Note: Descriptions are shown in the official language in which they were submitted.
9 ~
This is a divisional application of Serial No. 343~98B filed
January 18, 1980.
This invention relates to production of certain trans 5-aryl-
2,3,4,4a,5,9b-hexahydro-lH-pyrido [4,3-~ indole compounds,some of which
are new.
The parent application relates to novel 2-substituted derivatives
of the compounds of this application useful as tranquilizing agents and
their production.
1 ~3g9~
Following the introduction of reserpine and chlorpromazine in
psychotherapeutic medicine in the early 1950~s, great effort has been expended
in the search for other tranquilizing agents having improved biological
profiles, several of which are y-carboline derivatives, also known in the art
as derivati~es of pyrido[4,3-b]indole.
In U.S. 3,6~7,961 8-fluoro-2-[3-(4-fluorophenylanilino)propyl]-
1,2,3,4-tetrahydro-y-carboline was disclosed as a useul tranquili~er for warm-
blooded animals. In U.S. 3,755,584 structurally related compounds with fluorine
in the 6- or 8-positions and a specific p-substituted phenylalkyl moiety at
the 2-position were found to have similar activity.
U.S. 3,983,239 discloses hexahydro-y-carbolines of the formula
~ -(CH2)3c ~ F
* ~
where ~ is methyl or ethyl and R is hydrogen, methyl or ethyl. The stereo-
chemical relationship of the hydrogen a~oms attached to the carbon atoms at the
4a and 9b positions is noe mentioned in this reference. However, one would
expect them to be in a cis relationship based on the method of formation
of the hexahydro-y-carboline nucleus from a 1,2,3,4-cetrahydro-y-carboline
; precursor by catalytic hydrogenation in ehe presence of platinum, a method
well known in the art to introduce hydrogen atoms in a cis-configuration to a
carbon-carbon double bond. The compounds claimed are neuroleptic agents said
to be useEul in the treatment of schl7Ophrenia.
.
-- 2 --
i; . .
. .
1 16~99~
U.S. 3,991,199 discloses hexahydropyrimido¦4,3-b]indoles,
usPful as analgesics and sedatives, some of which are of interest as
tranquilizers, some as mucle relaxants and many of them show hypoten-
sive activity; the compounds disclosed are of the formula
X ~ Ra '
Y~a
and their pharmaceutically suitable salts, where the hydrogens attached
to the carbon atoms in the 4a and 9b positions are in trans relation-
ship to each other and where: when ya is -H, -Cl, -Br, -CH3, -tert-
C4H9 or -OCH3; and when ya is -CF3, Xa is -H- and Ra is, inter alia,
hydrogen, benzyl; benzyl ring-substituted with methyl, ~ethoxy or
chloro; phenehtyl; 3-phenylpropyl; 3-phenylpropyl ring-substituted with
chloro, bromo or methoxy.
.
'
~3~
~ lS3996
Recently issued Beligan patent No. 845,368 (Derwent No. 00043Y)
discloses 5-phenyl-hexahydro-~-carbolines, optionally substituted at
positions 2 and 4 by methyl or ethyl and at position 3 by alkyl having
from 1 to 3 carbon atoms, allyl or propargyl. They are said to be use-
ful as antidepressants.
Recent West German Offenlegungsschrift 2,631,836, Derwent No.
09738Y, discloses structurally related octahydropyrido [4',3':2,~ indolo
E ,7-a~ [1~ benzazepines which may be depicted by the above formula but
with an ethylenic bridge between the two benzene rings, ya and Xa are
hydrogen and Ra jS -CH2CH2COCH3 or -CH2CH2COC6H5. They are said to be
useful as analgesics and tranquilizing agents.
U.S. 4,001,263 discloses 5-aryl-1,2,3,4-tetrahydro-~-carboline
tranquilizers of the formula
xb ~N_Rb
7b
where Xb and zb may be hydrogen or fluoro and values of Rb include many
of the 2-substituents disclosed for the compounds of formula (I). It
is disclosed in the parent specification that the trans-2,3,4,4a,5,9b-
hexahydro-lH-pyrido ~4,3-b~ indoles of the parent application have markedly
superior tranquilizing activity when compared with the corresponding
1,2,3,4-tetrahydro-y-carbolines.
~ ~39~
The valuable tranquilizing agents of the parent application are
the 2-substituted-5-aryl-2,3,~,4a,5,9b-hexahydro-lH-pyrido C~3-~ indoles
of the formula
Xl ~ ~ N _ (CH2)n M ~
--- (I)
Yl
and the pharmaceutically acceptable acid addition salts thereof, wherein
the hydrogens attached to the carbon atoms in the 4a and 9b positions are
in a trans-relationship to each other and the 5-aryl-2,3,4,4a,5,9b-
hexahydro-lH-pyrido ~4,3-~ indole moiety is dextrorotatory; Xl and Yl
are the same or different and are each hydrogen or fluoroi Zl is hydrogen,
fluoro or methoxy; M is a member selected from the group consisting of
~ H ~OH
C , C , a mixture thereof and C-O and n is 3 or 4.
OH H
By the term "5-aryl-2,3,4,4a,5,9b-hexahydro-lH-pyrido ~,3-~ indole
moiety" is meant the moiety of the formula A
1 ~ ~ N-
---(A)
Yl
wherein the hydrogens attached to the carbon atoms in the 4a and 9b
gl 163~9~
positions are in a trans-relationship to each other and Xl and Yl are
as defined above. The preferred compounds of the invention are those
wherein said moiety (A) is dextrorotatory. The compounds of formula (I)
wherein said moiety (A) is levorotatory have been found to be considerably
less active as tranquilizing agents. Compounds of formula (I) having a
mixture of said dextrotatory and levorotatory moieties, including the
racemates, are of intermediate activity.
The compounds of the parent application are useful in methods
for the treatment ofschizophrenic manifestations in mammals which comprises
orally or parenterally administering to a mammal in need of such treatment
a tranquilizing amount of the compound.
The compounds of the parent application have a markedly and un-
expectedly superior tranquilizing effect over the above mentioned tranquil-
izing agents of the prior art.
Especially preferred tranquilizing agents of the parent applica-
tion are the following compounds wherein the trans-5-aryl-2,3,4,4a,5,9b-
hexahydro-lH-pyrido ~,3-~ indole moiety is dextrorotatory, and diaster-
eomers thereof.
trans-8-fluoro-5-(p-fluorophenyl)-2- G-hydroxy-4(p-fluorophenyl)buty~ -
2,3,4,4a,5,9b-hexahydro-lH-pyrido ~,3-~ indole,
trans-5-phenyl-2-E4-hydroxy-4-(p-methoxyphenyl)butyl~ -2,3,4,4a,5,9b-
hexahydro-lH-pyrido ~4,3-~ indole,
trans-8-fluoro-5-(p-fluorophenyl)-2- L4-hydroxy-4-(p-methoxyphenyl)buty3 -
2,3,4,4a,5,9b-hexahydro-lH-pyrido~4,3-~ indole,
trans-5-phenyl-2-(4-hydroxy-4-phenylbutyl)-2,3,4,4a,5,9b-hexahydro-lH-
pyrido-r4,3-~ indole,
trans-8-fluoro-5-(p-fluorophenyl)-2-(4-hydroxy-4-phenylbutyl)~2,3,4,4a,5,
9b-hexahydro-lH-pyrido~4,3-~ indole,
r
trans-5-phenyl-2- L3-(p-fluorobenzoyl)propy3 -2,3,4,4a,5,9b-hexahydro-lH-
pyrido C4,3-~ indole,
-- 6 --
1 1~399~
trans-8-fluoro-5-(p-fluorophenyl)-2- [3-(p-fluorobenzoyl)propy~-2,3,4,4a,5,
9b-hexahydro-lH-pyrido L4'3-3 indole,
trans-8-fluoro-5-(o-fluorophenyl)-2- ~-hydroxy-4-(p-fluorophenyl)buty~ -
2,3,4,4a,5,9b-hexahydro-lH-pyrido [4,3-b~ indole,
trans-5-phenyl-2- r-hydroxy-4-(p-fluorophenyl)buty~ -2,3,4,4a,5,9b-
hexahydro-lH-pyrido L4,3-~ indole.
The present invention provides a process for preparing a 4a, 9b-
trans-2,3,4,4a,5,9b-hexahydro-lH-pyrido ~,3-b~ indole of the formula
Xl ~ NH
--- (VIII)
Yl
wherein Xl and Yl are the same or different and are each hydrogen or
fluoro; characterized by reactin9 a 4a,9b-trans-hexahydro compound of the
formula
Yl
wherein R2 is benzyl, benzhydryl, ZlC6H4 CH(CH2)n
OH
or benzyl substituted by a methyl, methoxy, nitro or phenyl; Zl is hydrogen,
fluoro or methoxyi and n is 3 or 4; With a molar excess oF a lower alkyl
chloroformate ester, said lower alkyl having from one to four carbon atoms,
in the presence of reaction-inert solvent, followed by alkaline hydrolysis.
The present invention also provides a process for preparing a
dextrorotatory enantiomer of a compound of formula (VIII) by resolution
of the racemic compound by means of a salt of the racemic compound and
an optically actiVe acid.
~ ~63~9~
The present invention further provides valuable novel compounds,
useful as intermediates for the production of the compounds oF the formula
(I), dextrorotatory or racemic tricyclic secondary amines of the formula
2 ~ " ~
_- (XV )
~Y2
or acid addition salts thereof wherein the hydrogens attached to the
carbon atoms in the 4a and 9b positions are in a trans-relationship to
each other and one of X2 and Y2 is fluoro and the other is hydrogen or
fluoro.
The tranquilizing agents of the parent application of the formula
1 ~ ~ 1 (CH2)n M ~ (I)
~
Yl
wherein the hydrogens attached to the 4a and 9b-carbon atoms are in a
trans-relàtionship, the 5-aryl-2,3,4,4a,5,9b-hexahydro-lH-pyrido ~4,3-~ -
indole moiety (A) is dextrorotatory and Xl, Yl, Zl~n and M are as previous-
ly defined. As will be recognized by one skilled in the art, moiety (A)
contains two assymmetric carbon atoms at the 4a and 9b positions and two
resolved trans forms (d- and 1-) and a racemic form is possible for each
value assigned to Xl and Yl. The moiety (A), of course does not exist
alone, but may be derived, for example, from the free base of formula
(A-H)
Xl ~ ~ ~ -H
---(A-H)
\ y
-- 8 --
1 16~9~
from which the compounds of ~ormula (I) may be derived. Each of the
compounds (AH) exists as a dextrorotatory (d-)enantiomer, a levorota-tory
(l-)enantiomer and as mixtures o~ the two including the racemate containing
equal amounts of the d- and l-enantiomers. The dextrorotatory and levoro-
tatory isomers can be distinguished by their ability to rotate the plane
of plane-polarized light. The d-form is that which rotates the plane of
plane-polarized light to the right and the l-form is that which rotates
the plane-polarized
- 8a -
llli3g96
light to the left. A racemic mixture, containiug equal amounts of d- and
l-enantiomers, does not effect the plane of plane-polarized light. For
the purposes of the present invention? when determining whether a compound
is dextrorotatory or levorotatory, it is the effect of the compound on
light having a wavelength of 5893 Angstroms (the so-called D line of
sodium) which is to be considered. A moiety of formula (A), above, is
considered to be dextrorotatory if the hydrochloride salt of the free
base of formula (AH) rotates such light to the right.
The following reaction scheme is illustrative of the processes
which may be employed for synthesis of the 4a,9b-trans-2,3,4,4a,5,9b-
hexahydro-lH-pyrido[4,3-b~indoles of formula (VIII) wherein~Xl and Y
are as previously defined:
YI~OE 3~_R2 ~1)Blll/ether \0~11-22
Yl
(VI) (VII)
(VII) (1) ClCO2C2H51 ~ ~ I
(2) KOH~ C2H5H/H2 N
(~ I
1.
(VIII)
_ g_
~ 1~3~
A preferred value for R2 is benzyl for reasons of economy. Ho~ever, other
values of R2 which will also serve in the above scheme will be obvious to
those skilled in the art. Examples of such alternate values for R2 are
benzyl moieties substituted in the benzene ring by, for example, one or
more members selected from the group consisting of methyl, methoxy, nitro
and phenyl; and benzhydryl. A radical of the formula -(CH2)nÇHC6H4Zl wherein
Zl is hydrogen, fluoro or methoxy and n is 3 or 4 is also an alternative
value for R2.
The reduction of the tetrahydro-y-carbolines of formula (VI) to
form the 4a,9b-trans-hexahydro compounds of formula (VII) is carried out in
an ether solvent, usually tetrahydrofuran. In order to assure complete
reduction a molar excess of borane/tetrahydrofuran complex (BH3^THF) is
ordinarily employed and a 100 to 200% molar excess of said complex is pre-
ferred. While the reaction may be carried out at a temperature in the range
of about -10 to 80C., a temperature of from about 0 to 65 0. is preferred.
Ordinarilyg a solution of the starting material of formula (VI) in tetra-
hydrofuran is added to an ice-cooled solution of BH3.THF. After the addition
is complete the reaction mixture is heated to reflux and maintained at this
temperature for a period of about one to two hours or more. The reaction
is ordinarily carried out in the presence of an inert gas such as nitrogen.
When the reaction is substantially completed, the solvent is evaporated and
the residue is acidified with an excess of an acid such as, for example, 2
to 12 molar hydrochloric acid. A preferred acidulant is a mixture of equal
volumes of acetic acid and 5 molar hydrochloric acid. The acidified mixture
is ordinarily heated at reflux for 1 to 2 hours or more. The desired
product may then be isolated, for example, by evaporation of any residual
ether solvent and a portion of the acid mixture and the precipitated
product collected by filtration and washed. In an alternate method of
isolation of the product (VII), after the reflux period the reaction mixture
-- 10 --
1~3~9~
is filtered, the filtrate cooled and made alkaline by addition of, for
example, sodium hydroxide, potassium hydroxide or sodium carbonate. The
basic mixture is extracted with a water immiscible organic solvent such
as, for example,
- lOa -
~ IB39~
chloroform, methylene chloride or benzene, the extracts evaporated and the
residue purified by silica gel column chromatography, eluting, for example,
with ethyl acetate or mixtures of hexane/ethyl acetate.
The reduction of tetrahydro-y-carbolines by B113 THF followed by
acid treatment yields hexahydro-y-carbolines in which the hydrogens attached
to the carbon atoms in the 4a and 9b positions are in trans-relationship,
see, for example, United States 3,991,199.
The 2-ben~yl compounds of formula ~VII) are then converted to the
corresponding 2-hydrogen compounds of formula (VIII). In general, this may
be accomplished by treating the compound of formula (VII) with a molar excess
of a lower alkyl chloroformate ester such as, for example, the methyl, ethyl,
propyl or isobutyl ester in the presence of a suitable reaction-inert organic
solvent, followed by alkaline hydrolysis. Preferred as chloroformate ester
is ethyl chloroformate because of its ease of availability and efficiency.
By a suitable reaction-inert organic solvent is meant one which will substan-
tially dissolve the reactants under the conditions of the reaction without
the formation of byproducts. Examples of such solvents are aromatic hydro-
carbons such as ben~ene, toluene and xylene; chlorinated hydrocarbons such as
chloroform and 1,2-dichloroethane, diethyleneglycol dimethylether and di-
methylsulfoxide. An especially preferred solvent is toluene.
To the mixture of starting material of formula (VII) in said reac-
tion inert organic solvent is added up to about a ten molar excess of the
chloroformate ester. For reasons of economy a molar excess of about 3 to 5
is preferable. The resulting mixture is then heated at a temperature of from
about 80-150C., typically at the reflux temperature of the mixture, for pe-
riods of about 6 to 24 hours or more. Ordinarily~ refluxing is carried out
overnight for reasons of convenience. The reaction mixture is then evaporat-
ed in vacuo and the residue taken up in an alcohol-water mixture, an alkali,
for example, sodium hydroxide
~1
~39g6
or potassium hydroxide, is added in about 10-30 molar excess based on the
amount of starting material of formula (VII), and the resulting mixture heat-
ed at reflux, typically overnight. The solvent is then evaporated and the
residue partitioned between water and a water immiscible organic solvent such
as, for example, chloroform, methylene chloride or ethyl ether and the organ-
ic phase evaporated to dryness. The residual product of formula ~VIII) may
be used as is or further purified by standard methods known in the art, for
example, by column chromatography on silica gel.
In the case of compounds of the formula (VII) wherein both X and Y
are hydrogen and R2 is benzyl, the corresponding compound of formula (VIII)
may be obtained by catalytic debenzylation employing hydrogen and palladium-
on-carbon catalyst. The reaction is typically carried out employing the hy-
drochloride salt of the compound (VII) at a temperature of from about 50 to
100C, preferably 60-75C, and hydrogen pressures of about 20-100 p.s.i.
~1.4-7 kg/cm ) in the presence of a reaction-inert solvent, for example,
methanol, ethanol, isopropanol, ethyl acetate or mixtures thereof with water.
I~hen the hydrogen uptake is complete, the catalyst is removed by filtration
and the hydrochloride salt of the product of formula (VIII) is precipitated
by addition of a nonsolvent, for example, ethyl ether, benzene or hexane.
Alternatively, the free base of formula (VIII) may be isolated by evaporating
the filtrate from the debenzylation to dryness, partitioning the residue be-
tween aqueous alkali, for example sodium hydroxide, and a solvent such as
chloroform on ethyl ether. The free base is then isolated by standard meth-
ods such as those described above.
~' f
~1
~ 16~g9~
The free bases of formula (VIII) may also serve as precursors
for the novel compounds oE formula (II) as illustrated by the following
reaction sequenee wherein Xl, Yl, Zl and n are as previously defined.
O O O
~VIII~ + ~C-(CH )--COU Xl\~--~NC-(CH2)n_
(IX) ¦ (X)
'~
.
S (X) L~AI~ (CUZ)
(II)
The acylation of the compounds (VIII) to form the intermediates of
formula (X) may employ the aeids of formula (IX) or the eorresponding
acid chlorides or acid bromides. When the aeids oE formula (IX) are
employed in the acylation, approxlmately equlmolar amounts of said acid
LO and compound of formuLa (VIII) are contacted in the presence of a
reaction-inert organic solvent and certain condensing agents known in
the art for forming peptide bonds. Such agents include carbodiimides,
for example, dieyelohexylcarbodiimide and l-ethyl-3-(3-dimethylamino-
propyl) carbodiimide hydrochloride, and alkoxyacetylenes, for example,
lS methoxyacetylene and ethoxyacetylene. The preEerred condensing agent
-13-
1 ~399~
is dicyclohexylcarbodiimide Examples of said solvents ~hich ~ay be
employed are dichloromethane, chloroform, tetrahydrofuran, ethyl ether
and benzene. ~hile the reactlon may be carried out at a temperature of
from about -lO to 50C with satisfactory results, it is preferred to
employ a temperature of from about 0 to 30~C. At this temperature the
reaction is ordinarily complete in a few hours. The product of formula
(X) is isolated, for example, by iltering to remove insoluble ~aterial
and evaporation of solvent. The resulting product is ordinarily of
sufficient purity for use in the next step.
The intermediate of formula (X) is then reduced with lithium
aluminum hydride to obtain the desired compound of formula (II). The
reduction is preferably carried out in the presence of an inert gas such
as nitrogen or argon and under substantially anhydrous conditions.
Fro~ about 2 to 10 molar excess of lithium alu~inum hydride is suspended
in an ethereal solvent, for example, ethyl ether or tetrahydrofuran and
the mixture is preferably cooled to a temperature of about 0 to 10C.
The intermediate of formula (X), obtained as described above, is ordinarily
dissolved in the same solvent and the solution added dropwise. The
resulting mixture is then reacted, ordinarily at or about room temperature
for a period of from about 0.5 to 4 hours to attain substantial completion
of the reaction. The excess lithium aluminum hydride is then decomposed,
e.g., by cautious addition of water, the resulting mixture filtered and
the filtrate evaporated to dryness to provide the desired product of
formula (II) ~hich may be further purified, if desiredt by standard
methods known to one skilled in the art. Alternatively, the free base,
(II), may be converted to a salt such as, for example, the hydrochloride
addition salt by addition of anhydrous hydrogen chloride to a solution
of the base in a solvent such as ethanol, ethyl ether or mixtures
thereof. The precipitated salt may then be collected, e.g., by filtration.
The products (II) may be further purified, if desired, for example,
by column chromatography on silica gel.
.
-14-
~ 16~996
Oxidation of the compounds of formula (II) employing reagents
and conditions which are known to selectively convert secondary alcohols
to the corresponding ketones, provides the novel products of formula
1 \ ~ ~ JN-(CH2)n-,CI - ~ ~Z
rv
Yl
wherein Xl, Yl, Zl and n are as previously defined. Examples of such
oxidizing agents which may be employed in this reaction are potassium
permanganate, potassium dichromate and chromium trioxide and the preferred
reagent is chromium trioxide in the presence of pyridine. In carrying out
this reaction with the preferred reagent, the starting alcohol of formula
(VI) in a reaction-inert solvent, for example, dichloromethane, chloro-
form or benzene, is added to a mixture containing up to a ten molar excess
of chromium trioxide and a similarly large molar excess of pyridine and
the mixture stirred, ordinarily at room temperature, until the reaction
is substantially complete. Ordinarily,
- 15 -
1 1~3g~
from about 15 minutes to one hour will suffice. The product is iso-
lated, for example, by removal of insoluble material by filtration,
extracting the filtrate ~ith a dilute aqueous alkali such as
sodium hydroxide solution, drying the organic layer and evaporating
to dryness. The residual product may be further purified, if desired,
for example, by column chromatography.
As will be recognized by one ski-Lled in the art, the 4a,
9b-trans- compounds of formula (IV) and (V:[II) ~orm a single
racemate which can be resolved into a pair of enantiomers, one of
uhich is dextrorotatory and the other is levorotatory. The 4a, 9b-
trans- compounds of formula ~ , having an additional assymmetric
carbon atom in the 2-substituent, form two diastereomers, each of
which is resolvable into dextrorotatory and levorotatory enantiomersO
It has now been ~ound that the tranquilizing activity of the
compounds of formula ~~), resides in such compounds wherein the 5-
aryl-2,3,4,4a,5,9b-hexahydro-1~-pyridot4,3-b]indole moiety ~A) is
dextrorotatory. The corresponding compounds wherein moiety (A) is
levorotatory being of significantly lower activity. Active tran-
quilizing agents included within the scope of the invention, there-
fore, include the enantiomers of formula ~~) wherein said moiety (A)
is dextrorotatory as well as mixtures of enantiomers of formula (I)
wherein said moiety (A) is dextrorotatory and levorotatory, including
tha racemic mixtures. While the nature of the 2-substituent attached
to the ~oiety (A) to form the compounds of formula ~) is critical for
optimal tranquilizing activity, the stereochemistry of the 2-sub-
Stieuent is less important. Thus, compounds of formula (II) w~erein moiety
(A~ is dextrorotatory are highly active when a given 2-substituent of
- 16 -
~ 16399~
formula (CH2)nCHOHC6H4Zl is racemic, dextrorotatory or levorotatory.
The compounds of formula (II) as ordinarily obtained by the
above-described methods are a mixture o-f diastereomers. Methods for
the separation of such mixed diastereomers include fractional crystalli-
zation and chromatographic methods. The separation of mixed diastereomers
of formula (II) by fractional crystallization is ordinarily sufficient to
afford each of the diastereomers in a highly purified form. Of course,
column chromatography may be employed to further purify the diastereomers.
Solvent systems useful for the fractional crystallization of the above
diastereomers include, for example, mixed solvent systems containing both
a polar and non-polar solvent. Examples of such polar solvents include
ethyl acetate, methanol, ethanol, acetone and acetonitrile. Examples of
such non-polar solvents are hexane and its close homologs, benzene, toluene
and carbon tetrachloride. A preferred mixture of such solvents is ethyl
acetate and hexane.
The resolution of the single diastereomers of formula (I)
into the d- and l-enantiomers can be brought about by a variety of
methods known in the art for resolving racemic amines, see e. g.,
Fieser et. al., "Reagents for Organic Synthesis", Wiley & Sons, Inc.,
New York, (1967), Vol. I, p. 977 and references cited therein.
However, a particukarly useful method for obtaining the enantiomers
from the racemates of formula (I) is by esterification of a compound
- 17 -
~ 1~i39~6
~ fQrmula (II) with an optically active acid followed by separation
cf the diastereomeric esters by fractional crystallization or by
chromatography. The enantiDmeric ketones of formula (IV) are then
obtained by oxidation of the corresponding enantiomers of formula (II).
While a variety of optically active acids are known in the art for such
use, L-phenylalanine has been found to be especially useful for resolv-
ing the diastereomers of formula (II) according to the following
scheme in which (A) represents the 5-aryl-2,3,4,4a,5,9b-hexahydro-lH-
pyrido[4,3-b]indole moiety and t-Boc is t-butyl-oxycarbonyl.
dl-(A)-(CH2)n-CIHC6H4Zl +L C6H5CH2CI
OH NHt-Boc
- ( ) ( 2)n 6 4 1 CF3COOH
1COCH2C6H5_L
NHt-Boc
15(XVI) mixture of diastereomers)
dl-(A)-cH2)ncH e6H4Zl
1COCH C6H5-L - - ED (XVII, single diastereomer)
3 . ~ H20
(XVII mixture of diastereomers) (II, single enantiomer)
~ oxidation
(IV, single enantiomer)
- 18 -
1 ~3gg~
In the first step of the resolution scheme depicted abov~,
~lle single racemic diastereomer of formula (II~ is esterified with t-
Boc-L-phenylalanine by methods known in the art for esterification of
such compounds. In a particularly preferred procedure, the diastereomer
(II) is contacted with at least an equimolar amount of t-Boc-L-
phenylalanine in the presence of a reaction inert solvent and a
condensing agent at low temperature, preferably at about 0[ to room
temperature. Examples of suitable reaction inert solvents include
chloroform, methylene chloride, 1,2-dichloroe~hane, tetrahydrofuran
and ethyl ether. Preferred as solvent is chloroform and a preferred
condensing agent is dicyclohexylcarbodiimide. The reaction is
ordinarily complete within a few hours. The resulting ester of formula
~XVI) is recovered by well known methods and reacted in the cold,
preferably at -10 to 20~C. with a molar excess of trifluoroacetic
acid to remove the t-butyloxycarbonyl protecting group to provide
the amino ester of formula (XVII) as a mixture of diastereomers. This
mixture is then separated by fractional crystallization or chroma-
tography to provide the single diastereomers of formula (XVII). A
particularly convenient method for such separation is by column
chromatography on silica gel. The isolated single diastereomers are
then hydrolyzed in the presence of acid or base by well known methods
to provide the separated dextrorotatory and levorotatory enantiomers
_ 19 _
~ 1~399~
of formula (II). The latter enantiomers may then be oxidized,
for example, by means of chromic acid as described herein, to
provide the corresponding enantiomers of formula (IV).
An alternate method for providing the enantiomeric
compounds of formula (II) is by stereospecific synthesis in
which the resolved enantiomers of a tricyclic seconaary amine
of formula (VIII) are condensed with an enantiomeric precursor
of the 2-position substituent. In order to effect stereospecific
synthesis of the compounds of formula (II), a novel process
which conveniently achieves this goal to provide optically pure
compounds in high yield employing resolved reactants is
outlined below. Of course, this process is also useful for
providing racemic products when racemic reactants are employed.
:
1 + ~ Hz)q ~ CH2)n-bH C6H4Zl
(VIII) ~XIV) (II)
In the above reaction scheme, X Yl, Zl and n are as previously
defined and q is 1 or 2.
:
- 20 -
1 1~i3~
The optical isomers of amine (VIII) are obtained by rsso-
lution of the racemic compounds. The resolution is carried out by
means of a salt formed between the amine (VIII) and optically active
acid. While a variety of acids useful in the resolution of amines
are known in the art, see for example, Fieser et. al. cited above,
preferred acids which afford ready separation of the amine (VIII)
are the optical isomers (D- and L-) of N-carbamoylphenylalanine.
The latter are obtained by reaction of the isomeric phenylalanines
with sodium cyanate by methods known to one skilled in the art. The
resolution is achieved by reacting one of the isomeric N-carbamoyl-
phenylalanines, for example the L-isomer, with a racemic compound of
formula (VIII) in equimolar amounts in the presence of a sultable
reaction inert solvent to form a homogeneous solution of the salts. -
Upon cooling, the salt of one of the optical isomers of (VIII) is
obtained as a crystalline solid which may be further purified if de-
sired. The mother liquors containing primarily the salt of the
other isomer is evaporated to dryness and the salt decomposed by
aqueous base such as, for example, sodium carbonate, potassium hy-
droxide or calcium carbonate and the free base extracted by means of
a water immiscible solvent, typically ethyl acetate? dried and the
solvent evaporated to obtain a residue enriched in the second isomer
of the amine (VIII). This residue is then taken up in a reaction
inert solvent and treated with an equimolar amount of the other isomer
of N-carbamoylphenylalanine, for example, the D-isomer and the solution
cooled to precipitate crystals of the ~-carbamoylphenylalanine salt
of the second isomer of formula (V ).
~ 1 63~9~
Each of the salts containing a single enantiomer of the
amine (VIII) is then decomposed as described above to obtain, respectively,
the essentially pure dextrorotatory and levorotatory isomers of (VIII).
For the synthesis of each of the enantiomers of formula (II)
equimolar amounts of the resolved reactants of formula (VIII) and :(XIV)
are contacted in the presence of a reaction inert organic solvent under
reductive alkylation conditions. Methods for carrying out reductive
alkylation reactions have been reviewed, for example, by Emerson,
Organic Reactions 4, 174 (1948) and by Rylander in "Catalytic Hydrogena-
tion Over Platinum Metals", Academic Press, New York, 1967, p. 291-303.
The reaction may be effected with a wide variety of reducing agents known
to be useful for reductive
- 22 -
1 ~39~
alkylation of secondary amines with aldehydes and ketones such as,
for example, hydrogen in the presence of a catalytic amount of a
noble metal catalyst such as platinum, palladium, rhodium, ruthenium
or nickel; various metal hydride reducing agents such as sodium
cyanoborohydride, sodium borohydride and lithiu~ borohydride; and formic
acid. Preferred reducing agents are the noble metal catalysts and
sodium cyanoborohydride. Especially preferred noble metals are
platinum and palladium and most particularly preferred is palladium
for reasons of economy and efficiency in providing enantiomeric
products in high yield and with a high degree of optical purity.
In its preferred embodiment the amine of formula (VIII) is
contacted with an equimolar amount of lactol of formula (XIV) and one
of the above-mentioned preferred reducing agents in the presence of
reaction inert organic solvent at a temperature of from about -10 to
50D C. When the preferred re'ducing agent is sodium cyanoborohydride,
at least an equivalent amount is employed. I~hen the preferred noble
metal catalysts are employed, the reaction is carried out in the
presence of a molar excess of hydrogen.
As mentioned above, the noble metal catalyst is employed
in a "catalytic amount", which term is well understood by those skilled
in the art. When the noble metal catalysts and hydrogen are employed,
the reaction may be carried out at atmospheric pressure or at high
pressures up to about 10 atmospheres or higher with equal facility.
The factor which will ordinarily determine whether the reaction is
carried out at atmospheric pressure or higher pressure is the scale
on which reaction is carried out. For example, when carried out on a
- 23 -
1 ~639~
few grams or less of reactants, atmospheric pressure is more con-
venient; however, on a commercial scale, use of high pressure is
usually preferable.
Examples of suitable reaction inert solvents are the lower
alkanols, such as methanol, ethanol, isopropanol and n butanol, ethers
such as dimethoxyethane, diethyleneglycol dimethyl ether, ethyl ether
and isopropyl ether, glycols such as ethylene glycol and diethylene
glycol, and glycol monoethers such as a-methoxyethanol and diethyl-
eneglycol monomether ether.
While the reaction may be carried out with some success at
temperatures o~ from about -50 up to the reflux temperature of the
solvent, preferred reaction temperature is from about -10 to 50 C.
for reasons of convenience and efficiency. At higher temperatures,
racemization of products and other undesired side reactions may take place
to an appreciable extent. At temperatures lower than -10 C., the
reaction rate is very slow. The reaction ordinarily proceeds to
completion in fro~ about one to five hours. The products are then
isolated by standard methods and purified, if desired, for example,
by crystallization or chromatography. The desired enantiomeric
products are thus obtained in good yield and are of high optical
purity.
An alternative preferred product of the invention is obtained
by the above procedure using dextrorotatory amine (VIII) and racemic
lactol (XIV) in the above procedure. The product obtained, of formula
(II), is optically active due to the chirality of the amine moiety (A),
defined above. It is a highly active tranquilizing agent and also
- 24 -
9~
serves as an economical intermediate for oxidation by methods de-
scribed above, to the ketonic products of formula (IV).
2-Benzyl-5-phenyl-1,2,3,4-tetrahydro-q-carboline is ob-
tained by the Fischer indole suynthesis employing N,N-diphenylhydra-
5 zine and N-benzyl-4-piperidone. The mono or difluoro-substituted
starting tetrahydro-y-carbolines of formula (VI) wherein at least one
of Xl or Yl is fluoro and R2 is benzyl, are prepared from the corres-
ponding compounds of formula (VI) wherein E~2 ls hydrogen by reaction
with a benzyl halide such as benzyl bromide, in equimolar amounts.
10 The requisite compounds of formula ~VI, R2 ~ H) are prepared as de-
scribed in U.S. 4,001,Z63. The starting tetrahydro-~-carbolines (V)
are described in the same reference.
Except for the novel intermediates of formulae (VIII) and
~XIV) mentioned above, the other starting materials are either commer-
cially a~ailable, their preparation is explicitly reported in thechemical literature or they can be prepared by methods known to those
~killea in the art. For example, the phenylhydrazines are commercially
available or are synthesized by reduction of the phenyldiazonium
salt as reviewed by Wagner and Zook in "Synthetic Organic Chemistry",
John Wiley ~ Sons, New York, ~Y, 1956, Chapter 26; the l-substituted-
4-piperidones are commercial reagents or prepared by the method of
McElvain et al., J. Am. Chem. Soc., 70, 1~26(1948); ~he requisite
3-benzoylpropionic acids and 4-benzoylbutyric acids are either com-
merically available or prepared by modification of the procedure
25 Of "Organic Synthesis", Coll. Vol. 2, John Wiley ~ Sons, ~ew York,
NY, 1943, p. ~1.
- 25 -
~ 1~3~6
The following examples are provided solely for the purpose
of illustration and are not to be construed as limitations of the in-
vention, many variations of which are possible without departing
fro~ the spirit of scope thereof.
- 26 -
EXAMPLE 1
dl-trans-2-benzyl-2,3,4,4a,5,9b-hexahydro-5-phenyl-lH-pyrido-
[4,3-b]indole Hydrochloride
To a solution of 0.140 moles of borane in 150 ml. of tetrahydro-
furan stirred at 0 C., in a three-necked round bottom flask fitted with mag-
neiic stirrer, thermometer, condenser and addition funnel, and maintained
under a nitrogen atmosphere, was added a solution of 23.9 g. (0.071 mole) of
2-benzyl-5-phenyl-1,2,3,4-tetrahydropyrido[4,3-b]indole in 460 ml. of dry
tetrahydrofuran. The addition was carried out at such a rate as to maintain
the reaction temperature below 9 C. When the addition was completed the re-
sulting mixture was heated to reflux and maintained at this temperature for
one hour. The solvent was then evaporated in vacuo to afford a white solid
mass which was suspended in 40 ml. of dry tetrahydrofuran and heated, slowly
at first, with 180 ml. of a 1:1 by volume mixture of acetic acid and 5N hy-
drochloric acid. The resulting suspension was heated at reflux for one hour,
then cooled. Evaporation of tetrahydrofuran and part of the acetic acid re-
sulted in precipitation of a white solid which was separated by filtration
and washed with water. The solid was resuspended in tetrahydrofuran, fil-
tered, washed with ethyl ether and air dried to afford 16.7 g. ~63%) of the
desired trans-isomer. M.P. 256-260 C.
Evaporation of the mother liquor gave an additional 7.2 g. of prod-
uct.
When the above procedure is repeated, but employing the appropri-
ately substituted 2-benzyl-5-phenyl-1,2,3,4-tetrahydropyrido[4,3-b]indole as
starting material, the following 4a,9b-trans-compounds are obtained in like
manner as their hydrochloride salts.
- 27 -
~
X 9b
~f N-CH2C6H5
~y
-- Y X y_
H _-fluoro H o-fluoro
F H F m- fluoro
F p-fluoro F o-fluoro
EXAMPLE 2
dl-trans-5-Phenyl-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3=b]indole
A suspension of 4.17 g. dl-trans-2-benzyl-5-phenyl-2,3,4,4a,5,9b-
hexahydro-lH-pyrido[4,3-b]indole hydrochloride in 150 ml. of absolute
ethanol was hydrogenated at 50 p.s.i. and 60-70C. using 1.0 g. of 10% Pd/C
catalyst, over a two-hour period. The catalyst was removed by filtration and
to the filtrate was added sufficient ethyl ether to precipitate the hydro-
chloride of the desired produc~, 2.76 g. (87%), M.P. 235-237C.
The hydrochloride salt was converted to free base by partitioning
between ether and dilute sodium hydroxide solution. The ether layer was
dried over sodium sulfate and evaporated to afford the title compound ~97%
yield), M.P. 74-76C.
_ 28 -
~3~g~!
EYA~LE 3
dl-trans-8-Fluoro-5-(p-fluorophenyl)-2-~4-nydro~y-4~ fluor
--- phenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1~-pyrido[4,3-b]indole
hydrochloride and
_ -trans-8-Fluoro-5-(~-fluorophenyi)-2-{4-(p-fluorophenyl)-3-
butenyl~ 2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]indole hydro-
chloride
, ,, ~
I~ a lOOC ml. reactio~ vessel equipped with magnetic stirrer, dropping
funnel and maintained under a nitrogen atmosphere were placed 177 ml. of 0.94
molar borane in tetranydrofuran. The solution was cooled in an ice bath and to
the cold solution was added over 30 ~inutes a solution of 25 g. (0.0555 moLe)
of 8-rluoro-5-~o-fluorophenyl)-2-~4-hydroxy-4-(o-fluorophenyl)butyl~-2,3,4,5-
tetrahydropyrido~4,3-b]indole in Z95 ml9 of tetrahydrofuran. rne resulting
mixture was stirred at ambient temperature for 20 ~inutes, then heated at
reflux for t~o h~urs. T~.e reaction mi~ture was cooled and concentrated in vac-
uo to obtain a liquid residue. To this was added a mixture or 50 ~1. each of
acetic ac~d and 5~ hydrochloric acid ~hereupon vigorous gas evolutivn took
place. The mixture was heated at reflux for one hour, cooled to room temperatur~
and filtered. rne filtrate was cooled in ice and ~ade al~aline by addition of
50% (w/w) sodium hydroxide solution. ~le basic mixture was extracted twice
wieh 150 ml. portions of chloroform, the combined organic layers dried over
magnesium sulfate and evaporated to dryness in vacuo to obtain a yellow foamed
solid, 25 g. Silica gel thin-la-yer chro~atography, e~ploying a 1:1 by volume
hexane~ethyl acetate solvent system, revealed two products. The foamed solid
was chromatographed on a column of silica gel, eluting with 1:1 by volume
he~ane/ethyl acetate and ~onitoring the fractions by TLC. The fractions con-
taining only the faster moving ~roduct~ i.e. 8-fluoro-5-(~ fluorophenyl)-2-[4-
tp-fluorophenyl)-3-butenyl]-2~3~4~4a~5~9b-hexahydro-lH-pyrido[4~3-b]indole
were evaporated co dryness ta'~en up in acetone and converted to the hydrochlo-
ride salc by addition of anhydrous hydrogen chloride in acetone, the resulting
29 ~
. .
~ 163g~
whitc solid was collected by filtration and dried to obtain 1.5 g. of the 3-
butenyl compound, M.P. 270-273 C.
The fractions containing only the slower moving 8-fluoro-5-(~-
fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-
lH-pyrido[4,3-b]indole were concentrated, taken up in ethyl ether and con-
verted to hydrochloride salt by addition of anhydrous hydrogen chloride to
obtain 10.8 g. of this product, M.P. 241-245 C., a mixture of two diastereo-
mers.
The proportion of the faster moving 3-butenyl compound is in-
creased, up to 100%, by suitable increase in the acidity and period of heat-
ing at reflux in the acetic/hydrochloric acid mixture.
EXAMPLE 3A
When the procedure of Example 3 was repeated, but starting with 8-
fluoro-5-(o-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,5-
tetrahydropyrido[4,3-b]indole, the faster moving component from silica gel
chromatography was identified as trans-8-fluoro-5-(o-fluorophenyl)-2-[4-(p-
fluorophenyl)-3-butenyl]-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]indole, M.P.
141-142 C. The slower moving component was identified as trans-8-fluoro-5-
(o-fluorophenyl)-2-[4-hydroxy-4-(~-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexa-
hydro-lH-pyrido[4,3-b]-indole, M.P. 195-197 C. Each of the above products
was a mixture of diastereomers.
- 30 -
, /~
';~1
~1S~9~6
EXAMPLE 4
Employing the appropriate compounds of formula (V) as starting
materials in the procedure of Example 3, the indicated 4a,9b-trans-products
of formulae (II) and ~III) were obtained and separated in each case. In the
products of formula (III) m = n-l.
Xl j ( 2)n
~ (V)
1~ ( 2 ) n 1
C1l2)mC~I=CH
N ~ Y
~III)
Yl
- 31 -
3~g~
n X Y Z
3 F ~-fluoro m-fluoro
3 F ~-fluoro H
3 H p-fluoro p-methoxy
3 F H o-methoxy
3 H H ~-fluoro
4 F p-fluoro p-fluoro
4 F p-fluoro p-methoxy
4 F ~-fluoro H
4 F H o-fluoro
4 F H m-methoxy
4 El p-fluoro p-fluoro
4 H p-fluoro H
4 H H H
4 H o-fluoro ~-fluoro
3 H o-fluoro ~-fluoro
3 H m-fluoro m-fluoro
3 F o-fluoro p-methoxy
3 H m-fluoro H
4 F o-fluoro o-fluoro
4 F m-fluoro ~-methoxy
- 32 -
3996
EXAMPLE 5
l-trans-8-Fluoro-5-(_-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-
lH-~yrido[4,3-b]indole
A. To a solution of 5.6 g. (12.4 mmole) of _-trans-8-fluoro-5-
(p-fluorophenyl)-2-[4-hydroxy-4-(~-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexa-
hydro-lH-pyrido[4,3-b]indole in 40 ml. of toluene was added 5.3 ml. (55.7
mmole) of ethyl chloroformate. The resulting mixture refluxed overnight
then evaporated to dryness to obtain a residual gum. To the gum was added
200 ml. of a 9:1 by volume mixture of ethanol/water. After the gum was dis-
solved, 15 g. of potassium hydroxide was added and the resulting mixture re-
fluxed overnight. The solvent was evaporated in vacuo and the residue par-
titioned between water and chloroform. The organic extracts were washed
with water, dried over sodium sulfate and evaporated to dryness. The resid-
ual oil was taken up in ethyl acetate and passed through a silica gel column
eluting first with ethyl acetate to remove by-products then eluting the de-
sired product with 1:1 by volume ethyl acetate/methanol. The fractions con-
taining the title compound were combined and evaporated to dryness to obtain
1.5 g. (43%) of yellow gum which crystallized upon standing, M.P. 115-117C.
B. Alternately, dl-trans-2-benzyl-8-fluoro-5-(p-fluorophenyl)-
2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]indole hydrochloride is refluxed in
the presence of excess ethyl chloroformate or the corresponding methyl, iso-
propyl or n-butyl chloroformate esters, then hydrolyzed and worked up by the
procedure described above to obtain the title compound.
. ,
1 1639g5
EXAMPLE 6
Employing the appropriate starting material in each case and em-
ploying the procedures of Example 5A or 5B, the following products are simi-
larly obtained:
_ -trans-5-(p-fluorophenyl)-2 ? 3,4,4a,5,9b-hexahydro-lH-pyrido-
[4,3-b]indole,
dl-trans-8-fluoro-5-phenyl-2,3,4,4a,5,9b-hexahydro-111-pyrido-
[4,3-b]indole,
_ -trans-5-(o-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-lH-pyrido-
[4,3-b]indole,
dl-trans-5-(o-fluorophenyl)-8-fluoro-2,3,4,4a,5J9b-hexahydro-lH-
pyrido[4,3-b]indole,
_ -trans-5-(m-fluorophenyl)-8-fluoro-2,3,4,4a,5,9b-hexahydro-lH-
pyrido[4,3-b]indole,
_ -trans-5-(m-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-lH-pyrido-
[4,3-b]indole.
- 34 -
~ ~6~g~5
EXAMPI.E 7
dl-trans-2-(4-Hydroxy-4-phenylbutyl)-5-phenyl-2,3,4,4a,5,9b-
hexahydro-lH-pyrido[4,3-blindole Hydrochloride
A. To the suspension arising from the admixture of 865 mg. (4.20
mmole) of dicyclohexylcarbodiimide and 748 mg. (4.20 mmole) of 3-benzoylprop-
ionic acid in 30 ml. of dichloromethane at 0C. was added 1.0 g. (4.0 mmole)
of dl-trans-5-phenyl-2,3,4,4a,5,9b-hexahyclro-lH-pyrido[4,3-b]indole in 10 ml.
of the same solvent. The resulting mixture was stirred and allowed to warm
to room temperature over 2 hours. After cooling again to 0 C. the reaction
mixture was filtered, washed with dichloromethane and the filtrates evapo-
rated to obtain a residue of dl-trans-2-~(3-benzoyl)propionyl]-5-phenyl-
2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]indole which was used without purifi-
cation in the next step.
B. The residue from above was dissolved in 50 ml. of tetrahydrofuran
and heated to reflux. A filtered solution of lithium aluminum hydride in the
same solvent was added until gas evolution ceased ~molar excess), and the re-
sulting mixture was stirred at reflux for 5-10 minutes, then cooled. An-
hydrous powdered sodium sulfate, 17 g., was added followed by 0.5 ml. of
water. The resulting mixture was stirred at room temperature for 30 minutes,
filtered, and the filtrate evaporated to dryness in vacuo. The residue was
chromatographed on a column containing 80 g. of silica gel, eluting with 4:1
~v/v) ethyl acetate/methanol to afford the free base of the title compound
after evaporation of solvent. The free base was converted to the hydro-
chloride salt by dissolving it in ether, adding a saturated solution of an-
hydrous hydrogen chloride in ether until precipitation was complete~ filter-
ing and drying to afford 1.04 g., M.P. 222-224 C. Infrared spectrum (KBr),
~: 2.97, 3.43, 4.00 (broad), 6.25, 6.68, 6.88j 7.51, 7.96, 8.18, 8.45, 9.82;
Mass spectrum, M/e, 398, 292, 263, 249, 220, 207, 192 (100%); W (methanol)
245 ( = 0.653 x 104), 270 (~ = 0.914 x 104).
- 35 -
1 ~ ~3g~
EXAMPLE 8
Employing the appropriate starting material in each case selec~ed
from the free bases provided in Examples 2 and 5 and the appropriate 3-
benzoylpropionic acid> the following dl- rans-compounds were prepared by the
procedure of Example 9. Products were isolated as the hydrochloride salts
except as indicated.
1 ~ CH2CH2CH2CH ~ 1
Xl Yl Zl M.P., C. Yield, %
F F H 220-223 18
H H F 239-245 39
H H CH30 amorphous 54
solid (a)
F F CH30 45-48.5 (b) 31
(a) Mass spectrum, M/e: 428, 411, 263
(100%), 220, 206, 204; Infrared spec-
trum (KBr), ~: 2.98, 3.42, 4.07
(broad), 6.20, 6.26, 6.70, 6.88, 8.04,
8.54, 9.77, 12.05.
(b) Melting point and yield data are
for the frea base.
- 36 -
~i '
11~3~
EXAMPLE 9
Starting with the appropriate dl-trans-hexahydro-lH-pyrido[4,3-b]-
indole selected from the products of Examples 2, 5 and 6 and ~he appropri-
ately substituted 3-benzoylpropionic or 4-benzoylbutyric acid, the following
compounds are obtained by the method of Example 7.
1 ~ ( 2) n 1 ~ 1
Y
n X1 Yl Zl-
3 F p-fluoro m-fluoro
3 F _-fluoro o-methoxy
3 F H p-fluoro
3 H p-fluoro p-methoxy
3 H o-fluoro m-methoxy
3 F H H
3 H m-fluoro H
3 H H m-fluoro
4 F ~-fluoro p-fluoro
4 F p-fluoro ~-methoxy
4 F o-fluoro H
4 F H H
4 F H m-methoxy
4 H p-fluoro H
4 H m-fluoro o-fluoro
4 H o-fluoro p-methoxy
4 H H o-methoxy
3 H ~-fluoro p-fluoro
3 H o-fluoro o-fluoro
3 F m-fluoro p-fluoro
3 H _-fluoro ~-fluoro
1 1~3996
EXAMPLE 10
. _ .
dl-trans-5-Phenyl-2-[3-(~-fluorobenzoyl)propyl]-3,4,4a,5,9b-
hexahydro-lH-pyrido[4,3-b]indole Hydrochloride
In a 25 ml. reaction vessel equipped with magnetic stirrer and
maintained under a nitrogen atmosphere were placed 0.828 ml. (8.0 mg., 10.3
mmole) of dry pyridine and 10 ml. of dichloromethane. To the solution was
added 517 mg. (5.17 mmole) of chromium trioxide and the resulting dark red
suspension stirred for 15 minutes at room temperature. A solution of 359 mg.
(0.862 mmole) of dl-trans-5-phenyl-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-
2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]indole free base in 5 ml. of dichloro-
10 methane was added in one portion. The reaction mixture quickly changed to abrown suspension. This was stirred at ambient temperature for 30 minutes.
The insoluble material was removed by filtration, washed with dichloromethane
and the combined filtrate and washings were extracted with 20 ml. of 10% so-
dium hydroxide solution. The organic layer was dried (MgS04) and evaporated
to dryness in vacuo to afford a gum. The gum was purified by column chrom-
atography on silica gel, eluting with 1:1 by volume hexane/ethyl acetate.
The fractions containing the desired product were combined, evaporated to a
yellow gum, the gum taken up in ethyl ether and treated with anhydrous hydro-
gen chloride. The resulting suspension was evaporated to dryness, slurried
20 with 3 ml. of cold dichloromethane. A colorless solid formed which was col-
lected by filtration and dried to afford 20 mg. of the title compound, M.P.
244-246.5 C.
- 38 -
9 0
EXAMPLE 11
dl-trans-8-Fluoro-5-(p-fluorophenyl)-2-[3-(p-fluorobenzoyl)propyl]-
2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]indole Hydrochloride
To a 100 ml. flask containing 20 ml. of dichloromethane and 1.76
ml. (21.9 mmole) of pyridine was added 1.09 g. of chromium trioxide and the
resulting dark suspension was stirred at ambient temperature for 15 minutes.
Then was added in one portion a solution of 824 mg. (1.82 mmole) of dl-trans-
8-fluoro-5-(~-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a-
5,9b-hexahydro-lH-pyrido[4,3-b]indole free base (obtained from the hydro-
chloride salt by making an aqueous solution alkaline with sodium hydroxide,
extracting with dichloromethane and evaporating the extracts to dryness) in
10 ml. of dichloromethane. The resulting red-brown suspension was stirred at
ambient temperature for one hour and worked-up by the same procedure employed
in Example 10 to obtain 25 mg. of the desired product, M.P. 260-263 C.
- 39 -
~ ~399~
.
~ E~LE 12
Employing the approptiate starting ~aterial selected from the products
ob e~ine~ in ~Ya~ple 7, 8 and 9 and oxidi~ing by the procedure of Example 1
affords the follouing 4a,9b-trans compounds:
~ - (C~z) C
.' '. ,' ` '~ " '' .
Y~
S n~ Xl Yl Z 1
3 F p-fluoro H
3 H H p-fluoro
:. 3 ~ H ~-methoxy
~ 3 F E~fluoro p-methoxy
3 H p-fluoro p-met~oxy
-3 H o-fluoro m-methoxy
- 3 F H . p-fluoro
3 F H H
3 U H H
15 . . 3 F p-fluoro m-fluoro
3 H ~-fluoro H
4 F p-fluoro p-fluoro
: 4 F p-1uoro p-methoxy
, 4 F o-1uoro H
20 ` 4 F H H
4 F H m-methoxy
4 H ~-f;uoro H
4 H m-fluoro o-fluoro
4 H o-fluoro p-methoxy
4 H H o-methoxy
3 H p-fluoro p-fluoro
, 3 ~ o-fluoro o-fluoro
3 F m-fluoro ~-fluoro
3 H m-fluoro p-fluoro
.' I .
.
': . . .
~ 1639~
EXAMPLE 13
Separation of Diastereomers of dl trans-8-fluoro-5-(p-
fluorophenyl)-2-~4-hydroxy-4-(p fluorophenyl)butyl]-2,
3,4,~a,5,9b-hexahydro-lH-pyrido~4,3-b]indole
5 A. Five grams of the mixture of diastereomers of _-trans
8-fluoro-5-(p-fluorophenyl)-2-~4-hydroxy-4-(~ fluorophenyl)butyl]-2,
3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]indole hydrochloride provided
in Example 3 was converted to the free base by partitioning between
methylene chloride and 10% aqueous sodium hydroxide. The organic phase
was dried (~a2S04) and evaporated to a foam which was dissolved in
12.5 ml. of ethyl acetate and 45 ml. of hexane at the boiling point of
the mixture. After cooling over night, the precipitated product was
collected by filtration to obtain 2.24 g. of product, ~.P. 126-129 C.
This was recrystallized three times from ethyl acetate/hexane to give 1.22
g. of one diastereomer, designated as the a~-diastereomer, ~.P. 132-134 C.
This free ba~e was converted to the hydrochloride salt by addition of
an ethereal hydrogen chloride solution to a solution of the free base in
methanol to obtain 1.30 g., M.P. 259-260 C. High pressure liquid
chromatography analysis indicated that it was > 99% pure ~-diastereomer.
B. The mother liquor from the first crystallization, above,
was evaporated to a gum, dissolved in ethyl ether and converted to
hydrochloride salt by addition of ethereal hydrogen chloride solution.
The resulting crystalline solid was recrystallized three times from a
mixture of acetonitrile/methanol, ultimately affording 1.03 g. of the
second diastereomer, designated as the y~-diastereomer, ~.P. 237-
239 C
- 41 -
~ ~6~99~
High pressure liquid chromatography analysis of this produce
showed that it was about 95~, by weight, pure y~-diastereomer conta-
minated with about 5% of the ~-diastereomer.
EXAMPLE 14
Resolutions of diastereomers of _-trans-8-fluoro-5~~p
fluorophenyl)-2-hydroxy-4-(p fluorophenyl)butyl~-2,3,4,
4a,5,9b-hexahydro-lH-pyrido~4,3-b]indole.
A. Resolution of ~-Diastereomer into ~-Enantiomer and ~-
Enan.iomer.
A solution of 2.40 g. (5.3 mmole) of racemic ~-diastereomer,
obtained above, and 2.0 g. (7.5 mmole) of N-t butoxycarbonyl-~ phenyl-
alanine in 80 ml. of chloroform was cooled in the ice-bath yndèr a
nitrogen atmosphere. To the stirred solution was added 1.55 g. (7.5
mmole) of dicyclohexylcarbodiimide and the resulting mixture was stirred
for one hour at 0~ C. and another hour at room temperature. The pre-
cipitated solid (urea) was separated by filtration and washed with
methylene chloride. The filtrate and washings were evaporated in
vacuo and the residue was chromatographed on silica gel, eluting with
5:1 (by volume) methylene chloridelethyl acetate. The fractions con-
taining the desired esters of N t-butoxycarbonyl-L phenylalanine
were combined and evaporated in vacuo to obtain 2.5 g. of a white
amorphous foam.
To this foam was added 30 ml. of anhydrous trifluoroacetic
acid at 0 C. and the mixture stirred in an ice bath for 30 minutes
during which time solution occurred. The trifluoroacetic acid was re-
moved by evaporation in vacuo on a rotary evaporator without external
__
warming of the flask. The residual solid was dissolved in cold methy-
lene chloride and washed with cold 1% (w¦w) aqueous sodium bicarbonate
- 42 -
1 1639~)
solution until neutral to pH test paper. The neu~ral organic layer was
dried (MgS04) and the solvent was evaporated to obtain 1.6 g. of pale
yellow gum. The gum was purified by chromatography on 40 g. of
Merck 230-400 mesh silica gel eluting with 35:1 (v/v) ethyl acetate/
methanol. Fractions containing the L-phenylalanine ester of the ~-
enantiomer and those containing the _-phenylalnine ester of ~-enan-
tiomer were separated, and evaporated to dryness in vacuo to obtain
636 mg. and 474 mg., respectively.
A stirred solution of 625 mg. of the L-phenylalamine ester of
~-enantiomer in 10 ml. of methanol at room temperature was treated with
10% aqueous sodium hydroxide until cloudy and was then stirred for
30 minutes at room temperature. The methanol was removed by evapo-
ration under reduced pressure and 10 ml. of water was added. The
aqueous suspension was extracted with methylene chloride and the com-
bined organic layers were dried over magnesium sulfate. ~vaporation
of the solvent gave a pale yellow gum which was dissolved in acetone
(5 ml.) and treated with an excess of ethereal hydrogen chloride from
which the hydrochloride salt of the dextrorotatory a-enantiomer cry-
stallized as platelets, 380 mg., M.P. 251-255 C. [~]D = ~ 32.2
(C=1.67 in methanol).
Hydrolysis of the L-phenylalanine ester of the ~-enantio-
mer (474 mg. obtained above) similarly provided the levorotatory
~-enantiomer of 8-fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4-(p-fluoro-
phenyl)butyl]-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]indole hydro-
chloride, M.P. 252-255 C., [~]D = -33 0 (C=1.67 in methanol).
- 43 -
3~6 1 ~
HPLC analysis showed the a-enantiomer and the ~-anantiomer
were each of 99% or higher purity.
B Resolution of ~-Diastereomer into - and ~ Enantiomers. i
Y Y
The y~-diastereomer of trans-8-fluoro-5-~p fluorophenyl)-2-
14-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-lH-[4,3 b]
indole was reacted with ~-t-butoxycarbonyl-L phenylalanine, the re- .
sulting t-boc-L-phenylalanine ester reacted with trifluoroacetic acid
to remove the amino protecting (t boc) group, and the amino acid
esters chromatographed to separate the L phenylalanine esters of ~he
y-enantiomer and the ~-enantiomer as described in Part A above. The
separated y- and ~-esters were then hydrolyzed separately and purified
to obtain the dextrorotatory y-enantiomer and the levororatory ~-
enantiomer as the hydrochloride salts by the procedure described in ¦
Part A above.
y-enantiomer: M.P2~240-248 C. (der~)
[a]D = +3.1 (c=1.67, methanol)
~-enantiomer: ~.P2o240-248 C. (dec.)
1]D ~ -2.7 (c=1.67, methanol)
HPLC analysis showed that the y-enantiomer was about 95%
pure and the ~-enantiomer was of 977~ purity. The lower purity of these
enantiomers is expected in view of the above-mentioned contamination
of the y~-diastereomer with a~-diastereomer.
- 44 -
1~39~B
EXl~LE 15
A. D(-)-N-carbamoylphenylalanine
To a suspension of 16.52 g. (0.10 mole) D(+)-phenylalanine
in 75 ml. of water was added 12.4 g. (0.10 mole) of sodium carbonate
hydrate. To the resulting solution was added, with stirring, 12.17 g.
(0.15 mole) of potassium cyanate and the mixture was heated on the
steam bath (internal temperature 85-90 C,) for 1.5 to 2.0 hours.
After cooling in an ice bath, the reaction mixture was carefully
acidified to pH 1-2 with concentrated hydrochloric acid. The pre-
cipitate was collected by filtration, washed with ice water then with
ethyl ether to obtain 15 g. of crude product. This was recrystallized
by dissolving in 250 ml. of warm methanol, diluting with 400 ml. of
water, allowing to cool slowly to room temperature, then refrigerated
until precipitation was complete. The product was obtained as white
opaque needles in 58% yield after recrystallization, M.P. 203-204 C.
(dec.), [a]20 ~-) 40.7 (methanol).
B. L(+)-N-carbamoylphenylalanine
Employing L(-)-phenylalanine in the above procedure in place
of the D(+)-isomer afforded L(~)-N~carbamoylphenylalanine in 42%
yield after recrystallization, M.P. 205-207 C. (dec.), ta]D (+)
39.0 (methanol).
- 45 -
1 1~3g~
EXA~IPLE 16
Resolution of dl-trans-8-fluoro-5-~-fluorophenyl)-2,3,4,
4a,5,9b-hexahydro-lH~p~rido[4,3-b]indole.
A. Resolution of Enantiomeric N-carbamoylphen~lalanine Salts.
1. To one equivalent of dl-trans 8-fluoro-5-(p-fluorophenyl)
-2,3,4,4a,5,9b-hexahydro-lH-pyrido~4,3-b]indole free base dissolved in
a minimum amount of ethanol was added one equivalent o L(+) N carba-
moylphenylalanine. The mixture was heated on a steam bath whilP
adding additional ethanol until a homogeneous solution was obtained.
The solution was allowed to cool ~o room temperature and the pre-
cipitated white needles of the L(+) N carbamoylphenylalanine salt of
the (-) enantiomer of the free base were collected by filtration and
dried, M.P. 207-209 S., ~a]D - 5.9 methanol.
2. The ~other liquor from above was evaporated to dryness,
the residue partitioned between aqueous sodium carbonate and ethyl
acetate, the organic layer dried over magnesium sulfate and evaporated
in vacuo to afford a residual oil. The oil was dissolved in a small
amount of ethanol and treated with one equivalent of D(-)-N-carbamoyl-
phenylalanine. The mixture was warmed on the steam bath while adding
more ethanol until solution was complete. The solution was cooled
and worked up as above to afford a 92% yield of crude D(-)-N-carba-
moylphenylalanine salt of the (~) enantiomer of the free base. This
was recrystallized from ethanol (75 ml./g.) in 65% overall yield, ~.P.
209-211 C., ra]D = + 6.6 (methanol).
- 46 -
~ 163~
B. Isolation of Enanantiomeric Free Base Hydrochloride Salts.
1. The enantiomeric N-carbamoylphenylalanine salt obtained
in Part A, 1 was partioned between aqueous saturated sodium bicarbonate
and ethyl acetate, the organic layer dried over magnesium sulfate
and concentrated in vacuo without heating. The residual oil was dis-
- solved in anhydrous ethyl ether (50-100 m~./g.) and dry hydrogen
chloride gas is passed over the surface of the solution with swirling
to afford a white precipitate. The excess hydrogen chloride and ether
are removed by evaporation at reduced pressure and ambient temperature
to give (-)-trans-8-fluoro-5~ fluorophenyl)-2,3,4,4a,5,9b-hexahydro-
lH-pyrido[4,3-b]indo'e hydrochloride in about 96% yield. This was
recrystallized by dissolving in a minimum amount of boiling ethanol,
and addition of ethyl ether until the solution becomes turbid. The
product was obtained as small white crystals (75% recovery), M.P.
258-260 C., ~]D0 (~)40 9 (methanol).
- 2. In the same manner, (+) trans 8-fluoro-5-(~ fluoro-
phenyl!-2,3,4,4a,5,~b-hexahydro-lH-pyrido~4,3-blindole was obtained
from the salt provided above in Part A,2, in 96% crude yield and 75%
recovery upon recrystallization, M.P. 260-262.5 C., [~]2 (+)39.2
(methanol).
- ~7 -
~ lS3~
EX~MPLE 17
Resolution of dl-4-hydro~y-(p-fluorophenyl)-butyric acid.
A. Commercial y-(p-fluorophenyl)-y-butyrolactone~ 18.0 g.
(0.10 mole) was added to a solution of 14.0 g. (0.35 mole) of sodium
hydroxide in 100 ml. of water and the mixture heated at reflux for 40
minutes. After cooling to 0 C., 70 ml. of 6N~hydrochloric acid was
added at 0-15 C. for one hour. The white solid which formed was fil-
tered, washed with pentane and air dried to afford racemic-4-hydroxy-
4-tp-fluorophenyl)butyric acid, 18.43 g., (93% yield). When heated
to temperatures of about 100 C., the hydroxy acid was converted back
to the starting lactone.
B. The hydroxy acid obtained above, 18.43 g. (0.093 mole)
was dissolved in 200 ml. of ethyl acetate with gentle ~arming and to the
solution was added a solution of 15.04 g. (0.91 mole) of d-ephedrine,
L~]s78 = (+)11-4 (acetone), in 80 ml. ethyl acetate. The mixture was
stirred at room temperature over night during which timP a crop of
crystals formed, was removed by filtration and air dried to obtain
18.3 g., M.P. 97-99 C. This material was recrystallized by dissolving
it in a minimum amount of hot ethyl acetate and allowing to stand at
ambient temperature over night. After three such recrystallizations,
8.9 g. of the d-epedrine salt of 1-4-hydroxy-4-(~ fluorophenyl)butyric
acid, M.P. 105.5-106.5 C, was obtained.
This product was taken up in a mixture of lce cold 5%
hydrochloric acid (300 ml.) and ethyl acetate ~150 ml.), the aqueous
phase extracted five times with 100 ml. portions of cold ethyl
- 48 -
~ 1639~
acetate, the combined organic extracts washed with saturated brine and
dried ~MgS04). The solvent was evaporated in vacuo to a small volume
to obtain 3.8 g. of the l-enantiomer as crystals, ~. P. 98-104~ C.,
[~]578=(-)32.6. Upon recrystalliæation from methylene chloride,
the optical rotation was [~]578= (-)33.4C. An additional 0.4 g.
of product was obtained from the combined filtrates from the three
crystallizations above.
C. The first filtrate from Part B above was evaporated to dry-
ness in vacuo to obtain 15.5 g. of residue which was taken up in a
mixture of cold 5% hydrochloric acid and ethyl acetate and the aqueous
phase extracted with fresh ethyl acetate. The combined organic layers
were dried (MgS04) a~d solvent evaporated to obtain 8.19 g. (0.040
mole) of hydroxy acid. This was taken up in fresh ethyl acetate
(lOOml) and a solution of 6.60 g. (0.040 ml.) of l-ephedrine in 50
ml. of ethyl acetate was added. The mixture was stirred over night
at room temperature and the precipitated salt recovered by filtration
and air dried, 12.2 g., M.P. 101-104 C. The salt was recrystallized
four times from ethyl acetate to obtain 8 2 g. of the l-ephedrine salt
of d-4-hydroxy-4-(~-fluorophenyl) butyric acid , M.P. 105.5-107 C.
This salt was decomposed by treatment with ice cold 5% hydrochloric
acid and ethyl acetate as described in Part B above, to provide 4.0
g. of the d-hydroxy acid, M.P. 98-104 C., [~]578=(+) 33.1~.
- 49 -
~ ~S39~
EXAMPLE l$
d(+)-and l(-)-y(~-Fluorophenyl)-y-b~ltyrolactone
A. lt-)-4-hydroxy-4-(p-fluorophenyl) butyric acid provided in
Part B of Example 17, (250 mg., 1.26 mmole) was dissolved in 15 ml.
of ethyl acetate and several crystals of p-toluenesolfonic acid was
added. The mixture was heated at reflux for 25 minutes, cooled to room.
temperature, washed with saturated brine and dried (MgS04). The solvent
was evaporated to yield 216 mg. (91%) of the l-lactone as a white solid,
M.P. 52-54 C., la]578 = (-)4Ø
B. d(~)-4~hydroxy-4-(p-fluorophenyl) butyric acid when treated
in the same manner afforded the d-lactone, ~]578 = (+)4 3
.
EXANPLE 19
5-(p-Pluorophenyl)-2-hydroxytetrahydrofuran
A. To a solution of 594 mg. (3.0 mmole) of d(~)-4-hydroxy-4-
(p-fluorophenyl) butyric acid, [~]578 = 33.1 (acetone). in 25 ml. of
ethyl acetate was added 10 mg. of p-toluenesulfonic acid hydrate and
the mixture heated at reflux for 30 minutes. The solvent was evaporated
in vacuo, chasing the last traces of solvent with 20 ml. of toluene.
The residual lactone was taken up in 30 ml. of fresh toluene and
cooled under a nitrogen atmosphere to -74 C. by means of a dry ice/
acetone bath. ~o this was added~ dropwise over a 30 minute period,
4.2 ml. (3.3 mmole) of 0.804 M diisobutylaluminum hydride (Dibal)
in hexane while maintaining the mixture below -72 C. The reaction
- 50 -
~ 1639~
mixture was stirred for an additional 30 minutes at -72 to -74 C., quenched
with methanol and warmed to 0 C. The solvent was evaporated in vacuo, resi-
due triturated four times with boiling methanol and the methanol filtered.
The combined methanol extracts were evaporated to a viscous pale yellow oil
which was one spot by TLC. It was used as an intermediate without further
purification.
B. Levorotatory 4-hydroxy-4-(p-fluorophenyl) butyric acid obtained
above in Example 17 and the commercially available racemic compound were con-
verted, respectively, to the corresponding enantiomeric and racemic title
compounds by the procedure of Part A.
EXAMPLE 20
Starting with the appropriate d-, 1-~ or dl-4-hydroxy-4-arylbutyric
acid or 5-hydroxy-5-arylvaleric acid, or the corresponding lactone, in the
procedure of Example 19, Part A, provides the following compounds in like
manner.
~ ~CH2)q
Zl ~ ~ OH
~hen q is 1: When q is 2:
Zl Z
H H
o-F p-F
m-F o-F
p-OCH3 p-OCH3
m-OCH3 m-OCH3
~ ~3~
The requisite 6-aryl-6-hydroxyvaleric acid lactones are prepared
by the method of Colonge, et. al., Bull, Soc. Chim. France., 2005-2011
(1966); Chem. Abstr., 65, 18547d (1966).
EXAMPLE 21
Chiral synthesis of enantiomers of 8-fluoro-5-(~-fluoro-
phenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl-2,3,4,4a,5,
9b-hexahydro-lH-pyrido[4,3-b]indole
u-Enantiomer
5-(p-fluorophenyl)-2-hydroxyte~rahydrofuran obtained from d(+)-4-
hydroxy-4-(~-fluorophenyl) butyric acid in Example 19, Part A, 230 mg., was
dissolved in 30 ml. of methanol. Dextrorototary 8-fluoro-5-(p-fluorophenyl)-
2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b~indole free base, 404 mg. (1.25
mmole) was added, the mixture stirred for 15 minutes, 150 mg. of 10% pal-
ladium-on-carbon catalyst was added and the stirred mixture hydrogenated at
atmospheric pressure. When hydrogen uptake ceased, the catalyst was removed
by filtration and the solvent evaporated in vacuo. The residue was parti-
tioned between ethyl acetate and 10% aqueous sodium hydroxide. The aqueous
layer was extracted again with ethyl acetate, the combined extracts dried
(MgS04) and evaporated to dryness in vacuo. The residue was chromatographed
on 20 g. of silica gel and eluted with ethyl acetate. The fractions contain-
ing the desired product were combined, evaporated to dryness, taken up in
ethyl ether and converted to hydrochloride salt by addition of ethereal hy-
drogen chloride. Yield, 144 mg., M.P. 248-252 C., [~]D = (+)30.1
(methanol). 97.5% pure by high
1 lS399~
pressure liquid chromatography analysis.
~-Enantiomer
To a solution of 53 mg. (0~95 mmole) of potassium hy-
droxide in 50 ml. of methanol under a nitrogen atmosphere was added
613 ml. (1.90 mmole) of levorotatory 8-fluoro-5-(p-fluorophenyl)-2,3,
4,4a,5,9b-hexahydro-1~-pyrido[4,3-b~indole hydrochloride, ~]D =
(-)40.9 (methanol) and the mixture stirred until solution was co~plete.
To the solution was added 346 mg. (1.90 mmole) of levorotatory 5-
~p-fluorophenyl)2-hydroxytetrahydrofuran (from Example 19, Part B),
dissolved in a small volume of methanol and the resulting solution
stirred for 15 minutes at room temperature. The solution was cooled
to 5 C. and 120 mg. (1.90 mmole) of sodium cyanoborohydride in a
small amount of methanol was added over 20 minutes. The reaction
mixture was stirred at room temperature for 45 minutes, then 250 mg.
of potassium hydroxide was added and stirred until dissolved. The
solvent was evaporated in vacuo and the residue partitioned between
ethyl acetate and water. After reextraction of the aqueous phase, the
combined organic extracts were dried (~IgS0~) and evaporated in vacuo to
provide 1.014 g. of oil. This was chromatographed on 30 g. of silica
gel as described above to obtain 653 mg. of the desired product as an
oil. The oil was converted to the hydrochloride salt, as above, 400
mg., M.P. 252-257 C. (dec.), [a]D = (-)33.7 (methanol) which was
found to be 99% pure ~-enantiomer by HPLC. Reworking the mother liquors
afforded 80 mg. of a second crop, M.P. 254-258 C. (dec.). Total yield
56%.
- 53 -
~ ~63~
y-Enantiomer
In 23 ml. of methanol were dissolved 2.07 mg. (6.4 mmole) of d~+)-
8-fluoro-5-~-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]indole
hydrochloride, [~]D0 (+)39, and 1.3 g. (7.1 mmole) of levorotatory 5-(p-
fluorophenyl)-2-hydroxytetrahydrofuran and the solution stirred under a ni-
trogen atmosphere at room temperature for 15 minutes. Five percent pal-
ladium-on-carbon catalyst, 300 mg., was added and the mixture hydrogenated at
atmospheric pressure for 3 hours. The reaction mixture was worked up as de-
scribed above for the ~-enantiomer to obtain 2.4 g. of crude product as a
yellow foam. The foam was dissolved in 40 ml. of acetone and this was added
to 20 ml. of ethyl ether saturated with hydrogen chloride. The mixture was
filtered after standing at room temperature for two hours to obtain 980 mg.
of hydrochloride salt. The filtrate was evaporated to provide 1.7 g. of
foam. These were chromatographed separately on silica gel and the product
fractions treated again with hydrogen chloride to obtain, respectively, 140
mg., [~]D = ~+)1.4 (methanol) and 800 mg., [~]D = (+)1.7 (methanol). Both
crops had a melting point of 254-256 C. Each were found to be 98% pure y-
enantiomer by HPLC.
~-Enantiomer
1(-)-8-Fluoro-5-(_-fluorophenyl) 2,3,4,4a,5,9b-hexahydro-lH-pyrido-
[4,3-b]indole hydrochloride, [~]D = (~)40 9~ (968 mg., 3.0 mmole) and an
equimolar amount of dextrorotatory 5-(~ fluorophenyl) 2-hydroxytetrahydro-
furan obtained by the procedures of Example 16, Part B-l and Example 19, Part
B, were reacted by the procedure
- 54 -
.~
~ ~ ~39~i
described above for the a~enantiomer to provide 1300 ~g. of crude
~-enantiomer as a pale yellow gum. The gum was converted to hydro-
chloride salt, 835 mg., t57%), M.P. 240-250~ C. This was chromatographed
on 30 g. of silica gel and the eluted product fraction evaporated
and again treated with ethereal hydrogen chloride to provide 610 mg.,
M.P. 257-260 C., [a]D = (-)2.7 (methanol) which assayed 98%
pure by EPLC.
EXAMPLE 22
Employing the procedure of Example 16, the following dl-
trans-5-aryl-2,3,4,4a,5,9b-hexahydro-lH~pyrido[4,3-b~indoles were
each resolved into dextrorotatory and levorotatory enantiomers and
isolated as the hydrochloride salt.
Xl ~CI
Xl Yl y
H H
H ~-F
H o-F
F H
F o-F
F m-F
- 55 -
~ ~ ~3~9~
EXAMPLE 23
Starting with the racemic or enantiomeric 5-aryl-2,3,4,4a,5,9b-
hexahydro-lH-pyrido[4,3-b]indole hydrochlorides provided above and the d-,
1- or dl- isomer of a 5-aryl-2-hydroxytetrahydrofuran or 6-aryl-2-hydroxy-
tetrahydropyran, each of the enantiomers and diastereomers of the following
formula are prepared by the procedure of Example 21.
Xl ~C~(cll2)n--CIH~il
~1
When n is 3: When n is 4:
Xl Yl Zl Xl Yl Z
H H H F H H
H H p-F F H m-OCH3
H H p-OCH3 H p-F H
F p-F m-F H m-F o-F
F p-F o OCH3 H H o-OCH3
F H p-F H p-F p-F
H p-F p-OCH3 H o-F o-F
H o-F m-OCH3 F p-F p-F
F H H F p-F p-OCH3
F o-F H
H H H
- 56 -
~ t ~39~
When catalytic amounts of platinum~ rhodium, ruthenium or
Raney nickel catalyst are employed in place of palladium catalyst, and
the reductive alkylation described in Example 21 for the ~-enantiomer
is carried out at temperatures of from -10 C. to 50D C. and at
S pressures of from atmospheric pressure up to 10 atmospheres employing
the above-mentioned lactols and 5-aryl-2,3,4-4a,5,9b-hexahydro-lH-
pyrido[4,3-b]indoles, the above compounds are obtained in a like
manner.
When the reductive al~ylation employing the above reactants
are repeated, but employing sodium cyanolborohydride as the reducing
agent as described in Example 21 for the ~-enantiomer and reaction
temperatures of from -10 C. to 50 C., the above products are simi-
la~ly obtained.
- 57 -
~fi~9~
EXAMPLE 24
When each of the compounds provided in Examples 21 and 23 are oxi-
dized by the procedure of Example 10, the product obtained is of the follow-
ing structure.
l ~C~N ~ CH2 ) n ~ Z
~\Yl
When the starting alcohols of formula (I,IM=CHOH) have been derived from a
dextrorotatory or levorotatory 5-aryl-2,3,4,4a,5,9b-hexahydro-lH-pyrido-
[4,3-b]indole, the above products are obtained with retention of configura-
tion in the pyrido[4,3-b]indole moiety as evidenced by the optical rotation
of the products. Starting alcohols of formula ~l,m=CHOH), wherein, for ex-
ample, the pyrido[~,3-b]indole moiety is dextrorotatory and the 2-substituent
is either d-, 1 or dl, afford the same product.
- 58 _
,
~ ~3~96
EXAMPLE 25
A. dl-trans-8-Fluoro-S-(p-fluorophenyl) 2-r4-bydroxy-4-(p-
fluorophenyl(butyl]-2,3,4,4a,5,9b-hexahydro-lH-pyrido
~4,3-b]indole acetate
Five grams of dl-trans-8-fluoro-5-(p-fluorophenyl)-2-~4-
hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-lH-pyrido
~4,3-b]indole hydrochloride in 75 ml. of water is treated with 3 ml.
of water containing 1.0 g. of sodium hydroxide, and the liberated
free base extracted into 150 ml. of diethyl ether. The ether layer
is separated, dried over magnesium sulfate and treated with 1 ml. of
glacial acetic acid. The organic solvent and excess acetic acid
are removed under reduced pressure and the residue triturated with
hexane and filtered.
B. Enantiomeric trans~-8-Fluoro-5-(p fluorophenyl) 2-~4-hydroxy-
4-(p-fluorophenyl)butyl]-2,3,4,4a~5,9b-hexahydro-lH pyrido
[4,3-b]indole citrate
The hydrochlride salt of the y-enantiomer of the title com-
pound provided in Example 21 was converted to free base by the above
procedure. The ether was evaporated and the free base taken up in
ethanol. To the ethanol solution was added an equimolar amount of
anhydrous citric acid dissolved in ethanol and the resulting mixture
stirred for 15 minutes. The solvent was removed in vacuo to provide
the citrate salt.
In a similar manner pharmaceutically acceptable acid addition
salts are obtained by employing hydrobromic, sulfuric~ phosphoric,
maleic fumaric, succinic, lactic, tartaric, gluconic, saccharic or
p-toluenesulfonic acid and one of the compounds of formula (I) by
the above procedures.
- 59
~ 1~3~9~
EXAMPLE 26
Antagonism of ~mphetamine Stereotype in Rats
Test Procedures and Result_
The effects of the compounds of the present invention on prominent
amphetamine-induced symptoms were studied in rats by a rating scale modeled
after the one reported by Quinton and Halliwell, and Weissman. Groups of
five rats were placed in a covered plastic cage measuring approximately 26
cm. x 42 cm. x 16 cm. After a brief period of acclimation in the cage, the
rats in each group were treated subcutaneously ~s.c.) with the test compound.
They were then treated 1, 5 and 24 hrs. later with d-amphetamine sulfate, 5
mg./kg. intraperitoneally ~i.p.). One hour after amphetamine was given each
rat was observed for the characteristic amphetamine behavior of moving around
the cage. On the basis of dose-response data after amphetamine it was pos-
sible to determine the effective dose of the compound necessary to antagonize
or block the characteristic amphetamine behavior of cage movement for fifty
percent of the rats tested ~ED50). The time of rating chosen coincides with
the peak action of amphetamine which is 60-80 min. after treatment with this
agent.
Employing the above-described procedure, the following 4a,9b-trans
compounds were tested for their ability to block the behavior effects of
amphetamine, the results being reported as the ED50 in mg./kg. at the indi-
cated times:
~J
~Yl
- 60 -
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- 62 -
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EXAMPLE 27
Inhibitors of 3H-Spiroperidol Binding to Dopamine RecePtors
.
Test Procedures and ~esults
The relative affimity of drugs for dopamine binding sites have
been shown to correlate with their relative pharmacological potencies
irl affecting behavior presumably mediated by dopamine receptors, see
e.~., Burt et.al., ~lolecular Pharmacol., 12, 800-812 (1976) and re-
ferences c~ted therein. A superior binding assay for neuroleptic
receptors has been developed by Leyson et. al , Biochem Pharmacol ,
27, 307-316 (1978) using 3H-spiroperidol (spiperone) as the labeled
ligand. The procedure used was a follows:
Rats (Sprague-Dawley CD males, 250-300 g., Charles ~iver
Laboratories, Wilmington, MA) were decapitated, and brains were immed-
iately dissected on an ice-cold glass plate to remove corpus striatum
(~lO0 mg.lbrain). Tissua was homogenized in 40 volumes (1 g. + 40 ml.)
of ice-cold 50 mM. Tris (tris ~hydroxymethyl]aminomethane; tT~U~'I) HCl
buffer pH 7.7. The homogenate was centrifuged twice at 50,000 g.
(20,000 rpm) for 10 minutes with rehomogenization of the intermediate
pellet in fresh THAM buffer (same volume). The final pellet was
gently resuspended in 90 volumes of cold, freshly prepared (<1 week
old) 50 mM Tris buffer pH 7.6 containing 120 m~l NaCl (7.014 g./l.),
5 ~ ~Cl (0.3728 g./l.), 2 mM CaCI2 (0.222 g.ll.)~ 1 n~l MgCl2
(0.204 g.¦l/), 0.1% ascorbic acid (1 mg./ml.) and lO ~M pargyline
(100 ~1. stock/lO0 ml. buffer; stock = 15 mg./10 ~1. DDW). Ascorbic
- 66 -
~ ~i399~
acid and pargyline were added fresh daily. The tissue suspension was
placed in a 37 C. water bath for 5 mlnutes to insure inactiva.lon
of tissue monoamine oxidase and then kept on ice until used. The
incubation mixture consisted of 0.02 ml. inhibitor solution, 1.0 ml.
tissue homogenate and 0.10 ml. label t3H--spiroperidol, New England
Nuclear 23.6 Ci/mmole), prepared so as to obtain 0.5 nM in the final
incubation mediu~ (usually diluted 2.5 ~1. stock ~ 17 ml. DDW**).
Tubes were incubated in sequence for 10 minuees at 37 C. in groups of
three, after which 0.9 ml. of each incubation tube was filtered through
~natman GF/B filters using a high vacuum pump. Each filter was placed
in a scintillation vial, 10 ml. of li~uid scintillation fluor was
added and each vial was vigorously vortexed for about five seconds.
Samples were allowed to stand over night, until filters were trans-
lucent, vortexed again and then counted 1.0 minute for radioactivity.
Binding was calculated as fentamoles (10 15 moles) of 3H-spiroperidol
bound per mg~ protein. Controls (vehicle or 1 butaclamol, 10 7M;
4.4 mg. dissolved in 200 ~1. glacial acetic acid, then diluted to
2.0 ml. with DDW for 10 4M stock solution, kept refrigerated), blank
(d-butaclamol, 10 7M; 2 4 g for 10 4~1 stock solution, same protocol
as l-butaclamol), and inhibitor solutions were run in triplicate.
The concentration reducing binding by 50% (IC50) was estimated on
semi-log paper. Insoluble drugs were dissolved in 50~ ethanol ~1
ethanol incubation).
**DDW = Double Distilled Water.
- 67 -
1 1~3~
The results obtained with the various forms o:~ trans 8-fluoro-5-(~-
fluorophenyl)-2- [4-h~rdroxy-4~p-:LCluorophenyl)butyl]-2~3~4~4a~5~b-hexahydro-
lll-pyrido[4,3-b]indole hydrochloride are summarized in the table below.
Inhibition of H-Spiroperidol
Compound Binding, mM IC50
.
r~lixed c~ and y~ diastereomers 21
of Example 3
c~-diastereomer of Example 13 23
Dextrorotatory ~-enantiomer 22
of Example 14
Levorotatory ~-enantiomer1800
of Example 14
yô-diasteriomer of Example 13 23
Dextrorotatory y-enantiomer 25
of Example 14
Levorotatory ~-enantiomers350
of Example 14
- 68 -
