspondiny stereochemistry. The preferred stereG-
isomers are those in which the ~1 groups are alI ai:ial.
Particularly preferred are those compounds havincJ the
confiyuration
VII
.,
CH2-1H-C~i2 2
" ~ ~6
2)n
I
ORlC ORld
; 20 wherein the ORla and ORlC groups are in the trans configuration
as are the Ol~lb and ORld groups.
The compounds of formula I show hypotensive propcrties
in hypertensive rats and normotensive dogs. The compounds of
this invention, and the pharmaceutically acceptahle salts
thereof, are useful as hypotensive agents in mammals, ~
domestic animals such as dogs and cats. Daily doses of from
5 to 50 milligrams per kiloc~ram of animal body weicJllt, pref-
erably about 5 to 25 milligrams peE kilocJram of animal body
weight, can be administered orally or parenterally, in singlc
or divided doses.
-- 6 --
~$~37 HA143/55/56
The compounds of this invention includc indan
derivatives having the formula
VIII
CH2~ CH2 R2
0~0~ ~R6
~ , .
ORl ORl
naphthalen~ derivatives having the formula
IX
CH CH-CH -R
~ . , ~ ~)
.. . ~
ORl ORl
;, and benzocycloheptane derivatives haviny the formula
.`i
,:, X
CH2-cH-CH2 -R
ORl ORll ¦. 2
; ~ 6 ;~
' ~: . ORl ORl
;; 20 The naphthalene derivatives of formula IX are preferred.
: The fol.lo~ing examples are specific embodiments
of this invention.
~` .
... . . .
.- :.
HA143/g~/56
~i,xarrlple 1
3,4a,5~ -Decahydro~5-[2-hydroxy-3-[4 (2-methoxt~phenyl.)-1-
piperazinyl]~ro~yl]-2,3;4a,3a-trans-naphthalenetetrol,
tetraacetate ester
-
A) 3,4a,5_ is _ecahydro-5-(3-dirr~eth~l.aminoproPyl)-2,3;~a,8a-
tr~ -naphthalenetetrol, tetraacetate ester, N-oxlcle
A solution of 19.71g of 3,4a,5-cls-5-(3-dimethylarr.ino-
propyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester
and 9.25g of 85% m-chloroperbenzoic acid in 30 ml of chloro-
form is prepared at 0C and warmed over 3 ho~lrs to room
temperature. The solution is then partially evaporated ln
vacuo and filtered through 520g of neutral ~lumina ~ lution
with 1 liter each of chloroform and 20% methanolic chloroform
aives 24.3g of oil. Crystallization from ethyl acetate gives
14.3g of the ~l-oxide as a hyclroscoI~ic solid, meltinc~ ~oint
; 160-161C. The filtrate is evaporated ln vacuo to clryness to
give an additional 6.38c~ of solid (IR consistent ~itl cr~
for a total yield of 2Ø6nc3.
.) 3,4a,5~ -Decahydro-5-(2-propenyl)~2,3;4a,8a-trall.s-
na~hthalcnetetrol, tetraacetate ~ster
..
~n amount of 20.2y of the above M-oxide is heated in
a vacuum distillation set-up under 30 mm ~IcJ vacuum ~li.th nitrocl~n
bleed until all the solid has melted and vi.gorous qas evoiution
ceases. The vacuum is improvecl to 1 mm ~c~ ar~.d t}~e olefi.n
product distillecl as a pale yellow liquid, 13. n g (boiling
point 185-195 at 1 mm Hg), which solidifies on standing.
~ecrystallization frorn ether (75 - 1~0 rnl) gi.ves 8.6g cf a
fine crystalline solid, melting point 151~155.5C.
C) 3~4a~5-~1~-D~cahydro-5-~o~x.iranylmethyl)-2,3;~a~na~
naphthalenetetrol, tetraacetate ester
_
A solution of ~.09 of the ahovc tetra~ccta~e-olcfin
ancl 3.12cJ of 85.~ m-ch].orol~c~rlc~n~oic .Ici(l ir, lnO nll Or c~lororor
_ ~ _
HA143/55/56
is prepared at 0C and stirrecl at room tempera~ure for about
16 hours. I'he solutiorl is then suction filtered throuc3h a
pad of 5nc~ of neutral Alumina III. The alumina is ~.lashed
~ith 100 ml of chloroform and the combined filtrates evapor-
ated in vacuo to give 6.4g of a solid, melting point 135-159C.
D) 3,4a,5-ci.s-Decahydro-5-[2-hvdroxy-3-[4-(2-methoxy~henyl)-
l-pipera~zinvl]propvl]-2,3;4a,8a-trans-naphthalcnetetrol,
tetraacetate ester
.
~ solution of 1.5g of 1-(2-methoxyphenyl)pil~crazine
and 3.5g of the above epGxide in S0 ml of absolute ethanol
and 2Q ml of benzene is stirred in a warm water batll (50-55C)
for about 20 hours under a drying tube. The solvent is rcmoved
n vacuo to give 5.lg of a foam, which is crystallizecl frGm
ether to give 4.23g of the product as a crystalline ~olicl in
two crops. Recrystallization of 3.58g of the solid from cthyl
acetate (25-35 ml) gives 2.65g of the title compound, meltinc3
point 203-206C.
Anal. Calc'd. for C32H46N2O1o (618.7 (~/m):
C, 62.12; ~, 7.49; ~, ~.53
Found: C, 62.15; ~, 7.64; ~, 4.43
Example 2
3,4a,5-~L~-Decahydro-5-[2-hydroxy-3-[4-[3-(trifluorom ~ ~-
phenyl]-l-piperazinyl]propyl]-2~3;4a~8a-~ ~-naphthalenetetrol,
tetraacetate ester
A solution of 2.75g of 3,4,5a-cls-decahydro-5-~oxir-
anylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate
ester and 1.3g of M-(a,cx,a-trifluoro-m-tolyl)piperazinc in
20:50 benzene-absolute ethanol is heated to 55-G0C or ]8
hours. The solution is evaporated 1n V~lCUO and the resiclue
is crystallized from ~thyl acetate-heY.arl~ to give 2.7q o
solid in three crops. Recrystalli~ation frorn e~lyl acet~tc-
30 h~x~ne cJiVe~ ].. B5q of materi~l. q~he ].U5tl o~ n~ erilll is
_ g ~
~ HA143/55/56
combined ~ith 0.75g from a previous run and recrystallizecl to~ive 2.ng of the title compound, meltinc~ point 150- n40c.
Anal- Calc d- for C32~3N2O9F3(h57-7 ~/m)
C, 58.52; H, 6.60; M, 4.27i F, 8.68
Found: C, 58.30; H, 6.63; Il, 4.13i F, 8.56
xam le 3
P
:
3,4a,5-~is-5-[3-[4-[2-(Ethylthio)phenyll-l-p ~
h~droxypropyl]-decahydro-2,3;4a,8a-~xan~-naphthalenetetrol,
tetraacetate ester
A solution of 2.6g of 3,4,5a-cl~-decahydro~5-(oxiranyl-
10 methyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate estcr
and 1.4g of N-~(2-ethylthio)phenyl]piperazin~ in 20 ml of
benzene-50ml of absolute ethanol is stirrc.~d at 57C for a~,out
16 hours. l'he solution ls evaporated in vacuo and th~ re~ lue
crystallized from ether to give 3g of solid. T~o recrystal-
lizations fror.l ethyl acetate-methanol give 2.2g of the title
compound, melting point 230-232C.
Anal. Calc'd. for C33H48N2OgS (64~-82 g/m):
C, 61.09; ~-1, 7.46i N, 4.32; S, 4.94
Found: C, 61.27; ~, 7.74; N, 4.33; S, 5.00
Example 4
3,4a,5-cis-DecahYdro-5-[2-hydroxy-3-[4-(2-pyridinyl)-1~
piperazinyl]propyl]-2,3;4a,8a-~E~n~-naphthalenetetrol, te~ra-
acetate ester
3,4,5a-cls-Decahydro-5-(oxiranylmethyl)-2,3;4a,8a-
trans-naphthalenetetrol, tetraacetate ester, (2.10R~) is
dissolved in 50 ml of absolute ethanol and 20 ml benzene.
Freshly distilled 1-~2-pyridyl)piperazine (.766~) is added
and the resultin~ solution is heated to 50C+5, ~1ith stirring
for 15 hours. Solvent i5 removed in vacuo, and the r~s~ulting
foam is ta~.en up in 250 ml of ethanol from ~lhich it immediately
30 crystallizes to yield 2.3g of crystallille soli~. 'lhe solid
-- 10 --
7 HAl 4 3/5 5/ 5 6
is recryctallized fro~ ethyl acetate to yield 1. 26~ crystal-
line solid, melting point 225-229C.
E~a~.ples 5-13
Foll~winy the yroeedure of ~Y.ampl~ l, but au~stitutillg
the piE~erazin~ derivative listed in eolumn I for l-(2-methoxy-
phenyl)piperazine, yield the eompoun~. liste(7 in colu~,n I I .
Co].umn I Column II
5 l-phenylpiperazine 3,4a,5-cis-decahydro 5-~2--
hydro~y-3-(4-phenyl-l-r,i~)er-
azinyl)propvl]-2,3;4a,Ra-
trans-naphthalenetotrol,
tetraacetate ~ter
6 1-(2,6-dibromophenyl) 3,~a,5-ci.,-decahy~lro-5-[2-
piperazine hy~ro~y-'-~4-(2,F.-dihrorro-
~henyl)-l-ripera7.inyl]~rcpyl~-
2,3;4a,8a-trans-naphthalerc--
tetrol, tctraaeet;..Lc ester
7 l-(~-iGdephenyl)~iperaæin~ 3,~a,5-eic;-cleeahyclr~-5-r~-
hyclr~;~.y~[4- (2-i~dor-hcnyl )-
l-pi~r.lz.inyl]pro!~yl]-2,~;-
9a,8a-~rnris-naE)hl;half-nc-
t.~trol, tetraacetate e~tcr
8 l-(2-fluorophenyl)piper- 3,4a,5-ci.~-decahydro-5-[2-
azine hydroxy~[4-(2-~luorolJhenyl)-
l-piperazinyl~propyl]-2,3;4a,-
~a-trans-naphthalenetetrol,
tetraaeetate e.~ter
20 9 l-(3,4-dimethylphenyl) 3,4a,5-eis-deeahydro-5-~2-
piperaæine hydroxy-3-[4-(3,4-dimethyl-
henyl)-l-piperazinyl]~ropyl]-
2,3;4a-,8a-trans-naphthalene-
- tetrol, tetraaeetate ester
l~ l-(2,6-dimethoxy~henyl) 3,~a,5-ei.s-deeahydro-5-[~-
piperazine hydroY.y-3-[4-(2,6-dimetho~y-
phenyl)-l-pipera7.inyl]propyl~-
2,3;4a,8a-trans-naphthalene-
tetrol, tetraaeetate ester
ll l-(l-pyridyl)piperazine 3,4a,5-ei.s-~eeahydro-5-12-
hydroxy-3-[4-(l-pyrldlnyl)-
l-piperazinyl]propyl]-2,3;-
~a,8a-tran~-naphthalelletetrol,
tetraaeetate este~
~3~37 HA~43/55/56
. Colu3~ln I Colurr; JJ ;`
-- _.
121-(3 pyridyl)T?iperazine 3,4a,,~cis-decahy(lro-5~[2-
hydroxy-3-~-(3-pyridinyl)- r
; l-~iperazinyl]propyl]-2,3;-
4a,8a-trans-naphthalelletetrol,
tetraact?tate e~tcr
131-(4-pyridyl)pipt?razine 3,4a,5-cis-decallydro-5-[2-
h~ydro:cy-3-[4-(4-pyridinyl)-
l-piperazinyl]propyl]-2,3;-
~a,3a-trans-naj3~ht;halel~-tetrol,
tetraacetate e.ster
F.,ample 1~
3a,5-cis-3a,7a-5,6-trans-H-3exah clro-1-l2-h~clro~-3-,r4-(2-rrl-tho~-
phenyl)-l_e~erazinyl; ~ l-intit_ne-3~J,5,-"7a-tetrt)l, t~tr(l-
10 acetate ester, hydrochloridf.~
3a,5-fi~s-3a,7a;5,6-trc3n,-He~.ahy-lrc~-l-('-climethyl~mino-
ropyl)-131-i~ren ~ a-tctrol, tetr-3.-3cct~3tc? ~citer,
~-oxide
.~n amount of 2.ag of 85, m-chloro~erberzoic acid is ~3ddec~
to a solutiGn o 5.0g of 3a,5-cls-3a,7a;5,6-trans-
hexahydro-1-(3-dlMethylaminopropyl) in 50 ml of ch1OroLorm .It
- 0-5C. The cold bath is removed ancl thc mixturc- is sti3rcd
for 3-1/2 hours under nitrosen. The solution i.5 partial ly
evaporatecl in VaCUO and then chrornatoyraphe(1 on 98 c Gi r.cutral
~lumina III. ~lution with chloroform ar.d methanolic chlcrGforrn
20 yields, upon evaporation in vacuo, ~.6 y of thc ~!-o:~iclc as a
- white solid.
3a,5-çl~-3a,7a;5,6-_ran ~ Ya~ly~lro-l-(
indene-3a,5,6,7a-tetrol, tetraacetat~ ester
The above N-oY~ide (4.6 5) is vacuurn pyrolyze~d at 16n-190CC
under 12 m~ Hc~T vacuum. The product is vacuurr~ disti]led to givc
2.1 g of crude olefin at 185-195C under 0.25 rrm lig vacuurn.
Further ~urification by chromatoyraphy on 35 cJ of ncutral
Alumina III eluted with 15-2~ ethyl acetat-,-ie~anc Vie~-.'!-,
].O c~ oJ thc ol~fin as a whitc so]i(].
- 12 -
~ HA143/155/156
3a,5~cis-3a,7a~5,6-trans-Hexahydro-l-(oxiranylmethyl)-
-
lH-indene-3a,5,6,7a-tetrol, tetraacetate ester
-
An amount of 0.52 g of 85~ m-chloroperbenzoic acid is
added to a solution of 1.0 g of olefin in 25 ml of chloroform
and the solution stirred for about 16 hours at room temperature.
The solution is partially evaporated in vacuo and then filtered
through a column of 22 ~ of neutral Alumina III. Elution with
260 ml of 20-30% ethyl acetate-hexane yields 0.9 g of epoxide
as a white solid.
3a,5-cis-3a,7a;5,6-trans-Hexahydro-1-[2-hydroxy-3-[4-
(2-methoxyphenyl)-1-piperazinyl]propyl]-H-indene~3a,5,6,7a,
tetrol, tetraacetate ester, hydrochloride (1:1)
A solution of 0.9 g of epoxide and 0.43 g of _-methoxy-
phenylpiperazine in 20:50 benzene-absolute ethanol is stirred
for 18 hours in a 57C bath. The solvent is removed ln vacuo
and the residue chromatographed on 25 g of neutral Alumina III.
Elution with 150 ml of 25-30% ethyl acetate-he~ane yields 0.53 g
of forerun (mainly recovered epoxide). Elution with 200 ml of
35-40% ethyl acetate-hexane yields 0.57 g of the product as a
free base. The free base is converted to the hydrochloride
salt and recrystallized from ethyl acetate-ether to yield
0.5 g of the title compound, melting point 215-220C.
Anal. Calc'd. for C31H~4N2Olo. (641.16 g/m)
C, 58.07; H, 7.08; N, 4.37; Cl, 5.53
Found: C, 57.89; H, 7.00; N, 4.31; Cl, S.67
Example 15
3,4a-cis-Hexahydro-5-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-
piperazinyl]propyl]-2,3;4a,9a-trans-benzocycloheptanetetrol,
tetraacetate ester
A~ 3,4a-cis-Hexahydro-5-(3-dimethylaminopropyl)-2,3;4a,9a-
_ _
trans-benzocycloheptanetetrol, tetraacetate ester, N-oxide
___
A solution of 3,4a-cls-hexahydro-5-(3-dimethylaminopropyl)-
~13~
~ t~ HA143/55/56
2,3;aa,9a-trans-benzocyclohep~ar.etetrol, tetraacetate e~;'cr
(12.8 rr,mole) and rn-chloroperbenzoic acid (2.~ g) in chloro-
form (100 ml) is prepared at 0C and gradually warmed to
rooM temperature to yield the title ~-oxid(.
B) 3,4a-cis-llexahyclro 5-(2-propen~1)-2,3;4a,9a-trans-benY.
cyclo~eptanetetrol, t~traacetate ester
The above N-oxi~e (10.8 mmole) is heated in a vacuum
distillation set-up under 30 mm ~Ig vacuum Wit}l nitroqen hl.ee~
to yield the title olefin.
~ 10 C) 3,4a,5-~1~ exahydro- ~ .thyl.)-2,~;4~ L~Ul~-
: benzocycloheptanetetrol, tetraacetate est~r
A solution of the above tetraacetate-ole~in (5.9 r~nole)
and 85~ m--chloroperbenzoic acid (1.3 c3) in chlorofor~, (50 ml)
is prepared at 0C alld stirred at roorn temperat~rc for about
16 hours to yield the title epoxide.
` D) 3,4a~ lexahydrc-5-[2-hydroxy-3-[4-(2-n;etho~y~ nyl)-
l-piperazinyl]propyl]-3,~; r,~ ~clo~.epi,ane-
tetrol, tetraacetate ester
A solution o~ 1-(2-methoxyphenyl)piperazinc (5.0 mrllole)
and t~le above epoxide (5.0 mmole) in absolu~c eth.lrlol (50 ml)
20 and benzene (20 ml) is stirred in a ~.~arm :7atcr bath ~5n-r,5()
for about 20 hours under a dryiny tuhe to yield the ti.tle
compound.
- 14 -
HA143/55/56
~3~
Example 16
3,4a,S-~i~-5-~3-(3,6-Dihydro-4-pheIlyl-](2~)-pyridinyl)-2
~ hydroxypropyl]~ecahydro-2~3;4a~8a-trans-naphth~llenetetr
tetraacctate ~ster
A solution of 2.5g of 3,4a,5-cls-decahydro-5-
(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetra
acetate ester and 0.86g of 4-phenyl-1,2,3,6-tetrahydro-
pyridine in 20 ml benzene-50 ml absolute ethanol is stirred
at 55-57C for about 16 hours under a drying tube. The
solution is evaporated in vacuo and the residue is crys-
tallized from 30 ml of 1:2 ethyl acetate-ether to give 0.85g
of solid. A second crop yields 0.35g of solid. Re-
crystallization rom 2:1 ethyl acetate-ether yields l.ly
of the title compound, melting point 133-199C.
: Example 17
Decahydro-5-[2-hyclro~ (]~4~5~o-tetrahydrohen~flic;oauinolin
3(2H)-yl)propy_]-3,4a,5-~ 2,3,4a,8a-
tetraacetate ester
-
1,2,3,a,5,6-Hexahydrobenz[f]i.soquinolinc, mono-
hydrochloride (l.Og) is dissolved in 20 ml of ~ater, layered
over ~ith ether and neutralized with aqueous ammonia. The
organic phase is removed and the aqueous phase is re-
extracted with ether (two 20 ml portions). OrcJanics arc?
combined, dri.ed, filtered ancl strip~ed in vacuo to yield
0.75g of the free base, ~hich is dissolved in 20 ml of
benzene and S0 ml of absolute ethanol. ',4a,5-c -Dccah!~rG-
5-(oxiranylmethyl)-2,3;4a,8a-trans-nap}lthalcnctetrol,
tetraacetate ester (1.~13g) is addcd to the solution, and
the resultin~ solution is heated to 50C~S for 1~ hours.
Solvcnt is removed _ vacuo~ the residuc i.c taken up in
ethcr and the rcsulting ~o~dcr is recrystal].izcd Irom c~thyl
- - 15 -
~3~37 HA143/55/56
acetate to yield 1.17g of the title compounl.
Exam~le 18
.
3,4a,5~ -Decahydro-5-[2-hydrox~-3-~4-(2-phenvle~henyl)-
3,6-dihydro-1(2H)-pyridinyl]propyl]-2,3,4a,8a-tran.s-
naphthalenetetrol, tetraacetate ester
A) 1,2,3,6-Tetrahydro-4-(2-phenylcthenyl)-1-(pheny]-
methyl)pyrlc~lne, monohy rochlorlde
W-Benzylstyrylpyridinium bromide (59.0g) is
reduced by stirring in 750 ml of 50~ aqueous methanGl to
which 30g of sodium borohydride is ac'ded portionwise.
Methanol is removed in vacuo, the resultinc3 slurry is
filtered and the solids are partitioned bet~een water
and chloroform. Thc aqueous layer is re-e~tractcd with
chloroform. The chloroform extracts are combillccl, ~asllc?d
with aqueous sodium chloride, dried and strippt-~d to vield
33.2g of the titlc compound. Four c;rams of this I)roduct
is dissolved in absolute ethanol, acidified with arlhydrou
hydrogen chloride in isopropanol, yielding 3.7y of sclid,
~hich is recrystallized frorn methanci-isoprcpanol to ~ielc
2.72g of crystals, melting point 235-240C.
B) 1~2~3~6-Tetrahydro-4-t2-JJhenylethenyl)pyridinc
A solution of 46c3 1,2,3,6-tetrahydro-~-(2-
phenethenylj-l-(phenylmethyl)~yridine in 150 ml of toluene
is treated with 30.1~ of ~henyl chloroformatc and heated at
reflux for 12 hours. Solvent is removed ln vacuo to yield
62.7g of a solid. The above solid is heated to 130C with
the aid of an oil bath and 50g of po~der~d ~otassium hydro~ide
is added, portionwise. Heating is continued for 90 minutcs,
the mixture is cooled, taken up in 200 ml ~ater and e~.tracted
with chloroform. Organics are comhined, washed with ac~ueou~
sot~ium chloride, dried, filtcred ancl strip!)ctl to yiel~l ~3(J
- 16 -
.. .. .. . .
- . , : . , . ~ .. . : ,
HA143/55/56
of an oil which is taken up in ether, filtered and s~rippcd
to yield 33g of oil. Twenty-eight grams of the oil is
reflu~ed in 1 liter of he~ane, the solvent is decanted
from the oil, the oil is cooled to room temperature, filtered,
then cooled in an ice box to yield a crystalline product.
~ue to the poor differential solubility, this process is
repeated about eight times, yielding a total of 1.05c3 of
the free base.
C) 3,4a,5-c s-Decahydro-5-[2-hydrox~-3-l~-(2-~henylr3thcnyl)-
3!6-dihydro-1(2~)-pyridinyl]pro~yl]-2,3;4a,da-t_ans-
naphthalenetetrol, t~traacetate ester
1,2,3,6-Tetrahvdro-4-(2-phc3nylethenyl)pyric'ine
(1.04g) and 2.5q of 3,4a,5-cls-decahydro-5-(oxjranylrnelhyl)-
2,3;4a,3a-trans-naphthalc3ne-tetrol, tetraacetate c~ster -Ire
dissolved in 50 ml cf ~bsolutc eth~nol and 20 ml of bcn.~.en(?,
and heated at 55OC~5r~ for 15 hours. Solvcnt is cv~poratcd
in vacuo and the resulting gum cry.stallized from ether.
Solids are collected yielding 1.35g of browr~ solid WhiCIl is
taken up in ethyl acetate, decolorizcd ~ith activatcd
charcoal, filtered, hexane added and left standing. Resultin~
solids are collected and dried to yield l.Og of pow-ier,
melting point 133-185C.
r,xample 19
-
3,4a,5-~s-5-[3-[4-(2,3-Dihydro-2-he.nzoxazolyl)-3,6-dihy(lro-
1(2_)-pyridinyl]-2-hydr~yprop~l]-decahy-lro-2,3;
naphthalenetetrol, tetraacetate ~3stcr
A) 2-(4-Pyridinyl)benzoxa~ol~
A mixture of 2-aminophenol (10.9g), isonicotinic
acid (12.3g) and polyphor~phoric acid (250g) is h~atc~ under
a nitrogen atmo~ph~re at 210~C for 3 hours. rl~h~ mixture is
then cooled to 160C and slow]y poured i.lltO 1 liter of water.
The mi~ture is cooled by ~ddinc~ ic~ an(l nelltr~lize~l with
- 17 -
~ . ,
HA143/55/56
50'~ sodium hydroxid~ solutiorl yielding 16.2y of crude L)roduct.
Crvstallization from hexane yields 14.8g of the title compound,
meltinc3 point 129-131C.
s) 4-(2-senzoxazolyl)-l-(phenylmethyl)pyridi~ium chloricle
.
A solution of 117.0g of 2-(4-pyridinyl)benzoxazole
and 95.0g of benzyl chloride in 1 1iter of a 9:1 rnixture of
n-propanol and dimethylsulfoxide is heated at reflux for 72
hours. The solvent mixture is then removecl and the residue
suspended in 100 ml of ~ater. Th~ crystalline product ~!hich
separates is filtered, washed ~ith aCetOIIe, ar.d dried to
give 76.6g of product. Concentration of the rr,othcr 1i.4uors
gives an additional 27.~g of product, melting point 194-196C,
dec. Recrystallization from water and drying in a vacuum
at 100C for 5 hours raises ~o melting 1?0int to 216-217C, dec.
C) ?-(l-Benzyl-1,2,3,6-tetrahydro-4-pyridinyl)benzoxazolc~
To a stirred solution of 16.6g o 4-(2-benzoxazolyl)-
l-(phenylmethyl)pyridinium chloride in 1 liter of a 1:1 mixture
of alcohol and water is added a solution of 2.8~g of sodium
borohydride at a rat~ that maintains the ternperaturc oL t11e
mixture at 30-35ac. The reaction mixture is acidified ~lith hydrochloric
acid, concentrated to one-half volu~e and t~e cryitals filtered to
give 8.7g of the hydrochloride salt of the title cornPound,
melting point 227-228C, dec.
The mother liquors are madc alkaline with solid
sodium bicarbonate, extracted with chloroform and the extract
concentrated to give a gummy residue. Recrystallization of
this material from absolute alcohol gives 2.1g of ~he title
compound, melting pOil.t 129-130C.
D) 4-(2-Penzoxazolyl)-3,~-d hyc1ro 1 _ 1) T~-~riclinec;lrbox~
acl(l, 2 2._2-trichloroc:thyl est(r
~ v~ ololl~,]y ~ r(~c~ ¢~]~ io~ r l()'3.
` ~143/55/56
a.3¢1~1~3!7
2-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)benzo~azGle in
1 liter of dry toluene is added dropwise 96.4g of 2,2,2-
trichloroethyl chloroformate during 2 hours and the mixture
is heated at reflux for 1.5 hours. The reaction mixture is
then cooled, extracted with 250 ml of cold 10% hydrochloric
acid, with 250 ml of cold 10~ aqueous sodium hydroxide
solution, and with an equal volume of ~ater, dried (anhydrous
magnesium sulfate), and concentratcd. l'he oily re.sidue is
then further concentrated from an oil bath maintaine~cl at
50C und~r a vacuum of 0.2 nm of Hg to removc tho ramainio~
benzyl chloride. ;
The viscous oil is dissolved in 500 ml of hoiling
absolute ethanol and cooled to give, after filtration and
drying, 56.9g~ of crystallinc product, meltlng point 13~-135GC.
The mother liquors give, after concentration to one-half
volume and cooling an additional ll.Og of product identical
with that above.
~) 2-(1,2,3,6-Tetrahydro-~-pyridinyl)henzoxazole
~To a solution of 52.6g of 4-(2-~enzoxazolyl)-3,6-
dihydro-1(2H)-pyridinecarboxylic acid, 2,2,2-trichloro~thyl
ester in 1250 ml of glacial acetic acid is gradually addecl
92.5g of zinc dust and the reaction mixture~s~irred at room
temperature under nitrogen for 6 hours. The reaction nlixture
is filtered and concentrated on the rotary evaporator to givc
a viscous gum. This r.naterial is suspended in 500 ml of ~ater, `~
the pH ~djusted to 2-3, and the suspension extracted with
500 ml of ether in two portions. These are combi;ned, drie~
and concentrated to give 11.32g of unreacted startirlg ~aterial.
The separated turbid, a~ueous phas,o is filtered,
coolcd, madc strollgly alkaline~ and extractc(3 th~c ~inlo!;
-- 19 --
3/55/56
with 250 ml portlons Gf chloroform. The com~ine~ e~.tracts
are dried and concentrated to give 6.0g of crystal,
melting point 136-138C.
F) 3,4a,5-cis-5-[3-[4-(2,3-~ihydro-2-henzoxazolyl)-3,6-
dihydro-1(2~)-pyridinyl]~2-hydroxypropyl]-dec~hy~lro-
2,3j4a~8a-tra~-naphthalenetetrol~ tetraacetate e~ter
,
Three grams of 3,aa,5-cis-decahydro 5-(o.Yiranyl-
methyl)-2~3;aa~8a-trans-naphthalenetetrol~ tetraacetate
ester is dissolved in 50 ml of absolute ethanol and 20 ml
of benzene. To this is add~ 1.34g of 2-(1,2,3,6-tetra-
hydro-4-p~ridinyl)~enzoxazole and t~.e resultiny solution
is heated to 55C+5 for 16 hours. Solverlt is stripped
in vacuo and the resulting gum is taken up in e~her. The
ether solution is filtered, ailuted with he:cane an~i lcf~
standing. Solids are collectecl to yield 3~J of solid
.~hich is recrystallized from ethyl acetate anc~ he~ane to
yield 1.6g of the title compound, melting point 204-210C,
dec.
Example 20
3,4a,5-~-~-Decahydro-5-[2-hyc`roxy-3-(1,2,3,4-tetrahydro-2-
isoquinolinyl)~ropyl~-2,3;4a,8a-~r~ns-na~hthalenetetrol,
tetraacetate ester
A solution of 3.0g of 3,4a,5-cis-decahy(lro-5-
(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetra-
acetate ester and 0.94y of 1,2,3,4-tetrahy~roisoquinoline
in ethanol-benzene (50:20) is warmed in a 55~C bath for
about 16 hours. The solution is evaporated ln vacuo to
giue 4g of solid. T~70 recrystallizations from ethyl
acetate/ether/hexane yield l.9g of the title compound,
melting point 185-195C~
- 20 -
HA143/55/56
' '
EY~ample 21
3 ! 4a,5-cis-Decahydro-5-[2-hydro~y-3-(4,5,6,?-tetrahydro-1~
imldazo[4, ~ )pro~yl]-2,3;4a,8a-trans-naphtha-
lenetetrol
To a solution of 0.55g of sodium hydro~ide in
30 ml of absolute ethallol is added 1.35y of 4,5,6,7-tetra-
hydro-lH-imidazo[4,5-c]pyridine, hydrochloride. After
stirring for about 5 minut~s a solution of 3.0g of 3,4a,5-cls-
decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-na~hthalcne-
tetrol, tetraacetate ester in 3n:5~ etharlcl:~enzene is added
and the solution is stirred fGr about 16 hours at 40-45C. -~
The mixture is filtered and 'he filtrate is eva~orat~ n
vacuo to give 3.8y of foam. The foam is ciicsolve~l in 5~:2
ethanol:benzene and stirred for 24 hours at 55-58'C. 1~he
solvent is removed ln vacuo and the residue i'3 di~solvecl in
ethyl acetate, heated ~Jith activated charcoal and filtered.
After diluting with a small amount of ether and storing at
-15C for 3 days, 1.3g of solid is obtained. Recrystallization
from ethyl acetate (trace methanol) yields l.ny of th~ titlc
20 compound, melting point 214-216C.
..
~ 7 ~A143/S5/56
E~amples 22-23
Following the procedure of ~xample 16, kut substituting
the compound listed in column I for 3,4a,5~c -decahydro-S-
(oxiranylmethyl)-2,3;4a,~a-trans-naphthalenetetrol, tetra-
acetate ester, yields the com~ound listed in column II.
Column I Column II
22 3a,5-cis-3a,7a;5,6-trans- 3a,5-cis-3a,7a;5,6-trar.s-
hexahydro-l-(oxiranylmethyl)~ he~ahydro~ 3-(3,~-dih~Zro-
lH-indene-3a,5,6,7a-tetrOl, 4-phcny~-1(211)-pyridinyl)-
tetraacetate ester (see 2-hydroxyprop~Jl]~ indene-
United States patent No. 3a,5,6,7a-tetrol, tetra-
4,101,723 issued July 18, a~etat~ ~stcr
1978
23 3,4a,5-cis-hexahydro-5- 3~4a-ci.s-hcY.a}lydro-5-[3-
toxiranylmethyl)-2,3;4a,9a- (3,6-~ihyclro-4-phenyl 1(2~
trans-benzocyclohe~tanetetrol- pyridinyl)-~-hydrox~propyl]-
tetraacetate ester (see 2,3;4a,9a-trans-benzocyclo-
United States patent No. heptanetetrol, tetraacctate
4,101,723 issued July 18, ester
1978
~xamples 24-25
Follo~ing the procedur~ of r:~ample 17, but substituting
the compound li.sted in.column I for 3,qa,5-cis-decahydro-5-
(o~iranylmethyl)-2,3;4a,8a-trans-naphthalenctetrol, tetraacetate
ester, yields the compound listed in column II.
Column I C~].umn II
24 3a,5-cis-3a,7a;5,6-trans- 3a,5-cis-3a,7a;5,6-tr~ns- '
hexah ~ o-l-(oxiranylmethvl)- hexahydro-l-[2-hyclroxy-3-
l~l-indene-3a,5,6,7a-tetroi, (1,4,5,~-tetrahyclrohenz[f]-
tetraacetate ester isoquinolin-3(2}1)-yl)propyl~-
indene-3a,5,6,7a-tetrol,
tetraacetate estcr
3,4a,5-cis-hexahydro-S- 3,4a-cis-hexahyclro-5-~2-
(oxiranylmethyl)-2,3;4a,9a- hydro~v-3-(1,4,~6-tctra-
trans-benzocycloheptane- hydrobenz[~]isoq~inolin-
tetrol, tetraacetate ester 3(2H)-y3.)propyl]-~,3;4a,9a-
trans-benzocyclohc~tanetetrol,
tetraacct~te ester
- 22 -
B
~3~'7 HA143/55/56
Examples 26-27
~ollowing the procedure of Ex~mple 18, but substituting
the compound listed in column I for 3,4a,5-cis-decahydro-5-
~oxiranyl~.ethyl)-2,3;4a,8a-tr~ns-naphthalenetetrol, ~etra-
acetate ester, yields the compound listed in colun~n II.
Column I Colu~.n II
26 3a,5-cis-3a,7a;5,~-trans- 3a,5-cis-3a,7a;5,~-trans-
hexahydro-l-(oxiranylmcthyl)- he~ah ~ c-l- ! 2-~ydr ~ -
l~l-indene-3a,5,6,7a-tetrol, [4-(1-ph~.:nyleth~nyl)-~,6-
tetraacetate ester dihydro-1(2~ yridinyl]-
r~ropy~ nd~nr~-3~5/6
7a-tetrol, tetraLlcet~tc
~ster
'
27 3,4a,5-cis-heY.ahydro-5- 3,~a-cis-~c~ally~ro-5-[2-
(oxiran~lrn2thyl)-2,3;4a,9a- hydro~y-3-[4-(1-phenyl-
tràns-henzocycloheptane- ~thcnyl)-3,5-dihydro-
tetrol, tetraacetate ester 1(2l~)-pyri~inyl]propyl]-
2,3,4a,9a-trans-benzocyclo-
hcptanetctrol, tctra-
acetate ester
r;Y~amples 28-29
Following the procedure of Examnle 19, but substituting
the compound listed in columrl I for 3,4a,5-cl~-decahydro-5-(Gxiran~l-
methyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacet~te ester, yieid~
the compound listed in column II.
Column I Column II
28 3a,5-cis-3a,7a;5,6-trans- 3~,5-cis-3a,7a;5,6-trans-
hexahydro-l-(oxiranylrnethyl)- heY~ahydro-1-[3-[4-(2,3-
l~l-indene-3a,5,6,7a-tetrol, clihyclro-2-hen~ovazolyl)-
tetraacetate ester 3,6-dihy~ro-1(2~1)-pyridiny3
2-hvdroxypro~yl~-lH-indenc~-
- 3a,~,6,7a-tetrol, tetra-
. acetate ester
29 3,4a,5-cis-hexahydro-5- 3,4a-cis-he~:ahydro-5-[3-[4-
(oxiranylmethyl)-2,3;4a,9a- (~,3-(lihydro-2-henzoxa~oly
trans-benzocycloheptane- 3,6-dihyro-1(2~)~pyridir.;
tetrol, t2traacetate ester ~-hydro~.ypropyl~-2,3;4~, 9a
trar,s-benzocycloher)t~ne-
tetrol, tetraacetate ester
.
23 ~
E~ `
i.3'~ HA19 3/5 5/ 5 6
~am~lc~ 30-31
~ ollo~-~ing the procedure or ~:ample 20, but substituting
the compound listed in column I for 3,4a,5-cls-decahydro-S-~oxiranyl-
methyl)-2,3;4a,8a-tra~.~-naphthalenete~rol, tetraacetate ester, yieldc
Lhe co~ound listed ir. column II.
Column I Column II
-
3a,5-cis-3a,7a;5,6-trans- 3a,5-cis-3a,7a;5,6-trans-
hexahydro-l-(oxiranylmethyl)- hcxah~-o-1-[2-hy~lro~y-3-
lH~indene-3a,5,6,7a-tetrol, (1,2,3,4-tetrahydro-2-
t~traacetate ~ster icoquinolinyl)nro~yl]-lll-
indcne-3a,5,h,ia-te~rol,
tetraacet,ate estcr
31 3,4a,5 cis-~.exahydro-5- 3,4a-cis-hexahydxo-5-[2-
(oxiranylmethyl)-~,3;4a,9a- hydroxy-3-(1,2,3,4-tetra-
trans-benzocvcloheptar:e.- hy~ro-2-isoquinolinyl)-
tetrol, tetraacetate ester propvl]-~ 7 3;4a,9a-trans-
benzocycloheptan~tetrol,
tetraacctatc ester
Exam?les 32-33
Follo~Jing the procedurc of ~xample 21, but substituting
the compound listed in column I for 3,4a,5-cis-dccahydro-S-
(oxiranylmethyl)-2,3i4a,8a-trans-naphthalenc-tetrol, tctra-
acetate.ester, yields the compound liste~ ir. colulr!r. II.
Column I . Co].umn JI
32 3a,5-cis-3a,7a;5,7-trans- 3a,5-,ci.s-3a,7a;5,6-trans-
hexahydro-l-(oxiranylmethyl)- hexahydro-l-[2 hydroxy-3- .
l~l-indene--3a,5,6,7a-t~krol, ~4,5,6,7-tetrahydro-lJI-
tetraacetate ester imidazo[4,5-c]pyridin-5-
yl)propyl]-lll-inden~-3
5,G,7a-tetrol, tetra-
` . . acetate cster.
33 3,4a,5-cis-hexahydro-5-(oxi- 3,4a-cis-hexahydro-5-[2-
ranylmethyl)-2,3i4a,9a-trans- hydroxy-3-(4,5,6,7-tetra-
henzocycloheptanete~rol, ~ hydro-1ll-imidaYo[4,5-c]-
tetraacetate ester pyridin-5-yl)propyl]-2,3;-
. . . 4a,9a-trans-benzocyclo-
-. - . hrptanetc~L-ol, te.tra-
. acetar~ c~;t-r
.
~ r~7 HA1~3/55/56
E~ample 34
3,4a,5-~iLc-!jer.ih~-.l o=5-[2-1~dro~y-3-[4-[(l-oxopropyl)-
phenylarnino]~ c~ridin~ir~ ~ 3 ,~a-tran.s-
na~hthalenetetrol, tetraacc~.ate ester
3,4a,5-cis-Decahydro~S~(oxiranylmethyl)--2,3;4a,
8a-trans-naphthalenetetrol, tetraacetate ester 3.37g is
-
dissolved in 50 ml of absolute ethanol and 20 ml of benzene.
To this solution is added 1.75g of N-phenyl-N-~piperi
dinylpropanamide and the resulting solution is heated to
55C + 50 for 16 hours. The solvent is stripped off ln
vacuo and the resulting gum is taken up in ether and left
for about 16 hours to crystallize, yielding ~after drying)
3.9g of powder. Crystallization of the powder from ethyl
acetate-hexane yielding 3.lg of powder, melting point 153-
160C.
Example_35
1-[2-~i~droxy-3-[~l~-1,7,8a-4a,6,7,8a-1etra)is(acet~1Oxy)-
decah~ydro-1-naphthalenyl]propyl]-4-phenyl-4-pi~ dine-
carbonitrile
A soIution of l.ng of 4-cyano-4-phen~lpiperidine and
2.5g of 3,4a,5-cis-decah~ydro-5-(oY~irclnylmethyl)-2,3;4a,8a-
trans-naphthalenetetrol, tctraacetate estcr in 20ml henzene-
50ml ethanol is stirred at 55-57C for about lG hours under
a drying tu~e. The solution is eva~orcltcd ln va~uo to give
3.3c3 of oil. Chromatoyraphy on 80g of nelltral alun:ina llI
gives 1.06 of epoxide eluted with 60n rnl or. 20-25~ ethyl
acetate in hexane, and 1.4g of the desired product eluted
ith 750ml of 40-45~ ethyl acetate in hcxane. Cryctallization
of this latter matexial from ethyl ac~tate hexane gives t~o
crops of solid product. These are cornbined and dried ~n vacuo
to yield 0.97(1 of the title compound, rnelting ~)oint 165-174C.
- 25 -
~ HA143/55/56
r`xarr!3jlc 36
3,4a,5- Q -Decahydro-5~[2-hy~roxy-3-(~-hydroxy-~-J)henyl-l-
piperidinyl)propyl]-2 3;4a,3a-trans-naphthaleretetl~ol tetra-
acetate ester
A solution of 3.0g of 3,4a,5-cls-decahydro-5-(oxiranyl-
methyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate estcr
and 1.25~ of 4-hydroxy-4-phenyl piperidine in 50ml of al~solute
ethanol-20ml benzene is stir-ed at 57C for about 16 hours.
Crystallization from 2:1 cthyl acetat~-hexane cliv-s 3.5-~ o~
solid. Recrystallization from ethyl acctate-hcx-lnc (?0:5)
gives 2.11g of the title comr.ound, melting l~oint 13P-142C.
Example 37
3,4a,5-c s-Decahydro-5-[2-hydroxy-3-(3,4~dillydrosl~iro~2~
benzopyran-2,4'-plperidin]-1-yl)propyl]-2,3;4a,8a-tr~n.s-
na~hthalenetetrol, tetraacetate ester
A) 3,4-Dih~dro-1'-(phenylmethyl)spiro[~ }-~en~o~rarl-2 4'-
Eiperidine], hydrochloride (1:1)
4-(o-Methoxyphenethy])py~idine (40.5 y) and henzyl-
bromide (36.0 g) are heated on a steam cone iri 250 ml of
acetonitrilc for 6 hours. A~ter coolinc3 the rcaction mi~turc
is concentratcd in vacuo. Addition of ethyl acetatc CclUS~S
crystallization. The product is filtered, washed with etllcr
and dried over potassium hydroxide. rhe yield of a hydro-
scopic quaternar~ is 68.4 g, melting point il4-124C.
rhe above quaternary (60.6 g) is dissolved in 600 ml
of 1:1 methanol-water and 10 g of sodium 3~orohydride is added
portionwise at 35~40C. After addition, the solution is
allowed to stand for about 16 hours. It is then conccntrated
to about 400 ml and diluted with 3no ml of water. The product
is extracted with two 300 ml portions o~ c~.loroform. ~J33~.c
chloroform i5 dried, filtered and concentrated ln ~cuo.
The hydrochlori(1c salt is prepare(3 in isor~roE~anol-hydro-len
- 2~ -
~3~3~ HA143/55/56
ehloride. ~fter eoneentrating in vaeuo, eth~ aeetate is
added to the residue. The hydrochloride salt erystallizes
over a 16-hour period and ~s filtered to yie~d 5a cJ of product,
melting point 122-12soc.
The above product (54.0 y) is dissolved in 2sn ml
of 48% hydrogen bromicle. It is then heated at r~flux for
6 hours and coneentrated in vacuo. The resiclue is made
strongly basie with 10% sodium hydroxide and the prod-1ct is
extraeted with ehloroform. The ehloroform is dried, filtered
and concentrated in vacuo. This frec hase is dissolve(1 in
ethyl aeetate,and hydrogen chloride in isoproparol is added
until strongly acidic. The product is filter(d to yield
39.4 g~ Two grams are recrystallized frorn aeetonitrilc to
give the analytical sample, meltincJ point 243-245C.
B) 3,4-Dihydrospiro[2~ c-~n7.opyran-2,a -pir)cri(lirl(?
-
3,4-Dihydro-l -(phenylmethyl)spiro[21~ h,ellzo[~r~
2,4 -piperidine] (25.? g) is dissolved in 250 ml of anh~!drous
toluene. The reaetion mixture is eooled to 5C ard trichloro-
ethyl ehloroformate is added dropt~ise. The solution is
refluxed for 5 l1ourc and al1c~ed to stand at room tc~ )erature
for about 16 hours. It is then washed sec~u~ntially with
100 ml of 10~ sodium hydroxide, 100 ml of ~ater, 100 ml o~
10~ hydroehlorie aeid ~nd fir!ally ~ith 200 ml of ~,ater. Tne
toluene is dried, filtered and eoneentratcd in vacuo to
yield 32.0 g of product.
The above material is dissolved in 300 ml of glacial
acetic acid. Zine dust (30 g) is added portion~ise over a
30-minute period at 20C. The reaetion mixture i5 ~3tirred
at roorn temperature for about 16 llours, filtcrcd arld concen-
tr~ted in vacuo. Ihe r ;id~3c is h(e~ () Oll a 'i~(!aln (,Orl~ 30r
- 27 -
~3~3~7 HA143/55/56
15 minutes in 200 ml of 10~c sodium hydroxide. Product is
extracted with chloroform. The chloroform is dried, filtered
and concentrated in vacuo to yield 17.8 g of crude secondary
amine. Its h~drochloride salt was prepared in isopropar.ol-
hydrogen chloride. ~.fter crystallizing for about 16 hours,
the product is filtered to ~ield 11.1 g of the hydrochloride
salt of the title compound, melti.ng point 238-240C.
C) 3,4a,5-~L~-~ecahydro-5-[2-hydrox~-3-(3,4-dihyclrospiro-
[2H-l-henzopyran-2,4-piperidin]-1-yl)propyl]-2,3;4a,8a-
trans-naphthalenetetrol, tetraacctate ester
An amount of 1.7 y of 3,4-dihydrosplro[21l-1-bclllzopyran-
2,4'-piperidine] is added to a solution of 3.55 ~I o~ 3,4a,5-
cls-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalcnc-
tetrol, tetraacetate ester in 50:20 ml of ethanol-bcni~enc.
rrhe solution is stirrcd for about 16 hours at 55C and th~n
evaporated in vacuo. The residue is crystallizecl ovrr 3
days from 2:1 ether-hexane to give 3.6 g of ~solid. r~ec~ys~al-
lization from ethyl acetate-hexane gives 2.3 (1 oE thc tit]e
compound (thin-layer chromatoc3raph~ on alumina in ethyl acet:ate
developed in iodine indicatc:s thc ti-tle cornpound to bc thc
main isomer of two isomers), melting point 135-152C~
~xamPle 38
3,4a,5-c s-Decahydro-5-[2-hydroxy-3-[4-(2-h~dro~:yt-th~
piperidinyl]propyl]-2~3i4a~8a-~rn~-naphthalcnetetrol~ tetr,-~-
acetate estcr
~ solution of 2.5 g of-3,4a,5-cis-decahydro-5-(o~.ir~r.~i-
methyl)-2,3;4a,8a-tran~-naphthalenetetrol, tctraacctatc e.stcr
and 0.75 g of 4-ethanolpiperidine in 50 ml of abxGlutc eth,-lnol
and 20 ml of benzene is stirred at 55C ior 18 hour.-;. '~'hc
solvents are removed n vacuo and the reiidue i.s concen-tl^ated
in _ several times with bcnzene to livc a ~o,lrn-like pro(luct.
Crystnllization f-roM et~(~r (3ivc<s 2. 55 ~3 ;.lrld t~,c~r").5 ~3 (,f
- 28 -
HA14~/55/56
~3~
solid product. Recrystallization of the 3 g ~f solid
from 2:1 ethyl acetate-hexane gives 2.0 g of the title
compound, melting point 112-120C.
Example 39
3,4a,5-L~-5-[2-(Ace~~loY~y)-3-[4-[2-(acetyloY~y)eth-l]-l-
~iperidlnyl]~ropyl]-decahydro-2,3;4a,8a-trans-naphthalenc-
tetrol, tetraacetate ester
A mi~turc of 5 ml of acetic anh~dride and 1.25 g of
3,4a,5-c -decahydro-5-[2-hydroxy-3-[4-(2-hydroY.yethyl)-l-
piperidinyl]propyl]-2,3;4a,8a-trans-naphthalcr.etc~trol,
tetraacetate ester (see Exam~le 5) in 25 ml of dry pyridine
is stirred at room temperature for about 16 hours. The
solution is evaporated in vacuo. The residue i5 partitioncd
between ether and a saturated aqueous sodiuln ~ic~rhonate
solution. The aqueous layer i5 re-extracted witn ether,
and the ether extracts are comhincd, dried and c~/aIjoratcc'
in vacuo yieldlng 1.3 g of product~ r~ecryc~tallizatiorl rron,
1:9 ethyl acetate-hexane yields 1.22 q of the title compound,
melting point 125-144C.
~xample 40
3,4a,5~ -5-[3-(2,3-Dihydro-2-oxo-l~-henæimidazol-l-yl)-
l-pi~eridinyl~-2-hydroxypropyl]decahyclro-2,3;4a,8a-trans-
na~hthalenetetrol, tetraacetate ester
An amoun-t of 1.5 g of 3,4a,5-c -decahydro-5-(c)~iranyl-
methyl)-2,3;4a,8a-tran~-naphthalenetetrol, tetraacetatc cs~cr
is dissolved in 20 m] of benzene and 50 ml of a},,olute e~}larlol
and maintained at 50C~5 with a water ~ath. To this is
added 0.73 q of 4-(2-keto-1-~enzimidazolinyl)pipcri~ine and
stirrinq is continued for 36 hours. Solvent is strippcd
in vacuo, and the product is cry~tallized from cthyl acetate-
hexane to yicld 1.67 g of material, nlelting point 137-144GCo
~ 29 -
HA143/55/56
~xa~le 41
3,4a,5~ 5-[3-[4-(2-Benzoxazolyl)-l=piperidinyl]-2-
hydroxypropyl]-decahydro-2,3;4a,8a-naphthalenetetrol,
tetraacetate ester
A) 2-(4-Piperidinyl)~enzoxazole
A solution of 1.71 g of benæyl bromide in 10 rnl of
acetonitrile is added to a solution of 1.96 g c,f 2-(4-
pyridinyl)benzoxazole in 25 ml of hot acetonitrile. ~fter
10 minutes the product be~ins to crvstallize out of solution.
The mixture is heated on the steam hath for 2 hours and
then diluted with ether and filtered. The crude solid
is dissolved in 50 ml of 1:1 methanol-water and treated
portion~ise with 2 g of sodium borohydridc. The mixture
is diluted with water and 2.4 g of the solid product is
collected. The 2.4 y of solid is dissolved ir. 150 ml of
ethanol, 2 g of 5% paladium on car~on is added, and the
mixture is placed on the Parr hydrogenatGr under 50 psi
hydrogen. I'he mixture is filtered, and the filtr 2t~
evaporated in vacuo to give 1.4 g of the title compound.
B) 3,4a,5-~i~5-~3-[4-t2-Ben_o azolv~l)-l-pi~eridinyl]-2
hydroxypropyl]decahydro-2,3,4a,8a-~ -naphthalene~
tetrol, tetraacetate ester
A solution of 3.6 g of 3,4a,5-cis-decahydro-5-(oxiranyl-
methyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate est~r
and 1.4 g of the 2-(4-piperidinyl)benzoxazole in 20 ml of
benzene and 50 ml of absolute ethanol is stirred for 7.5 hours
at 55C and then for a~out 16 hours at room tenlperature under
nitro~en. The solution is evapora~ed in V2CUO and the
residue dissolved in hot ethyl acetate (30-90 ml), diluted
with hexane (30 ml) and crystallized on standin~ lo yivc
3.14 y OL ~olid. q'he solid is disso]vec] in }lOt
ethyl acctatc (50 ~ ), treated with l)arco, fi~erec'f aIcl
- 30 -
~ 3~ HA143/55/56
dilut~d ~ith h~Y.ane (20 ml). The solution c-ystallizes
to give 2.02 9 of the t tle compound, meltinq point 195-205~C.
Examples 42-43
Following the procedure of ~xample 34, but substituting
the compound listed in column I for 3,9a,5-cis-decahydro-5-
(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetra-
acetate ester, yields the compound listed in column II.
Column I Column II
42) 3a,5-cis-3a,7a;5,6-trans~ 3a,5-ci.s-3a,7~;5,fi-trans-
hexahydro-l-(oxiranyl'-''''~~ hexahydro-1~[2-hydro~y-3-
meth~-l)-lH-indene-3a,5,6,- [4-[(1-oxopropyl)phenyl-
7a-tetrol, tetraacetate aminoJ-l-pip~ridinyl~-
ester (see United St~tes pro~yl]~ indene-3a,5,6~-
patent No. 4,101,723 7a-tctrol, tet~aacet~te
issued July 18, 1978 ~.cter
43) 3,4a,5-cis-hexahydro-5- 3,4a,5-cis-hexahydro-5-
(oxiranylmethyl~-2,3;4a,- [2-hydroxy-3-[~-[(1-o~o-
9a-trans-~enzocycloheptane- propyl)phenylarnino~-l-
tetrol, tetraacetate ester piperidinyl]propyl]-2,3;-
(sec United States patent ~a,9a-trans-bellzocyclo-
No. 4,101,723 issued July heptanetetrol, tetr~-
18, 1978 acetate ester .
~:
~xa~ples 44-45 .
Follol,Jing the procedure of ~xample 35, but substituting
the compound listed in colu~.n I for 3,4a,5-cis-deca~.ldro-S- .
(oxiranvlmethyl)-2,3;4a,8a-trans-naphthalenctetrol, tetra- .
acetate ester yields the co~.pound listed in column II.
Column I Column 'LI
44) 3a,5-cis-3a,7a;5,6-trans- 1-[2-hydroxy-3-[cis-
- hexah~ro-l-(o~iranyl- 3a,5-3a,5,6,7a-tetra- '
methyl)-l~-indene-3a,5,6,- kis(acetyloxy)hcY.ah~ro- '
7a-tetrol, tetraacetate lH-inden-l-yl~propy]~-4~ .
ester . ph~nyl-4-piperidinecar~on-
itrile. ' .
- 31 -
.
1~ ' ' - - .
~ HAl~3/5S/56
45) 3,4a,'-cis~ ahydro-5- l-[2-hydrox~-3-[cis-
(oxiranylmethyl)-2,3;4a,- 1,8,9a-2,3,~a,9a~tetra-
~a-trans-benzocycloheptane- kis(acetyloxy)hexahydro-
tetrol, tetraacetate ester l-benzocycloheptanyl]-
Dropyl]-4-phenyl-4-
piperidinecarbor.itrilc
xamples 46-47
Follo~ing the proceaure of Example 36, but substituting
the co~pound listed in column I for 3,~a,5-~is-decahydro-5-
(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetra-
acetate ester, yields the compound listed in column II.
Column I Column II
1 0
46) 3a,5-cis-3a,7a;5,6-trans- 3a,5-ci.s-3a,73;5,6-trans~
he~ah~dro-l-(oxiranyl- hexahydro-l-[2-hydro~y-3-
methyl)~ indene-3a,5,6,- (4-hydroYy-4-1~henyl-l-
7a-tetrol, tetraacetate ~iT~eridinyl)yropyl]-l~l-
estcr in~ene-3a,5,6,7a~tetrol,
tetraacetatc e.~tcr
47) 3,4a,5-cis-hexahydro-5- 3,4a,5~cis-hexahydro-5-
(oxiranylmethyl)-2,3;4a,- [2-hydroxy-3-(4-hydroxy-
9a-trans-benzocycloheptane- 4-phenyl-l-piperidinvl)-
tetrol, tetraacetate e~.ter propyl]-2,3;4a,9a-trans~
benzocycloheptan~tetrol, .j
tetraacetate cster
Examples 48-49
Followir.g the procedure of ~:~ample 37, but substitùting
the compoun~ listecl in column I for 3,9a,5-cis-decahydro-5- .
(oxiranylmethyI)-2,3;4a,8a-trans-naphthalenetetrol, tetra-
acetate ester, yields the compound listed in colu.~n II.
Column I Columr, ~I
.
48) 'a,5-cis-3a,7a;5,6-trans- 3a,5-cls-3a,7a;5,6-trans-
hexahydro-l-(oxiranyl- hexahydro-l-[2-hydroxy-3-.
methyl)~ -indene-3a,5,6,- (3,4-di~.y~rospiro[211-l-
7a-tetrol, tetraacetate benzopyran-2,4'-piperidin]~
ester l-yl)propyl]-ll1-ind~r.e-
3a,5,6,7a-tetrol, tetra-
acetate ester
49) 3,4a,5-cis-hexahydro-5- 3,~.a,5-ci.s-hexah~dro-5-
~oxiranylmethyl)-2,3;4a,- [2-hydroxy-3-(3,4-dihydro-
~a-trans-benzocycloheptane- spiro[21~-henzopyran-2,4'-
tetrol, tetraacetate ester ~,iperidln]-l yl)propyl]~
~,3;4a,ga-trans-~enzocyclo-
heutanetetrol, t~traacetate
ester
: 32
.. ~ .
.
~ ,, . .
~ y
~ 3 7 HAl43/55/56
~xa~plcs 50~51
Followir,s the procedure of i;:a~plr 38, but substituting
the compound list~d in column I for 3,~a,5-cis-d~cahydro-5-
(oxiran~ylmethyl)-2,3;4a,82-trans-naphthaleneietr~l, tc';rc7-
acet~te ~stcr, yields the compoul1d listcd in colu~.n TI.
Column I Col~r JI
3a,~-cis-3a,7a;5,6-trans- 3a,5-cis-3a,7.~;5,6-traJ~s-
hexahydro-l-(oxiranyl- hexahydro-l-[2-11ydroYy-3-
meth~ indcn2-3a,5,~ -h~ydro~ct.h~l)-]-
7a-tetrol, tetraacetatc pip~.ri-7.inyl]~rc~p~
estcr indenc-3a,~ ,7;--~cttol,
t~txaac~tat~ cr
51 3,4a,5-cis-h~xahy~ro-5- 3,~a,5-cis-he~ hvclro-5-
loxiral1vlmethvl)-2,3;4a,9a- [2-hyrlro~-3-[4~
trans-benzocvcloher~tane- hydro:Jcth~l)-]-ripcr-
- tetxol, tetraacetatc cstex i~3ir;yl]!JroTjvll-2~3;4;2, .-t-
~rans-~enzoc~r-l(,h(-r~i:. e-
tetrJl, tctr~ cctate est:er
,-~aTnnles 52-53
Follo~ing the procrc7.ur~ o$ Pxanlp]es 38 and 39, but s~bstituting
~hr co-.~.pound listed in column I for 3,4a,5-cis-dcca'1vt~r~-r)-
- (oY.irar.ylmethyl)-2,3;4a,8a-trans-nal?ht}-alrnc!tctr(~l, tc~tnnl-
acetate ester, yields the compound listc~d in colllmn II.
Colu~n I ^ Col~lmn ~1
-- - -- .
52 3a,5-cis-3a,7a;5,6-trans- -3~.,5-ci.s-3a, 7~!~; 5, ~-t.raJ`5-
heY.ah~ldro-l~(oxiranyl- hcxah~dro-l~[~-(acctylo:.y)-
methyl)-l~ ndene-3a,5,~,- 3-[4-[2-(~lce~ylr,~ etb~l]-
7a-te~rol, tctraace~ate l-nipcric7ir.yll!~rpyl!-ll.-
estcx indenc-3;,5,~,7ci-t-~trol,
. tc~raace.ate e tcr -
53 3,4a,5-cis-hexahydro-5- 3,-1a,~-cis-~,exilhydro-5-
(o~:iranvlmethyl)-2,3;4a,9a- l2-(ac~tylo.~)-3-[4-[~-
trans-benzocvcloheptane- !acet,~lo:~y)ct!.yl]-l-pil,er-
tctrol, tetraacetate ester idinyl]propyl7,-2,3;4a,9a-
trans-b~n.~ocyclohcptanc-
tctrol, t~trailcct~c cs-cr
~ ~ i ~r
i
i
- 33 - ;
,~, ' "' . i
~143/55/56
E:~aJ,r,ies 54 55
Following the pl-ocedure of Exa~.ple 40, but substituting
he compound l~st~d in column I for 3,4a,5-cis-decahy~ro-S-
(oxiranvl~eth~ ;4a,8a~trans-r.aphtha,(!netctrol, ';~
acetate ester, yields the cor:.?o~r,d li~;t~d in col-rfi TI.
Col~.n I Cclur^.n I.
54 3a,5-cis-3a,7a;5,6-~rilr~ 3a,'-ci.s-3a,7.~;5,6-~raJls-
heYahyclro-l-(o~ir2nyl~ ~le:~a}ly(lro-1-[3-(2,~ lro-
methvl)-l~l-indene-3a,5,6,- ~-oY.o-].l~-henzilnidil7.Gl-l-vl)-
7a-tctrol, te~traacetatc 1-l)iperidirl~].~-2-hy~]ro~:v
ester ........................ I~ro5~yl]-lH-in(lene-3a,5~h~7a-
te~trol, tetraacetate estcr
55 3,4a,5-cis-h~i:ahydro-5- 3,~a,5-c~-hc~ y(lro-5-~3-
(cxiranylm~thvl)-2,~;4~,9a- (2,3-dihy~ro~ r~
trans-benzocycloheptane- benziJnidazol-l-y~)-l-
tetrol, tetl-aiioetate ester ~i~criclirly].]-2-h~-.lro~
p~ol)vl~- ,3;~, 9~ L~a~
benzoc~cloheptanc~ tro~l,
tetlaacotl!tc ester
~arn~le.c 56-57
- Follo~in~ the procedure cF ~xam!~lc- 41, but substituting
the_compound listed in column I for 3,4a,5-cls-decahy(lro-5-
(ox~lranylmethyl)-2,3;4a,8a-lrans-na~iht!lL-IleJletetrol, tet:ra-
acetate cstcr, yiel~ the corl!po~nd liste~ in colulnn Il
C`olu~ I Coll~ln I_
56 3a,5-cis-3a,7a;5,~-trans- 3a,5-ci.~-3a,7a;5,fi- ' Lan.r;-
he.Yahvdro-l-(oxiranvl- hexahv~ro-1-13-~ d- (2-
metny;)-l~l-indene-3L-l,5,6/- ~,enzo:ca701~ er-
7a-tetrol, tc-traac~tate idinyl]-2-hy~rG~v~rol~yl]-
este. lll-in~lcne-3a,5, r ~ 7a-tetrol,
tctLaacetate e~ter
57 3,4a,5-cis-he~ahydro-5- 3,4a,5-cis-hex~h~lro-~-
(o~iran~lmethyl)-2,3;4a,9a- 13-[~.-(2-benzox~oly~
trans-benzocyclohe~Jtane~ iperidinyl]-2-hydroXy- -
tetrol, tetraacetate eLter r~r~ yl]-2~3;4a~ trans-
~nzocyclollel)taJletet~ol~
tetraacetate ~ er
~ .
- 34 - -
