Description of the Related Art U. S. Patent No. 5,196, 415 discloses various dibenzo-1-carboxamido-1, 4- azabicyclo [3. 2.1] octanes (5-aminocarbonyl-5H-dibenzo [a, d]-cyclohepten-5, 10-imines) and methods for preparing such compounds. The methods disclosed there involve conversion of C5-unsubstituted-10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5. 10-imines into their N-tert- butylformamidine derivatives followed by formation of the C5-substituted ethyl ester. After removal of the tert-butylformamidine moiety from the nitrogen atom of the ring system, the ester functionality is replaced with an amide group by warming the ester in methanol with the appropriate amine derivative. If N-substitution is desired, the secondary amine is allowed to react with the appropriate alkyl halide in the presence of a suitable base. This series of reactions produces a racemic mixture of dibenzo-1-carboxamido-1 4- azabicyclo [3.2.1] octanes, i. e., a racemic mixture of 5-aminocarbonyl-5H- dibenzo [a, d] cyclohepten-5, 10-imines.

Racemic mixtures of 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5, 10-imines are known to have pharmacological activity as anticonvulsant agents. See, for example, Rogawski et al., 1991, J. Pharmacolog and E. rperimental Therapeutics, 259: 30-37 ; and Grant et al., 1992, J. Pharmacologv and Experimental T71erapeulics, 260: 1017-1022.

SUMMARY OF THE INVENTION The present invention provides a novel method for preparing dibenzo-1-carboxamido- 1, 4-azabicyclo [3.2.1] octanes, i. e., 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5, 10-imines, in good yield.

In a first aspect, the invention provides a process for preparing 5-aminocarbonyl-SH- dibenzo [a, d] cyclohepten-5,10-imines comprising replacing the 5-hydroxy group in a compound of formula I with a hydroxyamino group to yield a compound of formula II, a 5- hydroxyaminodibenzocycloheptene:

i il where Ra is lower alkyl and R, and R2 are as defined below for Formula A.

In this aspect the invention also provides novel compounds of formula II.

In a second aspect, the invention provides compounds of formula III and a process involving heating a solution of a compound of formula II to yield a 12-hydroxy-10,11- dihydrodibenzocycloheptene of formula III.

VIII where Ra is lower alkyl and R, and R2 are as defined below for Formula A.

Another aspect of the invention provides process wherein the 12-hydroxy group of the compound of formula III is reduced to yield a compound of formula IV.

where Ra is lower alkyl and R, and R2 are as defined below for Formula A.

In yet another aspect, the invention provides a process for producing a 4- hydroxyphenyl compound of formula V, which process involves cleaving the alkyl portion of alkoxy group ORa

v where Ra is lower alkyl and R, and R2 are as defined below for Formula A.

The invention also provides a method for preparing an N-formyl compound of formula VI which entails treating a compound of formula V with an alkyl formate. where R, and R2 are as defined below for Formula A.

In addition, the invention encompasses novel compounds of formula VI.

In still another aspect, the invention provides a process for removing the 4- hydroxyphenyl group from a compound of formula VI to yield a 12-Formyl-10, 11-dihydro- dibenzo cycloheptene imine carboxylate of formula VII.

where Rb is lower alkyl and R, and R2 are as defined below for Formula A.

The invention further provides a process for reducing the aminoformyl group to yield a cycloheptene imine carboxylate of formula VIII.

VIII where Rb is lower alkyl and R, and R2 are as defined below for Formula A.

Also encompassed within the invention are compounds of formula VIII.

In yet another aspect, the invention provides a process for converting the ester functionality of compounds of formula VIII to an aminocarbonyl group (formula IX) and, optionally, for alkylating the secondary nitrogen in a compound of formula IX.

where R,, R2, R4 and R5 are as defined below for Formula A.

The invention further encompasses novel intermediates involved in the inventive process for preparing compounds of formula I. It also encompasses methods for preparing those intermediates.

The invention further provides a process for converting compounds of Formula I into final product, i. e., a 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5,10-imine of Formula A.

DETAILED DESCRIPTION OF THE INVENTION In this document, all temperatures will be stated in degrees Celsius. All amounts, ratios, concentrations, proportions and the like will be stated in weight units, unless otherwise stated, except for ratios of solvents, which are in volume units.

As noted above, the invention provides processes and intermediates for preparing dibenzo-l-carboxamido-1, 4-azabicyclo [3.2.1] octanes. These compounds can also be referred to as 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5,10-imines. These compounds are encompassed by general formula A: wherein RI and R2 independently represent hydrogen, linear or branched alkyl of from one to about ten carbon atoms, alkenyl having from two to about ten carbon atoms, alkynyl having from two to about ten carbon atoms, hydroxyl, amino, alkylamino, alkoxy, cyano, nitro, haloalkyl, or mercapto; R3 is hydrogen, linear or branched alkyl having from one to about ten carbon atoms, alkenyl groups having from two to about ten carbon atoms, alkynyl groups having from two to about ten carbon atoms, hydroxyl, phenyl, haloalkyl, aminoalkyl, 1-phenylmethyl, 2- phenylmethyl, alkoxyalkyl, and hydroxyalkyl, any of the said groups being optionally substituted by alkyl, oxo, thio, alkoxy, hydroxy, amino, alkylamino, phenyl, haloalkyl and thio; and R, and R5 independently represent hydrogen, linear or branched alkyl groups of from one to about twenty carbon atoms, alkenyl groups from two to about twenty carbon atoms, alkynyl groups from two to about twenty carbon atoms, cycloalkyl groups of three to

about eight carbon atoms, cycloalkenyl groups of from three to about eight carbon atoms, and wherein R4 and R5 may be taken together to form a N-containing cyclic structure having two to about eight carbon atoms, any of the said groups being optionally substituted with one or more substituents selected from alkyl, haloalkyl, hydroxyalkyl, alkenyl, oxo, hydroxyl, alkoxy, thio, alkoxyalkyl, amino, halo, cyano, or mercapto.

Particularly preferred compounds that are prepared according to the invention are those where R,, R3, R,, R, and Rs are hydrogen.

In the most preferred processes and intermediates of the invention, the subsituents Ra and Rb are methyl groups.

The invention also encompasses intermediates suitable for use in the methods and processes of the invention. Thus, the invention encompasses within its scope compounds of formula INT-I : INT-I where X is NHOH; R. is H or alkyl ; and R, and R2 are independently hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, amino, alkylamino, alkoxy, cyano, nitro, haloalkyl, or mercapto.

In preferred compounds of Formula INT-I, R, and R are independently hydrogen or alkyl.

The invention also encompasses intermediates of formula INT-II :

INT-II where R is H or alkyl ; and R, and R, are independently hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, amino, alkylamino, alkoxy, cyano, nitro, haloalkyl, or mercapto.

In preferred compounds of Formula INT-II, R, and R are independently hydrogen or alkyl.

The invention also provides compounds of the formula INT-III INT-III where R, is H or alkyl ; and R, and R2 are independently hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, amino, alkylamino, alkoxy, cyano, nitro, haloalkyl, or mercapto.

In preferred compounds of Formula INT-III, R, and R, are independently hydrogen or alkyl.

The invention also encompasses intermediates of formula INT-IV:

INT-IV where R is H or alkyl ; and R, and R, are independently hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, amino, alkylamino, alkoxy, cyano, nitro, haloalkyl, or mercapto.

In preferred compounds of Formula INT-IV, R, and R, are independently hydrogen or alkyl.

The numbering system used herein to identify positions on the 10,11-dihydro-SH dibenzo [a, d] cyclohepten-5, 10-imine ring systems of the invention is as follows: The numbering system used herein to identify positions on the 5-Hydroxy-5H- dibenzo [a, d] cycloheptenes of the invention is as follows:

Where the term'alkyl'is used, either alone or within other terms such as'haloalkyl'or alkylamino'the term'alkyl'embraces linear or branched radicals having one to about ten carbon atoms. Preferred alkyl radicals are"lower alkyl"radicals having from one to about five carbon atoms.

The term'cycloalkyl'embraces radicals having from three to about ten carbon atoms, such as cyclopropyl and cyclobutyl.

The term"haloalkyl"embraces radicals wherein one or more of the alkyl carbon atoms is substituted with one or more halogens atoms, preferably selected from fluoro, chloro and bromo. Specifically embraced by the term'haloalkyl'are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. Examples of a polyhaloalkyl are trifluoromethyl, 2,2,2-trifluoroethyl and perfluoroethyl.

The term'alkenyl'embraces linear or branched radicals having from two to about ten carbon atoms and containing at least one double bond.

The term'alkynyl'embraces linear or branched radicals having from two to about ten carbon atoms containing at least one carbon-carbon triple bond.

The term'alkoxy'embraces linear or branched oxy-containing radicals having alkyl portions of from one to about ten carbon atoms, such as methoxy group. The alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo to provide haloalkoxy groups.

The term'alkylamino'embraces linear or branched nitrogen containing radicals where the nitrogen atom may be substituted with from one to three alkyl radicals of from one to about ten carbon atoms, such as N-methylamino and N, N-dimethylamino.

Specific examples of alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, neopentyl and n-pentyl. Typical alkenyl groups may have one unsaturated double bond, such as allyl or may have a plurality of double bonds.

By"racemic mixture"as used herein is meant a 50: 50 by weight mixture of two enantiomers.

The following group of representative products of the process and of this invention will be mentioned, to assure that the reader fully understands the overall purpose of the process:

As noted in U. S. Patent No. 5,196,415, the compounds preparable by the inventive methods are useful for treatment of patients with generalized epilepsy or partial (symptomatic) epilepsy. These compounds are also useful for treating drug craving in patients addicted to cocaine.

Administration of compounds within Formula I to humans can be by any technique capable of introducing the compounds into the bloodstream of a human patient, including oral administration, and by intraveneous, intramuscular and subcutaneous injections.

Compounds indicated by prophylactic therapy will preferably be administered in a daily dose generally in the range of 0.1 mg to 100 mg per kilogram of body weight per day. A more preferred dosage will be in the range of 1.0 to 50 mg per kilogram of body weight. A suitable dose can be administered in suitable sub-doses per day.

The active compound is usually administered in a pharmaceutically acceptable formulation, although in some acute-care situations a compound of Formula I may be administered alone. Such formulations may comprise the active compound with one or more pharmaceutically acceptable carriers or diluents. Other therapeutic agents may also be present in the formulation. A pharmaceutically acceptable carrier or diluent provides an appropriate vehicle for delivery of the active compound without undesirable side effects. Delivery of the active compound in such formulations may be by various routes such as oral, nasal, buccal or sublingual, or by parenteral administration such as subcutaneous, intramuscular, intravenous or intradermal routes. Delivery of the active compound may also be through the use of controlled release formulations in subcutaneous implants.

Formulations for oral administration may be in the form of capsules containing the active compound dispersed in a binder such as gelatin or hydroxypropylmethyl cellulose, together with one or more of a lubricant, preservative, surface acting or dispersing agent.

Such capsules or tablets may contain controlled release formulation as may be provided in a disposition of active compound in hydroxypropylmethyl cellulose.

Formulations for parental administration may be in the form of aqueous or non- aqueous isotonic sterile injection solutions or suspensions. These solutions or suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration.

In the following schemes, Rl-R5 are as defined above for Formula A and Ra and Rb represent lower alkyl.

The compounds of formula I are prepared according to the invention by Grignard addition of a suitable phenyl Grignard reagent to a dibenzosuberenone derivative. See Scheme I below. For example, a 4-haloanisole such as 4-bromoanisole may be converted into a suitable Grignard reagent in the typical manner in a solvent such as tetrahydrofuran (THF) or diethylether (ether). This reagent may then, as shown in Scheme I and Example 1, be reacted according to well-known procedures with an appropriate ketone to afford the desired 5-hydroxy-5- (4-alkoxyphenyl) dibenzocycloheptene 1. Preferred Ra groups are ethyl and, most preferably, methyl.

Scheme I The 5-hydroxy-5- (4-methoxyphenyl) dibenzocycloheptene 1 is conveniently converted into the corresponding 5-hydroxyamino 2 compound by treating the hydroxy compound 1 with hydroxylamine in a solvent such as, for example, dichloromethane, preferably with a buffer such as sodium acetate. This reaction, shown in Scheme I, is carried out at ambient temperature in the presence of an acid. A suitable acid is trifluoroacetic acid, used in excess.

Preferably, dibenzocycloheptene 1 is added to the hydroxylamine solution. The resulting mixture is preferably mixed for about three hours followed by aqueous workup.

Chromatography can then be carried out on the crude product; gradient elution with a solvent such as 30-50% v/v ether: hexanes affords the desired product 2 in about 80% yield. Also isolated are starting material and imine 9.

Scheme II

As shown in Scheme II, hydroxyamino compound 2 is heated, preferably refluxed, in a solvent such as toluene to afford hydroxyimine 3. In preferred embodiments, the solvent is degassed and the reaction allowed to proceed for at least 24 hours. Subsequent to producing hydroxyamine 3, that compound is treated with zinc and an excess of a weak acid to afford imine 4. The reaction producing the imine is preferably conducted at reflux using glacial acetic acid in a solvent such as ether or, more preferably, tetrahydrofuran. The zinc used in this process is preferably powdered.

As depicted in Scheme III, the alkoxy protecting group is subsequently removed from imine 4 to yield the 4-hydroxyphenyl compound 5. The protecting group may be conveniently removed using an excess of, for example, boron tribromide in a solvent such as dichloromethane at ambient temperature. The boron tribromide is typically added to a solution of alkoxyphenylimine 4. Reaction times of from about 5-24 hours are suitable. The deprotection is followed by treatment with an aqueous base, e. g., aqueous ammonia, for at least about 15 minutes, and preferably for about one hour. The pH is then adjusted to about 7 with an aqueous buffer such as, for example, phosphate. Extraction with an organic solvent affords 4-hydroxyphenyl imine 5. A preferred extraction solvent is ethyl acetate. The yield for the deprotection is generally in excess of 90%.

Scheme III

4-Hydroxyphenyl imine 5 may be converted into formyl compound 6 in either of two convenient reactions. In one method, phenolic imine 5 is heated with ethyl formate in a sealed tube to about 100°C. The reaction may be monitored for completion using, as an example, thin layer chromatography. Upon cooling and concentration, preferably in vacuo, formyl compound 6 is obtained in excess of 90% yield.

In an alternative method, phenolic imine 5 is dissolved in a solvent such as dimethylformamide (DMF) containing an excess of methyl formate, and the resulting mixture is then heated in a sealed tube for an amount of time suitable to allow complete conversion to formyl compound 6. Heating to about 100°C for approximately 10-24 hours is appropriate. After cooling and concentration in vacuo, aqueous workup, preferably using ethyl acetate as an extraction solvent, affords 6 in about 70% yield.

Scheme IV As shown in Scheme IV, the 4-hydroxyphenyl moiety is cleaved from formyl compound 6 using sodium periodate and ruthenium trichloride. Preferably, to a mixture of

formyl compound 6 in acetonitrile, carbon tetrachloride and water, is added disodium hydrogen phosphate and sodium periodate. Generally, large excesses of the phosphate and periodate salts are employed. Then, an aqueous solution of a catalytic amount of ruthenium trichloride is added, most preferably dropwise, and the resulting mixture heated to reflux. The reaction is typically complete in about 10-15 hours. However, the reaction may be allowed to reflux for a longer period, e. g., more than 20 hours. After cooling, the mixture may be filtered and extracted with an organic solvent. A preferred solvent is dichloromethane.

The aqueous phase is then adjusted to acidic pH using, for example, hydrochloric acid and re-extracted, preferably with dichloromethane. Aqueous washing of the organic extracts followed by concentration in vacuo yields a crude acid-formamide as an oil.

The crude acid-formamide is dissolved in, preferably, methanol and treated with an excess of diazomethane. Preferably, the treating is carried out in ethereal solution at ambient temperature for a short time, such as, for example, about 15 minutes. The reaction is quenched with, for example, 10% aqueous acetic acid. Following an aqueous workup, the 12- formyl-dibenzo [a, d] cyclohepten-5, 10-imine-5-carboxylate product 7 may be further purified using, for example, chromatography. A presently preferred extraction solvent for the workup is dichloromethane. A preferred elution solvent for the chromatography is 50-75% ether in hexanes.

The formyl group is then removed from imine carboxylate 7 by treating 7 with a strong acid, e. g., sulfuric acid, in an alcoholic solvent such as methanol. The reaction proceeds at ambient temperature and is generally complete in about 5-15 hours. The acid is then neutralized and the pH adjusted to about 8 with, for example, bicarbonate. Extraction with a solvent such as dichloromethane and removal of solvent under reduced pressure affords imine carboxylate 8.

Imine carboxylate 8 can be conveniently converted into the desired 1-carboxamido- 1, 4-azabicyclo [3.2.1] octane of Formula A by any of a variety of methodologies known in the art.

Scheme V NH NH C102Me HNR4R5 NH R3X NR3 I /\ R2 R /\ MeOH 'R base 0 N 4 O NR4 8 R5 R5 ''i'n h<5° A, where R3 = H A For example, as shown in Scheme V, the ester functionality can be replaced with an amide group by warming the ester in methanol with the appropriate amine derivative. If N- substitution is desired, the secondary amine (A, where R3 is H) is allowed to react with the appropriate alkyl halide (e. g., R3X where R3 is defined above and X is a halide) in the presence of a suitable base to afford a compound of Formula A.

The disclosures in this application of all articles and references, including patents, are incorporated herein by reference.

The invention is illustrated further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures and compounds described in them.

Example 1 5-Hvdroxy-5- (4-methoxyphenyl)-51H-dibenzo [a. d] cvcloheptene, 10

Magnesium powder (714 mg, 29.4 mmol) is suspended in THF (50 mL) with a small crystal of iodine and treated with 4-bromoanisole (4.68 g, 25.0 mmol) in THF (50 mL) over 15 minutes. The mixture is heated to reflux for one hour and cooled to 0°C.

Dibenzosuberenone (5.05 g, 24.5 mmol) in THF (50 mL) is added over 45 minutes, and after warming to ambient temperature for 90 minutes the deep purple solution is refluxed for one hour. The mixture is quenched with aqueous ammonium chloride and extracted into ether (3x100 mL). The combined organic phases are washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to yield a viscous yellow oil. Chromatography (gradient elution with 30-100% CH2Cl2 in hexanes) gives 10 (6.71 g, 87%) as white prisms.

M. pt. 131-132°C. on (300MHz, CDC13) 2.2 (1H, s, OH), 3.70 (3H, s, CH3), 6.58 (4H, s, ArH), 6.70 (2H, s, 10,11-H), 7.3-7.4 (4H, m, ArH), 7.45-7.55 (2H, m, ArH), 8.19 (2H, d, J= 8 Hz, ArH). (C6D6): 1.8 (1H, s, OH), 3.16 (3H, s, CH3), 6.42 (2H, br d, J= 8. 5 Hz, ArH), 6.56 (2H, s, 10,11-H), 6.68 (2H, br d, J = 8.5 Hz, ArH), 7.1-7.15 (4H, m, ArH), 7.3-7.3 (2H, m, ArH), 8. 34 (2H, d, J = 8 Hz, ArH). IR 3500,2931,1605,1505 cm-1. HRMS 314.1296 (314.1307 calcd. for C22H1802) ; Rf 0. 25 (silica, 33% ether in hexanes). Example 2 5-Hvdroxyamino-5-(4=methoxvphenvl !-5H-dibenzoEa. dlcycloheptene 11

To a suspension of hydroxylamine hydrochloride (928 mg, 13.4 mmol) and anhydrous sodium acetate (1.10 g, 13.4 mmol) in CH2C12 (8 mL) at ambient temperature is added trifluoroacetic acid (1.55 mL, 20.1 mmol), and the resulting mixture stirred vigorously for one hour. 10 (1.05g, 3.34 mmol) in CH2C12 (10 mL) is added dropwise, producing a deep green color. The mixture is stirred vigorously for a further three hours, quenched with aqueous sodium bicarbonate and extracted into CH2C12 (3x50 mL). The combined organic phases are washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to yield a bright yellow oil. Chromatography (gradient elution with 30-50% ether in hexanes) gives 11 (867 mg, 79%) as a white amorphous solid. Crystallization from ether-hexanes yields 11 as white needles. M. p.: 164°C (decomp.). bH (300MHz, CDCl3) : 3.72 (3H, s, CH3), 3.9 (1H, br s, NHOH), 5.8 (1H, br s, NHOH), 6.52 (2H, br d, J = 8.5 Hz, ArH), 6.60 (2H, br d, J = 8.5 Hz, ArH), 6.69 (2H, s, 10,11-H), 7.29-7.36 (4H, m, ArH), 7.43-7.50 (2H, m, ArH), 7.90 (2H, d, J = 8 Hz, ArH). IR 3270,2933,1605,1508 cm-1. HRMS 330.1492 (330.1494 calcd. for C22H2oNO2) ; Rf 0. 25 (silica, 50% ether in hexanes).

Imine 18 is also isolated (28 mg, 3%) as is starting material (194 mg, 18%).

Example 3 12-Hydroxv-5- (4'-methoxvphenvl 10, 11-dihvdro-5H-dibenzo [a, dcvclohepten-5. 10-imine.

12

11 12 (96%) A solution of 11 (800 mg, 2.43 mmol) in degassed toluene (48 mL, 0. 05M) is heated to reflux for 36 hours, cooled, and concentrated in vacuo to yield a pale yellow solid.

Chromatography (gradient elution with 30-50% ether in hexanes) gives 12 (769 mg, 96%) as a cream-colored, amorphous solid. The compound exists as a slowly interconverting mixture of diastereomers. bH (300MHz, CDC13) : 2.37 (1H, d, J = 17 Hz, major 11-Ha), 2.72 (1H, d, J = 16.5 Hz, minor 11-Ha), 3.57 (1H, br d, J = 17 Hz, major, minor 11- Hp), 3.90 (3H, s, minor CH3), 3.93 (3H, s, major CH3), 4.02 (1H, d, J = 4.5 Hz, major 10-Ha), 4.48 (1H, d, J = 4.5 Hz, minor 10-Ha), 5.9 (1H, br s, minor OH), 6.8-7.4 (1OH, m, major, minor ArH), 7.48 (1H, dd, J = 8.5,2.5 Hz, minor ArH), 7.60 (2H, br d, J = 9 Hz, major ArH), 7.82 (1H, dd, J = 8.5,2.5 Hz, minor ArH). IR 3500,3230,2903,1609,

1515 cm-1. HRMS 330.1484 (330.1494 calcd. for C22H2oNO2) ; Rf 0.2 and 0.35 (silica, 50% ether in hexanes).

The diastereomers are separable by flash chromatography but each rapidly converts to a similar mixture at ambient temperature Example 4 5- (4'-Methoxyphenyl)-10, 11-dihvdro-5H-dibenzo [a, cl] cvclohepten-5. 10-imine, 13 To hydroxylamine 12 (760 mg, 2.31 mmol) in THF (40 mL) is added activated zinc powder (1.51 g, 23.1 mmol) and glacial acetic acid (2.6 mL, 46 mmol), and the mixture is heated to reflux for 90 minutes. Once cooled, the mixture is filtered, treated with aqueous sodium bicarbonate to pH 8, and extracted into ether (3x50 mL). The combined organic phases are washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to yield 13 (721 mg, 100%) as a white foam. 6H (300MHz, CDC13) : 2.3 (1H, br s, NH), 2.69 (1H, d, J= 16.5 Hz, 11-Ha), 2.59 (1H, dd, J= 16.5,5.5 Hz, 11-hop), 3.86 (3H, s, CH3), 4.76 (1H, d, J = S. 5 Hz, 10-Ha), 6.9-7.4 (1OH, m, ArH), 7.66 (2H, br d, J = 9 Hz, ArH).

IR 3280,2931,1611,1515,1248 cm-l. HRMS 314. 1535 (314.1545 calcd. for C22H2oNO) ; Rf 0.3 (silica, ether).

Example 5 5-(4'-HvdroXvphenvl !-1011-dihvdro-5H-dibenzo [adlcvXlohepten-510-imine 14 To a solution of 13 (373mg, 1. 19mmol) in CH2Cl2 (25 mL) at 0°C is added a solution of boron tribromide in CH2CI2 (3.0 mL, 1.0 M, 3.0 mmol), and the mixture stirred at ambient temperature for 18 hours. Following treatment with saturated aqueous ammonia (2 mL) for one hour, and adjustment to pH 7 with aqueous phosphate buffer, the mixture is extracted into ethyl acetate (3x100 mL). This compound appears to be sparingly soluble in common extraction solvents; ethyl acetate is most effective.

The combined organic phases are washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to yield 14 (359 mg, >90%) as cream- colored cubes, m. p. 255-257°C. 14 is used subsequently without further purification. 6H (300MHz, CD30D) 2.67 (1H, d, J = 16.6 Hz, 11-Ha), 3.55 (1H, dd, J = 16.6,5.4 Hz, 11-hop), 4.72 (1H, d, J = 5.5 Hz, 10-Ha), 6.86 (2H, br d, J = 9 Hz, ArH), 6.95-7.0 (3H, m, ArH), 7.0-7.1 (1H, m, ArH), 7.15-7.25 (3H, m, ArH), 7.35-7.45 (1H, m, ArH), 7.53 (2H, br d, J = 8.5 Hz, ArH). IR 3250,2918,1612,1515,1253 cm-l. HRMS 299.1302 (299.1310 calcd. for C21Hl7NO) ; Rf 0. 25 (silica, ether).

Example 6 17-Formvl-5-(4'-hydroxYphenal !-10 11-dihvdro-5H-dibenzo [a. dlcvelohepten-5. 10-imine. 15 The title compound may be prepared by either of two methods as described below.

Method A: A solution of the crude phenol-amine 14 (17.8 mg, 59.5 pmol) in ethyl formate (1.0 mL, 12.4 mmol) is heated to 100°C in a sealed tube for 20 hours. The mixture is then allowed to cool and concentrated in vacuo to yield 15 (>90%) as an essentially pure cream-colored solid.

Method B: A solution of the crude phenol-amine 14 (359 mg,-1. 2 mmol) in DMF (10 mL) and methyl formate (20 mL, 320 mmol) is heated to 100°C in a sealed tube for 19 hours.

The mixture is allowed to cool and subsequently concentrated in vacuo to yield a yellow solution. To the solution water is added (40 mL), and the resulting mixture is extracted into ethyl acetate (3x60 mL). The combined organic phases are washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to-20 mL of a yellow solution. Dilution with an equal volume of ether and standing at 0°C affords 15 (285 mg, 73% from 13) as colorless cubes.

The title compound 15 has a melting point of 320-325°C (decomp). aH (300MHz, DMSO-d6): 2.72 (1H, d, J = 17 Hz, 11-Ha), 3.51 (1H, dd, J = 17, 5 Hz, 11-Hß), 5.78 (1H, d, J= 5 Hz, 10-Ha), 6.9-7.6 (12H, m, ArH, CHO), 9.9 (1H, br s, OH). IR 3300,2923,1639, 1585,1513 cm-1. HRMS 328.1344 (328.1338 calcd. for C22H18No2) ; Rf 0. 75 (silica, ether). Example 7 Methvl 12-Formvl-10, 11-dihvdro-5H-dibenzo [a. dlcvclohepten-5 10-imine-5-carboxvlate 7

To a suspension of 15 (45.2 mg, 138 mol) in a mixture of acetonitrile (3.0 mL), carbon tetrachloride (3.0 mL) and water (4.5 mL) is added disodium hydrogen phosphate (588 mg, 4.14 mmol) and sodium periodate (413 mg, 1.93 mmol). An aqueous solution of ruthenium trichloride (300 1, 0.01 M, 2.2 mol%) is added dropwise, and the mixture is then heated to reflux for 21 hours. Once cooled, the mixture is filtered through celite and extracted with CH2Cl2 (3x50 mL) The aqueous phase is adjusted to pH 2 with 2N hydrochloric acid and re-extracted with CH2Cl2 (3x50 mL). The combined organic acidic extracts are washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to yield the crude acid- formamide intermediate (23.5mg) as a colorless oil. 5H (CD30D, 300MHz) 2.68 (1H, d, J = 17 Hz, major 11-Ha), 2.88 (1H, br d, J = 17.5 Hz, minor 11-Ha), 3.49 (1H, br dd, J = 17. 5,5 Hz, minor 11-H), 3.64 (1H, dd, J = 17, 5.5 Hz, major 11-H, B), 5.59 (1H, br d, J = 5 Hz, minor 10-Ha), 5.77 (1H, d, J = 5. 5 Hz, major 10-Ha), 6.9-7.0 (1H, m, major, minor ArH), 7.05-7.3 (m, major, minor ArH), 7.44 (1H, br d, J = 7 Hz, major, minor ArH), 7.53 (1H, br d, J = 7 Hz, major ArH), 7.70 (1H, br d, J = 7 Hz, major ArH), 8.35-8.4 (2H, m, minor ArH, CHO), 8.76 (1H, s, major CHO).

The crude acid-formamide is dissolved in methanol (5 mL) and treated with excess diazomethane in ethereal solution (-750 jmol) at ambient temperature for 15 minutes. The

mixture is quenched with 10% aqueous acetic acid and extracted into CH2Cl2 (3x30 mL).

The combined organic phases are washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to yield a yellow oil. Chromatography (gradient elution with 50- 75% ether in hexanes) gives 16 (15.7 mg, 39%). 8H (300MHz, CDC13) 2.65 (1H, d, J= 17 Hz, major 11-Ha), 2.91 (1H, d, J = 16.5 Hz, minor 11-Ha), 3.48 (1H, br dd, J = 16.5,5.5 Hz, minor 11-hop), 3.75 (1H, dd, J = 17,5.5 Hz, major 11-hop), 3.89 (3H, s, minor CH3), 4.05 (3H, s, major CH3), 5.45 (1H, br d, J = 5.5 Hz, minor 10-Ha), 5.83 (1 H, d, J = 5. 5 Hz, major 10-Hα), 6.9-7.3 (m, major, minor ArH), 7.38 (1H, br d, J= 7 Hz, major, minor ArH), 7.47 (1H, br d, J = 7 Hz, major ArH), 7.55 5 (1 H, br d, J = 7 Hz, major ArH), 8.32 (1H, br d, J = 7 Hz, minor ArH), 8.38 (1H, s, minor CHO), 8.69 (1H, s, major CHO). IR 2923,1744,1675, 1276 cm-1. HRMS 294.1131 (294.1130 calcd. for C18Hl6N03) ; Rf 0. 3 (silica, 75% ether in hexanes).

Example 8 Methyl 10, 11-dihydro-5H-dibenzo [adlcvclohepten-5 10-imine-5-carboxylate 8 16 17 A solution of 16 (9.5 mg, 32 mol) in methanol (5.0 mL) is treated with concentrated sulfuric acid (3 drops) and stirred at ambient temperature for 15 hours. The mixture is then quenched with aqueous sodium bicarbonate to pH 8 and extracted with CH2Cl2 (3 mL). The combined organic phases are washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to yield the title compound 17 (8.7 mg, 100%) as a colorless oil. aH (300MHz, CDCl3) 2.4 (1H, br s, NH), 2.72 (1H, d, J = 17 Hz, 11-

Ha), 3.44 (1H, dd, J = 17,5.5 Hz, 11-his), 3.94 (3H, s, CH3), 4.78 (1H, d, J = 5.5 Hz, 10-Ha), 6.97 (1H, br d, J = 7 Hz, ArH), 7-7.25 (4H, m, ArH), 7.32 (2H, br d, J = 7 Hz, ArH), 7.65 (1H, br d, J = 7 Hz, ArH). IR 3307,2924,1742,1463,1255 cm-1. HRMS 266.1178 (266.1181 calcd. for C17Hl6No2) ; Rf 0. 2 (silica, 75% ether in hexanes).

Example 9 5-Aminocarbonyl-10, 11-dihvdro-5H-dibenzol a. dl cvclohepten-5 10-imine 17 19 Amino-ester 17 is converted into 2,3,6,7-Dibenzo-1-carboxamido-1,4- azabicyclo [3.2.1] octane 19 (5-aminocarbonyl-10, 11-dihydro-SH-dibenzo [a, d] cyclohepten- 5,10-imine) by heating the ester in methanolic ammonia as follows.

A solution of the amino ester 17 (0.53 g, 1.90 mmol) and sodium cyanide (10 mg) in anhydrous methanol (40 mL) which is previously saturated at 5°C with ammonia gas is warmed to 60°C in a sealed tube for 40 hours. After cooling to 5°C, the solid which forms is filtered, washed with H2O and air-dried affording 5-aminocarbonyl-10, 11-dihydro-5H- dibenzo [a, d] cyclohepten-5,10-imine (0.25 g, 1.0 mmol) 19. The filtrate is extracted with CH2Cl2 (3 x 50), the organic pool was dried (K2CO3) and evaporated under reduced pressure, affording an additional quantity of the title compound (0.19 g, 0.76 mmol).

Recrystallization of the combined samples from ethanol yields analytically pure material (0.37 g, 1.5 mmol, 78%). mp 235-236°C.

The invention and the manner and process of making and using it are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the claims.

To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude the specification.