WO2012121701A1

WO2012121701A1 - Process for the resolution of racemic (±)-10,11-dihydro-10-hydroxy-5h-dibenz[b,f]azepine-5-carboxamide

Info

Publication number: WO2012121701A1
Application number: PCT/US2011/027406
Authority: WO
Inventors: Santosh Richard Fredric CRASTA; Ashutosh Vijay Joshi; Manjunath Narayan Bhanu
Original assignee: Watson Laboratories, Inc.
Priority date: 2011-03-07
Filing date: 2011-03-07
Publication date: 2012-09-13

Abstract

A process for resolving racemic (±)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide comprising reacting (±)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide with S-ibuprofen or a pharmaceutically acceptable salt thereof to form a mixture of the SS and SR diastereomer esters of 10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide, followed by separating the SS-ibuprofen ester from the SR ibuprofen ester, and removal of the S-ibuprofen moiety to form S-(+)-10,l l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide with a chiral purity greater than 90%.

Description

PROCESS FOR THE RESOLUTION OF RACEMIC (±)-10,ll-DIHYDRO-10- HYDROXY-5H-DIBENZ[b,f]AZEPINE-5-CARBOXAMIDE

FIELD OF THE INVENTION

The present invention relates to a process for the resolution of racemic (±)-10,l l- dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide to yield the R and S stereoisomers, and a process for the preparation of (S)-(-)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,f]azepine-5- carboxamide, also known as eslicarbazepine acetate. BACKGROUND OF THE INVENTION

The pharmaceutical industry aggressively investigates compounds containing chiral centers to determine if one of the enantiomers possesses greater efficacy, fewer side effects or both. Because one isomer of a racemic mixture is often pharmacologically inactive or significantly less active, employing a racemic mixture of a chiral drug can be viewed as introducing an unnecessary impurity into a pharmaceutical product. One isomer of the racemic mixture may also produce unwanted side-effects. Isomeric molecules may also undergo different metabolic processes which further complicates pharmacokinetic issues. Accordingly, the U.S. Food and Drug Administration (FDA) often requires stringent investigation of active molecules that contain chiral centers to determine potential efficacy and safety issues.

One example of a drug that yields racemic mixtures is oxcarbazepine, which is the 10- keto analogue of carbamazepine. Although oxcarbazepine and carbamazepine are structurally similar and both are used for the treatment of epilepsy, oxcarbazepine was designed to avoid the oxidative metabolic transformation of carbamazepine and is claimed to be better tolerated. See Grant, S. M. et al, Drugs, 43, 873-888 (1992). Unfortunately, oxcarbazepine undergoes rapid and complete metabolism in vivo to form a racemic 10-hydroxy derivative of oxcarbazepine. See Schutz, H. et al, Xenobiotica, 16(8), 769-778 (1986). The existence of these chiral metabolites generated from oxcarbazepine has led to the development of (S)-(-)-10-acetoxy-10,l 1-dihydro- 5H-dibenz[b,fJazepine-5-carboxamide (eslicarbazepine acetate), which is a single-isomer drug specifically designed to avoid the formation of racemic mixtures of active metabolites. See U.S. Pat. No. 5,753,646, and Benes, J. et al, J. Med. Chem., 42, 2582-2587 (1999). Eslicarbazepine acetate is an anticonvulsant or antiepileptic drug which is used in the treatment of epilepsy, seizures, partial-onset seizures in adults with epilepsy, affective and attention disorders, anxiety, psychiatric disorders with underlying anxiety symptomatologies, mental disorders and/or other deficits in the sensory organs.

Eslicarbazepine acetate is re resented by the chemical structure:

eslicarbazepine acetate (I)

The synthesis and anticonvulsant properties of S-(-)-10-acetoxy-10,l l-dihydro-5H- dibenz[b,f]azepine-5-carboxamide are described in U.S. Patent No. 5,753,646. This patent also discloses the resolution of racemic (±)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide into its R and S optically pure stereoisomers.

Resolution of the racemic (±)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide has also been previously described in J. Med. Chem., 1999, 42, 2582-2587 and Epilepsia, 2000, 41(9), 1107-1111. These processes describe the formation of diastereomeric menthoxyacetate ester derivatives of racemic (±)-10,l l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide. Unfortunately, (+) or (-) menthoxy acetic acids are extremely expensive and not readily available. A further and very serious limitation of this method is the relatively low yield obtained from the optically pure menthoxyacetate ester, with yields around 20%, with a maximum yield of 50% for each isomer.

WO 2002/092572 discloses methods for the preparation of eslicarbazepine acetate by reacting racemic (±)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide with diacetyl L-tartaric anhydride, followed by diastereomeric separation in water to yield an insoluble precipitate of tartaric ester of (±)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide having an SRR configuration, while the mother liquor is enriched with a soluble RRR diastereomer. Next, deprotection of the SRR ester with alkaline NaOH in methanol yields pure S-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, and acetylation of the pure S-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide yields eslicarbazepine acetate.

WO 2007/012793 describes processes for the preparation of eslicarbazepine acetate by enantioselective reduction of oxcarbazepine in the presence of a catalyst, such as [RuX₂(L)]2 and a hydride source under controlled pH. During the disclosed process S-(+)-10,l l-dihydro-10- hydroxy-5H-dibenz[b,f]azepine-5-carboxamide is acetylated using 4-(N,N- dimethylamino)pyridine, pyridine, and acetic anhydride in dichloromethane to give substantially pure (S)-(-)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,f]azepine-5-carboxamide.

U.S. Published Application No. 2006/0194791 discloses an enantioselective reduction of oxcarbazepine in the presence of a chiral ruthenium catalyst, a hydride donor and triethylamine to give S-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide.

WO 2007/117166 discloses asymmetric hydrogenation of a double bond formed on the central azepine ring of a dibenzazepine in the presence of a hydrogen source and chiral catalysts, such as a ruthenium catalyst. Specifically, the double bond, which is asymmetrically reduced, is located at the ether linkage of the azepine ring. This asymmetric hydrogenation yields (S)-(-)- 10-acetoxy-10,l l-dihydro-5H-dibenz[b,f]azepine-5-carboxamide with a chiral purity of up to 94%.

All of the above recited patents, journal articles and patent applications are incorporated herein by reference.

The prior art resolving techniques generally involve either: (1) chiral reduction of oxcarbazepine with enantioselective catalysts to give the S or R isomer; or (2) racemic reduction of oxcarbazepine followed by esterification with expensive chiral acids to form diastereomers, which can then be separated using known enantiomeric separation techniques. However, resolution agents such as (+) and (-) menthoxy acetic acid, and (+) and (-) menthol are extremely expensive and not readily available.

SUMMARY OF THE INVENTION

The present invention provides a process for the resolution of (±)-10,l l-dihydro-10- hydroxy-5H-dibenz[b,f]azepine-5-carboxamide using S-ibuprofen or a pharmaceutically acceptable salt thereof. One embodiment of the present invention employs a reaction of S-ibuprofen or a pharmaceutically acceptable salt thereof and racemic (±)-10,l l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide to yield the SR and SS-ibuprofen diastereomer esters of (±)- 10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide. The SR and SS-ibuprofen diastereomer esters of (±)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide may be separated to yield the SS-ibuprofen diastereomer ester. Removal of the S-ibuprofen moiety from the SS-ibuprofen ester yields the (S)-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine- 5-carboxamide. The physical and chemical differences of the diastereomer esters enables the SS and SR compounds to be prepared and/or separated using less costly and less complex techniques then many of the known prior art methods.

An embodiment of the present invention for resolving racemic (±)-10,l l-dihydro-10- hydroxy-5H-dibenz[b,f]azepine-5-carboxamide using S-ibuprofen or a pharmaceutically acceptable salt thereof can be represented as follows:

i) reacting the racemic compound of Formula (III):

(III) with S-ibuprofen of Formula (IV) or a pharmaceutically acceptable salt thereof:

(IV) to form a mixture of the SS and SR ibuprofen diastereomer esters of 10,11-dihydro hydroxy-5H-dibenz[b,f]azepine-5-carboxamide of Formula (Va) [SS] and (Vb) [SR]:

ii) separating the mixture of ibuprofen diastereomer esters of Formulas (Va) and (Vb) to yield the SS-ibuprofen ester of Formula V(a) with greater than 60% chiral purity, preferably greater than 75% chiral purity, and most preferably greater than 85% chiral purity; iii) removing the S-ibuprofen moiety from the compound of Formula V(a) and to form (S)-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz b,f]azepine-5-carboxamide of Formula (VI):

(VI).

The resolved (S)-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide may be employed in the production of compounds such as (S)-(-)-10-acetoxy-10,l l-dihydro-5H- dibenz[b,f]azepine-5-carboxamide (eslicarbazepine acetate). Additional compounds that can be formed from the (S)-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide are recited in WO 2002/092572 and are incorporated herein by reference. DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for resolving the racemic (±)-10,l l-dihydro-10- hydroxy-5H-dibenz[b,f]azepine-5-carboxamide of Formula (III):

(III)

The process for resolving the racemic (±)-10,l l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide of Formula (III) is generally shown in the following reaction Scheme I:

SCHEME I As shown in reaction Scheme I, the process for resolving the racemic (±)-10,l 1-dihydro- 10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide of the Formula (III) comprises the steps of: i) reacting the compound of Formula (III):

with S-ibuprofen of Formula (IV) or a pharmaceutically acceptable salt thereof:

(IV) to form a mixture of the SS and SR ibuprofen diastereomer esters of 10,11-dihydro hydroxy-5H-dibenz b,f]azepine-5-carboxamide of Formula (Va) [SS] and (Vb) [SR]:

(Va) (Vb) ii) separating the ibuprofen diastereomer esters of Formulas (Va) and (Vb) to yield SS ibuprofen ester of Formula V(a); iii) removing the S-ibuprofen moiety from the compound of Formula V(a) to form the S- (+)-10,l l-dihydro-10-hydroxy-5H-dibenz b,f]azepine-5-carboxamide of Formula (VI):

(VI).

Methods of obtaining racemic (±) 10,1 l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide, the compound of Formula (III), are described in U.S. Patent No. 5,753,646, WO 2002/092572 and WO 2007/117166 and are incorporated herein by reference. One such method is the reduction of oxcarbazepine in an organic solvent in a presence of a reducing agent, such as sodium borohydride. Other suitable reducing agents include but are not limited to sodium borohydride, lithium aluminum hydride, hydrogen, nickel borohydride, diisobutylaluminum hydride, formic acid, hydrazine, sodium hydrosulfite, trichlorosilane, sodium hydroxymethanesulfmate, and mixtures of the foregoing. Suitable organic solvents include, but are not limited to, methylene dichloride, methanol, hexane, benzene, toluene, chloroform, diethyl ether, 1,4-dioxane or mixtures thereof.

One embodiment of the present invention involves reacting the racemic (±)-10,l l- dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide of Formula (III) with S-ibuprofen of Formula (IV) or a pharmaceutically acceptable salt thereof in a solution, and in the presence of a reaction catalyst. Examples of pharmaceutically acceptable salts of S-ibuprofen include, but are not limited to, chloride, bromide, iodide, succinate, fumarate, mesylate, citrate, tartrate and sulfate. The solvent for the reaction is an organic solvent such as methylene chloride, methylene dichloride, ethanol, methanol, propanol, isopropanol, acetone, methyl acetate, ethyl acetate, hexane, and mixtures thereof. The reaction catalyst may be any catalyst such as dimethylaminopyridine (DMAP) and dicyclohexylcarbodiimide (DCC), or a combination thereof. Other catalysts that can be employed in the reaction include mineral acid catalysts, hafnium (IV) salts and zirconium (IV) salts. The reaction mixture may be heated to assist in the formation of the SS and SR esters. In certain embodiments the reaction mixture is heated to about 20°C, preferably at least 25°C, and most preferably at least about 30°C. Once the SS and SR ibuprofen esters have been formed, the reaction mass is filtered and washed to produce a solid. The reaction product is a mixture of SS and SR ibuprofen diastereomer esters of 10,11- dihydro- 10-hydroxy-5H-dibenz[b,fJazepine-5-carboxamide.

The mixture of SS and SR ibuprofen diaestereomer esters of 10,11-dihydro-lO-hydroxy-

5H-dibenz[b,fJazepine-5-carboxamide can then be separated by techniques known in the art, such as diastereomeric crystallization, solvent based separation, chromatographic methods, or combinations thereof.

One method of diastereomeric crystallization involves obtaining a racemic mixture of the SS and SR ibuprofen diastereomer esters of 10,1 l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide, preferably in a crystal form, and placing the racemic mixture into a solvent so that the SS-ibuprofen ester is crystallized from the reaction mixture. The SS-ibuprofen ester is preferably crystallized at a chiral purity level of at least 90%. One embodiment of the diastereomeric crystallization of the present invention comprises placing a racemic mixture of the SS and SR powder into an organic solvent. The organic solvent may be any solvent, but a mixture of an organic ester and a Ci-C₆ alcohol is preferred. The organic ester may be selected from the group consisting of methylacetate, ethylacetate, propylacetate, butylacetate or mixtures thereof. The Ci-C₆ alcohol may be straight or branched alcohols and may be selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, pentanol, tertbutyl alcohol, isobutyl alcohol, or mixtures of the foregoing.

If a mixture of an organic ester and Ci-C₆ alcohol is used, the ratio of the mixed solvents should be about 1 :20 to 20: 1, preferably 1 : 15 to 15: 1, and most preferably 1 : 10 to 10: 1. In certain embodiments, the amount of the organic ester should exceed the amount of Ci-C₆ alcohol. In these embodiments, the amount of organic ester is at least twice the amount of the Ci-C₆ alcohol. Preferably, the organic ester is at least four (4) times the amount of the Ci-C₆ alcohol, and most preferably, the organic ester is at least eight (8) times the amount of the Ci-C₆ alcohol.

In a further embodiment the SS-ibuprofen ester product can be prepared using various solvent ratios, some of which are set forth below: Solvents/ ratio

*anic ester: d -C₆ alcohol / 85:15

*anic ester: Ci -C₆ alcohol / 85:15

or^ *anic ester: d -C₆ alcohol / 82:18

or^ *anic ester: Ci -C₆ alcohol / 85:15

or^ *anic ester: Ci -C₆ alcohol / 80:20

*anic ester: Q -C₆ alcohol / 80:20

or^ *anic ester: Ci -C₆ alcohol / 83:17

or^ *anic ester: d -C₆ alcohol / 75:25

The reaction mixture of an organic ester, a Ci-C₆ alcohol and racemic mixture of SS and SR ibuprofen diastereomer esters of 10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide may be heated to assist in the dissolution of the SS and SR esters. In certain embodiments the reaction mixture is heated to about 35°C, preferably at least 40°C, and most preferably to at least about 50°C. Once the SS and SR ibuprofen esters have been dissolved, the solution is cooled to selectively crystallize the SS or SR ibuprofen ester.

In this embodiment of the present invention employing a mixture of an organic ester and Ci-C₆ alcohol, the SS-ibuprofen ester is isolated as a crystal from the reaction mass with a purity of at least 90% or greater, preferably at least 92% or greater, and most preferably at least 95% or greater.

Another embodiment of the present invention separates the SS and SR ibuprofen diastereomer esters using a solvent based separation technique to obtain the SS-ibuprofen ester with a chiral purity ranging from 90-100%.

One method of solvent based separation involves obtaining the racemic mixture of the SS and SR ibuprofen diastereomer esters of 10,1 l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide, and placing the racemic mixture into a solvent so that the SS-ibuprofen ester can be separated from the SR ibuprofen ester. The SS-ibuprofen ester is preferably obtained at a chiral purity level of at least 90%. One embodiment of the solvent based separation of the present invention comprises placing a racemic mixture of the SS and SR powder into an organic solvent. The organic solvent may be any solvent, but a mixture of an organic ester and a halogenated Ci-C₆ compound is preferred. The organic ester may be selected from the group consisting of methylacetate, ethylacetate, propylacetate, butylacetate or mixtures thereof. The halogenated Ci-C₆ compound may be straight, branched or cyclical compounds and may be selected from the group consisting of chlorobutane, chlorobenzene, 1 ,2-dichlorobenzene, methylene chloride, methyl dichloride, trichloroethylene, 2,2,2-Trifluoroethanol, chloroform, 1 , 1 ,2-Trichlorotrifluoroethane, carbon tetrachloride, tetrachloroethylene, tetrafluromethane, ethylene dibromide, methylene chlorobromide, methyl bromine, n-butyl iodide, methyl iodide, n- propyl iodide, or mixtures of the foregoing.

If a mixture of an organic ester and the halogenated Ci-C₆ compound is used, the ratio should be about 1 : 10 to 10: 1 , preferably 1 :5 to 5 : 1 , and most preferably 1 :2 to 2: 1. In certain embodiments, the amount of the organic ester can be lower, equal to, or greater than the amount of halogenated Ci-C₆ compound. In preferred embodiments, the amount of organic ester is greater than the amount of the halogenated Ci-C₆ compound, and in a more preferred embodiment the organic ester is two (2) times the amount of the halogenated Ci-C₆ compound.

The reaction mixture of an organic ester, a halogenated Ci-C₆ compound and racemic mixture of SS and SR ibuprofen diastereomer esters of 10, 1 l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide may be heated to assist in the dissolution of the SS and SR esters. In certain embodiments, the reaction mixture is heated to about 25°C, preferably at least about 35°C, and most preferably at least about 40°C. Once the SS and SR ibuprofen esters have been dissolved, the solution is cooled and filtered, resulting in the formation of solid, which is the SS-ibuprofen ester.

In this embodiment of the present invention employing an organic ester and the halogenated Ci-C₆ compound the SS-ibuprofen ester is isolated as a solid from the reaction mass with a purity of at least 90% or greater, preferably at least 92% or greater, and most preferably at least 95% or greater.

Subsequent separation reactions after the initial isolation of the SS-ibuprofen ester by either solvent based separation, diastereomeric crystallization, or both, can produce the SS- ibuprofen ester of 10, 1 l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide with a chiral purity (or enantiomeric excess) greater than 95%, preferably greater than 99% and most preferably greater than 99.5%.

Once the SS-ibuprofen ester has been isolated the ibuprofen moiety may be removed from the SS-ibuprofen ester. The removal or cleaving of the ibuprofen moiety can be accomplished by known techniques. One embodiment of the present invention comprises dissolving the SS-ibuprofen ester in an organic solvent, such a Ci-C₆ alcohol as previously described. Once the SS-ibuprofen ester is in solution, a molar excess of a base is added to the solution to hydrolyze the SS-ibuprofen. The base employed can be sodium hydroxide, potassium hydroxide, sodium carbonate, ammonia, barium hydroxide, calcium hydroxide, lithium hydroxide, sodium amide, sodium hydride or other suitable bases known in the art. The base is preferably added to the SS-ibuprofen solution as a solution, and preferably as an aqueous solution. The reaction mixture may be heated to assist in the hydrolysis. In certain embodiments the reaction mixture is heated to about 20°C, preferably at least about 25°C, and most preferably at least about 30°C.

Once the hydrolysis is completed, the solvents are removed and the S-(+)-10,l 1-dihydro-

10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide is collected. The S-(+)-10,l l-dihydro-10- hydroxy-5H-dibenz[b,f]azepine-5-carboxamide is collected by known techniques such as titration, evaporation and/or filtration. The collected S-(+)-10,l l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide and may be washed with a suitable solvent and dried. The resulting S-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide exhibits a chiral purity of at least 90%, preferably 92%, and most preferably 95%>.

In a further embodiment, S-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide may be reacted with an acetylating agent, such as acetyl chloride, in an organic solvent to form the (S)-(-)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,f]azepine-5-carboxamide compound. Additional acetylating agents include, but are not limited to, acetic acid, formic acid, propionic acid, ethyl acetate, acetyl chloride, acetic anhydride, sodium acetate, potassium acetate, or mixtures thereof. Suitable organic solvents can be selected from the group consisting of methylene chloride, methylene dichloride, ethanol, methanol, propanol, isopropanol, acetone, methyl acetate, ethyl acetate, hexane, and mixtures thereof. The preferred organic solvent in the acetylation step is methylene dichloride. The above acetylation reaction can be performed in the presence of a catalyst, a preferred catalyst is pyridine.

Methods of preparing (S)-(-)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,f]azepine-5- carboxamide are described in U.S. Patent No. 5,753,646; WO 2002/092572; and WO 2007/012793 which are incorporated herein by reference. The chiral purity of the compounds described herein can be determined by any means known in the art. The chiral purity reported in the following examples was determined by high performance liquid chromatography (HPLC).

The (S)-(-)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,f]azepine-5-carboxamide, and other compounds prepared in accordance with the present invention may be mixed with at least one additional conventional pharmaceutical excipient to prepare a pharmaceutical dosage forms such as tablets, capsules or solutions.

EXAMPLES

Example 1

Step 1: Reduction of oxcarbazepine

100 gm of oxcarbazepine and 10.6 gm of sodium borohydride were dissolved in 300 ml of methylene dichloride in a dry round bottom flask. The solution was then cooled to 5-15°C. 300 ml of methanol was added to the above solution over 1.0 to 1.5 hours, and the solution was maintained at 20-30°C for 1.0 hour. The solution was then distilled under atmospheric condition until 300 ml volume of methanol remained. Next, 500 ml of distilled mineral water at 50°C was added to the solution. The solution was cooled to 20-30°C and maintained at this temperature for 15-30 minutes. The reaction mass was then filtered and the obtained solid was washed twice with 100 ml of distilled mineral water. The product, namely, (±)-10,l l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide (step 1 product) was dried in an oven at 70°C. The dry weight of the step 1 product was 90 gm (with a chemical purity of 99.4%).

Step 2: Esterification of (±)-10,ll-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide

25 gm of the step 1 product, 22.3 gm of S-ibuprofen, and 1.2 gm dimethylaminopyridine

(DMAP) were dissolved in 100 ml of methylene dichloride, stirred and cooled to 0-10°C. 22.3 gm dicyclohexylcarbodiimide (DCC) was dissolved in 50 ml of methylene dichloride and added to the above solution over 30 minutes. The reaction temperature was raised to 20-30°C and maintained at this temperature until the reaction was completed. The reaction mass was filtered and washed with 50 ml of methylene dichloride. The reaction mass was then washed twice with 50 ml of 0.5N HC1, followed by two washes with 50 ml of saturated sodium bicarbonate solution. The solution was then subjected to distillation where the methylene dichloride was distilled off and the resulting slurry was washed with 50 ml of hexane and filtered. The product, namely, the racemic mixture of SS and SR ibuprofen diastereomer esters of 10,l l-dihydro-10- hydroxy-5H-dibenz[b,f]azepine-5-carboxamide (step 2 product) was dried in an oven at 60-65°C. The dry weight of the step 2 product was 40.5 gm (with a chemical purity of 50:50 of the R:S esters).

Step 3(a): Diastereomeric crystallization of the SS-ibuprofen ester

5 gm of the step 2 product was dissolved in 100 ml of an ethyl acetate:methanol (9: 1) mixture at 50-60°C and maintained at this temperature for 30 min. The reaction mass was then cooled to 25-30°C within 1-2 hours, and further cooled to 0-5°C and maintained at this temperature for 15-30 minutes. The reaction mass was then filtered and the solid obtained was washed twice with 20 ml of hexane. The product was dried in an oven at 65°C, to obtain the SS enriched ibuprofen ester of 10,l l-dihydro-10-hydroxy-5H-dibenz[b,fJazepine-5-carboxamide (step 3(a) product) (with a chiral purity of 92% of the SS-ibuprofen ester).

Step 3(b): Solubility based separation of the SR and SS-ibuprofen esters

5 gm of the step 2 product was dissolved in 120 ml of an ethyl acetate :methylene dichloride (2: 1) mixture at 35-40°C and maintained at this temperature for 30 min. The reaction mass was then cooled to 25-30°C within 1-2 hours, and further cooled to 0-5°C and maintained at this temperature for 15-30 minutes. The reaction mass was then filtered and the solid obtained was washed twice with 20 ml of hexane. The product was dried in an oven at 65°C to obtain the SS-ibuprofen enriched ester of 10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide (step 3(b) product) (with a chiral purity of 95% of the SS ester).

Step 4: Removal of the S-ibuprofen moiety

4.0 gm of the SS enriched product of step 3(a) or 3(b) was dissolved in 25 ml of methanol and 10 ml of 3.0 N NaOH and stirred at 20-30°C. The heterogeneous reaction mass was stirred until complete hydrolysis was completed. The reaction mass was distilled under vacuum at 45°C to obtain a white solid which was slurried with 25 ml of distilled mineral water. The solid was filtered and washed with 25 ml of distilled mineral water. The solid was dried in an oven at 70°C, to obtain S-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide (step 4 product) (with an enantiomeric excess of 92%).

Step 5: Preparation of the S-(+)-10,ll-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide

The S-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide of Step 4 was converted into (S)-(-)-10-acetoxy-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide by dissolving the S-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide in a solution of acetylchloride, dichloromethane and pyridine as described in U.S. Patent No. 5,753,646. The reaction mass was heated until the reaction was complete, followed by cooling, filtering and washing. The reaction product is the (S)-(-)-10-acetoxy-10,l 1-dihydro- 10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide.

Example 2

Step 1: Esterification of (±)-10,ll-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide using S-ibuprofen chloride

218 gm of S-ibuprofen was dissolved in 225ml methylene dichloride and cooled to 5- 15°C. Thionyl chloride 92.4ml was added over 60-90minute at 5-15°C. The reaction temperature was raised to 20-30°C and maintained for 1-2 hours. Excess of thionyl chloride was distilled under vacuum below 50°C. The acid chloride was then cooled to 20-30°C and diluted with 225ml methylene dichloride.

225 gm of the step 1 product, 10.7 gm dimethylaminopyridine (DMAP) and 184 ml of triethylamine were dissolved in 1225 ml of methylene dichloride, stirred and cooled to 5-15°C. Ibuprofen acid chloride was added to the reaction mass at 5-15°C over a period of from 60 to 90 minutes and maintained for 15-30 minutes at 5-15°C. The reaction mass temperature was raised to 20-30°C. The reaction mass was then washed twice with 750ml of 0.2M sulfuric acid solution and 750ml of DM water. The solution was then subjected to distillation where the methylene dichloride was distilled off, stripped with hexane and the resulting slurry was washed with 225 ml of hexane and filtered. The product, namely, the racemic mixture of SS and SR ibuprofen diastereomer esters of 10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide was dried in an oven at 60-65°C. The dry weight was 358.9 gm (with a chemical purity of 48.71 :50.17 ofthe R:S esters).

Step 2(a): Diastereomeric crystallization of the SS-ibuprofen ester

350 gm of the product prepared by the process described within Example 2, Step 1 was dissolved in 4550 ml of an ethyl acetate: methanol (8:2) mixture at 60-70°C and maintained at this temperature for 60 min. The reaction mass was then cooled to 25-30°C within 1-2 hours, and maintained at this temperature for 12-16 hours. The reaction mass was then filtered and the solid obtained was washed twice with 175 ml of ethyl acetate. The product was dried in an oven at 65°C, to obtain the SS enriched ibuprofen ester of 10,1 l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide (with a chemical purity of 96.88%, and chiral purity of 99.2% of the SS-ibuprofen ester).

Step 2(b): Diastereomeric crystallization of the SS-ibuprofen ester in different solvent ratios and volumes.

The SS-ibuprofen ester product can be prepared using various solvent ratios and volumes, some of which are set forth below:

Step 3: Removal of the S-ibuprofen moiety

110 gm of the product that was prepared by the process described within Example 2, Step 2(a) was dissolved in 550 ml of methanol and NaOH aqueous solution (30 gm of sodium hydroxide dissolved in 55 ml of DM water). The heterogeneous reaction was stirred at 20-30°C until complete hydrolysis. The reaction mass was subjected to distillation under vacuum at 45°C to obtain an oil/solid and to it 220 ml of DM water was added and stirred at 20-30°C. The mass was neutralized with 440ml of dilute sulfuric acid. 330ml of hexane was further added to mass and stirred for 30-60 min. The mass was then filtered and washed with 110 ml of hexane and 220ml of DM water. The solid was dried in an oven at 70°C, to obtain S-(+)-10,l l-dihydro-10- hydroxy-5H-dibenz[b,f]azepine-5-carboxamide (with a chemical purity of 99.85% and enantiomeric excess of 98%).

The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein, any of the terms "comprising," "consisting essentially of and "consisting of may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

Claims

What is claimed is:

1. A process for resolving racemic (±)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide of Formula (III) comprising the following steps:

i) reacting the racemic compound of Formula (III) with S-ibuprofen of Formula (IV) armaceutically acceptable salt thereof:

(IV) to form a mixture of SS and SR ibuprofen diastereomer esters of 10,11-dihydro- hydroxy-5H-dibenz b,f]azepine-5-carboxamide of Formula (Va) [SS] and (Vb) [SR]:

(Va) (Vb) ii) separating the mixture of ibuprofen diastereomer esters of Formulas (Va) and (Vb) to yield SS-ibuprofen ester of Formula V(a) with greater than 60% chiral purity;

iii) removing the S-ibuprofen moiety from the compound of Formula V(a) and forming S-(+)-10,l l-dihydro-10-hydrox -5H-dibenz[b,f]azepine-5-carboxamide of Formula (VI):

(VI).

2. The process according to claim 1 wherein the reaction in step (i) is done in the presence of a catalyst.

3. The process according to claim 2 wherein the catalyst is selected from the group consisting of dimethylaminopyridine, dicyclohexylcarbodiimide, and mixtures thereof.

4. The process according to claim 1 wherein separating the SS and SR diastereomer esters of 10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide in step (ii) is conducted by diastereomeric crystallization.

5. The process according to claim 1 wherein separating the SS and SR diastereomer esters of 10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide in step (ii) is conducted by solvent based separation.

6. The process according to claim 1 wherein separating the SS and SR diastereomer esters of 10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide in step (ii) is conducted by solvent based separation and diastereomeric crystallization.

7. The process according to claim 1 wherein the reaction in step (iii) is conducted in the presence of a base.

8. The process according to claim 7 wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonia, barium hydroxide, calcium hydroxide, lithium hydroxide, sodium amide, sodium hydride, or mixture thereof.

9. The process according to claim 1, further comprising the following step:

iv) acetylating the S-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide of Formula (VI) to form (S)-(-)-10-acetoxy-10,l l-dihydro-5H- dibenz[b,f]azepine-5-carboxamide com ound of Formula (I):

(I)-

(S)-(-)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,f]azepine-5-carboxamide of Formula (I)

(I)- prepared by the process of claim 1.

11. A pharmaceutical composition comprising (S)-(-)-10-acetoxy-10,l l-dihydro-5H- dibenz[b,f]azepine-5-carboxamide of claim 10 and a pharmaceutically acceptable excipient.

12. The process according to claim 1 wherein the (S)-(+)-10,l l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide of Formula (VI) has a chiral purity of at least 90%.

13. The process according to claim 1 wherein the (S)-(+)-10,l l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide of Formula (VI) has a chiral purity of at least 95%.

14. The process according to claim 1 wherein the (S)-(+)-10,l l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide of Formula (VI) has a chiral purity of at least 99%.

15. A process for resolving racemic (±)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine- 5-carboxamide of Formula (III) comprising the following steps:

(III) i) reacting the racemic compound of Formula (III) with S-ibuprofen of Formula (IV) or a pharmaceutically acceptable salt th

in the presence of dimethylaminopyridine, dicyclohexylcarbodiimide or a mixture thereof to form a mixture of SS and SR ibuprofen diastereomer esters of 10,1 l-dihydro-10- hydroxy-5H-dibenz[b,f]azepine-5-carboxamide of Formula (Va) [SS] and (Vb) [SR]:

(Va) (Vb) ii) separating the mixture of ibuprofen diastereomer esters of Formulas (Va) and (Vb) to yield the SS-ibuprofen ester of Formula V(a) with a chiral purity of 85% or more by: a) diastereomeric crystallization; or

b) solvent based separation;

iii) removing the S-ibuprofen moiety from the compound of Formula V(a) with sodium hydroxide to form S-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide of Formula (VI):

(VI).

The process according to claim 15, further comprising the following step:

iv) acetylating the S-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5 carboxamide of Formula (VI) to form the (S)-(-)-10-acetoxy-10,l l-dihydro-5H dibenz[b,f]azepine-5-carboxamide compound of Formula (I):

(I)-

(I)- prepared by the process of claim 15.

18. A pharmaceutical composition comprising (S)-(-)-10-acetoxy-10,l l-dihydro-5H- dibenz[b,f]azepine-5-carboxamide of claim 17 and a pharmaceutically acceptable excipient.

19. The process according to claim 15 wherein the (S)-(+)-10,l l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide of Formula (VI) has a chiral purity of at least 90%.

20. The process according to claim 15 wherein the (S)-(+)-10,l l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide of Formula (VI) has a chiral purity of at least 95%.

21. The process according to claim 15 wherein the (S)-(+)-10,l l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide of Formula (VI) has a chiral purity of at least 99%.