MX2007005425A

MX2007005425A - Process for preparing quinoline compounds and products obtained therefrom

Info

Publication number: MX2007005425A
Application number: MX/A/2007/005425A
Authority: MX
Inventors: Dehnhardt Christoph; Megati Sreenivasulu; Sun Jerry
Original assignee: Dehnhardt Christoph; Megati Sreenivasulu; Sun Jerry; Wyeth
Priority date: 2004-11-05
Filing date: 2007-05-04
Publication date: 2008-10-03

Abstract

Methods for synthesizing tetrahydroquinoline-containing compounds of formula (II) are provided, along with synthetic intermediates and products associated with such methods.

Description

PROCESS FOR THE PREPARATION OF COMPOUNDS BASED ON QUINOLINE AND PRODUCTS OBTAINED FROM THEMSELVES FIELD OF THE INVENTION The present invention relates to methods for synthesizing tetrahydroquinoline compounds as well as intermediates and products associated with said methods. BACKGROUND OF THE INVENTION International Patent Application WO 03/091250, in the name of Ramamoorthy, discloses tetrahydroquinoline-containing compounds, methods for their preparation and methods for using them, such as, for example, psychotic and anti-obesity agents. It is sought to obtain alternative synthetic methods for these and other compounds containing tetrahydroquinoline. BRIEF DESCRIPTION OF THE INVENTION In one aspect, the present invention provides methods for the preparation of compounds containing tetrahydroquinoline by reaction of benzodiazepines with paraformaldehyde and suitable unsaturated portions such as alkanes (including dienes) or alkynes. In certain embodiments, the methods of the invention are directed to the preparation of the tetrahydroquinolines and involve the reaction of the REF. : 182002 benzodiazepines with one equivalent of solid formaldehyde, for example paraformaldehyde and an alkane or alkyne in the presence of a Lewis acid and a reaction solvent. Reaction solvents that are useful for the formation of certain tetrahydroquinoline-containing compounds include polar aprotic solvents such as alkyl nitriles (e.g., acetonitrile, propionitrile and but ironitrile), esters (e.g., ethyl acetate), chlorinated hydrocns (eg, methylene chloride), N-alkyl formams (e.g., dimethylformamide) and mixtures thereof. Certain preferred methods include the delivery of a compound of formula 1: wherein: R1 is alkyl, alkanoyl, aroyl, calkoxy or calkoxyaryl; R2 and R3 are, independently, hydrogen, hydroxy, alkyl, alkoxy, halogen, cxamido, calkoxy, perfluoroalkyl, cyano, alkanesulfonamido, alkennesulfonyl, alkanamido, amino, alkylamino, dialkylamino, perfluoroalkoxy, alkanoyloxy, alkanoyl, aroyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R6 and R7 are, independently, hydrogen or alkyl; n is 1 or 2; and contacting the compound of formula I with at least one equivalent of formaldehyde and a reagent with the formula R4-CH = CH-R5 or the formula R4-C = C-R5, in the presence of a Lewis acid and of a reaction solvent to form a compound of formula II: II wherein each R1, R2, R3, R6, R7 and n are as defined above; the formaldehyde equivalent is in solid form at some time prior to contact; R4 and R5 are, independently, hydrogen or alkyl of 1 to 6 cn atoms or taken together with the cns to which they are attached, form a cyclic group which is cycloalkyl, cycloalkenyl, alkyl with bicyclic bond, alkenyl with bicyclic bond, pyranyl or thiopyranyl in the that the sulfur atom is optionally oxidized to sulfoxide or sulfone; and the dotted line represents an optional double bond. Preferred methods of the invention further comprise contacting the compound of the formula II with an acid having a pKa less than 1 and forming a bis salt of the III wherein X is the counterion of the acid such as, for example: halogen, acid sulfate or alkyl- or aryl-sulfonate. The methods of the invention further include contacting the bis salt of formula III with the base, thereby forming a free base with formula IV: IV Preferred bases are alkali metal hydroxides, alkaline earth metal hydroxides, cnates, phosphates, organic bases and combinations thereof. Particularly preferred is sodium hydroxide in an aqueous solution. According to the invention, the free bases can be formed alternatively by contacting a compound of the formula II with a base. According to the invention, the free bases can also be prepared by contacting a compound of the formula I, in which R1 is replaced by hydrogen with one equivalent of formaldehyde and a reagent with the formula R4-CH = CH-R5 or the formula R4-C = C-R5 in the presence of a Lewis acid and a reaction solvent, in which the formaldehyde equivalent is in solid form, at least before contact. The free base of formula IV is formed, generally, as a racemic mixture. When a particular enantiomer is preferred, it can be provided substantially free of the corresponding enantiomer by isolation or separation methods known in the art, including, for example: high performance liquid chromatography and chiral salt resolution or by the techniques described in this document. The racemic compound of the formula is treated IV with a chiral agent to form a mixture d i e e r e or re i ca of it. In certain embodiments, the racemic compound of formula IV is treated with a chiral agent to form a diastereomeric mixture thereof. As used herein, the term "diastereomeric salt" refers to the adduct of a chiral compound of formula IV with a chiral acid. Subsequently, the resulting diastereomeric mixture is separated by suitable means to obtain the desired diastereomeric salt. Said means suitable for the separation of mixtures of re-organic mixtures are well known to one skilled in the art and include, but are not limited to, the methods described herein. It will be appreciated that, depending on the chiral acid used, there may be one or more portions of carboxylates present. In certain embodiments, the chiral acid has two carboxylate groups such as, for example: tartaric acid or a derivative thereof. The term "separated by appropriate physical means" refers to the methods of separating the mixtures into nanotech or mixtures. Such methods are well known in the art and include, among others: crystallization, distillation and crushing as preferred methods. The chiral agents and separation methods are described in detail in Stereochemistry of Organic Compounds, Eliel, E. 1. and Wilen, S. H., 1994, published by John Iley and Sons. In the preferred embodiments, the so-formed organic salts are contacted with organic to inorganic acids with a pKa lower than that of the chiral acid solved to form the desired enantiomeric salt. As used herein, the term "salt e n n t i orne r i ca" refers to the salt of the resolved chiral compound of formula IV, wherein said compound of formula IV is enriched in an enantiomer. As used herein, the term "enriched enan t i orne r i carne n t e" means that an enantiomer composes at least 85% of the preparation. In certain embodiments, the term "enantomerically enriched" means that at least 90% of the preparation is one of the enantiomers. In other embodiments, the term indicates that, at least 95% of the preparation is one of the enantiomers. Acids for salt formation include hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and acid.

Hydrochloric acid, mellic acid, succinic acid, trifluoric acid, mineral acids, acids, acids, acids, acids and their acids. combinations of the same s. Therefore, the representative salts are the ones that have, for example, the formula Va or Vb wherein each R2, R3, R4, R5, R6, R7 and n are as defined above and each Z is a counterion of the aforementioned acids. Examples of Z include, but are not limited to, halogens such as CI, Br and I, and ions that include HS04, H2P04, MsO (where Ms is mesylate), AcO (where Ac is acetyl), maleate and succinate. The inorganic salts once formed are preferably reactive to improve purity. Suitable solvents of the re c r i s t a 1 i z a tion include aqueous alcohols such Alkyl alcohols, for example: methanol, ethanol, isopropanol and butanol. In the preferred embodiments, the enantomeric salt is a compound of the formula G: is more than about 90 percent of the area of chiral purity, preferably greater than 95 percent, of the area of chiral purity, preferably greater than about 99 percent of the area of chiral purity (percentage of the HPLC area of the desired enantiomer relative to the area Total HPLC of stereoisomers (enantiomers)). The name of the free base of the compound of G is (9aR, 12aS) -4, 5, 6, 7, 9, 9a, 10, 11, 12, 12a-decahydrocyclopenta [c] [1,4] diazepino [6, 7, li j] quinoline. The salt, as observed in formula G, has an optical rotation (-). One skilled in the art will recognize that the optical rotation of G can change if it becomes a free base form.

The present invention also provides the compounds of formulas I, II, III, IV, G, Va and Vb in addition to other intermediates and synthetic products, made in accordance with the preceding methods. Preferably, said compounds are provided with a weight greater than about 90 percent. For example: the present invention provides the compounds of the formula V: V wherein X is the counterion of an acid with a pKa less than 1. The present invention also provides compositions comprising a diastereomeric salt of a diaroyl-L tartaric acid and a free base of the formula Vlb: Vlb wherein each R2, R3, R4, R5, R6, R7 and n are as defined above and neither R4 nor R5 are hydrogens.

In other embodiments, the compositions that are provided include, at least 90 percent of the HPLC area of a compound of formula 11: VII in less than an amount of about 10 percent of the HPLC area. Even in other embodiments, compositions that include a compound of formula III are provided: wherein each R2, R3, R4, R5, R6, R7, n and X are as defined above and a compound of the formula X: wherein each R2, R3, R4, R5, R6, R7 and n are as defined above or a salt thereof, in an amount less than about 10 percent of the HPLC area. Even in other embodiments, the compositions provided include a salt of a diaryl tartaric acid and a free base of the formula IV: IV wherein each R2, R3, R4, R5, R6, R7 and n are as defined above and a compound of the formula X wherein each R 2, R 3, R 4, R 5, R 6, R 7 and n are as defined above or a salt thereof (including salt thereof), in an amount less than about 10%. percent of the HPLC area. In other embodiments, compositions are provided that include a compound of the formula and one or more organic impurities in a total amount of about 2 percent of the HPLC area or less, or one or more residual solvents in a total amount of 1.0 weight percent or less. Other embodiments provide compositions containing a compound of formula G: and water in an amount of about 2.0 percent by weight or less, as measured by the KF titration and / or where G has an acid chloride content of about 12.8 percent by weight to about 14.8 percent of the weight, as measured by an ion chromatography, based on the total weight of the composition. Even other embodiments provide a compound of the formula G: as needle-shaped crystals and / or with an average particle size of less than about 25. In other embodiments, a method that includes a compound of formula VI VIII and the contact of the compound of formula VIII with at least one equivalent of formaldehyde and a reagent having the formula R 4 -CH = CH-R 5 or the formula R 4-C = C-R 5, in the presence of an acid of Lewis and a reaction solvent to form a compound of formula IX: where the formaldehyde equivalent is in solid form, at least before contact; R8 is a branched or linear alkyl group, an alkylic group having a sulphide, an aryl group or an arylalkyl group; and R4 and R5 are, independently, hydrogen or alkyl of 1 to 6 carbon atoms or taken together with the carbons to which they are attached, form a cyclic group which is cycloalkyl, c i c 1 or 1 quen i 1, alkyl with bicyclic bond, alkenyl with bicyclic bond, pyranyl or thiopyranyl in which the sulfur atom is optionally oxidized in sulfoxide or sulphon. DE S CRI PC I DETAILED OF THE INVENTION In the preferred embodiments, the compounds are prepared, according to the invention, according to the reaction scheme that is observed below: _ REACTION SCHEME 1 free base The compounds of the formula II are prepared preferably by contact with a compound of the formula I: I wherein: R1 is alkyl, alkanoyl, aroyl, carboalkoxy or carboalkoxyaryl; R2 and R3 are, independently, hydrogen, hydroxy, alkyl, alkoxy, halogen, carboxamido, carboalkoxy, perfluoroalkyl, cyano, alkanesulfonamido, alcansulfonyl, alkanamido, amino, alkylamino, dialkylamino, perfluoroalkoxy, alkanoyloxy, alkanoyl, aroyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R6 and R7 are, independently, hydrogen or alkyl; and n is 1 or 2, with one equivalent of formaldehyde, such as for example paraformaldehyde and an unsaturated reagent preferably having the formula R-CH = CH-R5 or the formula R4-C = C-R5 in the presence of an acid of Lewis and a solvent reaction and that forms a compound of the formula wherein: R1 is alkyl, alkanoyl, aroyl, carboalkoxy or carboalkoxyaryl; R2 and R3 are, independently, hydrogen, hydroxy, alkyl, alkoxy, halogen, carboxamido, carboalkoxy, perfluoroalkyl, cyano, at 1 ca nsu 1 f onami do, at 1 ca nsu 1 f on i 1, alcanamido, amino, alkylamino, dia 1 qu i 1 ami no, pe rf 1 or o 1 cox i, alkanoyloxy, alkanoyl, aroyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R4 and R5 are, independently, hydrogen or alkyl or are taken together with the carbons to which they are attached, form a cyclic group which is cycloalkyl, cycloalkenyl, alkyl with bicyclic bond, alkenyl with bicyclic linkage, pyranyl or thiopyranyl wherein the Sulfur atom is oxidized optionally on sulfoxide or sulfone; the dotted line represents an optional double bond.

R5 and R7 are, independently, hydrogen or alkyl; and Nos. 1 or 2. In accordance with the invention, the representative compounds are those in which R 1 is alkyl, alkanoyl, aroyl, carboalkoxy or cabox 1 cox a r i 1 o. Preferred compounds are those in which R1 is acetyl. As generally defined above, R2 and R3 are, each independently, hydrogen, hydroxy, alkyl, alkoxy, halogen, carboxamido, carboalkoxy, pe rf 1 or 1 quo 1 oo, cyano, a 1 c an su 1 ammonium, 1 ca nsu 1 f on i 1, alkanamido, amino, alkylamino, dialkylamino, pe rf 1 or cox i, alkanoyl, aroyl, aryl, arylalkyl, heteroaryl or heteroaryl 1 to 1 qu i 1 o; In the preferred embodiments, both R2 and R3 are hydrogens. As generally defined above, R4 and R5 are, independently each, hydrogen to alkyl of 1 to 6 carbon atoms or are taken together with the carbons to which they are attached, form a cyclic group which is cy 1 or 1 qui 1 o, cic 1 or 1 quen i 1 o, alkyl with bicyclic bond, alkenyl with bicyclic bond, pyranyl Thiopyranyl in which the sulfur atom is optionally oxidized to sulfoxide or sulfone. The dotted line represents an optional double bond. In the preferred embodiments, the optional double bond is not present. In certain modalities, R4 and R5 are taken together with the carbons to which they are attached to form the ring of c i c 1 or 1 qui 1 o. The cyclic groups formed by R 4 and R 5 are optionally substituted by one to three s and t t and t independently selected from halogen, alkyl and alkoxy. Particularly preferred compounds are those in which R4 and R5, taken together with the carbons to which they are bound, form a cyclopentyl moiety. R6 and R7 can be, independently, hydrogen or alkyl, both preferably being hydrogen. As generally defined and before, n is 1 or 2 and in the preferred embodiments it is 1. The compounds formed by the processes of this invention may contain asymmetric carbon atoms and consequently, produce optical isomers and di aestereosis. . While some formulas (such as, II, III, IV, etc.) in the present document are observed unrelated to the stereochemistry, the present invention includes all the optical isomers and diastereomers, as well as the pure, racemic and resolved stereoisomers R and S enant i orne ri cament, as well as the other mixtures of stereoisomers R and S and pharmaceutically accepted salts thereof. When an enantiomer is preferred, in some embodiments it may be provided its s t anc l e ement free of the corresponding enantiomer. "Substantially free", as used herein, means that the compound was made in a significantly greater proportion than an enantiomer. In preferred embodiments, at least about 95% by weight of the preferred enantiomer is present. In other embodiments of the invention, at least about 99% by weight of the preferred enantiomer is present. Preferred enantiomers can be isolated from the racemic mixtures by any method known to those skilled in the art, including high performance liquid phase chromatography (HPLC) and a chiral salt resolution or can be prepared in accordance with the methods described in the present document The term "diastereomeric salt", as used herein, is the adduct of a chiral amine, such as for example: wherein each R2, R3, R4, R5, R6, R7 and n is as defined above, with a chiral acid, such as 1-tartaric acid and, in the case of chiral resolution acids, with two carboxyl groups, includes stockings- and mono-salts. The term "salt n a n t i orne r i ca", as used herein, refers to the salt of the resolved chiral amine, such as for example: Go Vb wherein each R2, R3, R4, R5, R6, R7 and n are such a comma defined above. "Organic impurities", as used herein, refer to any residual material to organic derivative present in the desired product (such as those of formula IV or VI or salts thereof) and not They include residual solvents or water. The "total organic impurities" refer to the total amount of organic impurities present in the desired quinoline product. The percentage of organic impurities such as, for example, the total organic impurities and the single major impurity is established, unless otherwise specified in the present document as the percentage of the HPLC area relative to the total area of the HPLC chromatogram. The percentage of the HPLC area is reported at a wavelength where the desired product is absorbed and the maximum amount of impurities. The term "alkyl", as used herein, refers to the hydrocarbon group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms and more preferably 1 to 4 carbon atoms. The term "alkyl" includes, but is not limited to, linear and branched groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentilo, n- hexyl and isohexyl. The term "lower alkyl" refers to an alkyl group having 1 to 4 carbon atoms. Arylalkoxy, as used herein, refers to the group-0 (CH2) rAr, wherein r is 1-6. Alcanamide, as used herein, refers to the group - NHC (0) R wherein R is an alkyl group. Alkanoyl, as used herein, refers to the group-C (0) R wherein R is an alkyl group. Alkanoyloxy, as used herein, refers to the group -CO (0) R wherein R is an alkyl group. Alcansulfonamido, as used herein, refers to the group -NHS (0) 2R wherein R is an alkyl group. Alcansulfonyl, as used herein, refers to the group -S (0) 2R wherein R is an alkyl group. Alkoxy, as used herein, refers to the group -0R wherein R is an alkyl group. The term "aryl" used alone or as part of a larger group as for example in "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to the monocyclic, bicyclic or tricyclic ring systems having a total of six to fourteen ring components, wherein at least one ring in the system is aromatic and in which each ring of the system contains from 3 to 7 ring components. The term "aryl" can be used interchangeably with the term "aryl ring". The term "heteroaryl", used alone or as part of a larger group, such as in "heteroaralkyl" or "heteroarylalkoxy", refers to monocyclic ring systems having from five to six ring components and from 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. The term "heteroaryl" can be used interchangeably with the term "heteroaryl ring" or with the term "heteroaromatic". In certain embodiments, such as the heteroaryl ring systems include furanyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidyl, pyridazinyl, triazinyl, thiazolyl, triazolyl and tetrazolyl, to name a few. The groups containing aryl or heteroaryl moieties can be optionally substituted with one to three substituents independently selected from the halogen, alkyl or alkoxy groups.

Aroyl, as used herein, refers to the group -C (0) Ar wherein Ar is aryl, as defined above. Arylalkyl, as used herein, refers to the group - - (CH 2) r Ar wherein Ar is aryl, as defined above, and r is 1-6. Examples of the arylalkyl groups include benzyl, phenethyl, 3-phenylpropyl and 4-phenylbutyl. Heteroarylalkyl, as used herein, refers to the group - (CH 2) rHet, wherein Het is a heteroaryl group, as defined above, and r is 1-6. Carboxamido, as used herein, refers to the group-C (0) NH2. Carboalkoxy, as used herein, refers to the group -C (0) OR wherein R is alkyl. Carboalkoxyaryl, as used herein, refers to the group -C (O) O (CH 2) r Ar wherein Ar is aryl, as defined above, and r is 1-3. Preferably, Ar is phenyl and r is 1 to form a benzyl portion. Halogen (or halo), as is used herein, refers to chlorine, bromine, iodine and fluorine. Cycloalkyl and cycloalkenyl, as used herein, refer to saturated and partially unsaturated monocyclic hydrocarbon rings, respectively, containing from 3 to 8 carbon atoms and, preferably, containing rings of 5, 6 or 7 carbon atoms. In the case of cycloalkenyl, the hydrocarbon ring preferably contains one to two double bonds and, more preferably, a double bond. Cycloalkyl with bicyclic and cycloalkenyl bond with bicyclic bond, as used herein, refer to bicyclic saturated and partially unsaturated hydrocarbon rings, respectively, containing from 8 to 10 carbon atoms. "Binding", as used herein, refers to the fact that there is at least one carbon-carbon bond between two non-adjacent carbon atoms of the hydrocarbon ring. In the case of cycloalkenyl with bicyclic bond, the hydrocarbon ring preferably contains one to two double bonds and, more preferably, a double bond. The yield of the compound of the formula II is preferably greater than about 60% and, more preferably, greater than about 75%; more preferably it is greater than about 85% and even more preferably it is greater than about 91%. Performance, as used in this document and to Unless indicated otherwise, it refers to the performance of the immediate reaction rather than the general synthesis. According to the invention, preferred compounds are those in which n is 1. Particularly preferred compounds are those in which R1 is acetyl or hydrogen, R2, R3, R6 and R7 are hydrogen, n is 1, and R4 and R5 are taken together with the carbons to which they join to form a cyclopentyl group. Preferred compounds containing cyclopentyl are those with a stereochemistry and employed by the salt of the formula G: In some embodiments, the formaldehyde equivalent is added in solid form to the reaction solvent to form a reaction suspension or the solid equivalent of formaldehyde can be suspended in a reaction solvent and added to the reaction mixture. In some preferred embodiments, paraformaldehyde is used as the equivalent of formaldehyde and is added in amounts sufficient to consume a compound of formula I. In some embodiments, paraformaldehyde it is preferably added in amounts of at least about 0.90 molar equivalents, more preferably in amounts of 0.90 molar equivalents to about 1.10 molar equivalents and, more preferably, in amounts of about 1.0 molar equivalents to 1.05 molar equivalents, relative to the molar equivalent. initial compound of formula I. Paraformaldehyde is preferably in solid form. Suitable paraformaldehyde for the reaction is commercially available in granules (or other granular forms) and in powder, in various suppliers, such as Aldrich, Fluke, Celanese Chemicals, J.T. Baker, Mallinckrodt Laboratory Chemicals, Miljac Inc., SegO Int. Corp., Spectrum Chemicals Mfg., Total Specialty Chemicals Inc., US Chemicals Inc., Riedel- Haen, Acros Organics, Pfaltz & Bauer Chemicals, Derivatives, Lancaster Synthesis and EM Science. The preferred powder forms have at least about 10% of particles retained in a 200 mesh filter. The Lewis acids useful in the present invention are compounds that act as electron pair acceptor. The Lewis acids useful in the present invention include those of the formula TiX4, ZrX4., AIX3, BX3, SiX4, SnX2, SnX2, RyAIX (3-y), R (y) SiX4-y, RyBX (3-yy combinations) of them, in which X is a halogen or -OR; R is a alkyl or aryl; and y is 0-3. BF3 is particularly preferred. Preferably, the Lewis acid, such as BF3, is used in amounts of about 2 molar equivalents to about 4 molar equivalents, related to the compound of the formula I. The unsaturated reagent used in the formation of the compound of formula II is preferably an alkane (including mono- and dienes) or an alkyne. Preferred reagents include those of the formula R4-CH = CH-R5 or those of the formula R4-C = C-R5. Cyclopentene is particularly preferred. The unsaturated group, such as for example cyclopentene, is preferably used in amounts of about 2 molar equivalents to about 8 molar equivalents, related to the compound of formula I. The reaction solvents which are useful for the formation of certain compounds which contain tetrahydroquinoline include polar aprotic solvents such as alkyl nitriles (eg, acetonitrile, propionitrile and butyronitrile), alkyl esters (eg, ethyl acetate), N-alkyl formamides (eg, dimethylformamide) and chlorinated hydrocarbons (eg example, methylene chloride). In some embodiments, a reaction solvent capable of suspending the solid equivalent of formaldehyde is chosen. The preferred ones are solvents containing acetonitrile. Particularly preferred are reaction solvents containing almost all acetonitriles. Preferred solvents include those containing at least about 90 percent by weight of acetonitrile, preferably at least about 95 percent by weight of acetonitrile, and even more preferably, at least about 98 percent by weight of the weight of acetonitrile. The reaction solvent is preferably added in an amount sufficient to dissolve the compound of formula I. In some embodiments, the solvent is added in concentrations of, At least about 6 ml of the solvent per gram of the compound of the formula I. Particularly preferred reaction conditions stop the formation of the compounds of the formula 11 include making a contact of a compound of the formula I with about 2 molar equivalents to about 9 moles of cyclopentene and about 0.9 molar equivalents to about 1.2 molar equivalents of paraformaldehyde (preferably granules) in the presence of about 2.0 molar equivalents to about 4.0 molar equivalents of BF3 and acetonitrile (using approximately 5 to 20 ml per 1 g of the compound of formula I). In this embodiment, the reaction solvents that are particularly preferred are they contain at least about 90 percent of the weight of acetonitrile and, preferably, almost all of acetonitrile. The reaction temperature is preferably from about 20 ° C to about 50 ° C and, more preferably from about 30 ° C to about 45 ° C. According to Reaction Scheme I, the compounds of formula II can be converted, if desired, into a free base compound of formula IV by contacting a base in the presence of a suitable solvent or, alternatively, by contact with an acid in the presence of a suitable solvent to form a bis salt of formula III, followed by making a contact of the bis salt with a base to form the free base of formula IV. The conversion of a compound of the formula II into a bis salt of the formula III according to the invention is preferably carried out by contacting the compound of the formula II with an acid with a pKa of less than 1 in the presence of a suitable solvent for the formation of a bis salt of the formula III and at a sufficient temperature and time to form the bis salt. The acid is preferably added in an amount of at least about 2 molar equivalents and more preferably in an amount of at least about 2 molar equivalents up to about 4 molar equivalents related to the compound of formula II. Acids which may be used include, for example, hydrochloric acid, alkyl and / or aryl sulphonic acids, sulfuric acid, phosphoric acid, hydrobromic acid, iohydric acid and combinations thereof. Suitable preferred solvents for the formation of the bis salt include protic solvents such as alkanols and aprotic polar solvents miscible with water, such as dioxane or glyme and combinations thereof. Other examples of protic solvents include acetic acid to C1-C4 alcohols. Preferred alcohols include ethanol, methanol, 2-propanol or 1-butanol. The use of hydrochloric acid and denatured ethanol is particularly preferred. The conversion of a compound of the formula II into a bis salt of the formula III is preferably carried out in a mixture of about 3: 1 of alcohol and concentrated aqueous acid, more preferably in a mixture of about 2: 1 of alcohol and acid aqueous concentrate and, even more preferably, in a mixture of about 1: 1 alcohol and concentrated aqueous acid (by volume by weight). In the latter case, ethyl acetate is generally added to increase the recovery of the bis salt. In a preferred embodiment, the compound of the formula II is contacted with the Concentrated hydrochloric acid in the presence of ethanol under reflux conditions for a sufficient time to form the bis salt of the formula I I I. The bis salts of the formula I I I are preferably formed in yields of about 80% and more preferably about 85%. The bis salt of the formula I I I can be contacted with the base to form the corresponding free base compound of the formula IV. The bis salt and the base are preferably combined in the presence of a suitable solvent in which the bis salt is, at least partially, soluble, such as hot water (approximately 60 ° C to 80 ° C), polar solvents such as alkyl alcohols, such as for example the alcohols of Ci to C4 (for example, ethanol, methane, 2-propanol), dioxane to THE (tetrahydrofuran) or the combinations thereof to form the corresponding free base. The base is preferably added in an amount of at least about 2 molar equivalents and more preferably in an amount of at least about 2 molar equivalents up to about 3 molar equivalents related to the bis salt of the formula I I I. Preferred bases include alkali metal hydroxides to alkaline earth metal hydroxides, carbonates or phosphates, as well as organic bases and combinations thereof. Hydroxide is preferred sodium. Once the free base is formed, it can optionally be extracted using an extraction solvent. Preferred extraction solvents include solvents which are not miscible with water and which have, at least, partial solubility with a compound of formula IV: IV where R2, R3, R4, R5, R6, R7 and n are coded as defined herein. Examples of such solvents include alkyl ethers, alkyl acetates or aromatic hydrocarbons and combinations thereof, such as, for example, methyl tertiary butyl ether (TMBE), diethyl ether, toluene or ethyl acetate. The use of methyl tert-butyl ether is particularly preferred. Preferred methods for the preparation of the free base include the addition of a solution of sodium hydroxide (eg, NaOH in water) in a hot suspension (70 ° C-100 ° C) of salt-HCl-bis in water to form the free base as an oil that can be separated by extraction with TBME.

The free bases of the formula IV are prepared, for example, by contacting a compound of the formula II with a suitable base and, preferably in the presence of a suitable solvent for the formation of the free base. The preferred bases for this conversion are the strong inorganic bases, that is, those which completely dissociate in water under the formation of hydroxide anions. The base is preferably added in an amount of at least about 1 molar equivalent and more preferably in an amount of at least about 1 molar equivalent to about 10 molar equivalents related to the compound of formula II. Examples of such bases include alkali metals, alkaline earth metal hydroxides and combinations thereof. Potassium hydroxide is preferred. Examples of suitable solvents for use during the formation of the free base include polar solvents such as alkyl alcohols, such as the alcohols of Ci to C4 (e.g., ethanol, methanol, 2-propanol), water, dioxane or THF (tetrahydrofuran) or combinations thereof. Preferred solvents include Ci to C4 alcohols such as methanol, ethanol, 2-propanol, water and combinations thereof. The use of potassium hydroxide and methanol is preferred. In the preferred embodiments, the reflux is subjected to compound of the formula II in a mixture of methanol, water and potassium hydroxide in proportions of about 2 g of methanol / 1.5 g of water / O.7 g of potassium hydroxide per 1 g of the compound of the formula H. Alternatively, the free bases of the formula IV, according to the invention, can be prepared directly by contacting a compound of formula I, wherein R2, R3, R6 and R7 are defined as above and R1 is hydrogen, with one equivalent of formaldehyde, as per example for formaldehyde and a reagent having the formula R4-CH = CH-R5 to the formula R4-C = C-R5 in the presence of a Lewis acid and an alkyl nitrile containing the solvent, in which the equivalent of formaldehyde, the reagent, the Lewis acid and the reaction solvent are as described above, in relation to the formation of the compounds of the formula II. Preferably, the reaction conditions, including the proportions of the formaldehyde equivalent, the unsaturated reagent, the Lewis acid and the reaction solvent related to the compound of the formula I are as described hereinabove. In a preferred embodiment, about 1.1 molar equivalents of paraformaldehyde, about 8 molar equivalents of cyclopentene and about 3.5 molar equivalents of BF3 related to the compound of Formula I to produce a free base compound of formula IV. The generation of the free base of formula IV from a bis salt of formula III generally provides higher yields for the subsequent formation of the diastereomeric salt that stops the free base generated by direct hydrolysis with a strong inorganic base. further, the formation of a free base can be carried out from a bis salt, generally without using the highly caustic conditions. The chiral free bases of formula IV, whatever the form in which they were formed, can be resolved by the isolation or separation methods known in the art, including for example high performance liquid phase chromatography and salt resolution. or can be prepared using the methods described herein. In the preferred embodiments, the separation of the enantiomers is achieved through contacting the free base of formula IV with a chiral resolving acid and a solvent for a time and under certain conditions, to form the corresponding diastereomeric salt. Examples of useful resolution chiral acids include the monofunctional carboxylic acid, the difunctional carboxylic acid, the sulfonic acid, the phosphoric acid and the combinations of the same, which are relatively pure from the optical point of view, that is; at least eighty-five percent of a single enantiomer of the acid is present. The difunctional carboxylic acids include the tartaric acid esters, such as diaroyl- (eg, ditoluoyl-, dibenzoyl-) diacetyl, di-tert-butyl tartaric acid and combinations thereof. Examples of the monofunctional carboxylic acids are mandelic acid and its derivatives substituted by means of oxygen, and combinations thereof. Preferred solvents for use during resolution include polar protic and aprotic solvents which are capable of dissolving in a compound of formula IV and chiral acid and in which the diastereomeric salt sought has only limited solubility. Examples of such solvents include C2-C4 alcohols, such as ethanol, isopropanol, n-propanol, n-butanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, acetonitrile and combinations thereof. The diastereomeric salts thus formed are preferably in the yields of about 25%, more preferably about 30% and even more preferably 35% of a maximum yield of 50%. (The maximum yield is 50% since only one enantiomer can be obtained). It is preferable that the formation of salt is achieved by the use of diaroyl-1-tartaric acids, such as ditoluoyl-l-tartaric acid (DTTA). Preferred diastereomeric salts are those formed by contact, in the presence of a solvent, ditoluoyl-1-tartaric acid, with the free base of E: E to form the diastereomeric salts having formula F: F in which Tol is a toluoyl group. Particularly preferred is the use of ditoluoyl tartaric acid and a solvent containing isopropanol, ethyl acetate and combinations thereof. In one embodiment, it is preferable that the resolving chiral acid be in contact with the free base in an amount of about 0.2 molar equivalents up to about 0.4 equivalents molars related to the free base. In another embodiment, the reaction preferably includes the use of a solution having about 0.7 grams to about 1.3 grams of resolving chiral acid for approximately 10 ml of solvent (as an example isopropanol and / or ethyl acetate) which is added to a hot solution (with a temperature of about 70 ° C to about 80 ° C), having a concentration of about 4 ml to about 6 ml of the solvent (such as isopropanol) per gram of free base E. The diastereomeric salt formed, such as for example diastereomeric salt F, is then isolated by methods known in the art. For example: the chiral acid solution is resolved and the free base can be heated to almost the boiling point and then the resulting diastereomeric salt slowly cooled for a period of time, at room temperature or cooler (if desired). After cooling, the solution is filtered to isolate the crystals. Said process performed from the diastereomeric salt F generally result in crystals that are easily filtered. To increase the purity, the resulting diastereomeric salt can optionally be resuspended in a solvent, for example: isopropanol, at reflux for a sufficient time (as, for example, from about 1 hour to about 3 hours) and gradually cooled to recrystallize the salt. The preferred yields of the diastereomeric salts F are greater than about 25%, more preferably, greater than about 30% and even more preferably about 35% (the yield of 50% being the maximum possible yield) . The intended chiral purity of the diastereomeric salt is approximately greater than 80 percent of the HPLC area, more preferably approximately greater than 85 percent of the HPLC area and even more preferably approximately greater than 90 percent of the HPLC area relative to the total HPLC area of the diastereomeric salts. The resulting diastereomeric salt containing the desired enantiomer can be contacted, preferably in the presence of a suitable solvent for the isolation of the desired enantiomer, with an organic to inorganic acid with a pKa lower than the resolving chiral acid, to form the enantiomeric salt of desired resolution. Examples of such acids include hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, malic acid, succinic acid, trifluoroacetic acid, acetic acid, methanesulfonic acids, alkylsulfonic and arylsulfonic acids and the combinations of them. Suitable solvents for the formation of the enantiomeric salt include polar solvents such as for example ethanol, methanol, isopropyl acetate, ethyl acetate, isopropanol, n-propanol, n-butanol, tetrahydrofurane, acetonitrile and combinations thereof. Preference is given to using aqueous hydrochloric acid and concentrated ethyl acetate. In a preferred process, a suspension of the diastereomeric salt F in ethyl acetate and about 1 to 1.5 molar equivalents of hydrochloric acid (in concentrated aqueous form), related to the diastereomeric salt, is heated to reflux for about four hours to form the enantiomeric salt HCl G The resulting enantiomeric salt can be isolated by techniques known to those skilled in the art, such as crystallization followed by separation of the crystals. For example, in a preferred embodiment, the resulting enantiomeric salt solution can be gradually cooled to form enantiomeric salt crystals, followed by the filtrate to isolate the crystals. Subsequently, the isolated crystals can optionally recrystallized to increase the purity. For example, in a preferred embodiment the isolated crude enantiomeric salt is mixed with a suitable solvent and heated to dissolve the enantiomeric salt. Then the solution is cooled gradually to carry out the crystallization. Examples of the preferred solvents from which the enantomeric salts are recrystallized include protic solvents such as C 1 -C 4 alcohols including ethanol, methanol, isopropanol, n-propanol, n-butanol; aprotic polar solvents miscible in water, such as tetrahydrofuran, dioxane, acetone, acetonitrile, water and combinations thereof. The solvent of the recrystallization preferably used is an alcohol of Ci to C4 to the mixtures of alcohols of Ci to C4 with water. In a preferred embodiment, the crude enantiomeric salt G is dissolved in hot denatured ethanol (at about 60 ° C to about 75 ° C) and then water is added in a proportion of 1 ml of water for about 10 ml to 15 ml. of ethanol. The resulting solution is then cooled to approximately 5 ° C for more than 3 hours. The resulting enantiomeric salt G is easily filterable and has a needle-like crystal morphology. The crystals can optionally be further reduced in particle size by methods such as milling and / or micronization. Preferably, the enantiomeric salt G is reduced to the particle size to convert the needles into short rods preferably having an aspect ratio of less than three. Said reduction in the size of the needle-shaped particles facilitates the flow of the powder during the subsequent processing. Preferably, after reduction of the particle size, the average particle size (50%) of the enantiomeric salt G is less than about 25 microns and 90% of the particles is preferably less than about 70 microns, depending on the particle size. what is measured by laser diffraction (as in the case of a Malvern particle size analyzer or its equivalent). A compound formed of the formula G is preferably present in at least about 90 percent of the chiral purity area of the HPLC, more preferably almost 95 percent of the chiral purity area of the HPLC, and even more preferably at least 99%. percent of the HPLC area or 99.5 percent of the chiral HPLC purity relative to the total HPLC area of the stereoisomers. The preferred yields of the product through the preceding route are about 60%, more preferably about 70% and even more preferably about 80%. Although not wishing to be bound by any particular theory, it is believed that the conversion of a compound of the formula I in a compound of formula II by the use of a solid equivalent of formaldehyde, such as for example paraformaldehyde or trioxane, which can be gradually dissolved and / or decomposed in the formaldehyde in the reaction solvent, minimizes the formation of the corresponding methylene dimer. For example, when a solid equivalent of formaldehyde is used, such as for example paraformaldehyde or trioxane in acetonitrile, a composition is formed comprising a compound of formula II and preferably not more than about 10 percent of the HPLC area (determined by UV absorption at 220 nm), more preferably not more than about 5 percent of the HPLC area of the corresponding methylene dimer of formula VII: VII is formed (based on a total area of the HPLC chromatogram). When dimethoxymethane is used in acetonitrile, approximately 50 percent of the HPLC area of the corresponding methylene dimer is formed. When the aqueous formaldehyde solution is used, a dimer is formed of up to about 20 percent of the HPLC area and the starting compound of the formula I is degraded. it prefers powdered paraformaldehyde, particularly when used in a high solution (20 ml of acetonitrile per 1 g of the compound of formula I). Trioxane produced similar results to the paraformaldehyde granules with longer reaction times. The use of the paraformaldehyde granules leads to approximately 4 percent of the HPLC area of the methylene dimer formation. To the extent that the product of the reaction of this conversion is made in the synthetic scheme, the formation of dimeric forms of the corresponding bis salts, free bases, diastereomeric salts and enantiomeric salts is also minimized. The present invention provides, preferably, the compounds of the formula II and all the reaction products derived therefrom, as the compositions comprising the compounds of the formula II or derivatives thereof and less than, approximately, 10 times the percent of the HPLC area, more preferably less than about 7 percent of the HPLC area and even more preferably less than about 5 percent of the HPLC area of the corresponding methylene dimer (based on a total area of the HPLC chromatogram). Accordingly, the invention provides the compositions comprising the compounds of the formula II and less than about 10 percent of the HPLC area of their corresponding dimers of methylene, the compositions comprising the bis salts of the formula III and less than about 10 percent of the HPLC area of their corresponding methylene dimer, the compositions comprising the free bases of the formula IV and less than about 10 percent of the HPLC area of their corresponding methylene dimers, compositions comprising the diastereomeric salts of the invention and less than about 10 percent of the HPLC area of their corresponding methylene dimers and compositions comprising the enantiomeric salts of the invention and less than about 10 percent of the HPLC area of their corresponding methylene dimer, (based on the total area of the HPLC chromatogram). In a preferred embodiment, the process of the present invention provides a composition containing the enantiomeric salt G. In some embodiments, the composition contains the enantiomeric salt G in an amount of at least about 96.5 percent by weight and with more preferably, at least about 98 percent of the weight in an anhydrous base, based on the total weight of the composition. In some other embodiments, the composition containing the enantiomeric salt G, preferably contains and approximately 12.8 percent by weight up to about 14.8 percent of the weight and, more preferably, about 13.5 weight percent up to about 14.5 weight percent of GH HCl, as measured by ion chromatography based on the total weight of the composition. In other embodiments, the composition containing the enantomeric salt G preferably contains no more than 2.0 percent of the HPLC area of the total organic impurities and, more preferably, no more than about 1.5 percent of the area of HPLC of the total organic impurities related to the total area of the HPLC chromatogram. In other embodiments, the composition containing the enantomeric salt G preferably contains no more than 0.6 percent of the HPLC area of any single impurity such as the corresponding methylene dimer and, more preferably, no more than about 0.5. percent of the HPLC area of any simple impurity with the total area of the HPLC chromatogram. According to another embodiment, the composition containing the enantomeric salt G preferably contains no more than about 0.2 percent of the HPLC area of any simple impurity related to the total area of the HPLC chromatogram. According to another modality, the composition that contains the salt enanti orne R i ca G preferably contains no more than about 0.2 percent of the HPLC area of the total impurities related to the total area of the HPLC chromatogram. Even in other embodiments of the present invention, the composition with the enantiomer salt G preferably contains no more than about 2.0 percent by weight in water and more preferably no more than about 0.30 percent by weight. percent of the weight in water, as measured by the Karl Fischer titration, based on the total weight of the composition. In other embodiments, the composition contains G, at least one residual solvent in an amount of about 0.5 weight percent or less. Other embodiments provide compositions containing Compound G and at least one organic impurity or a residual solvent selected from at least one component of ethanol, ethyl acetate, isopropanol, methanol or a dimer compound of formula H. or a salt of it. In other embodiments of the invention, the composition containing the salt enriched ore G preferably contains no more than about the following residual solvents individually or in any combination: 0.5 percent by weight of ethanol, 0.5 percent of the weight of methanol, 0.5 weight percent of ethyl acetate, 0.5 weight percent of isopropanol and / or 0.5 weight percent of the methyl t-butyl ether based on the total weight of the composition. In the following synthetic scheme a representative synthesis of the compounds having the formula G is presented, which are discussed in greater detail in the following experimental examples. REACTION SCHEME 2 The preferred overall yield of syntheses of this type is greater than about 10%, more preferably, greater than about 15%, and even more preferably, greater than about 20%. The present invention also relates the compounds of formula IX and the methods for preparing them. Said compounds of formula IX are useful, for example, for the synthesis of psychotic and anti-obesity agents. In preferred embodiments, the compounds of formula IX are prepared by contacting a compound of formula VIII: with an unsaturated reagent that has the formula R4-CH = CH-R5 or the formula R4-C = C-R5 in the presence of an acid of Lewis, an equivalent of formaldehyde and a solvent of the reaction, thus forming a compound of formula IX: where the formaldehyde equivalent is found preferably in solid form, at least prior to contact. According to the invention, the representative compounds are those in which R4 and R5 are, independently, hydrogen or alkyl of 1 to 6 carbon atoms or taken together with the carbons to which they are attached, form a cyclic group which is cycloalkyl, cycloalkenyl, alkyl with bicyclic bond, alkenyl with bicyclic bond, pyranyl or thiopyranyl in that the sulfur atom is optionally oxidized to sulfoxide or sulfone. The cyclic groups formed by R 4 and R 5 can be optionally substituted by one to three substituents independently selected from halogen, alkyl or alkoxy. Particularly preferred compounds are those in which R4 and R5, taken together with the carbons to which they are attached, form a cyclopentyl group. R8 is an alkyl group with a branched or linear chain, such as, for example, methyl, ethyl, n-propyl, isopropyl, butyl or tertiary butyl; a heterosubstituted alkyl group, such as for example a protected ethylamino or ethoxy group, an aryl or an arylalkyl group. In the preferred embodiments, R8 is methyl or benzyl. The Lewis acids useful for the preparation of the compounds of the formula IX include those which are capable of depolymerizing the equivalents of formaldehyde and to those that facilitate the formation of aniline ions. Suitable acids include the aforementioned acids, for example those of the formula TiX4, ZrX4, AIX3, BX3, SiX4, SnX2, SnX2, RyAIX (3-y), R (y) SiX4-y, RyBX (3_y), in those that X is a halogen or -0R; R is an alkyl or aryl e and is 0-3 and combinations thereof. Boron trifluoride is particularly preferred. Suitable formaldehyde equivalents for the formation of the compounds of formula IX include those mentioned above, such as paraformaldehyde (including granules and powders), dimethoxymethane, formalin, trioxane, and the poly- and oligomeric forms of formaldehyde in general, as well as well as the formaldehyde solutions. Particularly preferred are the formaldehyde equivalents that are provided for the reaction in solid form, such as paraformaldehyde and trioxane. A preferred unsaturated reagent for use in the present invention is cyclopentene. Solvents that are useful for the preparation of compounds of formula IX include polar aprotic solvents such as alkyl nitriles (eg, acetonitrile, propionitrile and butyronitrile), esters (eg, ethyl acetate), N-formamide alkyl (for example, dimethylformamide), chlorinated hydrocarbons (for example, methylene chloride), and mixtures of same. Solvents containing alkyl nitrile are preferred. Particularly preferred are solvents containing almost all acetonitriles. Preferred solvents include those which contain at least about 90 weight percent nitrile alkyl, preferably at least about 95 weight percent nitrile alkyl, and even more preferably at least about 98 weight percent. percent of the weight of nitrile alkyl. The solvent is preferably added in an amount sufficient to dissolve the initial material. In certain embodiments, the solvent is added in concentrations of at least about 6 ml of the solvent per gram of the initial compound of formula VIII. Particularly preferred is the combination of boron trifluoride, paraformaldehyde and acetonitrile. Reaction temperatures of about 1 ° C to about 30 ° C are preferred. Related to the compound of formula VIII, in a preferred embodiment, the reaction to form the compounds of formula IX employs, from about 2 to about 4 molar equivalents of BF3, from about 2 to about 9 molar equivalents of cyclopentene and, they prefer about 0.9 to about 1.1 equivalents of paraformaldehyde (granules) in acetonitrile (using approximately 10 ml to approximately 20 ml per 1 g of initial material). The compounds of the formula IX are preferably formed in yields of at least 55%. In preferred embodiments, compounds of formula IX are formed in yields greater than about 60%, more preferably in yields greater than about 70%, even more preferably in yields greater than about 80% and with an even greater preference, in yields higher than, approximately, 90%. The invention is demonstrated in the following examples. The examples are illustrative and are not intended to limit the scope of the present invention. EXAMPLES Example 1 4-Acetyl-2, 3,4,5-tetrahydro-1H-1, 4-benzodiazepine (B) In a 10 1 covered reactor equipped with an overhead stirrer, a thermocouple, a condenser and positive nitrogen pressure, 6.8 1 of acetonitrile, 430.0 g (2.90 moles) of compound A (1, -benzodiazepine) were charged and 441.0 g (3.19 moles, 1.1 eq.) Of potassium carbonate. The stirred mixture was cooled to 0 ° C. Acetic anhydride (311.4 g, 3.05 moles, 1.05 eq.) In the form of drops was added to the mixture of the reaction over a period of 30 minutes. The reaction was monitored by HPLC demonstrating no more than 2% of compound A after 30 minutes. The reaction was quenched by the addition of butylamine (21.2 g, 0.29 moles, 0.1 eq.) And the inorganic solids were removed by filtering. The cake was rinsed with 1.1 1 of acet on i t r i 1 o. The filtered liquid was concentrated in a volume of 0.95 1 by vacuum distillation (42-55 ° C, 177-190 mmHg) and toluene (2.1 1) was added to the concentrate. The mixture was again concentrated in a volume of 1.20 1 by vacuum distillation and toluene (0.52 1) was added. The reaction mixture was cooled to 35 ° C and seeds were added (200 mg of compound B). Heptane (1.72 1) was added at 20 ° C and the mixture was cooled to 0 ° C for 1 h and at -5 ° C for 0.5 h. The product obtained from compound B was collected by filtration and the cake was rinsed twice with 0.55 1 of heptane. The yellow solid was dried for 24 hours under vacuum at 40 ° C to produce 515.5 g of compound B, (93% of theory). XH NMR (300MHz, DMS0-d6): 5 = 2.00 (s, 1.2H), 2.1 (s, 1.8H), 3.02-3.13 (m, 2H), 3.58-3.62 (m, 2H), 4.40 (s, 0.4H), 4.56 (s, 0.6H), 5.59 (s, 0.4H), 5.65 (s, 0.6H) 6.67-6.82 (m, 2H), 7.00-7.16 (m, 2H) ppm. Example 2 5-Acetyl-4, 5, 6, 7, 9, 9a, 10, 11, 12, 12a-decahydrocyclopenta [c] [1,4] diazepino [6, 7, 1-ij] quinoline] (C) In a 1.0 1 covered reactor equipped with an overhead stirrer, thermocouple, condenser, addition funnel and positive nitrogen pressure was added acetylbenzodiazepine (40.0 g, 210 mmol, 1.0 eq.), Paraformaldehyde granules (6.30 g, 210 mmol) ., 1.0 eq.), Acetonitrile (480 ml) and cyclopentene (86.0 g, 1.26 mol, 6.0 eq.). To the reaction suspension at 12 ° C, boron trifluoride etherate (80.5 g, 567 mmol, 2.7 eq.) Was added in 20 minutes. The reaction mixture was heated. The reaction was monitored by HPLC. After the reaction was completed, an aqueous solution of sodium hydroxide (50.0 g of NaOH in 250 ml of water) was added. The resulting mixture was filtered and the upper organic layer was washed with saline (50.0 ml). The organic layer was concentrated in 133 ml. Hot water (160 ml) was added to the hot concentrated mixture. The reaction mixture was cooled to room temperature and filtered. The cake was rinsed with a mixture of water and acetonitrile (5: 1, 60 ml, 2 times). The wet product (82.0 g) was dried in a vacuum oven for 20 h at 45 ° C to obtain compound C (52.8 g, yield 93%) as an off-white solid. HPLC (% area): 94.5% C, 3.15% impurity compound dimeric methylene bis [(±) -4, 5, 6, 7, 9, 9a, 10, 11, 12, 12a-decahydrocyclopenta [c] [1,4] diazepino [6,, 1-ij] quinoline] 1 H NMR (300 MHz, DMSO-d6): 5 = 7.17-6.94 (m, 2H), 6.85-6.73 (m, 1H), 4.81 (d, j = 13.7Hz, 0.4H), 4.56 (d, j = 15.3 Hz, 0.6H), 4.35 (d, j = 15.3Hz, 0.6H), 4.16 (m, 0.6H), 3.98 (d, j = 13.7Hz, 0.4H), 3.73 (m, 0.4H), 3.49 ( m, 0.4H), 3.30-2.81 (m, 4.6H), 2.63 (m, 1H), 2.21 (m, 2H), 1.98 (m, 4H), 1.57 (m, 2H), 1.27 (m, 2H) ppm. (two conformers at 25 ° C) composed of methylene dimeric impurity bis [(±) -4, 5, 6, 7, 9, 9a, 10, 11, 12, 12a-decahydrocyclopenta [c] [1, 4] diazepino [6, 7, 1-ij] quinoline]: 5 = 7.08-6.77 (m, 4H), 4.95 (m, 0.6H), 4.39 (m, 4H), 4.05 (ra, 0.4H), 3.29-267 ( m, 3H), 2.33-1.93 (m, 15H), 1.76-1.20 (m, 6H) ppm. LC / MS: (552 m / z) EXAMPLE 3 Salt of (-) - 4, 5, 6, 7, 9, 9a, 10, 11, 12, 12a-Decahydrocyclopenta [c] [1,4] diazepino acid [-] 6, 7, 1-ij] quinoline (R, R) -di-p-toluoyltartaric (F) by alkaline hydrolysis In a covered reactor (2 1) equipped with an overhead stirrer, a thermocouple, a condenser and positive nitrogen pressure , methanol (500 ml), water (140 ml) were charged and the mixture was cooled to 5 ± 5 ° C. Potassium hydroxide granules (284.7 g, 2263 moles) were added in 3 to 4 portions. The reaction mixture was heated to 35 + 5 ° C and Compound C was added (Scheme 2, 195.4 g, 0.650 moles). The reflux of the suspension was carried out for 18 hours. After cooling the reaction mixture to 0 ° C, water (385.0 g) was added followed by concentrated hydrochloric acid (325.0 g, 3.25 moles 5.0 eq.) To the reaction mixture. Ethyl acetate (600 ml) was added and the mixture was stirred for 15 minutes and then filtered. The cake was rinsed with acetate (1400 ml), and the rinses were kept separate from the mother liquor. The filtered layers were separated and the aqueous layer was extracted with rinses from the filtrate. The combined organic layers were concentrated in a volume of 450 ml. To the mixture was added ethyl acetate (850 ml). The solution was concentrated in a volume of 300 ml. The concentrate was distilled twice azeotropically with isopropanol (750 ml). Isopropanol (700 ml) was charged to the residue and the mixture was heated to 70 ° C. The hazy solution was clarified by filtering over celite (16 g) and rinsing with isopropanol (100 ml). The solution of E (racemic) was heated to 70 ° C and a solution of tartaric acid (DTTA) (75.4 g, 0.165 moles, 0.30 eq.) In isopropanol (600 ml) was added, keeping the internal temperature above the 70 ° C. Seeds were added and the reaction mixture was allowed to cool to 20 + 5 ° C over a period of 3 hours. The solid F formed by the filtrate was collected (filtration time = 15 min., Cake: height = 2.0 cm, diameter = 11.5 cm). The wet F crude (89.1 g) (87% chiral purity) was suspended in isopropanol (630 ml) and heated for reflux for 2 hours. The mixture was cooled to room temperature, the solid was collected by filtration and rinsed with isopropanol (155 ml). After drying at 40 ° C for twelve hours, F was obtained (65.8g, 24% yield, theoretical yield 50%), with 92% chiral purity. 1 H NMR (300MHz, DMSO-d 6): 6 = 7.86 (d, j = 8.0Hz, 4H), 7.32 (d, j = 8.0Hz, 4H), 7.14 (d, j = 6.6Hz, 2H), 6.81 ( dd, j = 6.3, 7.3Hz, 2H), 5.57 (s, 2H), 3.90 (dd, j = 13.8, 36.2Hz, 4H), 3.15 (m, 2H), 3.02-2.87 (m, 10H), 2.59 (1, j = 12.5Hz, 2H), 2.37 (s, 6H), 2.19-2.15 (m, 4H), 1.99-1.96 (m, 2H), 1.62-1.58 (m, 4H), 1.35-1.21 (m , 4H) ppm. Chiral HPLC: Chirobiotic V 3.9 x 150 mm 5 μp, eluent 1 1 Methanol / flow 0.9g NH4CF3C02: detection of 1.5 ml 220 nm UV, Retention time: E (S) = 4.71 min, E (R) = .38 min. EXAMPLE 4 Salt of (-) - 4, 5, 6, 7, 9, 9a, 10, 11, 12, 12a- Decanidrocyclopenta [c] [[1,4] ldiazepine [6,7, 1-ij] quinolin (R, R) di-p-toluoyltartaric acid (F) by acid hydrolysis Compound C (0.30 kg, 1.1 moles) was added to a mixture at 5-10 ° C concentrated HCl (2.5 eq, 0.274 kg, 2.77 moles) ) and ethanol (0.30 1, 0.23 kg). The suspension is subjected to reflux for 12 to 15 hours and the completion of the reaction was monitored by means of HPLC. After the reaction was complete, ethyl acetate (0.802 kg, 0.90 1) was added over 40 minutes. The reaction mixture was cooled to room temperature, filtered and washed with ethyl acetate (0.40 1, 0.356 kg) to achieve the D salt of dihydrochloride (0.291 g, 87%). XH RN (300MHz, DMSO-d6): 5 = 10.12 (m, 2H), 9.05 (m, 1H), 7.24 (d, j = 7.23Hz, 1H), 7.18 (d, j = 6.4Hz, 1H), 6.92 (dd, j = 6.4.7.3Hz, 1H), 4.13 (m, 2H), 3.44 (m, 1H), 3.09 (m, 4H), 2.93 (m, 1H), 2.67 (t, j = 12.6Hz) , 1H), 2.24 (m, 2H), 2.01 (m, 1H), 1.61 (m, 2H), 1.33 (m, 2H) ppm. Analysis calculated for C15H22Cl2 2: C, 59.80; H, 7.36; CI, 23.54; N, 9.30. The one found: C, 59.82; H, 7.70; CI, 23.42; N, 9.39. To provide a solution D was heated to 75 ± 5 ° C in water (0.870 1, 0.874 kg). The free base was generated in an aqueous solution of sodium hydroxide N to OH (0.249 kg 50/50 w / w in 0.119 kg water) and cooled to 35 ± 5 ° C in 1 hour before it was extracted with TBME (0.450 1, 0.329 kg). After changing the solvent in isopropanol (0.92 1, 0.710 kg), the organic layer was concentrated in (0.5 1, 0.459 kg). Isopropanol (0.920 1, 0.710 kg) was added to the concentrated mixture. An acid solution was added di-p-toluoyl-L-tartaric (DTTA) (0.23 eq, 0.101 kg, 0.26 moles) in ethyl acetate (1.20 1, 1.02 kg) as drops to the solution of the free base in 1 hour at 75 ± 5 ° C. The solution was cooled to room temperature in 6 hours. The product was filtered and washed with ethyl acetate (0.400 1, 0.352 kg). Finally, the crude F is mixed again in IPA (0.86 1, 0.667 kg) under reflux for 2 hours and then cooled to room temperature for 4 hours. The product was filtered and rinsed with IPA (0.153 kg, 0.2 1). The wet product (223.7 g) was dried in a vacuum oven for 24 hours at 40 ° C to achieve F (150.7 g, 32.3% yield of C). HPLC: 98.77%, Chiral purity: 90%. Example 5 Hydrochloride of (-) -4,5,6,7,9,9a, 10,12,12,12-decahydrocyclopenta [c] [1, 41diazepino [6,7, l-ij] quinoline] (G) To the suspension of F (72.0 g, 171 mmol) in ethyl acetate (860 ml) in a 2.0 1 flask, concentrated HC1 (20.0 g, 205 mmol, 1.2 eq.) Was added at room temperature. The suspension is refluxed for 3 hours and cooled to room temperature. It was filtered and washed with ethyl acetate (115 ml) to obtain the crude hydrochloride salt (46.0 g, G). The latter was heated to 70 ° C in ethanol (276 ml, 200 ml of test, denatured with 4% ethyl acetate) and then water (22 ml) was added. The solution was cooled to 5 ° C for 3 hours. The product was filtered and rinsed with ethanol (46 ml). The baked product (34.6 g) was dried in a vacuum oven for 20 hours at 40 ° C to achieve compound G (32.0 g, 70% yield) as a whitish solid. HPLC (% area): 99.45% Chiral purity (HPLC): 99.9%. The following table describes the analyzes of the different batches of G prepared according to Examples 1, 2, 4 and 5: Analysis Lot 1 Lot 2 Lot 3 Lot 4 Purity (HPLC) (% of area): 0.29% 0.43% 1.48% 0.51% A) Total organic impurities B) Greater single impurity 0. ll% to 0.21% and 0.58% 0.26% [RRT = 3.31] b [RRT = 3.31] b HCI content (% 14.1% 14.0% 13.8% 14.0% by weight) (ion chromatography) Water content 0.26% 0.10% 0.11% 0.12% (% p, KF) Chiral purity (% of Not analyzed Not analyzed 0.06% of 0.12% area) (HPLC) Enantiomer enantiomer Residual solvents% of wt) (GC) Acetonitrile ND, ND, ND, ND DL = 5 ppm DL = 8 ppm DL = 7 ppm DL = 2 ppm Cyclopentene Not analyzed Not analyzed ND, ND, DL = 0.0005% DL = 0.0001% Ethanol 0.06% 0.18% 0.48% 0.21% Ethyl acetate 0.001% ND, 0.01% 0.002% DL = 0.0010% Isopropanol ND, ND, ND, ND, DL = 0.0014% DL = 0.0061% DL = 0.0032% DL = 0.0010% Methyl-butyl ether Not analyzed Not analyzed Not analyzed ND, DL = 0.0003% ND = none detected. DL = detection limit. NMT = is not more than. RRT = relative retention time. a: Purity was evaluated by means of a preliminary development method. b: Current RTT = 3.22 (Variation due to the HPLC gradient). Including 6 (±) -4, 5, 6, 7, 9, 9a, 10, 11, 12, 12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline BF3 was added .OEt2 (2.2 ml, 17.5 mmol) in drops to a mixture of ben z odi az ep i na (0.74 g, 5 mmol), cyclopentene (3.6 ml, 40.0 mmol), diaphragm 1 of h id (165 mg , 5.5 mmol) in acetonitrile (20 ml) at room temperature. The mixture was heated at 45 ° C (oil bath) for 5 h. It was concentrated in vacuo. The residue was taken up in EtOAc (150 ml) and rinsed first with a mixture of Na 2 CO 3 and aqueous NaOH (200 ml), and then with saline (200 ml). The organic layer was dried and HC1 (1 N in diethylether, 10 ml) was added and the resulting precipitates were collected by filtration. The mixture was purified by vaporization chromatography flash on silica gel (5-15% MeOH in CH2Cl2) to produce E (0.70 g, 53% yield). Example 7 5-Benzyl-2, 3, 3a, 4, 5, 9b-hexahydro-lH-cyclopenta [c] quinoline N-Phenyl-benzylamine (4.58 g, 25.00 rimols) was dissolved in 57 ml of acetonitrile under the atmosphere of N2 Cyclopentene (10.22 g, 150.0 mmol) and paraformaldehyde (788 mg, 26.25 mmol) were added in one portion. The mixture was cooled to 1.5 ° C and BF30Et2 (8.87 g, 62.50 mmol) was added over a period of 2 minutes. The cold bath was removed after the addition was complete (reaction temperature = 9 ° C). The reaction was completed after 2 hours (HPLC). NaOH (10.5 g in 20 ml of water) was added and the mixture was stirred overnight. The layers were separated. An inorganic solid was filtered off and the organic layer was extracted with ethyl acetate (3 times, 10 ml). The combined organic layers were rinsed with saline and dried with MgSO4. Evaporation of the solvent and flash chromatography with heptane / ethyl acetate yielded 5-benzyl-2,3,3a, 4, 5, 9b-hexahydrolH-cyclopenta [c] quinoline (5.97 g, 91% yield). lH NMR (300MHz, DMSO-d6): 5 = 7.51-7.19 (m, 5H), 7.05 (d, j = 7.4Hz, IH), 6.88 (t, j = 7.4Hz, H), 6.57-6.52 (m , 2H), 4. 50 (dd, j = 16.5, 24.2Hz, 2H), 3.09 (dd, j = 5.0, 11.7Hz, 1H), 2.98-284 (m, 2H), 2.33 (m, 1H), 2.14 (m, 1H) , 1.94 (m, 1H), 1.63-1.40 (m, 4H) ppm. LC-MS: (263m / z). Example 8 5-Methyl-2, 3, 3a, 4, 5, 9b-hexahydro-lH-cyclopenta [c] quinoline N-methyl aniline (1.07g, 10.0 mmoles) was dissolved in 23 ml of acetonitrile under the N2 atmosphere . Cyclopentene (4.08 g, 60.0 mmol) and paraformaldehyde (300 mg, 10.0 mmol) were added in one portion. The mixture was cooled to 1.5 ° C and BF30Et2 (3.55 g, 25.0 mmol) was added over a period of 2 minutes. The cold bath was removed after completing the aggregate (reaction temperature = 9 ° C). The reaction was completed after 2 hours (HPLC). NaOH (10.5 g in 20 ml of water) was added and the mixture was stirred overnight. The layers were separated. An organic solvent was filtered off and the organic layer was extracted with ethyl acetate 3x10 ml. The combined organic layers were rinsed with saline and dried with MgSO4. Evaporation of the solvent and flash chromatography with heptane / ethyl acetate yielded 5-Methyl-2, 3, 3a, 4, 5, 9b-hexahldro-lH-cyclopenta [c] quinoline (1.08 g, 57% yield). 1 H NMR (300MHz, DMSO-d 6): 5 = 7.04-6.96 (m, 2H), 6.63-6.58 (m, 2H), 2.98-2.78 (m, 2H), 2.63 (t, j = 9.93Hz, 1H), 2.33 (m, 1H), 2.13 (9m, 1H), 1.93 (m, 1H), 1.60-1.34 (m, 4H) ppm. LC-MS: (187mlz) It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. - A method for preparing a compound of the formula II: characterized in that: R1 is alkyl, alkanoyl, aroyl, carboalkoxy or carboalkoxyaryl; R2 and R3 are, independently, hydrogen, hydroxy, alkyl, alkoxy, halogen, carboxamido, carboalkoxy, perfluoroalkyl, cyano, alkanesulfonamido, alcansulfonyl, alkanamido, amino, alkylamino, dialkylamino, perfluoroalkoxy, alkanoyloxy, alkanoyl, aroyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R6 and R7 are, independently, hydrogen or alkyl; n is 1 or 2; R4 and R5 are, independently, hydrogen or alkyl
I or they are taken together with the carbons to which they are attached, to form a cyclic group which is cycloalkyl, cycloalkenyl, alkyl with bicyclic bond, alkenyl with bicyclic bond, pyranyl or thiopyranyl in which the sulfide atom is optionally oxidized for the sulfoxide or sulfone; and the dotted line represents an optional double bond, comprising the reaction of a compound of formula 1: wherein: n, R1, R2, R3, R6 and R7 are as defined above, with at least one equivalent of formaldehyde equivalent and one reagent with the formula R4-CH = CH-R5 or the formula R4-C = C -R5, where R4 and R5 are as defined herein, in the presence of a Lewis acid and a reaction solvent to form a component of formula II, taking into account that the formaldehyde equivalent is in the form of a solid, less before the reaction. 2. The method according to claim 1 characterized in that the formaldehyde equivalent comprises paraformaldehyde.
3.- The method in accordance with the claim 1 or claim 2, characterized in that the reaction solvent comprises an alkylnitrile.
4. The method according to any of claims 1 to 3 characterized in that R1 is acetyl.
5. The method of compliance any of claims 1 to 4 characterized in that R4 and R5, taken in conjunction with the coals to which they adhere, form a cyclopentyl portion.
6. - The method according to any of claims 1 to 5 characterized in that R2, R3, R6 and R7 are hydrogen.
7. - The method according to any of claims 1 to 6 characterized in that n is 1.
8. The method according to any of claims 1 to 7 characterized in that the reaction solvent comprises at least about 90 percent of the weight of acetonitrile.
9. The method according to any of claims 1 to 8, characterized in that the production of the compound of the formula II is greater than 60%.
10. - A product characterized in that it is produced by the method according to any of claims 1 to 9.
11. The method according to any of claims 1 to 9, characterized in that it further comprises the reaction of the compound of the formula II with an acid with pKa less than 1 to form a bis salt of formula III wherein X is the counterion of an acid having a pKa of less than 1.
12. The method according to claim 11 characterized in that X is a halogen, acid sulfate or an alkyl- or arylsulfonate.
13. - The method according to claim 11 characterized in that the acid is hydrochloric acid.
14. A product characterized in that it is produced by the method according to any of claims 11 to 13.
15. The method according to any of claims 11 to 13 characterized in that in addition comprises the reaction of the bis salt of formula III with a base to form a free base of formula IV: IV.
16. The method according to claim 15, characterized in that the base is aqueous sodium hydroxide.
17.- The method according to the claim 15 or 16 characterized in that the free base of formula IV is extracted with an extraction solvent that is not miscible with water.
18. The method according to claim 1, characterized in that it further comprises the reaction of the compound of the formula II with a base to form a free base of the formula IV:
19. - The method according to claim characterized in that the base comprises an inorganic base strong .
20. The method according to claim 18 or 19, characterized in that the base and the compound of the formula II are contacted in the presence of a polar solvent.
21. The method according to the claim Characterized in that the base is potassium hydroxide and the polar solvent comprises methanol.
22. - A product characterized in that it is produced by the method according to any of claims 15 to 21.
23. - The method according to any of claims 15 to 21 characterized in that it also comprises the reaction of the free base of Formula IV with a chiral that resolves acid to form a diastereomeric salt.
24. - The method according to claim 23 characterized in that the chiral resolution acid is a monofunctional carboxylic acid, the dysfunctional carboxylic acid, sulfonic acid, phosphonic acid, or combinations thereof.
25. - The method according to claim 23 to 24, characterized in that the free base of formula IV and the chiral that resolve the acid react in the presence of a polar solvent that is capable of dissolving the compound of formula IV and is capable of to crystallize diastereomeric salt of the same.
26. - The method according to claim 25 characterized in that the acid is ditoluoyl tartaric acid and the polar solvent comprises isopropanol, ethyl acetate or combinations of these.
27. The method according to claim 25, characterized in that the diastereomeric salt produced is at least one of the formula F:
28. - A product characterized in that it is produced by the method according to any of claims 23 to 27.
29. The method according to any of claims 23 to 27 characterized in that they also comprise the contact of the diastereomeric salt and an acid with a lower pKa than the chiral that resolves the acid to form a corresponding enantomeric salt.
30. - The method according to claim 29 characterized in that the diastereomeric salt and the acid are contacted in the presence of a polar solvent capable of crystallize in the enantiomeric salt thereof.
31. The method according to claim 30, characterized in that the acid is hydrochloric acid and the polar solvent comprises ethyl acetate.
32. The method according to any of claims 29 to 31, characterized in that it also comprises the crystallization of the enantiomeric salt from a solution comprising the aqueous alcohol.
33. - A product characterized in that it is produced by the method according to any of claims 29 to 32.
34. The method according to claims 29 to 32, characterized in that the enantiomeric salt is at least one compound of the formula G : HCI G.
35. - A product characterized in that it is produced by the method according to claim 34.
36. - A method characterized in that it prepares a compound of the formula IV: wherein: R2 and R3 are, independently, hydrogen, hydroxy, alkyl, alkoxy, halogen, carboxamido, carboalkoxy, pe rf 1 or 1 qui 1, cyano, a 1 ca nsu 1 f onami do, a 1 their anion, alkanamido, amino, alkylamino, dia 1 qu i 1 ami no, per f luoroalkoxy, alkanoyloxy, alkanoyl, aroyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R6 and R7 are, independently, hydrogen or alkyl; n is 1 or 2; R4 and R5 are, independently, hydrogen or alkyl or are taken together with the carbons to which they are attached, form a cyclic group which is cyc 1 or 1 to 1 to 1, 1 to 1 or 1 to 1, alkyl with link bicyclic, alkenyl with bicyclic, pyranyl or thiopyranyl bond in which the sulfide atom is oxidized optionally for sulphoxide or sulfone; and the dotted line represents a double bond optional, which comprises the reaction of a compound formula I wherein: n, R2, R3, R6 and R7 are, as defined above, with at least one equivalent of formaldehyde and a reagent having the formula R4-CH = CH-R5 or the formula R4-C = C-R5, in the presence of a Lewis acid and a reaction solvent to form a compound of the formula IV, providing the formaldehyde equivalent in solid form, at least prior to the reaction.
37. - The method according to claim 36 characterized in that the formaldehyde equivalent comprises paraformaldehyde.
38. - The method according to claim 36 or claim 37 characterized in that the reaction solvent comprises an alkyl nitrile.
39.- The method of compliance with any of the claims 36 to 38 characterized in that R4 and R5, taken together with the carbons to which they adhere, form a cyclopentyl moiety.
40. - The method according to any of claims 36 to 39 characterized in that R2, R3, R6 and R7 are hydrogen.
41. - The method according to any of claims 36 to 40 characterized in that n is 1.
42. - The method according to any of claims 36 to 40 characterized in that the reaction solvent comprises at least about 90 percent of the weight of acetonitrile.
43. - The method according to any of claims 36 to 42 characterized in that it further comprises contacting the free base of the formula IV with a chiral that resolves the acid to form a diastereomeric salt.
44. The method according to claim 43 characterized in that the acid that resolves the chiral is ditoluoyl tartaric acid.
45. The method according to claim 44, characterized in that the diastereomeric salt produced is at least one of the formula F: F wherein Tol is a toluoyl group.
46.- A product characterized in that it is prepared by the method according to any of claims 43 to 45.
47. The method according to any of claims 43 to 45, characterized in that they also comprise the contact of the diastereomeric salt and an acid with a pKa lower than the chiral that resolves the acid to form a corresponding enantiomeric salt.
48. The method according to claim 47, characterized in that the acid comprises the hydrochloric acid and the diastereomeric salt and the acid are contacted in the presence of a polar solvent comprising ethyl acetate.
49. A product characterized in that it is produced by the method according to claim 47 or 48.
50. The method of claim 47 or 48 characterized in that it further comprises crystallizing the enantiomeric salt from a solution comprising the aqueous alcohol .
51. The method of claim 50 characterized in that the enantiomeric salt is at least one compound of the formula G: HCI
52. - A product characterized in that it is produced by the method of claim 50 or claim 51.
53. - A compound characterized in that it has the formula: wherein X is the counterion of an acid having a pKa less than 1.
54. The compound according to claim 53 characterized in that X is Cl.
55. A composition characterized in that it comprises a diastereomeric salt of a diaroyl acid. -L-tartaric and a free base of the Vlb formula: wherein: R2 and R3 are, independently, hydrogen, hydroxy, alkyl, alkoxy, halogen, carboxamido, carboalkoxy, perfluoroalkyl, cyano, alcansulfonamido, alcansulfonyl, alkanamido, araino, alkylamino, dialkylamino, perfluoroalkoxy, alkanoyloxy, alkanoyl, aroyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R4 and R5 are, independently, hydrogen or alkyl or are taken together with the carbons to which they are attached, form a cyclic group which is cycloalkyl, cycloalkenyl, alkyl with bicyclic bond, alkenyl with bicyclic linkage, pyranyl or thiopyranyl wherein the Sulfur atom is optionally oxidized to sulfoxide or sulfone; the dotted line represents an optional double bond, R6 and R7 are, independently, hydrogen or alkyl; and n is 1 or 2.
56. The diastereomeric salt according to claim 55, characterized in that the diaroyl tartaric acid is the ditoluoyl-L-tartaric acid.
57. - The diastereomeric salt according to claim 55, characterized in that it has the formula F: F where Tol is a toluo group
58. - A composition characterized in that it comprises: a) HPLC of at least 90% of the MPLC area of a compound of formula II: wherein: R1 is alkyl, alkanoyl, aroyl, carboalkoxy or carboalkoxyaryl; R2 and R3 are, independently, hydrogen, hydroxy, alkyl, alkoxy, halogen, carboxamido, carboalkoxy, perfluoroalkyl, cyano, alkanesulfonamido, alcansulfonyl, alkanamido, amino, alkylamino, dialkylamino, perfluoroalkoxy, alkanoyloxy, alkanoyl, aroyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R4 and R5 are, independently, hydrogen or alkyl or are taken together with the carbons to which they are attached, form a cyclic group which is cycloalkyl, cycloalkenyl, alkyl with bicyclic bond, alkenyl with bicyclic linkage, pyranyl or thiopyranyl wherein the Sulfur atom is optionally oxidized to sulfoxide or sulfone; the dotted line represents an optional double bond, R6 and R7 are, independently, hydrogen or alkyl; and n is 1 or 2; and b) a compound of formula VII: which is less than the amount of approximately 10 percent of the HPLC area.
59. - The composition according to claim 58 characterized in that R1 is acetyl, R2, R3, R6 and R7 are hydrogen, n is 1, and R4 and R5, taken together with the carbons to which they adhere, form a Cyclopentyl group.
60. - A composition characterized in that it comprises: a) a compound of the formula III: III wherein: R2 and R3 are, independently, hydrogen, hydroxy, alkyl, alkoxy, halogen, carboxamido, carboalkoxy, perfluoroalkyl, cyano, alkanesulfonamido, alcansulfonyl, alkanamido, amino, alkylamino, dialkylamino, perfluoroalkoxy, alkanoyloxy, alkanoyl, aroyl, aryl , arylalkyl, heteroaryl or heteroarylalkyl; R4 and R5 are, independently, hydrogen or alkyl or are taken together with the carbons to which they are attached, form a cyclic group which is cycloalkyl, cycloalkenyl, alkyl with bicyclic bond, alkenyl with bicyclic linkage, pyranyl or thiopyranyl wherein the Sulfur atom is optionally oxidized to sulfoxide or sulfone; the dotted line represents an optional double bond, R6 and R7 are, independently, hydrogen or alkyl; n is 1 or 2; and X is the counter ion for an acid with pKa less than 1; and b) a compound of the formula: a salt thereof, in less than about the amount, 10 percent of the HPLC area.
61. - The composition according to claim 60 characterized in that each of R2, R3, R6 and R7 are hydrogen, n is 1, X is Cl and R4 and R5, taken together with the carbons to which they adhere, form a Cyclopentyl group.
62. - A composition characterized in that it comprises: a) a diastereomeric salt of a diaroyl tartaric acid and a free base of the formula IV: wherein: R2 and R3 are, independently, hydrogen, hydroxy, alkyl, alkoxy, halogen, carboxamido, carboalkoxy, perfluoroalkyl, cyano, alcansulfonamido, alcansulfonyl, alkanamido, amino, alkylamino, dialkylamino, perfluoroalkoxy, alkanoyloxy, alkanoyl, aroyl, aryl , arylalkyl, heteroaryl or heteroarylalkyl; R4 and R5 are, independently, hydrogen or alkyl, and are taken together with the carbons to which they are attached, they form a cyclic group which is cycloalkyl, cycloalkenyl, alkyl with bicyclic bond, alkenyl with bicyclic bond, pyranyl to thiopyranyl in which the sulfur atom is optionally oxidized in sulfoxide to sulfone; the dotted line represents an optional double bond, R6 and R7 are, independently, hydrogen or alkyl and; n is 1 or 2 and b) a compound of the formula: or a salt thereof, in less than the amount of about 10 percent of the HPLC area.
63. The composition according to claim 62, characterized in that the diaroyl tartaric acid is di-p-toluoyl-L-tartaric acid; each of R2, R3, R6 and R7 is hydrogen, n is 1, and R4 and R5, taken together with the carbons to which they adhere, form a cyclopentyl group.
64. - A composition characterized because it comprises: a) a compound of the formula G: HCI G and b) one or more organic impurities in a total amount of about 2 percent of the HPLC area or less, or one or more residual solvents in a total amount of 1.0 we percent or less, or combinations thereof .
65.- The composition according to claim 64, characterized in that the compound G is present in an amount of at least about 96.5 percent of the we in an anhydrous base, based on the total we of the composition.
66.- The composition according to claim 64, characterized in that the organic impurities or residual solvents comprise at least one of ethanol, ethyl acetate, isopropanol, methanol or a dimer compound of the formula: or a salt of it.
67. - The composition according to claim 64, characterized in that the organic impurities or the residual solvents comprise at least one of the dimeric compound or a salt thereof or ethanol.
68. - The composition according to claim 64 characterized in that the hst single organic impurity is present in an amount of about 0.6 percent HPLC area or less.
69. - The composition according to claim 68 characterized in that the only major impurity is a compound of the formula: or a salt of it. The composition according to claim 64, characterized in that the total residual solvents are present in an amount of 0.5% by we or less. 71. - The composition according to claim 70 characterized in that the residual solvent comprises ethanol. 72. - A composition characterized in that it comprises: a) a compound of the formula G: and b) water in an amount of about 2.0 percent by we or less, based on the total we of the composition. 73. A compound of the formula G: HCI Characterized because it has sharp crystals. 74 The compound according to claim 73, characterized in that the needle-shaped crystals are reduced until they have an aspect ratio of less than about 3. 75 - A compound of the formula G: HCI G characterized in that it has an average particle size of less than about 25 microns. 76. The compound according to claim 75 characterized in that 90% of the particles have a particle size of less than about 70 microns. 77 - A composition characterized in that it comprises a compound of the formula G: HCI G wherein the acid chloride content ranges from about 12.8 percent by we to about 14.8 percent by we as measured by ion chromatography, based on the total we of the composition. The composition according to claim 77, characterized in that the compound of the formula G has a chiral purity of at least about 99.5 percent of the HPLC area in the composition. 79.- A method characterized for preparing a compound of the formula IX wherein: R8 is a branched or linear alkyl group, a hetero-substituted alkyl group, an aryl group or an arylalkyl group; and R4 and R5 are, independently, hydrogen or alkyl of 1 to 6 carbon atoms or taken together with the carbons to which they are attached, form a cyclic group which is cycloalkyl, cycloalkenyl, alkyl with bicyclic bond, alkenyl with bicyclic, pyranyl or thiopyranyl bond in which the sulfur atom is optionally oxidized in sulphoxide sulphone, comprises the reaction of a compound of the formula VIII: VIII with a reagent with the formula R4-CH = CH-R5 or the formula R4-C = C-R5 in the presence of a Lewis acid, and a solvent formaldehyde equivalent of the reaction to form a component of the formula IX, taking into account that the formaldehyde equivalent is in the form of a solid, at least before the reaction. 80. - The method according to claim 79 characterized in that the reagent is cyclopentene; the Lewis acid is boron trifluoride; one equivalent of formaldehyde is para-formaldehyde; the reaction solvent is acet oni t r i lo; R4 and R5 together form a cyclopentyl group; and R8 is methyl or benzyl. 81. - A product characterized in that it is made by the method of claim 79 or claim 80.