Note: Descriptions are shown in the official language in which they were submitted.
This inven-tion rela-tes to a novel process for produciny
3-substi-tu-ted-2-hydroxypropyl aryl e-thers, clinical
~-blockers of the formula.
P Q
YCH~CH-O
C~2 ~ R
X
wherein one of P and R combined toge-ther with Q shows lower
alkylene or alkenylene optionally interrupted by O, N or S
and optionally substituted by lower alkyl, lower aralkyl,
lower carboxylic acyl, or carboxy ox protected carboxy,
hydroxy, lower alkoxy, lower acyloxy, oxo, amino, lower
. alkylamino, lower acylamino, nitro, nitroso, lower alkylthio,
lower sulfonic acyl or halogen; remaining R or P is a
hydrogen or halogen; Y is a halogen, hydroxy, lower acyloxy,
amino, lower alkylamino, lower aralkylamino, lower acylamino,
di-lower alkylamino, lower alkyleneamino, N-lower alkyl-N-
lower aralkylamino, di-lower acylamino, N-lower alkyl-N-
lower acylamino or N-tri-lower alkylsilylamino. The process
comprises aroma-tizing a novel 2-(substituted methyl)-1,4-
0 dioxaspior[4,5]decene compound of formula (I)R Q
C H; ~
wherein Y, R, P and O are as defined above, X is a hydrogen
atom or halogen and the dotted line represents one or two
double bonds.
Recently, ~-blockers are being evaluated a-ttractively
as useful vasodilators as well as hypotensives. sy this
invention, a convenient and economical route for producing
these ~blockers is provided star-ting from less expensive
starting materials according to the followiny reac-tion
scheme. Namely, a cyclohexenone compound (II) or its
reactive derivative is condensed with a 3-substi-tuted
propyleneglycol compound (III) or its reactive derivative
in the presence of an acid catalyst (IV) -to yive a novel
2-(substituted methyl)-1,4-dioxaspiro[4,5]decene cornpound
(I) where X is a hydrogen atom or halogen and -the do-tted
line shows the presence, if X is a hydrogen, of two double
bonds or shows, if X is a halogen, one double bond, which
in turn is subject to aromatization to give
l(a)
the desired 3-substltuted-2-hyclro~y~ropyl aryl e-ther (v):
>~ CH2Y
o~R c HOH P
L X C~12H (III) or YCH2fH- ~ ~.R
(II) ~eactive deriva-tiv~ ~H2O
(I)
acid catalyst (IV)
aromati~ation
P Q
YC H 2 IEIOH ~--R
(V)
whereln P, Q, R, X and Y are as defined above and the
dotted line represents one or two double bonds.
Throughout this specification, the word lower for aryl
part preferably means C6 to C10 and for o-thers ~eans C1 to
C10; halogen represents chlorine, bromine or iodine; and
acyl may be an acid group of a carboxylic, sulfonic, sulfenic,
phosphoric or carbonic acid.
[1] Compounds
The novel 2-(substituted methyl)-1,4-dioxaspiro-[4,5]
decene compounds (I) are represented by the following
formula:
P
2F ~ R (I)
2 ~
in which P, Q, R, X and Y are defined as above and the
dotted line represents one or two double bonds.
In the above formula, representative lower alkylene as
the divalent group bridging n and P or R includes
trimethylene, tetramethylene, pentamethylene, propvlene
`~ ~' 2
and cyclohexane-1,4-diyl.
Representa-tive lower alkenylene as the di.valent group
bridging Q and P or R may be l-propene 1,3-diyl, 1-butene-.
1,4-diyl, 1-pentene-1,3-diyl or 1,3-bu-tadiene 1,4-diyl.
,~
25~
2(a)
ReE~rese~tati.ve examp1es o~ saic1 a:LkyLe1le or a.lker1y:1.elle
interruptéd })y a hetero atom selectecl Erom 0, N ~nd S in i-ts
chain include the divalent groups of ti1e following formula:
~ ~ ' . -N~ ' -N J' ~ ~ ~ ~N
H 1~ 5 l l
--S J `N ~ and ~N
Il
Io These compounds (I) are useful as intermediates for
preparing said R-blockers of formula (V) above by the aromati-
zation as given below in this specification.
~ ome of the representative compouncls (I) are l.isted
below although they are not exhaustive listing. (R=11~6~:
No. P-Q combined X Y
.
-CH=CEI-CII=CH- -H -Br
2 -CH=CE~-CH=CH- -Cl -Br
3 -CEI=CH-CEI=CH- - Br -Br
4 -CH=CE5-CH=ÇE5- -Br 2 6 4 3 P
-CEI=CH-CEI=CH- -Br -NIICH (CH3) 2
6 2 2 -H -Br -
7 -CE12CH2CONE1- -Br -Br
8 -CH2CH2CONE1- -Br -NHCH (CH3) 2
9 -CEI=CH-N (COCH3) - -Br -NIICII (CE13) 2
-CEI=CE-I-N (COC6E15) - -H -Br
11 -CEI=CH-N (COC6E15)- -Br -Br
12 -CEI=CM-N (COC6E15)- -Br 2 6 4 3 P
13 . -CEI=CE5-N (SO2C6H5 ) - -E-l -Cl
3 0 ~
14 -CH=C}I-N(S02C6115)- -Br -Cl
-CH=c~l-N(so2c6l~sc~l3-P)- -H -Cl
16 2 6 4 3 P -11 -Br
17 ,CI~ N (SO2cGll4cll3-p) ~ -~1 -NIICII (CH3) 2
18 -CII=CII-N (SO2C61I ~C113-p)- -Br -Cl
19 -Cl-l=Cil-N (SO2C6114CH3-p) - -Br -Br
( 2 6 4 3 P - Br -OH
21 ( 2 6 4 3 P -Br -OSo2c6H4cil3-P
22 -CH=CH-N (SO2C6H~,CH3-p)- -Br -N~ICH (CH3) 2
23 -CH=CH-N (So2c6~l4 3 -Br -NCil (CH3) 2
COCI~ 3
24 ( 2 6 4 3 P -Br -NC}3 (C}33) 2
COC6H5
-CH=CI-I-N (S2C6fl4CH3-P)- -Br -NCII (C}l3) 2
S02C6H4CH 3-p
26 ( 2 6 4 3 P -Br -NCII (Cl-13) 2
PO(OC2 5)2
27 ( 2 6 4 3 P -Br -NCl:l (CH3) 2
( 2 S 2
28 ( 2 6 4 3 P -Br -NCH(C113)2
~: . . COOCH 3
29-CII=CH-N (SO2C6H4CH3-p)- -Br -NCH (CH3) 2
SC6H4N02-o
30`-CH=CH-N (SO2C6H4CH3-p) - -Br -N (CH2) 5
312 6 4 3 - Br -NCII ( C}l 3 ) 2
COC (CH3) 3
32-CIl=CE-I-N (CHO) - -Br -NCH (CH3) 2
CC~ l9- t
3 0 _ _
,i
33 ~CH=CH-N(COCH3)- -Br -NCH(CH3)2
COCil3
34 -CH=C(CH3) N(SO2C6H4C113-p)- -Br -NHCH(CM3)2
35 -CH=C(C~13)-N(sO2c6~ c 3 -Br -Br
36 -cH=c(cH3)-N(cocH3)- -Br -NHC~Hg-t
37 -N=CH-S- (for Q-R) -Br -NHCH(CH3)2
2 2 -I ~Br
[2] Ketallization
l0 The novel 2-substituted methyl-l,4-dioxaspiro-[4,5J
- deeene eompounds (I) can be prepared by eondensing a ~;/
eyelohexenone compound (II) or its reactive derivative with
a 3~substituted propyleneglycol compound (III) or its reactive
derivative in the presenee of an aeid eatalyst (IV) for
dehydrating eondensation according to the following reaction
scheme:
2 P p
CHOH YCH2CH-O
O ~ R CH2H (III) CH O~ J
or reactive deriva- 2 ~
~X tive ~ X
(II) acid catalyst (IV) (I)
or reactive derivative
wherein P, Q, R. X, Y and dotted line are as defined above.
Said cyclohexenone eompound (II) is a substanee known
or easily produeible by a eonventional method from easily
available s~lbs-tanees. Its reaetive derivative ean be in
ke-tal, hemiketal, enol ether, aevl hemiacetal, di-acyl ketal,
enol ester, enamine or like form.
Said 3-substi-tuted propyleneglycol eompound (III) is~a
~ ~
substance knowrl or easily proclucil)le )~y a )cl~own rnethod from easily
available substances. Its reactive derivative can ~e in an-
hydro derivative (i.e. epoxide), N,N-di-lower alkyl-lower alkana-
mide acetal, glycol s~lfite, O,O-di-lower alkylenedioxysilicone
derivative, O,O-lower alkylidene derivative or llke reactive Eorm.
Sa1d acid catalyst (IV) can be a minera:L acid, lower
hydrocarbons!llfonic acid, strong lower carboxylic acid e.~.
halogenoacetic acid or Lewis acid. SpeciEic examples of these
include hydrochloric acid, sulfuric acid, phosphoric acid, acid
ion-exchange resins, oxalic acid, triEluoroacetic acid, methane-
sulfonic acid, ethanesulfonic acid, benzenesulfonic acid,
toluenesulfonic acid, ammonium chloride, calcium chloride, ferric
chloride, calcium acetylide, stannic chloride, zinc chloride,
boron trichloride, niagnesium chloride, alumin~lm chloride and
the like.
This reaction is carried out in an inert solvent. The
reaction can- be accelerated by removin~ water formed durin~
the reac-tion when free glycol (III) is used as the reagent.
PreEerable solvents are those which can dissolve the
cyclohexenone compound (II) or its reactive derivative and
3-substituted-propyleneglycol compound (III) or i-ts reactive
derivative used. More prèferable solven-ts include conventional
hydrocarbon-, halogenohydrocarbon-, ether-, ester-, N,N-di-lower
alkyl-lower alkanamide-, nitrile-, sulfoxide-, carboxylic acid-,
alcohol-, and like solvents and a mixture of two or more of these.
In some cases, compounds (II) or (III) can be used as
the solvent. For removing off the water formed during the
reaction, azeotropic dellydr~itiorl usin~ e.~. Dean-Stark trap
can preferably be app]ied. ~ddition oE an inert dryin~ material
e.g. Molecular Sievec, into the reaction medium is a]so
preferable cho:ice.
The reaction can be carried out at a temperature of ranye
minus 50C to 150C for up to.several days.
The reaction of this step is a 3ce-tallization well-known
-to those s3cilled in the art and wel.l documented e.~. in Organie
Functional Group Preparations , Volume IIT, pp. 2-53, ~cademic
Press, N.Y. ~1972) by Stanley R. Sandler and Wol~ Karo.
In a typical example of this ketall.ization, a solution of
a cyelohexenone eompound (II) in a haloyenhydrocarbon or
aromatle hydroearhon solvent (5 to 10 parts by w~ic~ht) is mixed
with a 3-substituted propyleneglycol (1 to 5 molar equivalents)
and an arylsulfonie aeid (0.01 to 0.1 molar equivalent), and the
mixed solution is refluxed with heatiny for 5 -to 20 hours under
azeotropie dehydration. (~mounts show ratios -to cyclohexenone
eompound (II)). ~he reaetion mixture is made alkaline Witl
aqueous alkali, extraeted with a wa-ter-irnmiscibl.e solvent,
washed, dried and concentrated -to give an objee-tive 1,4-dioxa-
spiro[4,5]deeene eompound (I).
In another example of this ]ce-tallization, a solution of
a eyelohexenone eompound (II) and an epihalohydrin (III in a
reaetive form) ~1 to 2 molar equivalen-ts) in a halogenohydro-
`- earbon solvent (5-to 20 parts by weight) is mixed with.a solution
of stannie ehloride (0.1 to 2 mo:lar equivalents) in the same
halogenohydroearbon soJvent (0.1 to 1 part hy wei.yht), and the
mlxture is leftstandiny for 3 hours at room -temperature. (~mounts
show ratios to said eyelohexenone compound (Il)). The reaction
mixture is made alkaline with aqueous alkali to pil 10 and ex-
traeted with a water-immiseible solvent. The ex-tract solution
is washeq, dried and eoncentrated to give an objective 1,4-
dioxaspiro[4,5]decene compound (I).
1,4--dioxaspirc)[~,5ldecene coln~)oulld (1) t~lus prep.nrc(l is
usually a diastereomer mi~ture due to two or three asymmetrlc
carbon atoms at the positions 2 and 4 of ],3--clioxolane ring
part and the pOsitiOIl linked to x group wl~cn satura-ted.
[3] llaloge,nation.
~ CtiOIl of a halogenating reacJent on l,~-dlo~aspiro[~,5]-
deeene eompo~nld (I) in wllicll X is hydrocJen (Ia) give the com-
pound (I) where X is halogen (Ib) aecordillcJ to the followiny
scheme:
llalogenating P\ ~Q
YCil2CH / ~ reag~ Y~ 2 ~ R
(Ia) (Ib)
wherein P, Q, R, Y ancl dotted line are as clefllled above and l-lal
is halogen.
Haloyenatlng reagents used here inc]ude molecular halogen,
bromine chloride, iodine chloride, quaternary ammonium perhalide,
N-haloamide, N-ilaloimide and other conventional halo~enating
reagents for -this type of reactions. The reaction is, if required
earried out in the presence of acid-acceptor and in a solvent
aeeording to a conventional manner to give the llalo~enated
produet (Ib). ~
[4] Other'~modifieation of 1,4-dio~asE)iro[q,5]decelles (I).
(1) Proteetion and deprotection of reactive groups ean be
made by a eonventional method;
(2) Whell Y is a leaving group, treatment witll a nueleo-
philie reagent e.g. amine, lower alkylamine, halogenating reagent,
water or llke, in a convelltional manner to give a corresponding
eompound wi-thir--the definition.
(3) When Y is amino, lower alkyl, l.ower aralkyl or lower
alkylidene ccm be introcluced -to glve a 1,4-dioxaspiro[4,5]~
decene compound (II) having -the corresponc1ing substitu-ted
amino for Y.
[5] Aromatization
According to the present invention the 1,4-dioxaspiro
[4,5]decene compounds (I) where the dotted line shows a
double bond and X is halogen, or alterna-ti~ely, the dotted
line shows two double bonds and X is hydrogen can be
aromatized to obtain the corresponding 3-substituted-2-
hydroxypropyl aryl ether (v) according to the following
reaction scheme: YCH2CHOH p Q
dehydrohalo- C 2 ~ - R
~ , r prototropi c
CH2 ~ aromatization
(I) (V)
wherein P, !, R, X, Y and dotted line are as defined above.
The aroma-tization is carried out by the action of a
base, acid, adsorbing agent, metal salt or heating.
Said starting 1,4-dioxaspiro[4,5]decene compound (I) in
which the dotted line shows a double bond and X is a halogen
can be prepared by the method as given in Sections [2] or
[3] of this specification above. Said 1,4-dioxaspiro[4,51
decene compound (I) where the dotted line shows two double
bonds and X is hydrogen can be made by a known dehy~rohalo-
genation with a base e.g. alipha-tic amine or aromatic amine,
if required under heating. An inorganic base and a Lewis
acid are also used as reagents for this reaction due to
dehydrohalogenation and prototropy.
When said aromatization is carried out with a base,
-the starting 1,4-dioxaspixo[4,5]decene compound (I) is
treated with an aliphatic amine e.y. lower alkylamine, di-
lower alkylamine, tri-lower alkylamine, lower al]cyleneamine,
oxa-lower
~~
15 .
9(a)
al]cyleneamine, di--lower cycloalkylamine, 1,5-dia%abicyclo
[5,4,0]-undecene-5, 1,4-diazabicyclo[2l2,2]octane, quinucl-
idine, 1,5-diazabicyclo[~,3,0]nonene-5; aroma-tic base e.g.
pyridine, picoline or quinoline; lower alkanoate, aroma-tic
carboxylate, lower alkoxide, phenolate, carbonate salt of
alkali metal; alkali metal hydroxide; or like bases.
Generally, t:his reaction requires a higher temperature e.g.
40 to 150C, for several hours to a few days. The mos-t
preferable base is a secondary amine of boilin~ point
between 80C to 200C.
When the said aromatization is carried ou-t with an acid,
the starting 1,4-dioxaspiro[4,5]decene compound (I) is treated
with a mineral acid, carboxylic acid, sulfonic acid or Lewis
acid. However, due to instability of the starting ketal
compound (I) to a proton acid, a non-protonic acid (i.e.
Lewis acid) is preferred for this step of the reaction.
When said aromatization is carried out with a Lewis
acid e.g. beryllium chloride, boron trichloride, boron
tribromide, magnesium chloride, aluminum chloride, silicon
tetrachloride, zirconium tetrachloride, titanium
tetrachloride, stannic chloride, antimony trichloride,
niobium pentachloride or tellurium tetrachloride; more
preferably beryllium chloride, boron trichloride, boron
tribromide, aluminum chloride, titanium tetrachloride stannic
chloride or other Lewis acid; the reaction proceeds at a
very low temperature e.g. -70 to 0C. The reaction condition
depends on the selected Lewis acid. A ca-talytic amount to
excess amount of the said Lewis acid per selec-ted s-tarting
compound (I), e.g. 1 to 6 molar equivalent, may be used.
~ 10
3~
Aromatiz.ation of thls type is sui-table :~or cornpounds (I)
having alkylamino or alkyleneamino as Y. ~rhis is done in
presence of an addi.tional reagent selected from tertiary
amines such as tri-lower alkylamine
. 25
.
~ lO(a)
.:,,
N-lower alkyl-lower all~yleneamino, N-lower al]cyl-oxa-lower
alky:Leneamine, N-lower aryl-di-lower alkylamine and
polycyclic aza-lower hydrocarbon e.y. 1,4-diazabicyclo[2,2,2]
octane, l-azabicyclo[2,2,2]octane, 1,5-diazabicyclo[5,4,0]
undecene-5, 1 5-diazabicyclo[4,3jO]nonene-5 and the like.
The amoun-t of the tertiary amine to be added is preferably
1 to 8 mola~ equivalents per the starting compound (I) for
accelerating the reaction and improving the yield.
This reaction is carried out at sub-zero to room temp-
erature, preferably at -80C to 20C. The reaction usually
is completed within 0.1 to 50 hours. The reac-tion time
varies considerably depending on the chosen reaction
conditions e.g. solvent, selected sort of Lewis acid and/or
the presence or absence and sort of the additional reagent.
In a typical example of this aromatization, a mixture
of 1,4-dioxasporin[4,5]decene compound (I), an oxa-lower
alkylene amine compound (5 to 10 or up to 30 parts by weight
when utilizing also as a solvent) and optionally an aromatic
hydrocarbon solvent (5 to 10 parts by weight) is heaced at
reflux for 5 to 10 hours, and diluted with water and ethyl
acetate. The formed or~anic la~er is taken up and washed,
dried and evaporated to give the objective 3-substituted-2-
hydroxypropyl aryl ether (V).
In another typical example of thls aromatization, a
solution of 1,4-dioxasporin[4,5,]decene compound (I) and a
tri-lower alkylamine (1 to 8 molar equivalents) in a
halogenohydrocarbon solvent (10 -to 20 parts by wei~ht) cooled
at -50 to -10C is mixed dropwise with a solution of a
stannic halide (1 to 5 molar equivalents) in the same or
~3i 11
diffexent halogenohydrocarbon solven-t (1 to 10 par-ts by
weight), kept at the same -temperature for a Eew minutes,
wa.rmed to room temperature and left standing _
~0
ll(a)
at -the same tempera-ture Eor 1 -to 10 hours. (~moun-ts show
ratios to the 1,4-dioxasporin[4,5~decene compouncl (I)). The
reaction mixture is evaporated, made alkaline with aqueous
alkali, shaken and extracted with a water-immiscible solvent
and extract solution worked up as usual to give an objective
3-substituted-2-hydroxypropyl aryl e-ther (V).
Said a~omatization with an adsorbing agent can be
carried out with e.g. alumina, silica yel, magnesium silicate,
calcium carbonate, zinc oxide, etc.
The above aromatizations are carried out in an inert
solvent e.g. hydrocarbon- ~e.g. benzene, toluene, xylene,
ligroin), halogenohydrocarbon- (e.g. chlorobenzene, dichlo-
romethane, dichloroethane, trichloroethane, chloroform),
ether- (e.g. diethyl ether, dibutyl ether, dioxane),
nitrohydrocarbon- (e.g. nitrobenzene, nitromethane), ester-
(e.g. ethyl benzoate, ethyl acetate), amine-, amide-, nitrile-
or alcohol-solvent or a mixture of two or more of these.
When the selected reagent is a liquid, it may also serve as
a solvent.
When said dehydrohalogenation in part [5] is carried
out by the action of a base or Lewis acid, this aromatizat-
ion often follows immediately to allow the two reactions to
proceed in one handling -to obtain the objective 3-substituted-
2-hydroxypropyl aryl ether (V) directly from the 1,4-
diozaspiro[4,5]decene compound (I). However, as the reaction
course of this simultaneous dehydrohalogenatiorl and
aromatization has not been elucidated, intermedicay of the
diene compound (I) is still open to argument especially in
30 ~j 12
J ~
the case of the Lewis acicl ca-talvzing reac-kion.
The above said aromatization products can be isola-ted
by removing unreacted star-ting materials, excess reagent,
solvent,
/
:~, 12(a)
., .~
f~ ~
i~y~ od~le~: (L(-. ~ro~ c r~lel;o~ t~ )S! ~1 c'ollvelltiol~
manner (e.cJ. concent.rati.oll, wasl~:irlc~, aclsorl)t;,orl, extraction,
preeip:itation erystal:lization) and purifyincJ l)y a eonventional
method (e.q. fraetioncll extraetion reerystallization waslling
adsorption, elutioll, ehromato(Jraplly).
If required, tl-le reaetion pro~luets o.r Cl-llde material ean
be used as the startincl Materia:Ls Eor sueeecclillcJ reaetions
witl-out isolatiou or furthe~ uriEieation.
The produet 3-substitutecl-2-hydroxypropyl aryl etlleF (V),
10 is a ~-bloeker for treatincJ eireulatory diseases as explained
above. Tlle eompound (V) ean be, if required, del)roteeted/
proteeted or modifiecl at the P, Q R or Y c~roup to obtain more
pharmaeologieally preferable substanees and serve as interme-
diates therefor.
15 [6] Examples
FollowincJ examples are cJiven to furthc-r illustrate -the
embodiment oE tllis inventiorl, but not intell(lecl-to restrie-t the
seope thereof. In the examples struetural formulas are plair
formulas negleetillcJ stereoehemieal strueture. ~ll "p~rts'
20 showincl the amoullt of material are part.C~ by weiclllt.
~ ;ample :[. (Ketalli.~.ation)
__
cll~ol~ ~ cll ~ ~t~
Y ~ C i C~
~ mixtllrc of tllc eyelohe~erlone eompo~ d (2) (100 parts),
p-to]uenesul~01lie aeid (O.l molar ecluiv.llellt) 3-substituted-
prOpyleneCJlyCOl COlllpOUllCI (3) (1 to 5 molar ec~ivalents) ancl
30 toluelle (500 to 500() ~arts) is refLuxe~ ~or al)c)ut 2 to 43 hours
13
~Ir~der aZ~:`OlI~OI~.i.C' (lr~ls~(lrc~ io~ C?I: c~t:~o~ , tllC? r(,~ ioll
mixture is neutra1 ize~cl with di ~.ul ed aqlleous sod:ium hyd:roxide and
toluene layer 1s separatcd. Tht-~ oryanic l.ayer i.s washed with
wa-ter, clried an(l concelltrated -to dryncss under reduced pressure.
l'he ob-taincd rc~c;idue is puri~i.ed to clivc~ tht~ ob jractive 2- (Y-
substituted methyl)-l,~l-c~i.oxaspori~ ,5¦rlec~crle compoul1d (I)
haVi.llCJ the yllySi.Ca L COllS tallt. givr?ll in thC? rol:Lowing table I,
Parts l to 7.
When Y is a basic group, it should be nelltra Lized be:Eore-
] O hancl wi-th a suitable acid r~-.g. pr--toluellcsulfollic acicl.
./ . _ .. _ . _ . _ . . . . .
-r~ _~ ___ _ _ ~
.,. Ul
O S ~~ ,I~ ~ ~ [~
~n t)~ ~ ~.0 . N ~ ~J~
E E. r E ~ i-- ~: r~ E.
tn t~Ln ~ O r~) r~) n r o
o co ~ o ~ ~ tx~ r-
~ r~~ ~ ~ ~ ~ ~1 ~O t~
r I r~ t~ 1~ t~) ~1~ 3~ ~O _
n,1 1 l l 1-- E. rd
~> ~Ir) r I i~t~ r ~r~ tO I t~
. Ln to ~to E~ I r~ o ~ c~
N t~~ ~ ~ ~ ~ ~ ~ O
C t~ ~0 N ~ r~ ~1 ~ ~
l C~ ~ N
~) ~ ~ I Cl`\ N ~ ~
r~l~r I C~N N ~:1~ r I ~ I ~C ~r
t~ E.E~ E.E~ E. E. N ~o Lt~ r I E~
a P.Ln 1-~- t~ ~ . . ~ ul ~
t~N tOI~ tV 1~ t~ r~ ~o ~ to
~ . . . . . ~ t\j _ "~ -
--~;) t`l ~ N t~ 1~ Ul ~t> ~~ rt~
l l l l l N ~ N Ln r~l
~ . 1'- ~-- t~ O t~ ~r t,o r~ O r.;~
~O r-l r. ~ C~ ~ N
~~ ~ ~ ~ ~t\l ~ r r~ ~ ~
Zr~l t~'l N ~)LD~ ~ I ~ ~0 1~1
~_ __._ _. _ ~
r--l r--l tN
E~ r-l t--
~1 t~ 1 ~1~ r I r--l
E. .n t I~ t~ r.~
r~ O . O C~l ~ O
;r i ~l) r I r~l ~ r--l t ) ~O
~ E. ~ _ r-l
~ ~O t~ t~ Irl ' O
O r I ~ O t-- ~1
~O ~O t~ ~O tO t~ )
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Detailed p]-eparatiol-l oE the COmpOU11Cl NO. ] 0 ill preCedillCJ
Table I is given to illustrate a representative of -the ketalli-
æation .
Br Cll2Cl Cl~
SO2 ~ SO2
~ C113 - ~ -SO
In a three necked flask equipped Witil a thernlometer, a
stirrer and reElux condenser havinc~ Widmer-type water trap
filled with ~iolecular Sieves are placed 4-oxo-5-bromo-1-benzene-
sulfonyl--4,5,6,'7-tetrahydroil~dole (loo pclrts), ~-chloro-1,2-pro-
panediol (311 parts), p-toluenesulfonic acid monol~ydrate (3
parts) and toluene (4500 parts), and the mixture is refluxed for
7 hours 20 minutes whi.le drying ~hc refluxin(~ azeotrop;.c mi~ture.
After coolïnc~, tlle reaction mix-ture is adiusted to pll 9 with 2.5N
aqueous sodium hydroxide with stirrincJ, and the formed toluene
layer is separated. The water layer is wasl-lecl ~ith benzene
~200 parts). Toluene layer and benzelle washincl are combined,
washed twice with water (500 parts) and dried over anhydrous
sodium sulEate (500 parts). Tlle dryinc) acJent i.s fi.ltered off,
and the filtrate is concelltrated under rccluced pressure. The
obtained residue (143 parts) ls dissolved in benzelle (300 parts),
stirred Witll active charcoa] (50 parts) for 30 minutes and
filtered tl~rouc~ll a filtcr-~c?d of silicc~ous earth. T~le fi.ltrate
is concentra-ted under reduced ~ressure, and stirri.ncJ of re~sulted
residue with a small amoullt of ether and hexallc? afEords amor-
phous powder. This is collectcd by filtration, washed with a
22
mixture of C't~ . alld I~C`,~all(' all(~ ie(l to ~JiVC? ~ I.LOrOl'll('l:ln~L-
5-b:romo-l-bell,7,elleciu:LEorlyl--4,5,6,'7-letl-ahyc:lroillck>le-~l-spil^o-2'-
[1 3]-dioxo:Lane di.astereomer mixture (122 parts):in 97~ yield.
Example I-2.
An example o:c react:ive clerivative o~ 3-s~1bstituted propylelle-
glycol compouncl (3) in O O-isopropyli.clene :~onn.
C`1120S02 ~C~Cll3 o 1 QS02 ----~C~)-Cll3
Br ~ `C(c~i3)2 r ~ ~
I 2IICl S2
C~ I
3 C1l3
~ mixture of 3-p-tolucnesulfonyloxyprol~ylelleglycol acetonide
(2 molar ecluivalents) 5-bromo-1-p--toluenesul~ollyl-4-oxo-~ 5 6
7-tetrahycdroinclole (100 parts) hydrochloric ac.~d (1 ~olar
ecluivalent) and benzene (500 to 2000 parts) is reEluxed for 21
hours under azeotr.opic dehydration. ~fter coo.l.incJ thc reaction
mixture is adjustecl to pll 10 Witil 5N-sodium llydroxi(le sllcken and
wa-ter layer drained. Organic layer :is wasi-ed with water (100
parts) and clri.ed over anllyd:rous sodium sul~ate (50 parts). Ihe
drying agent is removed by filtration. ~`he ~iltrate is tllell
concentrated under reduced pressure at a temperature below 50C
to leave amorpl~ous 4 -p-toluencsulfonyioxy-l-p-toluenesulfonyl-
5-bromo-4 5 6 7-tctrahyd:roilldole-4-spiro-2 -[1 3]-dioxolane
diastereomer mixt.urc in ~2~i yicld. rlle product is sllown in
Table I ~art 6 No. 18.
~: Example I-3.
An example o~c reactive clerivative o~ 3-sub tituted pro-
pyleneglycol compound (3) in all~lydro form.
23
~ t -
CH Br I ~ sr
Brb~ ?~ o
S2SI1C~ 2
~) `
C~13 C~13
A mix-ture of 5-bromo-l-p-toluenesulEc>nyl-4-o~o-~,5,6,7-
tetrahydroindole (lO0 parts), epibromohydrin (1.2 molar equi-
valents) and stannic chloricle (O;l molar equivalent) in carbon
tetrachloride (1500 parts) is kept at 0C to 2C for 19 hours.
The reaction mixture is carefully mixed with 5M-sodium hydroxide
to ad~ust at pH lO, shaken and organic layer separated. By
washing w:ith water, drying and concell-tratioIl, the organic layer
gives 72.3~ yield oE 5-bromo-~'-bromometllyl-l-p-toluenesul-
fonyl-4,5,6,7-tetra11ydroinclole-~-spiro-2'-~],3]clioxolane
diastereomer.
The physical cons-tants of the product is shown in Table I,
No. 15.
Example II. (Halogenation)
\ NIIC}I(CH )
NHCI-l(Cll3)2 /' 3 2
-25 ~ir~ tion Br ~ _
~_~ 3 50~ _ <O >--C113
2~1
r~ ,~
]) with cul)ric l:~rolllicle.
To a solu-tion o-E 4'-isopropylam:inolnetllyl-1-r~)-toll:lellesul-
fonyl-4,5,6,7-tetrallydroirldole-4-splro-2'-[1,3]-dioxolane
(lO0 parts) in t-butanol (2000 parts) is adcled cupric bromide
(2.5 molar equiva:Lents) ancl the mixture is l-eatecl uncler reflux
for 4 hours. ~fter coolinc~, the mixture is ilterecl to remove
solicl material and adjusted at pll lO with 5N-sodium hydroxide
aqueous solu-tion. Tlle mixture is extracted with ethylene chlo-
ride. The orcfanic layer is separated, washed with water, dried
.. ~
and concentrated to aEford 5-bromo-4'-isoproE)yLaminomc-thyl-l-p-
-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]dioxolane
in 70~ yielcl.
2) with pyridine hydrobromide bromine complex.
To a solution of 4'-isopropylaminomet}lyl-1-p-toluenesulEonyl-
4,5,6,7-tetrailydroindole-4-spiro-2'-[1,3]dioxolane (100 parts)
in dioxane (1000 parts) is added pyridine hydrobromide-bromine
complex (2 molar e~luivalents) and heated at 'lO to 50C Eor 1
hour. After coolinc~, -the mixture is diluted with 5N-sodium
hydroxide aqueous solution and e~tracted with dichloromethane.
The extrac-t solution is wa~;hed wi-th wa-ter, dried and concentrated
to afford 5-bromo-4'-isopropylamillometllyl-l-p-toluellesulEonyl-
4,5,6,7-tetrahydroilldole-4-spiro-2'-~l,3]dioxolane in 656 yield.
The products are shown in 'I'able I, No. 19.
F.xample III. (ll~lodification oE the struc ture)
(1) Acylatioll. I~CO
) C11NlICTI C11-0 ~ ( 3 2 2~
(ld) Cll O / ~ acylatincJ(~) 2
i~r reacJent Br
3 ,.;~
.
To an icc~-coc)lecl mixture o~ a corn~our-d (lc:l) (1.00 p,-lrts)
and a base (and a solvent) is added to acylatinc~ reayent
(1 -to 9 equivalents), and the mixture is :let ~tand until the
startinc~ compound disappears. The reaction mixl:ure is con-
eentrated under reduced pressure and washe~d to remove the base.
The remainin~ re~iclue is dissolved in dich:Lorollletllane and water,
and formed organ:ic layer is separated. Tlle orcJ(ll)ic layer is
washed with water, dried and concen-trated under reduced pressure.
The residue is purified to yive the correspondinq acylate` (le).
Table Il illustra-tes some reaction conditions.
/
... . .. ..... .
26
- ~--~ ----~ ~
rl - - ~ --~ ~- -
E~ O n~~ r-l r-l I--
_ l
-. ~1 r , ~-1 r-l ~s~ ~ . ~
= ~ ~ =
~,ot~
- - '~ O
U O I J~; Z ~) _ r"~ ~ (~ 7;
,1 ~ Ll~ o n ~i~ ~ co O ~ In
U~ r~ 1~ ~ ~ ~ ~ ~C ~ ~ :C
~q ~ ~ ~4~n ~ Ln
, 1 Q Q ~ r~
r~ ~ ! I r~
'C~ r~7 ~ 0
b o
~ ' , ' 1 ; ~
r' ~ ~1 ~ C) . - - .. .
~U [~ _ _ _
H O 1 1l ~ Z--U~ = _ _
.n ~, ~ = ~ _
.
27
Detai.:l.ed react:io~ roceclurc~ or 'L'a~:lc LI, Mc.. 2 i';
given below as a representat.ive example.
No. (2)
(CE13)2C ~ ¦ ,
Br~ J ~ co Br~
SO
2 f2
0 ~ t~
Cil3 C~13
To a solution of 4'-isopropylaminomethyl-1-p-toluene-
sulfonyl-5-bromo-~,5,6,7-tetrallydroindole-4-sE~iro-2'-[1,3]-
dioxolane (100 paîts) is dissolved in pyridine (343 parts) and -
placed in a -three necked flask equipped with a stirrer and a
thermometer is added benæoyl chloride (35 parts) dropwise at 0C
to 5C.. ~fter standing at room temperature Eor 14 hours, tlle
reaction mixture is evaporated to remove pyridinc at below 70C.
Obtained residue lS dissolved in clichloromethane (300 parts) and
washed -three times with water (50 parts). ~queous washings are
combi.ned and washed wi-th dichlorometllane (50 parts). Dichloro-
methane solution and dichloromethalle washialcJ are combined,
washed with water (30 parts), are dried over anhydrous sodium
sulfate. ~fter 1 hour, the drying agent is removed by filtration,
and obtained filtrate is concelltrclted to drynes~s under reduced
pressure. Obtained resiclue (132 parts) is dissolved in dichloro-
~;~ methane (270 parts), let stand for half an hour with active
charcoal (30 parts), and filtered throucJIl ~lorisil filter-bed.
Resulted filtratc is concentrated under reduced pressure to
dryness at below 30C and obtained residue is triturate~d in a
28
srnal:l alllOu]lt oE a mi.~turc oE l~e~ cllc all(l dicll~ >t-olnc~tll.lllc~ to
give amorphous powder. Tl-e product .is col].ect~cl by Eiltration
and dried to give 4'-(N-isopropyl-N-bellzoylaminomethyl)-l-p-
toluenesulfonyl-5-hromo-4,5,6,7-tetrahytlroinclole-4-spiro-2'-
[1,3]-dloxolane (111 parts) in 91~5~o yield.
2) Mucleopllil.i c substitlltioll at Y.
l l (Leaviny group) ~-- /`~ ( )
3r ~ ~ ll2 ~ 3)2,
N N
50~- C ~ - C113 2 ~ ~ Cll3
A solution o~ 4'-cllloromethyl-5-bromo-1-p--toluen~sulfonyl-
4,5,6,7-tetrahydroindole-4-spiro-[i,3]-dioxolane (100 parts) in
isopropylamine (890 parts) is placed in a seal.ed tube and heated
on boiling water batll for 7 hours. The reactioll mixture is
evaporated to remove isopropylarnine. I'llc resiclue is dissolved in
dichloromethalle, washed with water, dried and concentrated to
afford 4'-isopropylaminomethyl-5-bromo-1-p-toluenesulfonyl-
4,5,6,7-tetrahydroindole-4 spiro-[1,3]dioxolane in 60~o yield.
The physical constallts are givcn in Table :[, No. 19.
The same product can be prepared in 70 to 80o yield by
heating 4'-bromomethyl-5-bromo-1-p-toluenesulEollyl-4,5,6,7,-
te-trahyclroindole-4-spiro-[1,3]dioxolane or 4'-p-toluenesulfonyl-
. oxymethyl-5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrallydroindole-
4-spiro-2'-[1,3]dioxolalle in isopropyla~ lc for 1~ hours.
.
~,
O . . -- -- _ . _ . . _ . . . _ _ . . _ . . . _ . .
29
;3 ~ ~;
2 < _~ 3 I -~
I-leatin3 of 4'-bromometllyl-5-bromo-]-p-toluellesulEollyl-4,5,
6,1--tetrahydroinclole-4-spiro-2'-[:L,3~dio~olalle wi-th piperidine
at 80C for 3 hours affords 4'-piperidinometllyl-5-bromo-1-p-
toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spi.ro-2'-[1,3]dioxolane
in~75% yield.
3) O-~cylation.
i ~ "1",~,
2 ~ --CM3 SO2~ )/~~ 3
To a solution of 4'-hydroxymethyl-5-bromo-1-2-toluelle-
sulfonyl-4,5,6,7-tetrahydroindole-4-spiro-[1,3]dioxolane (100
par-ts) in dichloromethane (2000 parts) is added a solution oE
p-toluenesulfonyl chloride (1.1 molar equivalent) and pyridine
(1.2 molar equivalents) in dichlorometllalle (500 parts), and the
mixture is kept at room temperature for 10 hours. The mixture
is evaporated, and the resi(luc is dissolved in ethyl acetate,
washed with water, dried and evaporated to give 4'-p-toluene-
sulfonyloxyMe-tl~yl-5-l)romo-1-1:~-toluerlesulEollyl-4,5,6,7-tetrahydro-
.. ~, . .
indole-4-spiro-[1,3]dioxolane in 87~- yicld. The physical cons-
tants are given in Table I, l~o. 18.
Example JV (Aromatization with an organic base)
~ 1113r ~ 2 ,~?
2 ~ base (6~ C'~12
Br (5)
~ mixture of a 2-substltuteci-l.,~-d:i.oxaspiro[~,5]clecene
(l) (lO0 L)arts), a bas~ (~i) (l -to 5 molar equivalents) ancl a
solvent (500 -to 2000 parts) ~re heatc-?cl at 75 to 120'C Eor 3 -to
S0 hours. ~fter coolincJ, the react.ion mi~ture is di].uted with
water and ethyl acetate. Formed orqanic layer is separated and
washed with waterr dried and concelltrated to dryness. The
residue is purlfied to c~ive a 3-substituted-2-hydroxypropyl aryl
e-ther (5).
. Reaction conciitions are ~iven in Tabl.e :[II and physical
lS constants of some p oducts are qlven in T.1:le IV.
20
. ~O
,~
... . .. . _ .
3 _ _..... ........... ---
31
. . ~ ~ r l 1 ~
~-~ .r~
. . O ,1.0~ .
0\~ ;d ~ ~c~
O L. ~ O
b~ o ~ cl rl O r-l
a) o In u) ~; ~1 ~ n~ ~r d'
~' ~ r~ nl -I ~ .~: O
Lr~ ~1 .C ~ O n)
_, ~ _ _ 1~ n~ _ ~U_ _ _.~.. _
.~ . Q,
~ O b~ O b~
O~:4 . b b~ ;r I
~ cr, ~ ~d I u~ ~r . u~
n. ~ ~ ~ ~ ~ n~ ~ ~-
O r~ 1~ ~ r~
- __ ___ ._ _ ,~
Ln
~D C~ '
E~ ~ ~1 ~ ~ ~r
. _ _
. ~ ~ .
,-1 .
a) ~ u .~ o a) O In
E~ ~- co I~ ~1 ~1 cr co
_~ _~ . . _ _ .
r
~ . r~
.L~ l r~ :~, 7- r~ ~
a) ~ l r) r~l ~ ~ ~Q r_) r~ ~~ cr,
~ S~ l m In r~ r~ ~D In r~ ~; ,
,~ rd l ~ n r ) c~ r ) ~o ~ D O r~
O P~ ~ ~O l l ~D
cl~ ~ I . r ) .,1 .,1 r_~ :I
_ . _ _ ~
* ~ 7 ~) cr~ ~ co ~:) r~ .~ Ln r~ ~1
U~ Q) ~ ~ ~o ~D r- ~ n
n~ rn n~ m n m ,~ m m m ~ m
m n~ ~
m~ a a a a a a
n~
~ _ ,
,1 ~ o o o o o o
3 )~ o o o o o o
c Ll ,~ ~ ,~ ~ ,~ ,~
~l _
n~ ~C r- r-
., ,1 . I ~ r~
O ::~ ,_1 ~ I O I O
S~ ~ ~. ' O ~ ~ ~.--- rJ
f~ ,~ ?~ l l l l l
, I -- r~ __ _ _ . - _ _.
O O ~ tll _ _ _
a) _ ,..... __ __ __
Q O
n~ ~ ~1 ~ r~ ~r Ln
. , ~ _ _ _ . .
32
Ln ~ __ ~. _ ~D
_l _ a~ In r~
O ~ r~ ~n _
. . ~3 1: .n In _~ _ _ . -~
E~ ~ -I ~-- r~
~ U _ O r-lr--I
E~'' .-, ~--- 1~1 ~) ~ '
~ 5~ ~ . .
a) ~ ~ ~ co
r n~ æ ~ z m ll ,
~ P~ O D ~ ~ ~1~ O
__ ~1 o _ o o 'n 'n
NO ~ C ---U~ N _ N N
H I / = _ = m m
z _ ~_-- m c
33
3'~
.__ ~_ __ _
-,.
,~
~n
i_ ~ i N ~D I N
tn o ~ i- ~ Ln ~ i~
~ i~ r~ ~ ~ i-- i~ In r~)
o ~ In ~ t~l ~ t~ ~ tn
r~)~C ~1 . o ~D .
m O ~ . t~ ~ . ~ t,~
~ ~C E~ i-- ~J t~) X ` ri~ I
a) ~ ~ ~ Ln n .~ ~c
r) ~c~ l i-~ ~n ~~c tJ~ ~-) tn r~ ~ .n Ln
~-1 ,1 t~ t~ t4 t~) ~ O t~ r-;
(i) ~l ~ i- ltn ~ tn r~l o
~ n., . . ~ ~ ~ ~, ~
~.,~ ., ~1~ r) .~, t~ [~
N OI ~1 .~ ~C ~ ~-J~ C4 ~C ~C i--
'C i~)~ t`l ~ r4t.~l t~ -- ~ I ,~ r~ ~1 i-
_~C rs~ i-i_ ~ ~c ~D ' i; o
~D ' ~ ~ ~ E~ ~D i-- r--I r4 t.\l t S`
~_ t~ ~ ~C O t3 ~ ~ _~ t~ Ln
r~)N ~C ~~t~ ~ ~N r~)
~1~ ~ ~1 i_~ ~ r4 ~, N t~) I n I
i-) i--~n ~c ~ t4 N I Lt) ` ,~: I I r~)
r~ n~~ ~, N t~~C ~ i~ ~ ~ ~ ~ r~) O
O Ql~D in ~c ~~D ~ t~ ~D r~l ~C ~ i~ O -
-- h t4 i`_ ~ .-- E~ c~ ri ~
Q .~ I ~:) r i-- ~ O E~ i- t`l Ln
..~1 ~ t~l r~ t4 iI-- t~ t\l O
~1 ~ Dt~l r~ ~tS~ ~ t;~ . ~ ` ~C
t~J ~ ~ ~C ~11 t,~l
r~ r~ i ~ r~7 ~ O I i- ~_ t~ t`~
__ _ _ , _ __
~ ~ ~ ~.
t4 U~ O
~1c4 0 i_ i-- ~ i-- t~l
7 m .~. ~
~; ~1
. _
rno ~o ^~1 ~o ~ r~l o cn
:~ ~ Io i-- ~~ ~ ~ i~l ~ LO
c~ x ~O ~, m In ~, Ln ~1 ,~
\~'~~C ~ ~ ~ ~ ~ r~
1 0 1~ ~ ~ ~ o~ ~ ~ ~ ~
/ rO ~r i~ o cr
.. o o i~ r~ r~ Ln ~ Ln
(~)~r;r~ ~r ~or~ ~ r~ ~ r~ ~
O N H ~ ~ i I r I r~ ~1 r~~) ~1
i~ __ ___ ~ ___
i~
~C
i_) r~l
_~ ~ ~
- Li 3 r t_) ~1
A æ
s, ~ ., u'~ Iu"''
h ~ ~ ~ ''
> ~ ,,,, _ /
tl) _
Q . Z ~1 (~I r~
i~ __~ _, . . - - ~ _ ~
3'1
3~2~
_ ~ ~
. ,~c ~ ,c
~n ~ ~ F. u~ I .
~: Ll~ r-- tN r~ 1 a~
O ~ ~ ~ ~O O ~'
~ N . N ~ ~ ~
Ul ~ ~C ~ 'C ~o t~
Lt~ I Ln
a) ~ ~ ~ c ~ ~ ~
,~ S~0 1~1 ~L) ,C ~ ~C ~C
r l rl_~ ~ ~-' ~D r-l (~) (~)
~ n, o ~ F F. r~ rl
N O r~) ~ ~I ~r ~
.~ ~) r~ r7 r-l ~1' 1 (N
~_ ~ In ' _~ O ~ ~ 00
~)N ~) ~CN ~D O ~C ~r
. r~~n t~l F.~c ~ .
C~ ~. In . N ~C
C ) ` RJ~O ~ ~ ~
~L ~C ~D ~C r-l
br~ I~ r~ I ~ ) F.
o ~n~ I r- ~n ~ l r(~ F~
~`1 0 i~ r~ ~) CO l r~ Ln ~
P~. ~ m . ~ c ~ l ~ ~ ~ .
r-l ~ ~ r-l ~ ~ I
Z~ ~ ~D ~ ~ D r-l (~') I
_ ................. __ I .
~ ~ ~ 1 ~
O~ r-l O ~ ~ ~ O r~ ~ r~ ~
r-l Ln r- ~o o~ ~ ~ o~ u co ~ ~o
I r-l r-l r-l r-l m In r-l ~ n ~ r I
F r-l r-l ~ r-l ~1 ~) r I rl r-l
V ~ ~ ~ ~ ,
. ~ ~O ~ r-l O ~O ~D ~1 O~ O ~' O ~1
~~D o~ ~ ~ ~ ~o r~ ~ n ~o ~ m
r-lr-l r-l mr-l ~) r-l~ ~ r I ~ ~ r~l ~
U ~< r-i~; r-l r-l r-l r I r-l 1 ~I r-l `~
~~ ~'.
o ~r; o ~ ~n ~ ~ ~ ~ ~
O r~ r-- o r~o r I a~ O ~ ' r I
r~1' r~ ~I~ ~ ~o r-- u, ~ r i O
~. (~ ~) r-l ~) n r~ ~1' ':i~ r~ n Ln ~, r-l
HI r~ r-lI r~ r I~ r-l r-l r~l ~ r I r I
._ __ _ _
~ ~ '~ ~c~ ~ /[~ 3 ~
. o ~C o ~ ~; I ~
O ~C ~ - f~ ~ ~
~~ z._ o ~ . ~. Z, ~, o U~-Z.-O
_ . .
.~ ~C~
t, ~,
l ~, I 1.
~ ~) ~ ~,-1 , ~1 I~''J
~, ~ . ~, `` ~,
- \ 1(~ ~ r
P~ .~_u~ ~ -u~ ~ u~ I j~-.-U~
.. _ ~ _ _ .
a)
O ~ I n ~o r~
~ ~ __~
3V~
- -
Ln
~ l ~ o
U) ~ ~ r~ .
~: u) ~ ~o l -
o ~ ~ ~
.C~ O D I LD
t~ ~ C ~ '
a) t~
:~ r ~ .,. N
~--I r i U1 E~ ~
n Ln
~1
. .
N O ~1 ~ ~
5~ ~_) l rc)
~_ ~ O LD
rl ~D ~ ~
~~ r-l E:. (~) ~D
U E~ ~I
C ) ~J r-l ~D ~
~ (~) CO ~ CO -
P~ ~ CO ~ -
Z ~ ~ I
_ .
.
r- r-
Ci`l ~D
E~
O r-l ~ _~
. ~ 7
O
~_1 C;~
X Ln .-1 o
~C ~ .
O ~ Irl
~ ~ ~D 1~
H ~) ~I r I
_ .
.'
' ~
~.......... ~
1 3 . `.
. ~
H . ~_ .
a) .
Q .
O o~
E~ ~ __
,
3~
E'.Yample lV~ rc~nlal:i7clt:ioll wi 11~ [l)
. ~
(CE13)2/1N ~ (Cll3)2CI~
~ Br ~ ~ _CO ll
~ !~N~ DBU ~ \N~
~0,
[~ ~3
C~l
~ 3 Cl]3
In a three necked flask equipped with a st:irrer and a
thermometer ls added 4'-(N-isopLopyl-N-hen~oylclmillomethyl)-l=
p-toluenesulfonyl-5-bromo-4,5,6,7-tetrahydroindole-4-spiro-2'-
[1,3]dioxolane (100 parts) and dissolved in a rni~ture of 1,5-
diazabicyclo[5,4,0]-5-undecene (51 parts) and N,N-dirnethylforma-
mide (319 parts). After stirriny for 2~ hours at 85C, the
solution is cooled, diluted Wit}l ethyl acetate (300 parts) and
washed thrice with water (50 parts). Aqueous washincls are com-
bined and washed with ethyl acetate (50 par~s). 1`he etllyl
acetate solutiol~ and ethyl acetate washillcls are combined, washed
with water (30 parts) and dried over anllydrous soclium sulfate
(50 parts). ~fter 1 hour, the drying acJent is fil-tered ofE and
filtrate concentrated to dryness under reduced pressure.
Obtained residue (83 parts) is dissolved in ethyl acetate (200
parts), stirred for 30 minutes with active charcoal (10 parts)
and filtei-ed tllroucJIl diatomaceous filtcr-bed. The filtra-te
concentratecl under reduced pressllre. ,rl'lle rcsiclue is triturated
`~ with a smalL amount o~ hexalle to .separate amorpllous powder. This
is collected l~y Eiltratioll alld dr;.e(l to a:r~ol-d 4- (N-isopropyl-N-
benzoyl-3-amino-2-hydro~yprol:,oxy)-l-p-toluenesulfonylindole
(35 parts) in 41o yield.
37
E~Yam~le IV-2 (~romati~atiol1 witll mor~ ol i ll e )
(C1l ) C11N11~- (C113)2C11M11- ~ r-
110 ~ N~
SO2 SO2
C113 C113
In a flask equipped with a refl~lx eol1denser is plaeecd
4'-isopropylaminomethyl-5~bromo-l-p-toluenesulfonyl-4;5,6,7-
tetrahydroindole-4-spiro- 2 1 ~ [ 11 3]dio~ola11e (lOO parts) and
morpholine. The solution is reElu~ed for 20 llours. ~Eter
cooling, the r~aetion mi~ture is eoneentra~ed in vaeuo -to leave
resin. Chromatoc3rapllie purifieation of the resin affords
4-(3-isopropylamino-2-7lyclro~yprol~oxy)-l-p--tolue1lesulfonyli1ldole
(2~l parts) in 29o yiel~1. This sllowed the sam~ physieal eharaete-
risties with an authe1ltie sample.
Example V (Aromatization with a l.ewis ~cicl)
N~ICH(C113)2 N11C~I(C113)2
2 ~ CE-12
I ¦ NSO- ~ \-C11 1 l--~
C11-0 ~ 2 3 IC11011 ¦ ~NSO2 ~ - C113
CH20 ~ , 2
/ Lewis ~eid
(l) Br (5)
- 25 To a solutio1l ol ~'-iso1~ro1)y k~ lc)l,letl~l-5-~romo-l-p-
tuloenesulfo1lyl-4,5,G,7-te-tra1lyclroi1lc101e-~-s~,iro-2'-[l,3~-
`~s dioxolane (l) (lOO part:s) an~ a hase oE a11 adc1itio1lal reagent
is added a solutio1l oE a Lewis acicl in a solverlt at sub~.ero
temperature. '1`1le resu]l-i1-1(J rni~ture is warmed to room temperature
a1ld s-tirred for tlle ~iven time. ~fter conce1ltrat:ion, the mixture
3~
is shakerl with aclueolls so(:lium llydroxi.c-lc~ alld el:hy:l acetate~
Tlle orc3anic layer i.s taken, waslled with water, clr;ed and
concentrated. l'he resiclue ls crysta].lized From lle~ane-acetone
to giv~ tlle objective 3-isopropylaminc)-2-115~clrc)x$/prop5~l-l-p-
toluenesulfollyl-~-indol.yl ether.
The rcaction condit:Lolls are i.llustratecl ial 'I`able V.
Physical constants o the products are cJ;.ven on 'rable IV.
~ .. /,
_
3S~
. ~ ___ 1~ ~ r~ \ \ _
r o~ _ _ _~_ __.,
Q~
Q~ O L~ ~ \ \ \ .
U I 0~ . ~O \ ~\1 .
. _. _ __ ___ __ __ ~ ~
a) J ~J ~) (~l O ~11 ~ r
r ~ n ,~
__ ~ : _ ~ ~__ __ ~
J ~ ~ ~ o ~ o
~ î ~ ,~ ~ ~ ~ ~n
Q~ U o n = o~ co o o
~_ l l l ,_1 _. _.. ~ ~ .
a ~ ~r~ ~ ~r~7 ~ ~
n .n I n .n n
J ~ :r' ^ ~ ^ ~, ~ :~ ~ _~
;~ o ~ O a) ~ O ~ O ~ u u
~ E ~ .n O O ~ r I ~ r-i O _ ~ ~
~ ' I¢ ~' Z ~' Z Z ~ ~; `~ ~ ~ , Z ~'
_ _ . ~ ~
_ ~ ~ r~ r~ (\1_~
lr~ or~ o~ o r~ o r~ Or I O ~1 0 ~1 0
O~1 .~1 .,-1 . r~ il U U ~ C1
E U vl U vl U ~m -- m ~' vl ,~ vl vl m
~-- . . . ~_
'~'' .
,~ 3 t~ (~1 t~l ~1 ~
o ~ ~ ~ ~î ~ vl ~1 ~ ~ vl
a)' ,~ O ~. .c: ^ o ~r~u, c~ ^ u ~ c~
,~ ~ ~ ~. ~() ~ ~. ~1~ ~ ~ t~l
_ ~ ~I J~ ~ ~ r~ I~r~ r~ ~ ~ ~1 ~ ~r ~ ~ _ ~ r~
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V~ ~ ~ U ~ _ ~ _
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. -.................. ,. _ _. __ __ __
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Ql ~ ~ r--l ~ r--l ~ O ~
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. ~ ~ ' ~ O ~ o O ~ ~ ~ ~`
~1 ~1 ~ ~ . ~ ~ I r~ In ~ \ I ~ I
O ~ . C~ o U O ~ ~ ~C ~~ ~ ~,,J \
_ i _ ~, _ ,~ _' t~ ,~ ~,~ Z~
-- ~; -- z. -- æ -- ~;
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~ ~ Ln ~Ln ~l Ln ~Ln ~Ln ~ ~n ~ Ln ~ Ln
3 0O ~O .O ~ ~. ~) .O ~ ~) ~ C
O E~ ~r~ ~ ~ ~r~ ~ r~ C ~ ~ ~ ~ N 1~ r~
~ tn ~~n ~ ~n ~~n ~ ~n -~ ~n ~ ~n ~ cn ~~
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~Q~ t~ t~ .
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s~ a) ~ ~ ~o ~ ~, ~ ~ ~ ~ ~1
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.'- ~ ~ r~ lC ~~C ~Irl L~- ~ Ln~ I~ ~ ~c~ ~ Ln ~ r~
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ri~ ~ ~ t) Ln~- r~ ~_ ~ ~ ~ ~ ~ ~
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42
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~- ~ h O ~ U ~ O ,~O q ~ h
rrd ~ h r~l r.~ Z O ~n ~~;
-~, p, ~ rr~ ~ ,~ ~ ~~ r~ r~
o P~ t~ ~ ~ ~ .~- .. ~a
~ v~ -- . _, ~_ .____ .. _ _. .
_ _ _ ~
~ . ~
Q O ~ In ~D ~ c~ O
rr~ ~; r.~ ~ ~ r.~l r~l r.~l ,'.
E~ . _ . __ .__
~3
.3~
Ex~mple V-l. (Aromati %ation ~.i t ll Stc~ iC cll:lor:icle)
_ _ __
C112N11C}-E(C113)2 , ~, NEICII(C113)2
Br- ~ SnCl~ N
S2~ C~113 SO2~ cl-T3
~'o a solut~ion of q'-isopropylaminomethyl~5-bromo-l-p-
toluenesulfonyl-4,5,6,7-tetrahydroindo]e~-spiro-2'-~l,3]dioxo-
lane (lO0 parts) and triethylamine (143 parts) in dichloromethane
(1500 parts) is dropwi.se added a solution of stannic chloride
(80 parts) in dichloromethane (500 parts) at -60C with stirring.
The mixture is warmed to room temperature, stirred for 5 hours,
concentrated and shaken with aqueous 5N-sodium hydroxide and
ethyl acetate. The ethyl acetate ]ayer is separat~d, washed
with water, dried over sodium sulEate and concentrated under
reduced pressure to c3ive crude product (73 parts) in 87.9%
yield. This is triturated in etllyl acetate to ~3ive pure ~}- (2-
hydroxy-3-isopropylamillopropoxy)-l-p~toluellesul.fonylillcloie
(56.4 parts) as amorphous solid in 67, yield.
NMK: 3 3 0.97d(6.511z)611, 2.29s311, 2.5G-2.90m311,
3.76-4.20m3E-1, 6.71-7.92m9EI.
(I-ICl salt of the product) m.p. 225-226C (decomp.).
NMR: 3 3 l.2~ 511z)611, 2.29s3EI, 2.76-3.58m, 3.93-4.53
m31-1, 5.92brsll-I, fi.73-7.00m211, 7.l5-7.961n7}l, 9.09brs2H.
(I-lBr salt oE the product) m.p. 235-238C (decomp.).
(HI salt of thc product) m.p. 227.5C (c1ecomp.).
30 ~
~'1
Lxample V-2. (~romatizatio1t wit:1I bo~on tric1-11Oride)
I T C~12~11c~l(cl~3)2 ~ -_ N~IC~l(C~13)2`
Br~ ~ r ~ BC13
r-~ I
SO- ~ >-C11 SO-/'!~ C11
I`o a solution of 4~-isopropylami1Iomet1ly]-~-bromo-l-~-
toluenesulEonyl-4,5,G,7-tetra1-1ydroi1I(lole-4-s~?iro-2'-[l,3]dioxo-
lane (lO0 parts) in dichloroethane (lO00 parts) is added a
solution of boron -trichloride (2 molar equivaletIts) in dich:loro-
ethane (500 parts) at -19C. The mixture is let warm to room
temperature and stand for 50 hours. The reaction mixture is
washed wit1I aqueous sodium hydroxide at pll lO and water, dried
and concentratecl. The residue is crystal]i~.ed from hexane-
benzene to give 4-(2-hydroxy-3-isopropylaminopropoxy)-l-p-
toluenesulfo1Iylindole in 71Po yield.
~xample VI. (~roma-tization witll a base or acid)
YC11 CHO1-1
~ -~ 2 ~ J
C112O base or ac]cI
(l) (5)
~ cyc]ohexadiene compound (l) is treated with a base
under a reaction condition ~iven on Table VI to a-Eford the
corresponding 3-substituted-2-1IydroxypLopy] aryl ether (5).
~- ~
~ ~5
.a~
__ _ _
`O
rl ~ .
~ C r~l r J (~I
_ _ _
~` o . O
C) O o o ~n n
E~ -- (\I ~1 r-l .. ~
___ __ _ _ _ _
'.~
C _~ r O 1~ r-l ~~
r-l 11~ ~ ) ~ o O o ~ O
O Pl ~ I (~I ~ O ~_ ~
~ ~ ~_) O ~ ~
__ _ _ - _ _
r~ . _~
~ ~ 0~ ~0 ~
1~ ~ ~ ~1 P I r--I O O
~ P~ m ~ rl <~I ~J
Q; - C:~ :I: U~ _
~__ __~ . _l
O O O O
P ~ r_l r-J r-l r-l
_ . - -
r~ . ~ _. . _ .: . _ _
O ~ .
~1 .11
_ _ ..
~ ~ _ ~
O
~; r-l ~ (~) ~
.r . . . . ~ ~. . _ _
46
~;xcln~ c~ V! L (I)('~ 1 t)rotc~ cl (1ro~
a) Pindo:lo]
i-C 1I N~ ~T-~ C3117N~
IlO ~ ilO O
` 1 N
,J ~ 11
~~
Cl-13
To a solution of 4-(3-isopropylam;no-2-hyclroxypropoxy)-
l-p-toluenesulEonylindole (100 parts) in ethallol (500 parts)
placed in a flask equipped with a reflux condenser is added
aqueous lN-sodium hydroxide (36 parts) and the mixture is
refluxed for 4 hours. Resulted rcaction mixture is acidifiecl
with lN-sulfuric acid (11 parts) concelltrclted under nitroc~en
atmosphere until crystallization starts and kept in a refri~e-
rator overnight. Separated crystals are col]ected by filtration
and washed with diluted ethanol. The crude Grystals tllus
obtained are recrystallized ~rom ethanol to qive ~ -(3-isopropyl-
- 20 amino-~-hydroxypropoxy)indolG as co]orlec;s nGcclles (a5 parts) in
75.5~ yield m.p. 172-173C.
The crystals are identified as pindolol by comparing with a
pindolol sample (m.p. 172.5-173C) by mixed meltincJ point deter-
mination and comparison on tllin-layer chromatocJrams IR-spectra
and proton-macJIletic rcsollallce spcctra.
b) Un-lcr collditiolls s:imilar to a) al)ovc lly(lrolysis oE Table V:[I
s carriecl out.
y ~
~ --'Q
~7
Table v:r:r lly~ro] ysi.s
Startillg Mate:rial ProducL
__ ._ __ _ __~_ __ _ m . p
__ _ _______ I____
3 71 `N i-C311.7NI-1- `~1 173
C~13CO S2 C ~ C113 ~1
~ _ _ _ 1-____ _ ~
. t-C;UgCO,
.. _ _ _____ - '~ 1
3 71 " , ll
~CO
_ . _
i-C3E~7N- ll " ll "
C~1-3~-SV2
. _ __ ___, _ _ _ _
. 3 7 " . Il " ~ ll
<~NSo2
____ __ ___ _.
3 7~ ~j .
t-C4H90CO . CHO ~, . ,l ,l
__ ____ __ _ _ __ I
4 91 -~ i-C4H9NH- ,l -156
C113CO COC~13
-=~C,~I3 - ____.
i-C3H7NH- ~ 3 7 ~N~--C~13 95
S02~ C113 ~1 -97
_ _ ___. _______ ____
t-C~119N~l- `N' 3 t-C~ NII- ,l 13,330
,~ . COC113 . _ _
___ _______ __ _
4~
3~
r~an1plc VlIl (ColtilIlous rctIctio~
a) 6-(3-Isol)ropyIImino-2-l-lydro,~$~propoxy)l)ellzotl~iazole
Br ~ ~ ~
~ J 13r >~
N~
N
(Cil ) CIINII ~`I -
N=,,i
A mixture oE 6-oxo-5-bromo-4,5,6,7-tetrahydroben~othiazole
(lOO parts), 3-isopropylamino-1,2-propanediol (67 parts), p-
toluenesulfonic acid monohydrate (99 parts) and toluene (1550
parts) is heated under reflu~ for 21 hours wiIiIe dryiny the
refluxinJ azeotropic mixture accorclincJ to the mcthod described
in l~xample I. ~Eter coolinc3, the react;on mi.Yturc is adjusted
to pH 9 by addincJ aqueous 2.5N-sodium hydroxide and formed oryanic
layer is separated. The oryanic layer is washed with water,
dried over anhydrous sodium sulEate, and concelItrated under re-
duced pressure. Remaininc3 9 -isopropylaminomethyl-5-brorno-4,5,
6,7-tetrahydrobenzothaizole-6-spiro-2 -ll,3]-dioxolane (156
parts) is dissolved i~I piperidine (1560 parts), and stirred for
49 hours on an oil bath he~ted at 95 to 100C. Tlle reaction
mi~ture is conccntrated under reduced pressure to leave residue
which is mixod with ethyl acetate ani water, shaken and Eractiona-
ted to separate EvrmecI oryanic layer. the oryanic layer is
waslIed with water, driel over anlIydrous .odium sulEate, and
concentrated uncIe-^ recluced preC.surt. Residue (172 parts) is
49
t~
recrys ta L:Li zecl :L'rom e l llano] -llycl l ocll lo:l-i c aci.cl c~ ivin~J G- ( 3-
isopropy1amino-2-llydroxypropoxy) benzoLIliazol.e (65 parts) in
57~ yield. m.p. 132-134C (hydrochloride trihydrate).
b) Accordinc3 to ~xamples I to V combi.llecl, a series oE reactions
is carried out in a manner simila]- to above a) to give the
compounds 1isted in 'I'able VII:L.
1CQ I ~,~ Q ~ ~
(1)
Y ~--I'` -I /
110 0 ~"
. ~ Q
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, .
.
,
. , . - .
, ~
'
.
.. ~ .
. _
- - - - - - - - - - - -
t~O r-l tI) t O t~O 1~ ~1 0 ~ t~') N O tO ~J~ I ~
t~l ~r ~D ~0 ~D 1~ ' r-l N tl~ tlO Lr~ Lrl ~r ~D ~D ~D
r-l r I O O O O O O ~r ~r t.~ ) tX) In 11-) ~1
Z r--I r~ r~ r~ r--I r I r ~
.. . . _ __ __ ~_~ ......... ~.
N rY) ~r~ Ln Ln Ln Ln t~ r-l O ~D ~1 N r I O t~
U~ r I O ~r t~~) ~r ~D I~ lo t~o tJ~ ~D Ln Ln Ln 1~ L(~)
r ~ tO tX) t~ t~O t~O t t~ tX) ~~ I~ ~ 1- Ln LO ~ ~
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(~ r-l 1~ 1~ Ln 1- Lt~ (~ tO t~ ~ ~ Ll') t~ t~l t~l
, ~ ~D ~L~ t~ ~ ~D Ln l.n ~~ n ~ In tr) ,~ o t3
~ ~D tO t~ tX) t~ 't~ tS~ t~) ') t,O t,O~D ~D tl::) t~)
r r_) ~ D ~0 ~D ~D ~) ~D ~D ~D ~D Ll~ IJ-) ~(~1 ~ ~r
)~ . .. _ ,
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E~ 'd 'd 'a 'd rd 'd ~d 'd~ ro ra 'd rl ~ rd ra ~d
r,l~ O ~ U ~. O ,L- ~ L-' O ,L- O L~O ~ O ~:
r~~ r~l ~ r--I ~ r--l ~ r-l ~ r~ ~) r-l ~) r I ~ r-~ _~
W ra O rd O rd o rd rd rd Ord O rd O
~ 4 r_) W t~ W t_) ~ O r4 ~) r4 0 W C.) W
._ _ . _ _,_ _
, .
O O O O O O O
t~ ~D t~ t~ tX~ t~ Ln
r- ~n o t~ ~t~ r Ln r`~)
r-l r-l t;~ r~ r-l N r I r--l
N ~t~ I r-l O 1-- ~_t-- r-l I--
~-- Ln Ln t~ t~ ~r r-l !-- ~ )Ln tY-
r-l r-l tr~ r--ltl ) r~ _) t~ ~4 r I r-l
Q~ Q~ Q~ Q~ Q~ Ql ~ n,
_. _ . _ __ ~ _ __
~ . (~ ' t.~ [~ t~
~ . t~) t~ 5~ IT4~ ~4 ~4
. r~) ~ ~C O ~t~') ~t~ ~~) r-l ~r
.~ rl ~) rl -IJ -rl r_) .1 ~ l
~ ~ ~4 ~4 ~ ~ r-l )~1
z ~; .~ ~ ~. ~ ,_~ m
I
. . .
H F~ ~ <~J ~ I > --~ ~ ~
r~ , _ _ .__ _ _ __
td Z r-l t~l tY~ ~r In ~D 1 _ tlO
1~ ~_r - . ~ . _ _ ~ __. ____ __ ~ _
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