MXPA97007834A - Preparation of 5-aminocarbonil-5h-dibenzo - [a, d] ciclohepten- 5,10-quiral imines, through opt separation - Google Patents

Abstract

In the present invention, a process for separating a racemic mixture of 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5,10-imas, in the component enantiomers, processes comprising the recrystallization of the diastereomeric tartrate salts, is described.

Description

PREPARATION OF 5-AMINOCARBONI L- 5H-DIBENZO- [a, d] CICLOHEPTEN-5, 10-QUIRAL IMINAS, THROUGH OPTICAL SEPARATION FIELD OF THE INVENTION This invention relates to the field of pharmaceutical chemistry, and provides an advantageous process for separating racemic mixtures of 5-aminocarbonyl-5H-dibenzo [a, d] cycle epten-5, 10-imines. More specifically, the present application relates to the optical separation of enantiomers, ie, chiral antipodes of the 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5, 10-imines, by recrystallization of a mixture of salts of the amines.

BACKGROUND OF THE INVENTION U.S. Patent No. 5,196,415 discloses various 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5, 10-imines and methods for preparing those compounds. The methods described in it involve the conversion of 10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5, 10-imines not REF. : 025848 substituted in C5, in its derivatives of N-terbutylformamidine, followed by the formation of the substituted ethyl ester in C5. After removal of the terbutylformamidine portion, from the nitrogen atom of the ring system, the ester functionality is replaced with an amide group by heating the ester in methanol with the appropriate amine derivative. If an N-substi tution is desired, the secondary amine is allowed to react with the appropriate alkyl halide, in the presence of a suitable base. When the initial reaction employs a racemic mixture of 10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5, 10-imines unsubstituted at C5, the resulting product is a racemic mixture of 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5, 10-imines. The racemic mixtures of 5-aminocarbonyl-5H-dibenzo [a,] cyclohepten-5, 10-imines are known to have pharmacological activity as anticonvulsant agents. See, for example, Roga et al., 1991, J. Pharmacol ogy and Experimen tal Therapeuti cs, 259: 30-37; and Grant et al., 1992, J. Pharma cology and Experimen t al Therapeu ti cs, 260: 1017-1022.

The separation of diastereomers by chromatographic methods is well known. However, different diastereomers, enantiomers (optical antipodes of chiral compounds) can not be separated by standard chromatographic methods; Pure enantiomers should be prepared, either by chiral synthesis delayed or through optical separation. Optical separation is empirical - and highly specific for the enantiomers to be separated. It is well known that salt formation and solubility parameters are very critical to obtain a system, to achieve separation of enantiomers from a racemic mixture. Much experimentation is necessary to find the appropriate combination for each individual separation. Among the most difficult to separate enantiomers are those in which the molecules possess a high degree of spatial symmetry around the chiral centers. Such a situation is found in the case of the dibenzo [a, d] cyclohepten-5, 10-imines wherein the characteristics are structural around the nitrogen of the central amine are virtually identical for the two enantiomers, as shown in Scheme 1 later. In the case of the 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5, 10-imines such as those described in U.S. Patent No. 5,196,415, the R group found in Scheme 1 represents a primary amide functionality.

Scheme 1 lü l In Scheme 1, the formula l_a is a 5H-dibenzo [a, d] cyclohepten-5, 10 imine substituted at the 5-position and the formula lb_ shows the line of symmetry, represented by the dashed line. Although the general class of 5H-dibenzo [a, d] cyclohepten-5, 10 imines substituted at position 5, of the structure the former was first described 20 years ago, only one method has been described for carrying out a optical separation for 5-dibenzo [a, d] cyclohepten-5, 10-imines. British patent application GB 2004872 (Anderson et al.) Describes the optical separation of 5-met il-10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine. The methods described in British patent application GB 2004872 require an acid and a solvent that are substantially different from the materials used in the present Jta method. In addition, the compounds in the racemic mixtures separated by the procedures outlined in that patent are much simpler than the structure 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5, 10-imine. In fact, the methods described in that patent are not capable of separating racemic mixtures of 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5, 10-imines.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a method for separating racemic mixtures of 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5, 10-imines of formula 2. These racemic mixtures can be prepared by the method described in US Patent No. 5,196,415. Thus, the invention provides methods for preparing chiral compounds of formula 2. The inventive methods involve the optical separation of racemic mixtures of 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5, 10-imines, i.e. Formula 2_: wherein each Ri and R2 is independently selected from hydrogen, linear or branched alkyl groups, from one to about 20 carbon atoms, alkenyl groups from 2 to about 20 carbon atoms, alkynyl groups from 2 to about twenty carbon atoms, cycloalkyl groups of 3 to about 8 carbon atoms, and wherein Ri and R2 can be taken together to form a cyclic structure containing N, having from 2 to about 8 carbon atoms, and any of those groups is optionally substituted with one or more substituents selected from alkyl, haloalkyl, hydroxyalkyl, alkenyl, oxo, hydroxyl, alkoxy, thio, alkoxyalkyl, amino, halo, cyano, or mercapto, and wherein R3 and R4 are independently selected from hydrogen, alkyl groups or linear or branched from 1 to about 10 carbon atoms, alkenyl groups from 2 to about 10 carbon atoms, alkyl groups uinyl of 2 to about 10 carbon atoms, hydroxyl, amino, alkylamino, alkoxy, cyano, nitro, haloalkyl, and mercapto, and wherein R 5 is selected from hydrogen, linear or branched alkyl groups of 1 to about 10 carbon atoms, alkenyl groups of 2 to about 10 carbon atoms, alkynyl groups of 2 to about 10 carbon atoms, hydroxyl, phenyl, haloalkyl, aminoalkyl, 1-phenylmethyl, 2-phenylmethyl, and alkoxy, and wherein Ri and R5 taken in the form together, they can form a cyclic structure containing two nitrogen atoms, possessing from 2 to about 6 carbon atoms, wherein any of the groups is optionally substituted by alkyl, oxo, thio, alkoxy, hydroxy, amino, alkylamino, phenyl, haloalkyl and thio. The invention involves first forming a mixture of diastereomeric salts of the amines, followed by subsequent recrystallization of the solid mixture to produce a product containing an enantiomer in an enantomeric excess. The mixture of salts is recrystallized in a solvent system based on ethanol / water. That solvent is capable of dissolving both enantiomers at a first temperature but only one enantiomer at a second temperature, lower than the first. The invention also involves first forming a mixture of tartrate salts of the amines, followed by subsequent recrystallization of the mixture, to produce a product containing a certain enantiomer in certain enantiomeric excess. The mixture of tartrate salts is dissolved in a solvent system capable of dissolving both enantiomers, at a first temperature, but only one enantiomer at a second temperature, lower than the first.

DETAILED DESCRIPTION OF THE INVENTION In this document all temperatures are presented in degrees Celsius. All quantities, ratios, concentrations, proportions and the like shall be presented in units by weight, unless otherwise stated, except for solvent ratios, which are volumetric units. Where the term "alkyl" is used, either alone or among other terms such as "haloalkyl" or "alkylamino", the term "alkyl" embraces linear or branched radicals having from one to about ten carbon atoms. Preferred alkyl radicals are the "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 in which one or more of the carbon atoms is substituted with one or more halogen atoms, preferably selected from fluoro, chloro and bromo. Specifically encompassed by the term "haloalkyl" are the monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. Examples of a polyhaloalkyl are trifluoromethyl, 2,2,2-tri? Uoroethyl 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, which contain at least one carbon-carbon triple bond. The term "alkoxy" embraces linear or branched radicals containing oxy groups, having alkyl portions of one to about ten carbon atoms, such as the methoxy group. The alkoxy radicals may be further substituted with one or more halogen atoms, such as fluoro, chloro or bromo to provide haloalkoxy groups. The term "alkylamino" embraces linear or branched nitrogen containing radicals, wherein the nitrogen atom may be substituted with an amount of one to three alkyl radicals or one to ten carbon atoms, such as N-methylamino and N, N-dimethylamino. Specific examples of alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertbutyl, secbutyl, neopentyl and n-pentyl. Typical alkenyl groups may have an unsaturated double bond, such as allyl or may have a plurality of double bonds. By "enantiomeric excess", as used herein, is meant more than one enantiomer than the other enantiomer. By "racemic mixture", as used herein, is meant a mixture of 50:50 by weight of two enantiomers. By "optical separation" or "separation", as used herein, is meant a process for separating a racemic mixture into two components that are enantiomers or optical isomers.

The following group of representative products of the process and this invention will be mentioned, to ensure that the reader fully understands the overall purpose of the process: U.S. Patent No. 5,196,415 discloses that compounds that can be separated by the methods of the invention are useful for the treatment of patients with generalized epilepsy or with partial (symptomatic) epilepsy. These compounds are also useful for the treatment of desires for ingesting drugs, in patients addicted to cocaine. The administration of compounds that are within the formula 2_, to humans, can be through any technique capable of introducing the compounds into the bloodstream of a human patient, and include oral administration, and by intravenous injections, intramuscula is and subcutaneous The 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 dose will be in the range of 1.0 to 50 mg per kilogram of body weight. A suitable dose can be administered in adequate 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 2 can be administered alone. These 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 delivering the active compound, without undesirable side effects. The supply of the active compound in these formulations can be carried out through various routes such as oral, nasal, buccal or sublingual, or through parenteral administration such as subcutaneous, intramuscular, intravenous or intradermal routes. The delivery of the active compound can 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 hydroxypropylmethylcellulose, together with one or more lubricants, preservatives, dispersing or surface active agents. These capsules or tablets may contain a controlled release formulation, which may be provided in an array of the active compound in hydroxypropylmethylcellulose. Formulations for parenteral administration may be in the form of sterile solutions for injection, isotonic, aqueous or non-aqueous, or in the form of suspensions. Solutions or suspensions may be prepared from sterile powders or granules having one or more of the aforementioned carriers or diluents for use in the formulations for oral administration. The racemic mixtures of formula 2 are separated using the process outlined in scheme 2. E s qu ema 2 racemic mixture 2 +) - ta rtá ri co filtered mixture of salts diastereomeric tartrate 1. Dissolve in ethanol / water 2. Cool 3. Separate the filtrate (5R, 10R) -5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5, 10-imine Filtrate containing (5S, IOS) -5 -aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5,10-imine and (5R, 10R) -5-aminocarbonyl-5H-dibenzo [a, d} cyclohepten-5, 10-imine 1. D - (-) - tartaric acid ethanol,? 2. Cool 3. Separate the filtrate (5S, IOS) -5-aminocarbonyl-5H-dibenzo [a, d] • cyclohepten-5, 10-imine In Scheme 2, the definitions of Ri / R2, R3, R4 and 5 are as previously provided for formula 2_. Thus, the invention provides processes for separating or separating racemic mixtures of 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5., 10-imines, in their enantiomeric components. The process comprises selectively crystallizing a first tartrate salt, from a mixture of tartrate salts of the 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5, 10-imines. The separated products contain an enantiomeric excess *, either one (5R, 1 OR) -5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5, 10-imine or one (5S, 1 OS) - 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5,10-imine. (5R, 10R) -5-aminocarbonyl-5H-di-benzo [a, d] cyclohepten-5, 10-imines (3a_) and (5S, IOS) -5-aminocarbonyl-5H-dibenzo [a, d] ] cyclohepten-5, 10-imines (3b_) can be represented as follows: 3b The definitions of Ri, R2, R3, and R4 in 3_a_ and 3_b are as previously provided for formula 2_. The racemic 5-aminocarbonyl-10,1-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine can be prepared in accordance with the procedures set forth in U.S. Pat. No. 5,196,415, from racemic 10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine. The separation of the racemic material is essentially a recrystallization of diastereomers of different solubilities from an appropriate solvent system. A mixture of salts teriomeric dias (for example (+) - acid salts of a chiral acid) is dissolved in the solvent; when cooled, it crystallizes in a single terioomer. A single enantiomer of the amine is obtained after the subsequent neutralization of the acid. The filtrate is saved for the subsequent separation of the other enantiomer by recrystallization of the terioomer days of the (-) - acid salt. More specifically, the racemic material is separated into its component enantiomers by first preparing a mixture of diastereomeric salts by treating the racemic amine mixture with a chiral acid, in a suitable solvent, preferably at elevated temperature. The acid is preferably tartaric acid, ie optically pure D - (-) - or L - (+) - tartaric acid. In preferred embodiments, the tartaric acid is L - (+) - tartaric acid. Representative solvents for this step include mixtures of water and alcohols such as ethanol. Any solid not dissolved in the solvent is removed. Cooling the resulting solution provides a mixture of diastereomeric tartrate salts, either of D - (-) - tartaric acid or of L- (+) - tartaric acid. The resulting mixture is then dissolved in a solvent capable of dissolving both diastereols at a high temperature, but capable of maintaining only one of the terioid days in solution, upon cooling. A solvent such as this provides a single diastereomer in an enantomeric excess. Suitable solvents for performing this separation include mixtures of ethanol and water. Preferred ethanol / water mixtures have volumetric ratios, from ethanol to water, from about 0.1: 1 to 10: 1. Particularly preferred ethanol / water mixtures have volumetric ratios of ethanol to water of about 1: 1. Upon cooling the solution of diastereomeric salts, only one diastereomer crystallizes, typically with an enantiomeric excess of at least 90%. The particular diastereomer can be isolated by separating the crystals from the solvent, through some suitable means, such as, for example, filtration. In preferred embodiments, the first isolated diastereomer is the L - (+) - tartaric acid salt. The resulting filtrate, which contains the other diastereomer, is retained for a further separation of the other enantiomer. The separated enantiomer can be released from the isolated salt of the individual diastereomer by treating the crystalline tartrate salt, preferably the L- (+) - tartrate salt, with a suitable base. Suitable bases are those capable of raising the pH of the solution to a level where 100% by weight of the amine is present as the free amine. Representative bases include various metal hydroxides such as sodium hydroxide, potassium, and preferably ammonium hydroxide. The amount of base is preferably used in a molar excess of the acid. The free amine of the individual enantiomer is then isolated by extraction and removal of the solvent. It can be subsequently purified by recrystallization. The separation or resolution of the other enantiomer, from the filtrate containing the other diastereomer, is achieved by first releasing the free base of the amine by treatment with a suitable base, followed by extraction and removal of the solvent. The resulting free amine is then combined at elevated temperature, in a suitable solvent, with the opposite enantiomer, of the chiral acid used above. That is, if the acid was L- (+) - tartaric acid, in the previous steps, then the acid to be used in the present is D- (-) - tartaric acid. After cooling the solution, any crystal is separated and redissolved in a solvent capable of dissolving both diastereomers at elevated temperature, but capable of maintaining only one diastereomer in solution, upon cooling. Suitable solvents for this step include mixtures of ethanol and water. Particularly preferred ethanol / water mixtures have volumetric ratios of ethanol to water of about 1: 1. Upon cooling the solution of diastereomeric salts, only one diastereomer crystallizes, typically in an enantomeric excess of at least 90%. The diastereomer is a salt of the previously separated enantiomer. The individual diastereomer can be isolated by separating the crystals from the solvent through any suitable means, such as, for example, filtration. The second separated enantiomer can be released from the isolated salt of the individual diastereomer, by treatment of the crystalline tartrate salt, preferably the D- (-) - tartrate salt, with a suitable base, as described above. The individual enantiomer-free amine is then isolated by extraction and removal of the solvent. Subsequently, it can be purified by recrystallization. Optical rotations of the separated materials can be taken using a polarimeter, such as, for example, a Randolph Autopol polarimeter. The absolute configuration of the separated enantiomers can be determined by X-ray analysis of individual crystals. The descriptions, in this application, of all articles and references, including patents, are incorporated herein by reference. The invention is further illustrated by the following examples, which should not be considered as limiting the scope or spirit of the invention, to the methods and compounds described therein.

Example 1 Preparation of 5-aminocarbonyl-l, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5, 10-imine A mixture of 10.1-dihydro-5H-dibenzo [a, d] cyclohepten-5, 10-imine (5.18 g, 25.0 mmol), N'-tert-butyl-N, N is heated at reflux for 6 days. dimethylformamidine (12.84 g, 100.0 mmol) and a few crystals of ammonium sulfate in anhydrous toluene. Evaporation of the solvent and purification of the crude product, by column chromatography, using 7% triethylamine in hexanes, as eluent, produces N-tert-butylformamidinyl-10,1-dihydro-5H-dibenzo [a, d] cyclohepten-5 , 10-imine (6.98 g, 24.1 mmol, 96%): mp 63-64 ° C. A solution of this material (5.80 g, 20.0 mmol) in anhydrous ethyl ether (150 L) is treated at 5 ° C under a nitrogen atmosphere, with a 1.25 M solution of secbutyllithium in cyclohexane (20.0 mL, 25 mmol). . The red-colored solution is allowed to stir at this temperature for 40 minutes, then treated with ethyl chloroformate (2.40 mL, 25.0 mmol). The color of the solution changes immediately to pale yellow, and the analysis of the reaction mixture, by gas chromatography, demonstrates the complete consumption of the initial material. The reaction mixture is treated with ethanol (100 mL) and H2SO4 (0.56 mL, 10.0 mmol), and the ether is evaporated under reduced pressure. The ethanolic solution is heated under reflux for 4 hours, then diluted with 0.5 N HCl (100 mL) and extracted with Et20 (3 x 100). The aqueous part is made alkaline by the addition of INN NaOH, and extracted with Et20 (3 x 100). The combined organic portion is washed once with H20 (100 mL), then dried over K2C03 and concentrated to dryness yielding 5-ethoxycarbonyl-l, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5, 10 -imine (3.37 g, 12.1 mmol, 60%). The hydrogen chloride salt is formed by passing a stream of anhydrous HCl gas through an ethereal solution of the secondary amine: m.p. 229-230 ° C. A solution of the preceding amino ester (0.53g, 1.90 mmol) and sodium cyanide (10 mg) in anhydrous methanol (40 mL), which has been previously saturated at 5 ° C with ammonia gas, is heated up to 60 ° C in a sealed tube, for 40 hours . After cooling to 5 ° C, the solid that formed is filtered, washed with H20, and air dried to produce 5-aminocarbonyl-10,11-dihydro-5-aminocarbonyl-5H-dibenzo [a, d ] ci-clohepten-5, 10-imine (0.25g, 1.0 mmol). The filtrate is extracted with CH2C12 (3 x 50), the organic part is dried (K2C03) and evaporated under reduced pressure, to yield an additional amount of the title compound (0.19 g, 0.76 mmol). Recrystallization of the combined samples, in ethanol, gives the analytically pure material (0.37 g, 1.5 mmol, 78%): m.p. 235-236 ° C.

Example 2 1. Separation of (5R, 10R) -5-aminocarbonyl-5-aminocarbonyl-5H-dibenzo [a, d] ci-clohepten-5, 10-imine A mixture containing 3.0 g (12 mmol) of water is heated to boiling. -aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5, 10-imine (mp 235-237 ° C) and 1.86 g of L - (+) - tartaric acid in 30 mL of ethanol and 20 mL of water, and the small amounts of solids that do not dissolve are separated by filtration while the solution is hot. The resulting solution is cooled for 4 hours at room temperature and then overnight at -10 ° C to provide 2.1 g of salt L - (+) - tartrate. This salt is dissolved in 20 L of boiling ethanol / water solution, 1: 1. After cooling for 4 hours at room temperature and overnight at -10 ° C, 1.53 g of crystals are obtained. The filtrate is saved for later use in part 2 of this example. The crystals are treated with an excess of concentrated ammonium hydroxide and the resulting mixture is extracted with methylene chloride. The methylene chloride layer is removed and the residue is crystallized from 10 mL of ethanol / water, 5: 1, to provide 0.699 g of (5R, 1 OR) -5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten -5, 10-imine, mp = 213 ° C. 2. Separation of (5S, IOS) -5-aminocarbonyl-5H-dibenzo (a, d) cyclohepten-5, 10-imineThe filtrate saved in part 1 of this example is treated with an excess ammonium hydroxide solution, and the resulting mixture is subsequently extracted with methylene chloride. Removal of the solvent provides 1.93 g of free, crude base. This material is combined with 1.16 g of D- (-) - tartaric acid in 35 mL ethanol / water, 1: 1, boiling. The mixture is cooled for 4 hours at room temperature and then overnight at -10 ° C to provide 1.75 g of crystals. The crystals are collected in 35 L ethanol / water, 1: 1, hot, and cooled to provide 1.31 g of crystals. The crystals are treated with excess ammonium hydroxide solution and extracted with methylene chloride. After removing the solvent, the residue is recrystallized from ethanol / water, 5: 1, to provide 0.724 g of (5S, IOS) -5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5, 10- imina, pf 213 ° C. 3. Preparation of isocyanate derivatives of 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5, 10-imine The S - (+) - naphthylethyl isocyanate derivative of (5S, 10S) -5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5,10-imine is prepared by mixing equal molar amounts of the separated amine, prepared in part 1, above, and S- (+) - naphthyl isocyanate (94% enantiomeric excess) in methylene chloride, and concentrated. The analysis by NMR ~ H, at 200 Mhz, of the resulting urea derivative, shows a doublet at 1.48 ppm, which corresponds to 96% of the mixture, and a doublet at 1.38 ppm, which corresponds to 4% of the mixture. A similar reaction is carried out with a mixture of racemic 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5,10-imine. The analysis by NMR ~ H, at 200 Mhz, of the urea derivative, of the racemic amine, presents a pair of methyl doublets, of equal intensity, at 1.38 ppm (J = 6.8 Hz) and at 1.48 ppm (J = 4.7 Hz) . 4. Melting point of 5% racemic mixture The addition of 5% by weight of the enantiomer 5S, 10S to the 5R, 10R pure material, provides a material having a melting point of 190-236 ° C.

. Optical rotation and X-ray crystallography The optical rotation of the enantiomer obtained from the separation with L - (+) - tartaric acid is -21.2 °. The optical rotation of the enantiomer obtained from the separation with acid D- (-) -tartaric is + 22.6 °. The X-ray analysis in individual crystals of the enantiomer, which shows a positive rotation (+) in the ORD, indicates that the absolute configuration of the chiral centers in C-5 and in C-10 is S, the absolute configuration of ( -) enantiomer, is therefore C-5R and C-10 R.

Now it describes the invention and the way and process to carry it out and use it, in complete, clear, concise and exact terms, to allow any person experienced in the technique to which the present one belongs to, to make use of the same It should be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made thereto without departing from the spirit or scope of the invention as set forth in the claims. To particular note and distinctly claim the matter of interest related to the invention, the following claims conclude the specification. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property:

Claims (9)

1. CLAIMS 1. A process for separating a racemic mixture of 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5, 10-imines, in their component enantiomers, characterized in that it comprises selectively crystallizing a first diastereomeric salt from a mixture of two diastereomeric salts of the 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5, 10-imines in a mixture of ethanol and water.
2. 2. A process according to claim 1, characterized in that the mixture of salts is prepared using a single enantiomer of tartaric acid.
3. 3. A process according to claim 2, characterized in that the ratio volume, of ethanol to water, in the mixture of ethanol and water, is from about 0.1: 1 to about 10: 1.
4. 4. A process according to claim 3, characterized in that the volume ratio of ethanol to water, in the mixture of ethanol and water, is about 1: 1.
5. 5. A process according to claim 4, characterized in that the tartaric acid is L- (+) - tartaric acid.
6. 6. A process according to claim 4, characterized in that the tartaric acid is D- (-) - tartaric acid.
7. 7. A process for separating a racemic mixture of 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5, 10-imines in their component enantiomers, characterized in that it comprises: (a) selectively crystallizing a first tartrate salt from a solution in ethanol and water, tartrate salts of 5-aminocarbonyl-5H-dibenzo [a, d] cyclohepten-5, 10-imines, the mixture of diastereomeric tartrate salts is prepared using a first enantiomer of tartaric acid; (b) separating the first tartrate salt from the solution; (c) forming a second tartrate salt in the solution obtained in (b), and the second salt is prepared using a second enantiomer of tartaric acid.
8. 8. A process according to claim 7, characterized in that the first enantiomer of tartaric acid is L- (+) - tartaric acid.
9. 9. A process according to claim 8, characterized in that the second enantiomer of tartaric acid is D - (-) - tartaric acid. < • 10. A process according to claim 9, characterized in that the volume ratio of ethanol to water, in the solution, is approximately 1: 1. 12. A process according to claim 11, characterized in that it further comprises (d), separating the second tartrate salt from the solution.