FIELD OF THE INVENTION

The present invention belongs to the field of organic chemistry and relates to new salts of 2-methyl-4- (4-methyl-1- piperazinyl) -10H-thieno [2,3-jb] [1,5] benzodiazepine (herein¬ after referred to by its generic name "olanzapine") with acids selected from the group of acetic, benzoic, hydrochloric, ben¬ zenesulfonic, and perchloric acid, methods for their produc¬ tion, their use for olanzapine purification, and a method for their conversion to polymorphic form I of olanzapine. Olanzapine has shown to have high activity with regard to the central nervous system and is also useful for the treat¬ ment of schizophrenia, schizophreniform disorders, acute ma¬ nia, mild anxiety states and psychosis. TECHNICAL PROBLEM

According to prior art processes, solvents like acetoni- trile are used for the purification of olanzapine free base and for the production of form I. However according to ICH guidelines these solvents are not recommended for use in the final steps of preparation of pharmaceuticals since they are harmful. Beside this they often do not lead to satisfactory overall yields of olanzapine form I. Moreover, these prior art processes often do not lead to olanzapine having a purity which is satisfactory for the preparation of pharmaceutical formulations as impurities are present, which are hard to re¬ move according to prior art processes . Consequently, there still is a need for an improved proc- ess to prepare purified olanzapine form I avoiding the afore¬ mentioned drawbacks and which results to olanzapine which has a purity making it very well suitable for the preparation of pharmaceutical formulations.

Further, there is a need for precursors which allow the easy preparation of polymorphic forms of olanzapine or the conversion to other forms of olanzapine.

These problems are solved by the present invention.

BACKGROUND OF THE INVENTION

GB 1 533 235 discloses antipsychotically effective thie- nobenzodiazepines by a generic formula which also covers olan- zapine. EP 0 454 436 describes olanzapine explicitly. The de¬ scribed process for its synthesis further involves crystalli- zation from acetonitrile and the melting point of the crystal¬ lized compound was determined to be at 195 0C. EP-B-733 635 claims crystalline form II of olanzapine. This polymorphic form is said to be more stable than the mate- rial obtained according to EP 0 454 436 which is designated "form I olanzapine". Both form I and form II of olanzapine are characterized by e. g. X-ray data. The preparation of the more stable form II of olanzapine is effected by dissolving techni¬ cal grade olanzapine in ethyl acetate and crystallization from the resulting solution by any conventional process, such as seeding, cooling, scratching the glass of the reaction vessel or other common techniques. WO 02/18390 discloses the monohydrate form I and the di- hydrate form I of olanzapine, a process for production thereof and a process for production of form I of olanzapine which comprises the steps of stirring olanzapine monohydrate form I or crude olanzapine or form II of olanzapine in methylene chloride at reflux, cooling, filtering and drying. It is also described that a repeating of the process described in EP 0 454 436 Example 1, subexample 4 did not lead to formation of form I of olanzapine. WO 03/101997 relates to processes for the preparation of form I of olanzapine by regulation of the pH-value of the so¬ lution. WO 03/055438 discloses crystallization from ethanol and the consequent transformation of the ethanol solvate to poly¬ morphic form I of olanzapine. US 5,637,584 discloses the (mono)methylene solvate form ■ of olanzapine and a method for its conversion to polymorphic form I of olanzapine. EP-B-733 634 relates to three specific solvates of olan¬ zapine namely the methanol, ethanol and 1-propanol solvates and a process for production of form II olanzapine by drying the corresponding solvates. In WO 03/097650 two new mixed solvate forms, the mixed water/methylene chloride and water/DMSO solvate, methods for preparing them, and their transformation to polymorphic form I are disclosed. WO 2004/006933 discloses the preparation of form I, some pseudopolymorphic forms, namely isopropanol solvate, acetoni- trile/methylene chloride/water and acetonitrile/water mixed solvates of olanzapine, polymorphic form A, and processes for the preparation thereof.

Various processes are known from prior art for the prepa¬ ration of olanzapine, such as GB 1 533 235, EP 0 454 436, EP- B-733 635, WO 2004/065390 and WO2004/000847.

SUMMARY OF THE INVENTION

The present invention provides novel salts of 2-methyl-4- (4-methyl-l-piperazinyl) -lOH-thieno [2,3-Jb] [1, 5] benzodiazepine or olanzapine useful as intermediates in the isolation of olanzapine from complex reaction mixtures. These salts can be used for the production of olanzapine base which has suitable purity for pharmaceutical use and can easily be converted to anhydrous olanzapine polymorphic form I, in high yields.

DETAILED DESCRIPTION OF THE INVENTION

As mentioned above according to prior art processes, olanzapine free base is isolated from reaction mixtures using crystallization from solvents like methylene chloride and ace- tonitrile. These procedures are used for the purification of olanzapine free base and for the production of form I but of- ten they do not lead to satisfactory overall yields of form I of olanzapine. Moreover, these prior art processes often do not lead to olanzapine having a purity which is satisfactory for the preparation of pharmaceutical formulations as impuri- ties are present, which are hard to be removed according to the prior art processes.

Consequently, there is still a need for an improved proc¬ ess for the preparation purified olanzapine avoiding the afore-mentioned drawbacks and which results in olanzapine which has a purity making it very well suitable for the prepa¬ ration of pharmaceutical formulations.

Further, there is a need for precursors which allow the easy preparation of polymorphic forms of olanzapine or the conversion to other forms of olanzapine.

These problems are solved by the present invention.

In the production of olanzapine by conventional synthetic processes, the final reactions usually yield complex reaction mixtures from which it is difficult to isolate a product with pharmaceutically acceptable purity. Therefore additional puri¬ fication steps are needed as described in e.g. EP 0 454 436 where recrystallization from toxic and therefore pharmaceuti¬ cally undesirable acetonitrile, or expensive and lengthy chro¬ matographic methods need to be used. The substance prepared in such a way is not of a pharmaceutically most desired polymor¬ phic form, therefore additional crystallizations are neces- sary.

The present invention solves these problems by isolation of olanzapine of formula I: in the form of salts of formula II:

n HX

wherein X represents the acetate, benzoate, chloride, dichlo- ride, benzenesulfonate, or perchlorate anion. The salts of formula II can either contain n = 1 or n = 2 equivalents of the added acid.

The salts of formula II may be prepared with widely used ac- ids, such as acetic, benzoic, hydrochloric, benzenesulfonic and perchloric acid, in a surprisingly simple and efficient way. These salts according to the invention can be isolated with minimal additional steps, after completion of conversion of intermediates to olanzapine, and are well suited for the conversion to olanzapine form I, through olanzapine dichlo- roraethane solvate, of the appropriate purity.

Thus, the invention provides a process for preparing olanza- pine by using the compound of formula II, i.e. the salts ac¬ cording to the invention.

The olanzapine prepared can in a first embodiment be a salt of olanzapine which is different from the salts according to the invention.

In a second and preferred embodiment the olanzapine prepared is olanzapine of form I. This is preferably obtained by con¬ verting the salts according to the invention to the olanzapine dichloromethane solvate and this solvate is then converted to the desired form I olanzapine. It is also possible to convert the salts first of all to the water isopropanol solvate of olanzapine, then converting this mixed solvate to the olanza¬ pine dichloromethane solvate and subsequently converting this solvate to olanzapine of form I.

It is further preferred in the process according to the inven¬ tion that the salts are prepared from a reaction mixture. In this embodiment the particular advantage of the present inven- tion is apparent that, despite the presence of a complex mix¬ ture, it is possible to isolate in high purity the salts of the invention which can subsequently be converted to olanza¬ pine, preferably form I olanzapine, having also a high purity.

The reaction mixture is preferably a mixture which is obtained by the process for preparing olanzapine as disclosed in WO 2004/065390. Explicit reference is made as to the details of this process which therefore become subject matter of the pre¬ sent invention.

It is particularly preferred that the reaction mixture is ob- tained by a reaction which comprises the conversion of the in¬ termediate 2,4-bis (4-methyl-1-piperazinyl) -3-propylidene-3H- [1, 5]benzodiazepine or 4-amino-2-methyl-1OH-thieno [2,3- b] [1, 5] benzodiazepine hydrochloride to olanzapine. Such con¬ version processes are disclosed in the mentioned WO 2004/065390.

It is further preferred that the reaction mixture is treated with an acid selected from acetic, benzoic, hydrochloric, ben- zenesulfonic and perchloric acid. This will lead to formation of the salts according to the invention.

In a particular preferred embodiment, the process according to the invention will use the benzoate salt of olanzapine, i.e. X is the benzoate anion in formula II.

Thus, the invention also provides in a general aspect the use of the salts according to the invention as intermediates for the purification of olanzapine.

The invention also provides the use of these salts as interme¬ diates for the production of olanzapine isopropanol water sol¬ vate, olanzapine dichloromethane solvate, anhydrous olanzapine or olanzapine of form I.

The invention also provides a pharmaceutical composition which comprises the salts according to the invention. In the following further details as to the invention will be given.

The isolation of the salts can be done by a person skilled in the art exploiting the procedures widely used in the chemical synthesis and in particular in the following ways: After evaporating evaporatable components or solvents from the com- pleted synthetic reaction mixture of olanzapine, extracting of the mixture with an organic solvent and water in order to re¬ move water soluble impurities, separating of the water layer from the organic solvent layer, evaporating of the extraction solvent, dissolving the residue in another appropriate solvent or mixture of solvents and adding an acid as such, or a solu¬ tion of that acid. After the salt precipitates it is collected by filtration.

As an extraction solvent a solvent, or a mixture of sol- vents of low miscibility with water, can preferably be used, e.g. acetates (e.g. methyl, ethyl, n-propyl, i-propyl, or bu¬ tyl acetate), chlorinated solvents (e.g. dichloromethane, chloroform or similar solvents), or ethers (e.g. diethyl ether, diisopropyl ether, or t-butyl methyl ether) .

As solvents for dissolving the residue after the evapora¬ tion of the organic extraction layer, a solvent can preferably be selected from the group of lower alcohols (e.g. methanol, ethanol, isopropanol, n-propanol, n-, i- or t-butanol) , ke- tones (e.g. acetone, methyl ethyl ketone, or diethyl ketone) , nitriles (acetonitrile, or propionitrile) , acetates (e.g. methyl, ethyl, n-propyl, i-propyl, or butyl acetate) or ethers (e.g. diethyl ether, diisopropyl ether, or t-butyl methyl ether) , or mixtures of them, or even their mixtures with wa- ter. As acid, an organic or inorganic acid can be selected form the group consisting of acetic, benzoic, hydrochloric, benzenesulfonic and perchloric acid. The acid can be in its pure form, or in form of a mixture with a solvent or water.

Another procedure of isolation of salts can in particular be effected in the following way: After the evaporation of evaporatable components or solvents from the completed syn- thetic reaction mixture of olanzapine, the extraction of the mixture with an organic solvent and acidified water follows. By this procedure impurities soluble in organic solvent are removed, while olanzapine remains in the water layer. By sepa¬ rating the solvent from the water layer, adding a new portion of organic solvent and making the water layer alkaline, olan¬ zapine is present in the organic layer. After the separation of layers, evaporation of the solvent or solvents from the or¬ ganic layer, dissolving the residue in another appropriate solvent, or mixture of solvents, addition of an acid as such, or a solution of that acid follows. After the olanzapine salt precipitates, it is collected by filtration.

As an extraction solvent, usually solvents or mixtures of solvents of low miscibility with water can be used, preferably acetates (e.g. methyl, ethyl, n-propyl, i-propyl, butyl ace¬ tate) , chlorinated solvents (e.g. dichloromethane, chloroform or similar solvents), or ethers (e.g. diethyl ether, diisopro- pyl ether, t-butyl methyl ether) .

As solvents for dissolving the residue after the evapora¬ tion of the organic extraction layer, a solvent can preferably be selected from the group of lower alcohols (e.g. methanol, ethanol, isopropanol, n-propanol, n-, i- or t-butanol) , ke- tones (e.g. acetone, methyl ethyl ketone, diethyl ketone) , ni- triles (acetonitrile, propionitrile) , acetates (e.g. methyl, ethyl, n-propyl, i-propyl, butyl acetate), or ethers (e.g. di¬ ethyl ether, diisopropyl ether, t-butyl methyl ether) , or mix- tures of them, or even their mixtures with water.

As acid an organic or inorganic acid can be selected from the group of acetic, benzoic, hydrochloric, benzenesulfonic, and perchloric acid. The acid used can be in pure form, or in form of a mixture with a solvent or water.

The water layer can be made alkaline using usual bases employed in organic synthesis, e.g. bases of earth alkaline metals, or organic bases, such as lithium, sodium, potassium, calcium hydroxides, hydrogen carbonates or carbonates, ammo¬ nia, trimethyl- or triethylamine.

The procedure can be simplified in such a way that the extraction solvent is not evaporated, but that the above men- tioned acid or solution of acid is added, after the separation of the water layer, directly into the extraction solution.

The procedure can also be simplified further in a way that extraction is omitted, and the above mentioned acid or the solution of the acid is added into the solution of the re¬ action mixture, after the evaporation of evaporatable compo¬ nents. In this case the solvent can preferably be selected from the group of lower alcohols (e.g. methanol, ethanol, iso- propanol, n-propanol, n-, i- or t-butanol) , ketones (e.g. ace- tone, methyl ethyl ketone, diethyl ketone) , nitriles (acetoni¬ trile, propionitrile), or acetates (e.g. methyl, ethyl, n- propyl, i-propyl, butyl acetate) , or a mixture of them, or even their mixtures with water. The procedure can be simplified even further such that evaporation of evaporatable components is omitted, and the above mentioned acid or the solution of the acid is added into the solution of the reaction mixture, usually with the addi¬ tion of a solvent. In that case a solvent can preferably be selected from the group of lower alcohols (e.g. methanol, ethanol, isopropanol, n-propanol, n-, i- or t-butanol) , ke¬ tones (e.g. acetone, methyl ethyl ketone, diethyl ketone) , ni- triles (acetonitrile, propionitrile) , or acetates (e.g. methyl, ethyl, n-propyl, i-propyl, butyl acetate), or a mix¬ ture of them, or even their mixtures with water.

In a further embodiment the isolation of olanzapine salt can be simplified further such that extraction is omitted. This embodiment is particularly useful for reaction mixtures ob¬ tained according to the processes described in WO 2004/065390. After the evaporation of evaporatable components or solvents form the completed synthesis reaction mixture of olanzapine, the residue is diluted with a high boiling point solvent, mis- cible with water, e.g. alkylated or partly alkylated glycols, polyglycols or glycerol (e.g. diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol monoethyl ether, glycerol, 1,2-isopropylidene glycerol), dimethyl sulfoxyde, tetrahydro- thiophene-1, 1-dioxyd or mixtures thereof and a low boiling point solvent immiscible with water e.g. dichloromethane, chloroform, isopropyl acetate, diethyl ether, diisopropyl ether, methyl-t-butyl ether, preferably dichloromethane. After filtration of the solid, the filtrate is treated with base, preferably with a hydroxide of a group I and II metal (e.g. sodium hydroxide, lithium hydroxide, potassium hydroxide, mag¬ nesium hydroxide, calcium hydroxide, barium hydroxide) . The salt of organic acid is filtrated off and the low boiling point solvent of the filtrate is distilled off. The residue is diluted with organic solvent selected from the group of lower alcohols (e.g. methanol, ethanol, isopropanol, n-propanol, n-, i-, or t-butanol) , ketones (e.g. acetone, methyl ethyl ketone, diethyl ketone) or nitriles (acetonitrile, propionitrile) or mixture of them, with acetone being preferred, and treated with organic or inorganic acid selected from the group of ace¬ tic, benzoic, hydrochloric, benzenesulfonic and perchloric acid. According to this procedure olanzapine salt according to the invention of high purity is obtained.

The structures of the preferred salts prepared by proce¬ dures above were confirmed by the usual analytical methods such as NMR spectrometry, IR spectrometry, elemental analysis, and the determination of melting point. Using 1H-NMR spec¬ trometry made it obvious, that although olanzapine contains three potentially salt forming groups, the 1:1 compounds (mo¬ lar ratio) are isolated in the cases of salts with acetic, benzoic, benzenesulfonic and perchloric acid. The exception is hydrochloric acid, where surprisingly both, the dihydrochlo- ride and the monohydrochloride, salts can be isolated by vary¬ ing reaction conditions.

The salts prepared in this way can be further purified by recrystallization from appropriate solvents, if necessary.

The olanzapine salts of the invention, which are prepared by the procedures above, can be converted to the olanzapine free base by extraction or crystallization.

Extraction can be done using organic solvents and alka¬ line water media. As alkaline media water solutions of sodium carbonate, sodium hydrogen carbonate, or hydroxide, or potas¬ sium equivalents of them can be used. In place of them, solu¬ tions of ammonia or other organic amines can be used as well.

As extraction solvent a usual extraction solvent as de¬ fined above can be used. After the separation of layers, the organic layer is evaporated to the oily residue, which is dis¬ solved in an appropriate solvent and crystallized.

Crystallization can be done by suspending the olanzapine salt in an appropriate solvent and converting it by adding a base.

In a preferred embodiment the form of mixed water isopro- panol solvate is prepared by usual extraction in organic sol¬ vents and alkaline water media. As alkaline media water solu¬ tions of sodium carbonate, sodium hydrogen carbonate, or hy¬ droxide, or potassium equivalents of them are used. In place of them solutions of ammonia or other organic amines could be used as well.

As extraction solvent a usual extraction solvent as de¬ fined above can be used. After the separation of layers, the organic layer is evaporated to the oily residue, which is dis- solved in isopropanol. The mixed solvate precipitates after the addition of the appropriate amount of water. The procedure can be simplified in the way that the extraction is omitted. In this case the olanzapine salt is suspended in isopropanol. After addition of the appropriate amount of water solution of base, the solid transforms to olanzapine water isopropanol solvate. The product is collected with suction, again. As base again water solutions of sodium carbonate, sodium hydrogen carbonate or hydroxide or potassium equivalents of them can be used.

Transformation of olanzapine water isopropanol solvate to dichloromethane solvate is preferably achieved by dissolving olanzapine water isopropanol solvate in dichloromethane, con¬ centrating the solution by evaporation and collecting solid olanzapine dichloromethane solvate. The yield of the solvate depends on the proportion between olanzapine and dichlo- romethane.

The transformation of olanzapine dichloromethane solvate to olanzapine form I can preferably be effected by slurring solid olanzapine dichloromethane solvate in isopropanol and collecting the solid olanzapine form I by suction.

The procedure for the preparation of olanzapine form I can be simplified such that the isolation of olanzapine water isopropanol solvate is omitted. In this case the olanzapine salts, prepared by the procedures above, can be converted to the olanzapine free base in the form of dichloromethane sol¬ vates, such as disclosed in US 5,637,584, WO 2004/006933, and SI P-200400073, by usual extraction using dichloromethane and alkaline water media. As alkaline media water solutions of so- dium carbonate, sodium hydrogen carbonate, or hydroxide, or potassium equivalents of them can be used. In place of them solutions of ammonia or other organic amines could be used as well. After the separation of layers, the organic layer is partially concentrated and the solid olanzapine dichlo- romethane solvate is collected by suction. Dichloromethane as extraction solvent can be replaced by any other usual extrac¬ tion solvent as defined above. If the solvent is different from -dichloromethane, then the organic layer must be evapo¬ rated first and the residue is dissolved in dichloromethane.

' Olanzapine dichloromethane formed in this way can pref- erably be converted to olanzapine form I by the method defined above.

The present invention is further illustrated by the following Examples.

EXAMPLES

Olanzapine acetate

Example 1 The mixture of 0.5g of • 4-amino-2-methyl-1OH-thieno [2, 3- b] [1, 5] benzodiazepine hydrochloride (about 92% purity), 0.67 ml of dimethyl sulfoxide, 2.25 ml of toluene, and 1.75 ml of JW-methylpiperazine was refluxed for 4 hours. The solvents were evaporated in vacuum, a small portion of water was added and extracted with dichloromethane. The organic phase was dried with brine and sodium sulfate, filtered and the solvent re¬ moved by evaporation. The residue was dissolved in acetone and 0.15 ml of acetic acid were added. The mixture was agitated overnight and the product was collected by suction. After dry¬ ing, the yield was 0.30 g, mp (uncorrected) 190-1930C. The structure of the compound was confirmed by 1H-NMR (DMSO-d6) : δ 1,91 (3H, S, CH3COO"), 2.21 (3H, S, 4'-CH3), 2.27 (3H, d, J=I.2 Hz, 2-CH3), 2.38 (4H, m, 3'-CH2), 3.33 (4H, m, 2'-CH2), 6.34 (IH, d, J=I.2 Hz, 3-CH), 6.66-6.88 (4H, m, 6,7,8,9-H), 7.60 (partially exchanged 2H, s, NH2+) . Example 2 To the solution of 1.0 g olanzapine in 50 ml of isopropanol, 2.5 ml of acetic acid were added. After the solvent was re¬ moved in vacuum, 2.5 ml of isopropanol were added, and the mixture was cooled. The precipitate was collected by suction and dried. The yield was 0.30 g. The IR spectrum was identical to the spectrum of the substance prepared in Example 1.

Olanzapine benzoate

Example 3 The mixture of 0.5g of 4-amino-2-methyl~20ff-thieno [2, 3- b] [1, 5]benzodiazepine hydrochloride (about 92% purity) , 0.67 ml of dimethyl sulfoxide, 2.25 ml of toluene, and 1.75 ml of JNT-methylpiperazine was refluxed for 4 hours. The volatile com¬ ponents were evaporated in vacuuo, a small portion of water was added and the mixture was extracted using dichloromethane. The organic phase was dried by brine and anhydrous sodium sul- fate, filtered and the solvent was removed by evaporation. The residue was dissolved in acetone and 0.318 g of benzoic acid was added. The mixture was agitated overnight and the product was collected by suction. After drying, the yield was 0.69 g, mp 205-2090C. The structure of the compound was confirmed by 1H-NMR (DMSO-d6) : δ 2.23 (3H, S, 4'-CH3), 2.27 (3H, d, J=I.2 Hz, 2-CH3), 2.41 (4H, m, 3'-CH2), 3.34 (4H, m, 2'-CH2), 6.34 (IH, d, J=I.2 Hz, 3-CH), 6.66-6.88 (4H, m, 6,7,8,9-H), 7.45- 7,65 (4H, m, benzoate), 7.92-7.98 (2H, partially exchanged, m, benzoate, NH2+) .

Example 4 The substance was prepared from 4-amino-2-methyl-10H- thieno [2,3-b] [1, 5] benzodiazepine hydrochloride as above. After extraction, drying and evaporation of the solvent, the residue was dissolved in isopropanol and 0.318 g of benzoic acid was added. The mixture was agitated overnight and the product was collected by suction. After drying, the yield was 0.64 g. The IR spectrum was identical to the spectrum of the substance prepared by the Example 3.

Example 5 The mixture of 0.20 g of 4-amino-2-methyl-1Off-thieno [2, 3- b] [1, 5] benzodiazepine hydrochloride (about 92% purity) , 1.2 ml of dimethyl sulfoxide, and 0.52 ml of iV-methylpiperazine was heated at 115°C for 16 hours. The cooled reaction mixture was extracted with isopropyl acetate and water. The organic layer was washed with brine, dried by sodium sulfate, and filtered. To the solution 0.092 g of benzoic acid were added. The mix¬ ture was agitated overnight and the product was collected by suction. After drying, the yield was 0.144 g. The IR spectrum corresponds to the spectrum of the Example 3.

Example 6 The mixture of 3.0 g of 4-amino-2-methyl-10H-thieno [2, 3- b] [1, 5] benzodiazepine hydrochloride (about 92% purity), 4 ml of dimethyl sulfoxide, 13.5 ml of toluene, and 10.5 ml of N- methylpiperazine was refluxed for 4 hours. The solvents were evaporated in vacuum. The residue was dissolved in acetone and 1.477 g of benzoic acid were added. The mixture was agitated overnight and the product collected by suction. After drying, the yield was 2.82 g. The IR spectrum corresponds to the spec¬ trum of Example 3.

Example 7 To the solution of 1.0 g olanzapine in 50 ml of isopropanol, 0.41 g of benzoic acid were added and the solution was agi- tated. The precipitate was collected by suction and dried. The yield was 1.06 g. The IR spectrum was identical to the spec¬ trum of the Example 3.

Example 8 The solution of 2,4-bis (4-methyl-1-piperazinyl) -3-propylidene- 3H- [1, 5]benzodiazepine (3.81 g, 10 mmol) (preferred according to WO 2004/065390) , pyridinium p-toluenesulfonate (5.29 g, 21 mmol) and sulphur (1.15 g, 35.8 mmol) in benzonitrile (100 ml) was stirred at 1400C for 8.5 h, cooled to 900C and concen¬ trated to form an oily residue. The residue was diluted with dichloromethane and 2-propanol (60 ml, 1:1) . The precipitate was filtered off and washed with dichloromethane and 2- propanol (15 ml, 1 : 1) . The filtrate was extracted with HCl (50 ml, 0.5 M) . The organic phase was diluted with dichlo¬ romethane and 2-propanol (100 ml, 1 : 1) and extracted with HCl (50 ml, 1 M) . The organic phase was again extracted with HCl (50 ml, 2M) . The combined aqueous phases were made alka¬ line with 5 M NaOH at a pH of 10, and extracted with dichlo- romethane (150 ml) . Benzoic acid (1.832 g, 15 mmol) was added to the organic phase. The solution was concentrated to form an oily residue and suspended in isopropyl acetate. The solid was collected by suction and dried. The IR spectrum was identical to the spectrum of the substance prepared in Example 3.

Example 9 The solution of 2,4-bis (4-methyl-1-piperazinyl) -3-propylidene- 3H- [1, 5] benzodiazepine (42.5 g, 112 mmol), pyridinium p- toluenesulfonate (56.1 g, 223 mmol) and sulfur (12.2 g, 380 mmol) in benzonitrile (860 ml) was stirred at 14O0C for 12 h, cooled to 900C and concentrated to 10%. Triglyme (60 ml) was added, the residue was cooled and diluted with dichloromethane (120 ml) . The precipitate was filtered off and washed with di- chloromethane (30 ml) . Sodium hydroxide (9.38 g, 234 mmol) and water (6 ml) were added to the filtrate. The mixture was stirred over night to form a suspension. The precipitate was filtered off and washed with dichloromethane (30 ml) . Dichlo- romethane was evaporated under reduced pressure, the residue was diluted with acetone (150 ml) and treated with benzoic acid (16.4 g, 134 mmol) . The obtained solid was collected by suction and dried, the yield was 15.4 g. The IR spectrum was identical to the spectrum of the substance prepared in Example 3.

Olanzapine dihydrochloride

Example 10 The mixture of 3 g of 4-amino-2-methyl-1OH-thieno [2, 3- b] [1, 5]benzodiazepine hydrochloride (about 92% purity) , 4 ml of dimethyl sulfoxide, 13.5 ml of toluene, and 10.5 ml of N- methylpiperazine was refluxed for 4 hours, cooled and water was added. The mixture was extracted with 30 ml of isopropyl acetate. The organic layer was washed with brine and 1 ml of concentrated hydrochloric acid was added. After the separation of the oily product, 10 ml of isopropanol was added, and the mixture was agitated overnight. The solid was collected by suction, washed with a small volume of isopropyl acetate and dried to a constant weight. The yield was 1.3 g, mp 225-2300C (decomp.) . The structure of the compound was confirmed by 1H- NMR (DMSO-d6) : δ 2.31 (3H, d, J=I.2 Hz, 2-CH3), 2.81 (3H, S, 4'-CH3) , 3,5 (m, 3' (or 2') -CH2), 3.89 (4H, m, 2' (or 3') -CH2) , 6.69 (IH, d, J=I.2 Hz, 3-CH) , 7.04-7.36 (4H, m, 6,7,8,9-H), 9.51 (IH, s, 10-H) , 11.70 (IH, broad s, exchanged in D2O, NH+), 11.93 (IH, broad S, exchanged in D2O, NH+) . Example 11 After refluxing the reaction mixture as in Example 10, the volatile components were removed in vacuuo and the residue was dissolved in acetone. After addition of 0.95 ml of concen- trated hydrochloric acid, the mixture was agitated overnight. Volatile components were removed and 10 ml of isopropanol and a new portion of 0.95 ml of concentrated hydrochloric acid were added. The mixture was agitated for one hour. The solid was collected by suction, washed with isopropanol and dried to a constant weight. The yield was 3.15 g. The IR spectrum cor¬ responds to the spectrum of the previous Example.

Example 12 After the acetone solution of the reaction mixture was pre- pared as in the previous Example, 1.9 ml of concentrated hy¬ drochloric acid were added. The mixture was agitated over¬ night, the solvent removed by evaporation in vacuuo and 20 ml of acetone were added. Then 4 ml of isopropanol were added, the solution was agitated for additional 2 hours, the solid was collected by suction and dried to a constant weight. The yield was 3.7 g. The IR spectrum corresponds to the spectrum of Example 10.

Olanzapine hydrochloride

Example 13 To the solution of 1.0 g (3.20 mmol) olanzapine in 50 ml of isopropyl acetate, 0.30 ml (3.35 mmol) of concentrated hydro- chloric acid were added and agitated. The volatile components were evaporated in vacuuo and fresh solvent was added. After the agitation, the precipitate formed was collected by suction and dried. The yield was 1.01 g, m.p. 250-2700C (decomp.) . The IR spectrum was different compared to the spectrum of the product of Example 10. The structure of the compound was con¬ firmed by 1H-NMR (DMSO-d6) : δ 2.29 (3H, d, J=I.2 Hz, 2-CH3) , 2.77 (3H, s, 4'-CH3) , 3,35 (m, 3' (or 2'J-CH2), 3.98 (4H, m, 2' (or 3'J-CH2), 6.50 (IH, m, 3-CH), 6.8-7.1 (4H, m, 6,7,8,9- H) , 8.3 (IH, broad s, 10-H) , 11.5 (IH, broad s, NH+) .

Olanzapine benzenesulfonate

Example 14 To the solution of 1.0 g (3.20 mmol) olanzapine in 50 ml of isopropyl acetate, 0.53 g (3.35 mmol) of benzenesulfonic acid hydrate were added and agitated. The precipitate formed was collected by suction and dried. The yield was 1.3 g, mp (un- corrected) 168-1700C. The structure of the compound was con¬ firmed by 1H-NMR (DMSO-d6) : δ 2.28 (3H, d, J=I.2 Hz, 2-CH3) , 2.81 (3H, s, 4'-CH3), 3,23 (m, 3' (or 2') -CH2), 3.35 (4H, m, 2' (or 3') -CH2), 6.43 (IH, m, 3-CH), 6.7-7.0 (4H7 m, 6,7,8,9- H), 7.25-7.35 (3H, m, PhSO3H), 7.55-7.65 (2H, m, PhSO3H), 7.9 (IH, br. s, 10-H) , 9.7 (IH, br. s, NH+) .

Olanzapine perchlorate

Example 15 The mixture of 0.5g of 4-amino-2-methyl-10H-thieno [2, 3- b] [1, 5] benzodiazepine hydrochloride, 0.67 ml of dimethyl sul¬ foxide, 2.25 ml of toluene, and 1.75 ml of JV-methylpiperazine was refluxed for 4 hours. The solvents were evaporated in vac- uuo, a small portion of water was added and the mixture was extracted with dichloromethane. The organic phase was dried by brine and sodium sulfate, filtered and the solvent removed by evaporation. The residue was dissolved in isopropanol and 0.22 ml of 70% perchloric acid were added. The mixture was agitated overnight and the product collected by filtration. After dry- ing, the yield was 0.63 g, mp (uncorrected) 180-1830C. The structure of the compound was confirmed by 1H-NMR (DMSO-d6) : δ 2.29 (3H, d, J=I.2 Hz, 2-CH3), 2.82 (3H, s, 4'-CH3), 3.25 (m, 3' (or 2') -CH2), 3.35 (4H, m, 2' (or 3') -CH2), 6.45 (IH, S, 3- CH), 6.65-7.05 (4H, m, 6,7,8,9-H) , 7.87 (IH, br. s, 10-H) , 9.67 (IH, br. s, NH+) .

Example 16 To the solution of 1.0 g olanzapine in 50 ml of isopropanol, 0.3 ml of 70 % perchloric acid were added and the mixture was agitated. The precipitate was collected by suction and dried. The yield was 0.60 g. The IR spectrum was identical to the spectrum of the previous Example.

Olanzapine water isopropyl solvate

Example 17 The mixture of 1.0 g of olanzapine dihydrochloride prepared by the procedure as in the Example 12, 6 ml of isopropanol, 0.77 ml of triethylamine, and 1.5 ml of water was agitated for about 1.5 hour. After collecting the product by filtration and drying in vacuuo at room temperature to a constant weight, the yield was 0.64 g. Loss on drying at (14O0C) : 13.1%. The IR spectrum and NMR spectrum correspond to the structure. Olanzapine dichloromethane solvate

Example 18 The mixture of 5.0 g of olanzapine benzoate, prepared by the procedure as in the Example 3, 100 ml of dichloromethane, 12 ml of IM NaOH solution, was agitated for about 0.5 hour. The layers were separated and the organic layer was washed with brine and anhydrous sodium sulfate. The solution was concen¬ trated to about 1/10 of the starting volume by distillation in vacuuo. During the distillation the temperature dropped down to about 100C and the product (olanzapine dichloromethane sol¬ vate) crystallized. After collecting the product by suction and drying in vacuum at room temperature to a constant weight, the yield was 1.8 g. The loss on drying at (14O0C) was 9.9%. The IR spectrum and NMR spectrum correspond to the structure.

Example 19 The mixture of 1.0 g of olanzapine dihydrochloride prepared by the procedure as in the Example 11, 20 ml of dichloromethane, 0.77 ml of triethylamine, and 6 ml of water was agitated for a few minutes. The layers were separated and the organic layer washed with brine and anhydrous sodium sulfate. The solution was concentrated to about 1/5 of the starting volume by dis¬ tillation. After collecting the product by filtration and dry- ing in vacuum at room temperature to a constant weight, the. yield was 0.45 g. The IR spectrum corresponds to the spectrum of the previous Example.

Example 20 2.0 g of olanzapine water isopropanol mixed solvate, prepared by the procedure as described in Example 17, were dissolved in 24 ml of dichloromethane. The solution was concentrated to about 1/5 of the starting volume by distillation. After col- lecting the product by filtration and drying in vacuum at room temperature to a constant weight, the yield was 1.6 g. The IR spectrum corresponds to the spectrum of the previous Example.

Olanzapine form I

Example 21 The mixture of 1.0 g of olanzapine dichloromethane solvate, prepared by the procedure as in Example 18, and 2.5 ml of iso- propanol was agitated for about 0.5 hour. The solid was col¬ lected by filtration and dried. The yield was 0.79 g. The IR spectrum corresponds to the literature data for olanzapine form I.

Example 22 The mixture of 0.24 g of olanzapine dichloromethane solvate, prepared by the procedure as in Example 19, and 0.6 ml of iso- propanol was agitated for about 0.5 hour. The solid was col- lected by filtration and dried. The yield was 0.19 g. The IR spectrum corresponds to the literature data for olanzapine form I.