Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
o ~ ~
This is a divisional application of Serial No. 343,988 filed
on danuary 18, 1980.
The parent application relates to certain trans-2-substituted-5-
aryl-2,3,4,4a,5,9b-hexahydro-lH-pyrido ~4,3-~ indole derivatives useful
as tranquilizing agents, a process for their production.
This application relates to novel 5-aryl-2-hydroxytetrahydrofuran
derivatives which are useful as intermediates for producing the compounds
of the parent application.
.
q~
-- 1 --
7`
Following the introduction of reserpine and chlorpromazine in
psychotherapeutic medicine in the early l950's, great effort has been expended
in the search for other tranquilizing agents havin~ improved biological
profiles, several of which are y-carboline derivatives, also known in the art
as derivatives of pyrido[4,3-b]indole.
In U.S. 3,687,961 8-fluoro-2-~3-(4-fluorophenylanilino)propyl]-
1,2,3,4-tetrahydro-y-carboline was disclosed as a useful tranquilizer for warm-
blooded animals. In U.S. 3,755,584 structurally related compounds with fluorine
in the 6- or 8-positions and a specific ~-substituted phenylal~yl moiety at
the 2-position were found to have similar activity.
U.S. 3,983,239 discloses hexahydro-y-carbolines of the formula
~- (CH2) 3CO~F
. l2
where R 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 not mentioned in ~his reference. However, one would
expect them to be in a cis relationship based on the meehod of formation
of the hexahydro-y-carboline nucleus-from a 1,2,3,4-tetrahydro-y-carboline
; precursor by catalytic hydrogenation in the presence of platinum, a method
well ~nown 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 useful in the treatment of schizophrenia.
Q~,'
U.S. 3,991,199 discloses hexahydropyrimido~4,3-b]indoles,
useful as analgesics and sedatives, some of which are of interest as
tranquilizers, some as mucle relaxants and many of them show hypoten-
sive actlvity; the compounds disclosed are of the formula
xa~N-Ra
and their pharmaceutically suitable salts, where the hydrogens attached
to the carbon atoms in the 4a and 9b positions are in trans relation-
shlp to each other and where: when ya i8 -H, -Cl, -Br, -CH3, -tert-
C4Hg or -OCH3; and when ya is -CF3, Xa i8 -H; and Ra ls, inter alia,
hydrogen, benzyl; benzyl ring-substituted with methyl, methoxy or
chloro; phenehtyl; 3-phenylpropyl; 3-phenylpropyl riDg-substituted with
chloro, bromo or methoxy.
~3
.
_ .
' o ~
Recently issued Belgian 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 useful
as antidepressants.
Recent West German Offenlegungsschrift 2,631,836, Derwent No.
09738Y, discloses structurally related octahydropyrido~4',3':2,~indolo
[~,7-al~[l~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 is -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-y-carboline
tranquilizers of the formula
b
\~,~ N_Rb
~ N~J
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 has
unexpectedly been found that the trans-2,3,4,4a,5,9b-hexahydro-lH-pyrido
r4 3-1~ indoles of the parent-application have markedly superior tranquili-
zing activity when compared with the corresponding 1,2,3,4-tetrahydro-y-
2Q carbolines.
-- 4 --
~1~4~Q
The valuable tranquilizing agents of the parent application are
the 2-substituted-5-aryl-2,3,4,4a,5,9b-hexahydro-lH-pyrido ~4,3-~ indoles
of the formula
Xl ~ l - (CH2)n -M ~
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 fluoro; 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-b] indole
moiety" is meant the moiety of the formula A
Xl ~ N-
(A)
\
Yl,
wherein the hydrogens attached to the carbon atoms in the 4a and 9b
1~4~û.
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 ofsaid dextrorotatory andlevorotatory moieties, including the
racemates, are of intermediate activity.
The present invention provides new enantiomeric and racemic
compound of the formula
~OJ~
Zl ~ OH
wherein Zl is fluoro, and a process for preparing the compounds by
reducing a corresponding lactone of the formula
Zl~
with a metal hydride.
The compounds of the parent application have a markedly and
unexpectedly superior tranquilizing effect over the above mentioned
tranquilizing agents of the prior art.
~'6'1~Q,
A method for providing the enantiomeric compounds of formula (II)
is by stereospecific synthesis in which the resolved enant;omers of a
tricyclic secondary amine of formula (VIII) are condensed with an enantio-
meric precursor of the 2-position substituent. In order to effect stereo-
specific 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
reactans are employed.
~ ~ H ~ ~ o3 ~ ~f ~ (CH2)3-CH -
10 ~ ~
Yl Yl
(VIII) (XIV) (II)
In the above reaction scheme, Xl, Yl and Zl are as previously defined.
~ ~6~Q i
The optical isomers of amine (VIII) are obtained by resolution
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., " Reagents for Organic Synthesis",
Wiley & Sons, Inc., New York, (1967), Vol. I, p. 977 and references cited
therein, 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-carbamoylphenylalanines,
for example the L-isomer, with a racemic compound of formula (VIII)
in equimolar amounts in the presence of a suitable 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 desired. 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 hydroxide or calcium carbonate and the free base extracted by
means of a water imiscible 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 N-carbamoylphenylalanine salt of
the second isomer of formula (VIII) .
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).
The five membered lactols (XIV) are novel compounds, and may be
pr~pared from the known compounds of the formula (XI) or the corresponding
nitriles as shown below, wherein Zl is as defined above.
Z~C6H4,C, (CH2)2COOH ZlC6H41CH (CH2)2cooH
OH
(XI ) (XI I )
Zl C6H4 ~ Zl C6H4 /~OH
(XIII) (XIV)
Q1'
The ketoacid of formula ~XI) is reduced conveniently, e. ~.,
by means of sodium borohydride by methods known to those skilled in
the art to provide the corresponding hydroxy acids of formula (XII) (or
the corresponding nitrile if cyanoXetones corresponding to (XI) are
employed, followed by hydrolysis of the hydroxynitrile to provide
the hydroxy acid). The hydroxy acids are readily converted to lactones
(XIII) by warming under dehydrating conditions, preferably in the
presence of a reaction inert solvent, typically ethyl acetate, and in
the presence of a catalytic amount of acid, typically p-toluenesul-
fonic acid. The reaction mixture is ordinarily heated at reflux forabout one hour, cooled, washed with brine, dried and the lactone
j isolated by evaporation of solvent.
The lactone (XIII) is reduced by means of a metal hydride
reducing agent to provide the lactol of formula ~ . While a variety
of metal hydride reducing agents may be employed with some success to
provide the desired lactols, preferred reducing agents are diisobutyl-
aluminum hydride, sodium borohydride~ lithium borohydride and the
former is especially preferred. The reaction is carried out in the
presence of a reaction inert organic solvent and a reaction inert gas
such as argon or nitrogen. When the preferred diisobutylaluminum
hydride is employed as reducing agent, the reaction is carried out at
a temperature of from about -80 to -70 C. Approximately equimolar
a unts of the two reactants are employed. The reaction is ordinarily
complete in a few hours or less. The reaction mixture is quenched
- 10 -
~ ~ 6 ~
by addition of a lower alkanol, e. ~., methanol, warmed to a
temperature near room temperature and the solvent evaporated in vacuo
and the lactol isolated by standard methods which will be known to
those skilled in the art.
As mentioned above, when enantiomeric compounds of formula
(II) are desired by the reaction of amine (VIII) and lactol (XIV),
resolved reactants are required. In order to obtain resolved isomers
of ~ ), the resolution of the corresponding racemic hydroxyacid
precursors of formula ~XII) is carried out.
The resolution of racemic hydroxyacids ~__) is carried out
in a manner analogous to that described above for the resolution of
amine~ (VIII), e. g., by fractional crystallization of the salts em-
ploying first e. ~., d-ephedrine to precipitate one isomer of (XII);
the othèr iComer of ( ~ iq then precipitated with the antipode of
ephedrine and the two salts decomposed to obtain the dextrorotatory and
levorotatory i~omers of ( ~ , each of which is converted to lactol
( ~ as de~cribed above. For the synthesis of each of the enantiomers
of formula (~ equimolar amounts of the resolved reactants of formula
(VIII) and ( ~ 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 Hydrogenation Over Platinum Metals", Academic Press,
New York~ 1967, p.291-303. The the reaction may be effected with
a wide variety of reducing agents known to be useful for reductive
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
S cyanoborohydride, sodium borohydride and lithium 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 ln 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 i~ert organic solvent at a temperature of from about -10 to
50 C. When the preferred reducing agent is sodium cyanoborohydride,
at least an equivalent amount is employed. ~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 a~mospheres 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
- 12 -
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
al~anols, 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 ~~methoxyethanol and diethyl-
eneglycol monomether ether.
While the reaction may be carried out with some success at
temperatures of from about -~0 up to the reflux temperature of the
solvent, preferred reaction temperature is from about -lO to 50 C.
for reasons of convenience and efflciency. At hlgher 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 from 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 amlne (VIII) and racemlc
lactol (XIV) in the above procedure. The product obtained, of formula
~ ~(II), is optically active due to the chirality of the a~ine moiety (A),
; defined above. It is a highly active tranquili~ing agent and also
- 13 -
~ ~ ~A~`O ''
serves as an economical intermediate for oxidation to the ketonic
products.
The requisite 3-benzoylpropionic acids (XI) are either
commercially available or prepared by modification of the procedure of
"Organic Synthesis", Coll. Vol. 2, John Wiley & Sons, New York,
NY, 1943, p. 81.
- 14 -
~ 164~
The following exa~ples are provided solely for the purpose
of illustration and are not to be construed as limitations of the in-
vention, ~any variations of which are possible without departing
fro= the spirlt of scope thereof.
'
:~ :
- 15 -
~ ~4~,
E~AMPLE 1
-
dl-trans-2-benzyl-2,3,4,4n,5,9b-hexahydro-5-phenyl-lH-pyrido-
[4,3~b]indole_Hydrochlor _e
To a solution of 0.140 moles of borane in 150 ml. of tetrahydrofuran
stirred at 0 C. in a three-necked round bottom flask fitted with magnetic
stirrer, thermometer, condenser and addition funnel, and maintained under a
nitrogen atmosphere, was added a solution of 23.9 g. (Q.071 mole) of 2-benzyl-
5-phenyl-1,2,3,4-tetrahydropyrido[4,3-b]indole in 460 ml. of dry tetrahydro-
furan. The addition was carried out at such a rate as to maintain the reac-
tion temperature below 9 C. When the addition was completed the resulting
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 whi~h
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 hydrochloric
acid. The resulting suspension was heated at reflux for one hour, then
cooled. Evaporation of tetrahydrofuran and part of the acetic acid resulted
in precipitation of a white solid which was separated by filtration and
washed with water. The solid was resuspended in tetrahydrofuran, filtered,
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 appropriate-
ly 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.
- 16 -
.,~ ,~
~., S ~ Ci O ~,'
X 9b
CH2C6H5
X Y X Y
H p- fluoro H o- fluoro
F H F m-fluoro
F _- 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 hy-
drochloride of the desired product, 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.
~ ~ 6~
EXA~LE3
A. D(-)-N-carbamoylphenylalanine
To a suspension of 16.52 g. (0.10 mole) D(+)-phenylalanine
in 75 ~. of water was added 12.4 g. (0.10 mole) of sodium carbonate
S 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 58Z yield after recrystallization, M.P. 203-204 C.
(dec.), [a]20 (-) 40.7 (methanol).
B. L~+)-N-carbamoylphenylalanine
Employir.g L(-)-phenylalanine in the above procedure in place
of the D(+)-isomer afforded Lt+)-N~carbamoylphenylalanine in 42%
yield after recrystallization, M.P. 2G5-207 C. (dec.), 1]D (+)
39.0 (methanol).
- 18 -
a~l~
EX~LE 4
Resolution of dl-trans-8-fluoro-5-(p-fluorophenyl)-2,3,4,
4a?5,9b-hexahydro-lH~Pyrido[4,3-b]indole~
A. Resolution of Enantiomeric N-carbamoylphenylalanine Salts.
1. To one equivalent of _ -trans 8-fluoro-5-(p-fluorophenyl)
-2,3,4,4a,5,9b-hexahydro-lH-pyridot4,3-b]indole free base dissolved in
a minlmum amount of ethanol was added one equivalent of L(+) N carba-
moylphenylalanine. The mixture was heated on a steam bath while
adding additional ethanol until a homogeneous solution was obtained.
The solution was allowed to cool to room temperature and the pre-
cipitated white needles of the L(+) N carbamoylphenylalanine salt of
the (-) enantiomer of the free base were co}lected by filtration and
dried, M.P. 207-209 C., ~a]D ~ 5.9 methanol.
2. The mother 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.lg.) in 65~ overall yield, M.P.
20~-211 C., ¦a]D = ~ 6,6~ (methanol).
_ 19_
a,
B. Isolation of Enanantiomeric Free Base Hydrochloride Salts.
l. The enantiomeric N-carbamoylphenylalanine salt obtained
in Pairt A, l was partioned between aqueous saturated sodium bicarbonate
and ethyl acetate, the organic layer drled over magnesium sulfate
and concentrated in vacuo without heating. The residual oil was dis-
solved in anhydrous ethyl ether (50-100 ml./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-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-
lH-pyrido[4,3-b]indole hydrochloride in about 96% yield. This ~as
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., ~a]20 (-)40.9 (methanol).
2. In the same manner, ~) trans 8-fluoro-5-(p fluoro-
phenyl)-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]indole was obtained
~rom the salt provided above in Part A,2, in 96% crude yield and 75%
recovery upon recrystallization, M.P. 260-262.5 C., ~]D (~)39.2
(me~hanol).
- 20 -
~ ~ ~4~ 0 ,-
~YA~LE 5
Resolution of dl-4-hydroxy-(p-fluorophenyl)-butyric acid.
A. Commercial y-(p-fluorophenyl)-r-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-(~-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 warming and to the
solution was added a solution of 15.04 g. (0.91 mole) of d-ephedrine,
1a]578 ~ ~)11.4 (acetone), in 80 ml. ethyl acetate. The mixture was
stirred at room temperature over night during which time a crop of
crystsls formed, was removed by filtration and air dried to obtain
18.3 g., M.P. 97_99D 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-(p fluorophenyl)butyric
acid, M.P. 105.5-106.5 C. was obtained.
This product was taken up in a mixture of ice cold 5%
hydrochloric acid (300 ml.) and ethyl acetate (150 ml.), the aqueous
phase extracted five times with 100 ml. portions of cold ethyl
- 21 -
C` ~ ,`
acetate, the combined organic extrac~s 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, M. P. 98-104 C.,
[~]57~-(-)32.6. Upon recrystallization 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
mlxture 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 8.1g g. tO.040
mole) of hydroxy acid. This was taken up in fresh ethyl aceta~e
(lOOml) and a solution of 6.60 g. (0.040 ml.) of l-ephedrine in 50
ml. of ethyl acetate was added. The mixture wa~ 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 decomposet by treatment with ice cold 5% hydrochloric
acid and ethyl acetate as described in Part B abo~e, to provide 4.0
g. of the d-hydroxy acid, M.P. 98-104 C., []578=(+) 33.1.
- 22 -
~ ~ ~4~ J~
EXAMPLE 6
d(+)-and l(-)-y(p-Fluorophenyl)-y-butyrolactone
A. 1(-)-4-hydroxy-4-(p-fluorophenyl) bueyric acid provided in
Part B of Example $, (250 mg., 1.26 mmole) was dissolved in 15 ml.
of ethyl acetate and several crystals of p-toluenesulfonic 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., ~a]578 = (-)4Ø
B. d(+)-4-hydroxy-4-(p-fluorophenyl) butyric acid when treated
in the same manner afforded the d-lactone, ~]578 ' (+)4 3
EXAN2LE 7
5-(p-Fluorophenyl)-2-hydroxytetrahydrofuran
A. To a solution of 594 mg. (3.0 mmole) of d(+)-4-hydroxy-4-
(p-fluorophenyl) butyric acid, ~a]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. To 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
- 23 -
mixture was stirred for an additional 30 minutes at -72 to -74C.,
quenched with methanol and warmed to 0 C. The solvent was evaporated
in vacuo, residue 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.
Levorotatory 4-hydroxy-4-(p-fluorophenyl) butyric acid obtained
above and the commercially available racemic compound were converted,
respectively, to the corresponding enantiomeric and racemic title compounds
by the procedure of Part A.
EXAMPLE 8
B. Starting with the appropriate d-, 1-, or dl-4-hydroxy-4-
arylbutyric acid or the corresponding lactone, in the procedure of
Example 7, Part A, provides the following compounds in like manner.
~ 0~1~
Zl ~ OH
Zl : o-F , m-F
- 2~ -
0 ~
The requisite 6-aryl-6-hydroxyvaleric acid lactones
are prepared by the method of Colonge, et. al., Bull. Soc. Chim.
Erance., 2005-2011 (1966); Chem. Abstr., 65, 18547d (1966).
EXAMPLE 9
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
~-Enantiomer
5-(~-fluorophenyl)-2-hydroxytetrahydrofuran obtained from
d(+)-4-hydroxy-4-(~-fluorophenyl) butyric acid in Example 7, 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% palladium-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 partitioned
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 containing the desired product were combined, evapo-
rated to dryness, ta~en up in ethyl ether and converted to hydro-
chloride salt by addition of ethereal hydrogen chloride. Yield,
144 mg., M.P. 248-252 C., [~D = (+)30.1 (methanol). 97.5% pure
by high
- 25 -
;~'
~ ~ 6
pressure llquid chromatography analysis.
B-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-(r fluorophenyl)-2,3,
4,4a,5,9b-hexahydro-lH-pyridot4,3-b]indole hydrochloride, 1]D =
(-)40.9 (methanol) and the mixture stirred until solution was complete.
To the solution was added 346 mg. (1.90 mmole) of levorotatory 5-
(~-fluorophenyl)2-hydroxytetrahydrofuran (from Example 7 , Part B),
~ dissolved in a small volume of methanol and the resulting solution
8tirred for 15 minutes at room temperature. The solution uas 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 hydroxite was added and stirred until dissolved. The
solvent was evaporated in vacuo and the residue partitioned betueen
ethyl acetate and water. After reextraction of the agueous phase, the
combined organic extracts were dried (MgS04) 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.), ¦U]D = ( - )33.7 (methanol) which was
found to be 99Z pure B-enantiomer by HPLC. Reworking the mother liquors
afforded 80 mg. of a second crop, M.P. 254-258 C. (dec.). Total yield
56Z-
1 ~6'1~
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 llydrochloride, [c~]D (+)39, and 1.3 g. (7.1 mmole)
of levorotatory 5- (l~-fluorophenyl) -2-hydroxytetrahydrofuran and the so-
lution stirred under a nitrogen atmosphere at room temperature for
15 minutes. Five percent palladium-on-carbon catalyst, 300 mg.,
was added and the mixture hydrogenated at atmospheric pressure for
3 hours. The reaction mixture was worked up as described above for
the c~-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 pro-
vide 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.,
[C~]D = (+)1.7 (methanol). Both crops had a melting point of 254-256
C. Each were found to be 98% pure ~-enantiomer by HPLC.
ô-Enantiomer
1(-)-8-Fluoro-5-(_-fluorophenyl) 2,3,4,4a,5,9b-hexahydro-
lH-pyrido[4,3-b]indole hydrochloride, [c~]D = (-)40.9, (968 mg., 3.0
mmole) and an equimolar amolmt of dextrorotatory 5-(~-fluorophenyl)
2-hydroxytetrahydrofuran obtained by the procedures of Example 4.
Part B-l and Example 7, Part B, were reacted by the procedure
~ ~ .
described above for the ~-enantiomer to provide 1300 mg. of crude
~-enantiomer as a pale yellow gum. The gum was converted to hydro-
chloride salt, 835 mg., (57%), 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., [~ D = (-)2.7 (methanol) which assayed 98% pure
by HPLC.
EXAMPLE 10
Starting with the racemic or enantiomeric 5-aryl-2,3,4,4a,5,
9b-hexahydro-lH-pyridol [4,3-~ indole hydrochlorides provided above
and the d-, 1- or dl- isomer of a 5-aryl-2-hydroxytetrahydrofuran each
of the enantiomers and diastereomers of the following formula are
prepared by the procedure of Example 9.
X1 ~ N-(CH ) CH
~,
~X,
Y
Xl Yl Zl
H H p-F
F p-F m-f
F H p-F
- 28 -
~ ~ 6~a,
When catalytic amounts of platinum, rhodium, ruthenium or
Raney ni.ckel catalyst are employed in place of palladium catalyst, and
the reductive alkylation described in Example 9 for the ~-enantiomer
is carried out at temperatures of from -10 C. to 50~ C. and at
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 alkylation employing the above reactants
are repeated, but employing sodium cyanolborohydride as the reducing
agent as described in Example 9 for the ~-enantiomer and reaction
temperatures of from -10 C. to 50 C., the above products are simi-
larly obtained.
- 29 -
~ ~ 6`~
EXA~IPLE 11
Antagonism of Amplletamine Stereotype in Rats
Test Procedures and Results
~ e 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.lkg. intraper-
itoneally ~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
possible 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 indicated times:
1 ~ -R
[~
Yl
- 30 -
., ~,,
0 ~
~ ~ ~ ol
o o e~
l l o ~ ~ ~ ~ ~ o
O
o o ) l v v o v v
.
E J _~ ~_I
al V :~ O ~ ~1 ~ ~ o
~ C 0 ~ ~ ~ O O O O ~
0 E3 o ,~ O -I
~ ~ _ o o o o o V O V V
~i o
' ~
.~ ~
o ~ I O ~ ~ ~ O .
~rl O O ~ O O ~l - O ~ ~ O
E U
s ~ ~ o v o o V
V ~
8 ~ ~
C .
o
C " ~ . ,~
V
, ~ ~ ~ , ~ ~ _
O ~ ~ ~ 5 1 ~ ~
:~ c ~ `~ ~ o -- ~o c~--o ~o ~--o
v ~o~ s~ o iiJ 5 ~ O
O ~O ~ o
~ ~ O
OD ~ U
o
o
_I C ~ ~ ~ ~ ~
Ll O ~ O O O O O O
0 4)
V Q) E
~ 1 3: 5 ~ ~ 1~ ol 4 4 4
o
.c
C~, ,
e ~ ~
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C ~'~X~ 5~ Z ~ ~ P~
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3/
t 16~0 ,`
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N`J O N C
~t~E~ ~ w
NAZ: ~ ~ ~ w X
. I N 0 0 0
r~ U) t') _~ I O
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~/) ';C ' ~ N N O O --
t~
n~ a v,
~ s
aU7 o ~ ~,~
U~ N O ~
f-l~ ~ I O N
5~ , o N
_I~ 0 5 S::
O
.,1
3 ~.
w
I ~ I a~
i~
w ~--~ ^
~ ~ I O
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~ h r~
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~ ~ ~ ~ ~1 ~ V) .,~
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W ~ ~ ~ ~ ~ o
X ~_ , ~, W o
L~ X~ ~ ~ ~ Z ~ w
32
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C
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a) ,~ ~a
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'~ C ~4 ~: I ~ I I O O
v ~ ~ a~ ~ o ,~ o o o ~11 ~ O ~
t O C C ~ ~ A O _i O --i 0 I V A O V
1~ ~ ~ rl ~1
O J O
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JJ O ~ . . O C`J
o ~ o
o,,c ~ ~ . o I I ~
V _tO ~ '1 ~1 1 0
~1 I ~ I ~ ~ I o o
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v ~
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C O O ~ O
~ ~ o I I _I o _I .
c ~ ~~ I I ~ ~ I ~ I
1 ~ .. .. I . . ~1 - _I
o 4~ 0 :~ ~ ,1 ~ O O O _I O ~ V o o V
~q ~ ~ O
3 O O
O ~ O S U
I V
~; v ~ v
o ~o .n ~o ~ I I
C
c
U I ~ v
've
c ~ ~-a ~ c~
g -- c~--o ~7--o c~--o
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u c~ co ~ t~
~I) ~ ~ C
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8 ~ 3 C
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o V C,
E u~
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O O
x .
P ~0 V ~
U~ o U~ o
,~ ~ ~
~ ~ 33
