CA1164007A - 5-(fluorophenyl)tetrahydro-2-furanol - Google Patents

Abstract

A B S T R A C T

Novel 2,5-disubstituted tetrahydrofuran of the formula wherein Z1 is fluoro is prepared by reducing the corresponding lactone of the formula.

Description

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~

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.

~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 ~ ~ 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 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 ~ ~ ~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.

~ 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.

' :~ :

~ ~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.

.,~ ,~

~., S ~ Ci O ~,' X 9b X Y X Y
H p- fluoro H o- fluoro F H F m-fluoro F _- fluoro F o-fluoro 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).

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).

~ ~ ~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 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.

~ ~ ~4~ J~

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 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 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.

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).

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 ;~' ~ ~ 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 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.

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

~ ~ 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.

~ ~ 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 ., ~,, 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 ~ ~
~o C ~'~X~ 5~ Z ~ ~ P~

~ o U~ o t 16~0 ,`

~ t~ N ~, S
N`J O N C
~t~E~ ~ w NAZ: ~ ~ ~ w X

. I N 0 0 0 r~ U) t') _~ I O
N N I 1 4_~
~/) ';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
_~
~ ~ w ~t~
~ ~ O ~ ~

O ~ O ~ w ~ ~ w ~ h r~
N ~ ID ~ ~ a- (D
~ ~ ~ ~ ~1 ~ V) .,~
~ ~ ~ ~ 8 ~ ~ ~ zo ~ ~
W ~ ~ ~ ~ ~ o X ~_ , ~, W o L~ X~ ~ ~ ~ Z ~ w ` ., C

o .. .... .. ...
. c~ ~ o o c~ . o a~

.1 o~
lllllllllll ~ l l ~ .
`J
a) ,~ ~a ~ c --~
D O ~ . ~ ~ O C~
^ I C-rl O Ul I .
~ ~ O V h O ~ ~ r~ O
'~ 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
~ ~q ~ ~ ~
JJ O ~ . . O C`J
o ~ o o,,c ~ ~ . o I I ~
V _tO ~ '1 ~1 1 0 ~1 I ~ I ~ ~ I o o .1 V IJO ~ 0~ ~ ~1 O ~1 O ~ ~1 O
~ O u~ ~ O 0 0 o o -1 '' I ~d -I
v ~
~ ~ ~ 'v ~ ~
^ ~ ~ ,~ _l 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

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 ~n g m ~d~C ~--O ~ `D ~D
u c~ co ~ t~
~I) ~ ~ C
~ ~ o O `D
o ~
~ ~ ~ v ~ c ~
v ~c o ~ ~2 o o ~ ~ ~ o ~ ~
8 ~ 3 C
1 o a~
~ D ~ P ~ ~J ol o V C, E u~
--I O ~J
O O
x .
P ~0 V ~

U~ o U~ o ,~ ~ ~
~ ~ 33

Claims (8)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing enantiomeric or racemic compounds of the formula:

wherein Z1 is fluoro, wherein a corresponding lactone of the formula:

is reduced with a metal hydride.

2. An enantiomeric or racemic compound of the formula wherein Z1 is fluoro, whenever prepared or produced by the process of claim 1 or by an obvious chemical equivalent thereof.

3. A process according to claim 1 wherein a lactone is employed in which Z1 is p-fluoro.

4. A compound according to claim 2 wherein Z1 is p-fluoro, whenever prepared or produced by the process of claim 3 or by an obvious chemical equivalent thereof.

5. A process according to claim 1 wherein the metal hydride is diisobutylaluminum hydride, sodium borohydride or lithium borohydride.

6. A process according to claim 1 wherein diisobutyl-aluminum hydride is employed as said metal hydride and said reduction is effected in a reaction-inert solvent under a reaction-inert gas at -80° to -70°C.

7. A process according to claim 1 wherein said lactone employed as starting material has been prepared by cyclizing a compound of the formula:

wherein Z1 is as defined in claim 1.

8. A process according to claim 7 wherein the cyclization is effected by heating in the presence of an acid catalyst.