HUP0300875A2 - Process for preparation of hydrates of olanzapine and their conversion into crystalline forms of olanzapine - Google Patents

Abstract

The subject of the invention is a process for the production of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (hereinafter olanzapine). The subject of the invention is also a process for converting these anhydrates into the pure crystalline form of olanzapine, which is hereinafter referred to as form 1. The subject of the invention is also the conversion of form 2 of olanzapine to form 1. HE

Description

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Process for the preparation of Olanzapine and its conversion into crystalline forms of Olanzapine

The present invention relates to a process for the preparation of 2-methyl-4-(4-methyl-1-piperazinyl)-1OH-thieno[2,3-b][1,5]benzodiazepine (hereinafter referred to as Olanzapine). The present invention also relates to a process for converting these hydrates into a pure crystalline form of Olanzapine, hereinafter referred to as Form 1. The present invention also relates to the conversion of Form 2 of Olanzapine into Form 1.

More specifically, the present invention relates to a process for the preparation of hydrates of Olanzapine and the conversion of these to crystalline forms of Olanzapine Form 1 by recrystallization from a solvent. The structure of Olanzapine can be described by Formula I.

Olanzapine is useful in the treatment of psychotic patients and mild anxiety disorders. The preparation of Olanzapine and its acid salts, which have pharmaceutical properties, particularly in the treatment of central nervous system disorders, is described in U.S. Patent No. 5,229,382.

No specific polymorphic crystalline form of Olanzapine is disclosed in U.S. Patent No. 5,229,382. European Patent No. 733635A1 claims Form 2 of Olanzapine. The process disclosed in this patent describes the preparation of Form 2 from ethyl acetate. This patent describes the product referred to as Form 1 in U.S. Patent No. 5,229,382.

In addition, EP 733635A1 discloses the d values of Form 1 and Form 2 based on their X-ray diffractograms. The values are as follows:

d value d value Form 1 Form 2 9.94 10.26 8.55 8.57 8.24 7.47 6.88 7.12 6.37 6.14 6.24 6.07 5.58 5.48 5.30 5.21 4.98 5.12 4.83 4.98 4.72 4.76 4.62 4.71 4.53 4.47 4.46 4.33 4.29 4.22 4.23 4.14 4.08 3.98 3.82 3.72 3.74 3.56 3.69 3.53 3.58 3.38

3.50 3.25 3.33 3.12 3.28 3.08 3.21 3.06 3.11 3.01 3.05 2.87 2.94 2.81 2.81 2.72

2.75 2.64

2.65 2.60

2.63

2.59

It is worth mentioning that EP 0 831 098 A2 describes the preparation of a series of Olanzapine dihydrates, namely dihydrate B, dihydrate D and dihydrate E. The d values of these forms are listed in EP 0 831 098 A2 from X-ray diffractograms.

Attempts were made to obtain Olanzapine Form 1 by recrystallization of Olanzapine from acetonitrile as described in Example 1 and Sub-Example 4 of U.S. Patent No. 5,229,382. The procedure is described herein for reference: A mixture of 100 g of 4amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine HCl, 350 mL of N-methyl piperazine, 465 mL of DMSO, and 465 μΐ of toluene was heated to reflux. The reaction mixture was refluxed for 19 hours, then cooled to 50 °C and water was added. The reaction mixture was cooled to 0-10 °C and stirred at the same temperature for 6 hours. The separated crude

Olanzapine was filtered off and dried in an oven to constant weight (76.5 g). The crude product was added to 750 ml of boiling acetonitrile. The mixture was stirred for an additional 5 minutes. The mixture was filtered to remove insoluble solids. The filtrate was treated with activated charcoal and then distilled. The filtrate was concentrated to a minimum volume, cooled to 0-5 °C, kept at the same temperature for 1.0 hour, and then filtered. The compound was dried in an oven to constant weight (51.6 g).

The polymorphic form obtained from these experiments was characterized by X-ray powder diffraction on a Rigaku D/Max 2200. As can be clearly observed, the d values of this product (Figure 1) are similar to those of Olanzapine Form 2 obtained in EP 733635A 1. It therefore follows that recrystallization of Olanzapine results in Form 2, not Form 1.

Accordingly, the present invention provides a novel process for the preparation of hydrates of Olanzapine, which differs from the process described in the literature. These hydrates will be referred to for simplicity as Olanzapine 1 monohydrate and Olanzapine 1 dihydrate.

Accordingly, the present invention further provides a novel process for the preparation of Olanzapine Form 1 by recrystallization of Olanzapine or its hydrates from dichloromethane.

The present invention also provides a novel process for converting Olanzapine Form 2 to Olanzapine Form 1.

Accordingly, the preparation process for Olanzapine 1 monohydrate consists of the following steps:

a) a mixture of 4-amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride, N-methyl piperazine, DMSO and toluene is refluxed for 5-20 hours;

b) cooling the mixture to 20-90 °C;

c) water is added;

d) the mixture is cooled to -5 - +25 °C and then stirred for 2-10 hours;

e) the mixture is filtered and washed with water; and

f) Dry at 30-50 °C until constant weight.

According to the present invention, the process for preparing Olanzapine 1 dihydrate comprises the following steps:

a) a mixture of 4-amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride, N-methyl piperazine, DMSO and toluene is refluxed for 5-20 hours;

b) cooling the mixture to 20-90°C;

c) water is added;

d) the mixture is cooled to -5 - +25 °C and then stirred for 2-10 hours;

e) the mixture is filtered, washed with water; and

f) dried at room temperature until constant weight.

The preferred ratio of 4-amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride, N-methyl piperazine, DMSO and toluene that can be used to prepare the monohydrate and dihydrate is as follows:

N-methyl piperazine (2.0-8.4 moles relative to 1.0 mole of 4-amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride).

DMSO (2-8 times volume relative to 1.0 mol of 4-amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride).

Toluene (3-8 times volume to volume of 1.0 mol of 4-amino-2-methyl10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride).

According to the present invention, Olanzapine Form 1 is prepared by refluxing a suspension of Olanzapine or its hydrates in dichloromethane, where the dichloromethane used is in a ratio of 4.5-13 volume/weight of Olanzapine, to obtain a clear solution. The resulting solution is then treated with activated carbon and then filtered. After completion of this step, the filtrate is cooled to 0-5 °C and then stirred at the same temperature for 60-90 minutes. The precipitated solid is filtered off and then washed with dichloromethane. The product dried in a drying cabinet at 60-70 °C until constant weight is Olanzapine Form 1.

For our studies, we use the process described in U.S. Patent No. 5,229,382 to prepare crude Olanzapine, and the process described in EP 733 635 A1 to prepare Olanzapine Form 2. However, other methods can be used to prepare crude Olanzapine and Olanzapine Form 2, and any method that can be used to prepare crude Olanzapine and Olanzapine Form 2 can be used in the process of the present invention.

The following examples are provided for illustrative purposes only and are not to be construed as limiting the scope of the invention in any way.

Example 1

Preparation of Olanzapine monohydrate-1 kg of 4-amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride, 42 liters of N-methyl piperazine, 40 liters of dimethyl sulfoxide and 95 liters of toluene are heated to reflux temperature. The reaction mixture is kept at reflux temperature for 17 hours and then cooled to 40-50 °C. 95 liters of water are slowly added at 40-50 °C. The reaction mixture is cooled to -0.6 -1.2 °C and then stirred at this temperature for 6 hours. The precipitated crude Olanzapine is filtered off and then washed with 10 liters of water. The product is dried for 10 hours and 50 minutes at 30-5-31.8 °C. Yield: 20 kg. A 20 gram sample of the above material was further heated for 72 hours to obtain a product with a moisture content of 5.22%.

Example 2

Preparation of Olanzapine dihydrate-1

200 grams of 4-amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride, 420 ml of N-methyl piperazine, 200 ml of dimethyl sulfoxide and 940 ml of toluene are heated to reflux temperature. The reaction mixture is kept at reflux temperature for 12 hours and then cooled to 40 °C. 940 ml of water are slowly added at 40-44 °C. The reaction mixture is cooled to 0-5 °C and then stirred at this temperature for 5 hours. The precipitated crude Olanzapine is filtered off and washed with 100 ml of water. The resulting solid is air-dried (25-35 °C) for 24 hours (Yield: 241 grams).

Example 3

Production of Form 1

35.0 grams of crude 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3-b][1,5]benzodiazepine were suspended in 160.0 ml of dichloromethane. The solution was heated to reflux temperature to obtain a clear solution. The resulting solution was then treated with 3.5 grams of activated carbon and filtered. After completion of this step, the filtrate was cooled to 0-5 °C and stirred at the same temperature for 1 hour. The precipitated solid was filtered and washed with 10.0 ml of cold dichloromethane. The product dried in an oven at 658 °C to constant weight was Olanzapine Form 1 (yield: 22.0 grams).

Example 4

Conversion of Form 2 to Form 1

A stirred suspension of 20.0 grams of pure 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3-b][1,5]benzodiazepine in 90.0 ml of dichloromethane was heated to reflux to give a clear solution. The clear solution was filtered and cooled to 3-5 °C and stirred at this temperature for 1 hour. The crystalline solid was filtered off and washed with 4.0 ml of dichloromethane. The product, dried to constant weight at 60-70 °C, was Olanzapine Form 1 (yield: 12.7 grams).

Example 5

Preparation of Form 1 from Olanzapine Monohydrate-1

25.0 grams of 2-methyl-4-(4methyl-1-piperazinyl)10H-thieno-[2,3-b][1,5]benzodiazepine monohydrate 1 prepared according to Example 1 were suspended in 325.0 ml of dichloromethane. The solution was heated to reflux temperature to obtain a clear solution. The resulting solution was then treated with 2.5 grams of activated carbon and filtered. After this step, the filtrate was evaporated to a minimum volume, then cooled to 2-4 °C and stirred at this temperature for 90 minutes. The precipitate was filtered off and washed with 10.0 ml of chilled dichloromethane. The product dried in a drying cabinet at 60-70 °C to constant weight was Olanzapine Form 1 (yield: 16.5 grams).

Example 6

Preparation of Form 1 from Olanzapine Dihydrate-1 Grams of 2methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine prepared as described in Example 2 were suspended in 520 ml of dichloromethane. The suspension was heated to reflux temperature to obtain a clear solution. The resulting solution was then treated with 4.0 grams of activated carbon and filtered. After this step, the filtrate was concentrated to a minimum volume, cooled to 0-2 °C and stirred at this temperature for 1 hour. The precipitate was filtered off and washed with 10.0 ml of dichloromethane. The product dried in an oven at 65-70 °C to constant weight was Olanzapine Form 1 (yield: 26.0 grams).

The crystalline forms mentioned in Examples 1-6 were analyzed for structural and analytical data, such as powder X-ray diffraction, differential scanning calorimetry and infrared absorption spectroscopy. The results obtained are discussed and the corresponding figures are attached (Figures 2-19).

The X-ray diffraction patterns obtained with the materials prepared in Examples 1-6 presented here were obtained on a Rigaku D/Max-2200 XRay Powder Diffractometer with a copper K-ray source with a wavelength of λ=1.54 Angstrom. The samples were scanned between 3 and 45 degrees 2Θ.

The d values for monohydrate-1 in Example 1 are shown below (Figure 2).

d value I/Io

10.0176100

6.89957

6.356712

6.171411

3.875651

4.726222

4.590434

4.49377

4.431513

4.341410

4.14116

3.866923

3.785726

3.64809

3.570115

3.44513

3.25004

3.20654

2.96465

2.87153

2.85722

The d values of dihydrate-1 in Example 2 are shown below (Figure 5).

d value I/Io

9.9949100

9.68877

7.04182

6.41172

6.12056

5.45346

5.2358 2 4.8230 33 4.7162 9 4.5717 15 4.4847 6 4.3924 8 4.3080 4 4.2070 3 4.0735 3 3.9974 3 3.9242 9 3.8438 12 3.7699 9 3.7386 13 3.6837 3 3.6509 4 3.6072 5 3.5256 11 3.4242 2 3.1773 2 3.1207 2 2.9917 2 2.9569 3 2.8733 2 2.8483 2 2.7895 2

The X-ray diffraction patterns of the products prepared as described in Examples 3-6 are identical to those of the materials described in EP 733 635 A1.

Below is a brief description of the accompanying figures.

Figure 1 shows the characteristic X-ray diffraction pattern of form 2 obtained by recrystallization from acetonitrile (Vertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees)).

Figure 2 is a characteristic X-ray diffraction pattern of Olanzapine monohydrate-1 (Vertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees)).

Figure 3 is a typical infrared absorption spectrum of Olanzapine monohydrate-1 in potassium bromide (Vertical axis: Transmission (%); Horizontal axis: Wavenumber (cm ¹ )).

Figure 4 is a typical differential scanning calorimetry thermogram of Olanzapine monohydrate-1 (Vertical axis: mW; Horizontal axis: Temperature (°C)).

Figure 5 is a characteristic X-ray diffraction pattern of Olanzapine dihydrate-1 (Vertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees)).

Figure 6 is the characteristic infrared absorption spectrum of Olanzapine dihydrate-1 in potassium bromide (Vertical axis: Transmission (%); Horizontal axis: Wavenumber (cm ¹ )).

Figure 7 is a typical differential scanning calorimetry thermogram of Olanzapine dihydrate-1 (Vertical axis: mW; Horizontal axis: Temperature (°C)).

Figure 8 is a typical X-ray diffraction pattern of Form 1, recrystallized from crude Olanzapine in dichloromethane (Vertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees)).

Figure 9 is a characteristic infrared absorption spectrum of Form 1 in potassium bromide, recrystallized from crude Olanzapine in dichloromethane (Vertical axis: Transmission (%); Horizontal axis: Wavenumber (cm- ¹ )).

Figure 10 is a typical differential scanning calorimetry thermogram of Form 1, recrystallized from crude Olanzapine in dichloromethane (Vertical axis: mW; Horizontal axis: Temperature (°C)).

Figure 11 is a typical X-ray diffraction pattern of Form 1 obtained by the conversion of Olanzapine Form 2 to Form 1 in dichloromethane (Vertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees)).

Figure 12 is the characteristic infrared absorption spectrum of Form 1 in potassium bromide, obtained by the conversion of Olanzapine Form 2 to Form 1 in dichloromethane (Vertical axis: Transmission (%); Horizontal axis: Wavenumber (cm- ¹ )).

Figure 13 is a typical differential scanning calorimetry thermogram of Form 1 obtained by the conversion of Olanzapine Form 2 to Form 1 in dichloromethane (Vertical axis: mW; Horizontal axis: Temperature (°C)).

Figure 14 is a typical X-ray diffraction pattern of Form 1 obtained by the conversion of Olanzapine monohydrate-1 in dichloromethane to Form 1 (Vertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees)).

Figure 15 is a typical infrared absorption spectrum of Form 1 in potassium bromide, obtained by the conversion of Olanzapine monohydrate-1 in dichloromethane to Form 1 (Vertical axis: Transmission (%); Horizontal axis: Wavenumber (cm- ¹ )).

Figure 16 is a typical differential scanning calorimetry thermogram of Form 1 obtained by the conversion of Olanzapine monohydrate-1 to Form 1 in dichloromethane (Vertical axis: mW; Horizontal axis: Temperature (°C)).

Figure 17 is a typical X-ray diffraction pattern of Form 1 obtained by the conversion of Olanzapine dihydrate-1 in dichloromethane to Form 1 (Vertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees)).

Figure 18 is a characteristic infrared absorption spectrum of Form 1 in potassium bromide, obtained by the conversion of Olanzapine dihydrate-1 in dichloromethane to Form 1 (Vertical axis: Transmission (%); Horizontal axis: Wavenumber (cm ¹ )).

Figure 19 is a typical differential scanning calorimetry thermogram of Form 1 obtained by the conversion of Olanzapine dihydrate-1 to Form 1 in dichloromethane (Vertical axis: mW; Horizontal axis: Temperature (°C)).

Claims (4)

PATENT CLAIMS [1,5]benzodiazepine (Olanzapine monohydrate-1) is stirred in dichloromethane at reflux temperature until a clear solution is obtained; b) the solution is then treated with activated carbon; c) filtering the solution and retaining the filtrate; d) cooling the filtrate to below 0-5 °C; e) then stirred for 60-90 minutes; f) the precipitated solid is filtered off, washed and then dried at 6070 °C until constant weight. 17. The process according to claim 16, characterized in that the amount of dichloromethane used in step a) is in a volume/weight ratio of 4.5-13 relative to the 2-methyl-4-(4methyl-1-piperazinyl)-1 OH-thieno[2,3-b][1,5]benzodiazepine hydrochloride. 18. The process according to claim 16, characterized in that in step f) the solid is washed with dichloromethane. 19. A process for the preparation of Olanzapine Form 1 from Olanzapine Form 2, characterized in that the following steps are used: a) 2-methyl-1 OH-thieno [2,3-b] [1,5] benzodiazepine hydrochloride (Olanzapine form 2) is stirred in dichloromethane at reflux temperature until a clear solution is obtained; b) the solution is filtered and cooled to 0-5 °C; c) stir for 60-90 minutes; d) the precipitated solid is filtered off, washed and then dried at 60-70 °C until constant weight. 20. The process according to claim 19, characterized in that the amount of dichloromethane used is 2-methyl-10H-thieno[2,3- · · · · · 2ΐ J. It is 4.5-13 volume/weight ratio compared to [b][1,5]benzodiazepine hydrochloride. 21. The process according to claim 19, characterized in that in step d) the solid is washed with dichloromethane. Ádán Szentpéteri Jr. Patent S.B.G. & K\Patent Law Firm 1. Compound which is Olanzapine monohydrate-1. 2.78952 5. A process for the preparation of Olanzapine monohydrate-1, characterized in that the process comprises the following steps: a) a mixture of 4-amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride, N-methyl piperazine, DMSO and toluene is refluxed for 5-20 hours; b) cooling the mixture to 20-90°C; c) water is added; d) the mixture is cooled to -5 - +25 °C and then stirred for 2-10 hours; e) the mixture is filtered and washed with water; and f) Dry at 30-50 °C until constant weight. 6. The process according to claim 5, characterized in that the ratio of the amount of 4-amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride to N-methyl piperazine varies between 1:2.0-8.4. 7. The process according to claim 5, characterized in that the volume of dimethyl sulfoxide is 2-8 times the molar amount of 4-amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride. 8. The process according to claim 5, characterized in that the volume of toluene is 3-8 times the molar amount of 4-amino-2-methyl-10H-thieno-[2,3b][1,5]benzodiazepine hydrochloride and dimethyl sulfoxide. 9. A process for the preparation of Olanzapine dihydrate-1, characterized in that the process comprises the following steps: a) a mixture of 4-amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride, N-methyl piperazine, DMSO and toluene is refluxed for 5-20 hours; b) cooling the mixture to 20-90°C; c) water is added; d) the mixture is cooled to -5 - +25 °C and then stirred for 2-10 hours; e) the mixture is filtered and washed with water; and dried at room temperature until constant weight. 10. The process according to claim 9, characterized in that the ratio of the amount of 4-amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride to N-methyl piperazine varies between 1:2.0-8.4. 11. The process according to claim 9, characterized in that the volume of dimethyl sulfoxide is 2-8 times the molar amount of 4-amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride. 12. The process according to claim 9, characterized in that the volume of toluene is 3-8 times the molar amount of 4-amino-2-methyl-10H-thieno-[2,3b][1,5]benzodiazepine hydrochloride. 13. A process for the preparation of Olanzapine Form 1 from Olanzapine dihydrate Form 1, characterized in that the following steps are used: a) 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (Olanzapine monohydrate-1) is stirred in dichloromethane at reflux temperature until a clear solution is obtained; b) the solution is then treated with activated carbon; c) the solution is filtered and the filtrate is retained; d) the sample is cooled to 0-5 °C e) then stir for 90 minutes f) the precipitated solid is filtered off, washed and then dried at 6070 °C until constant weight. 14. The process according to claim 13, characterized in that in step f) the solid is washed with dichloromethane. 15. The process according to claim 13, characterized in that the amount of dichloromethane used in step a) is in a volume/weight ratio of 4.5 to 13 relative to the 2-methyl-4-(4methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride. 16. A process for the preparation of Olanzapine Form 1 from Olanzapine Monohydrate Form 1, characterized in that the following steps are used: a) 2-methyl-4-(4-methyl-1-piperazinyl)-1OH-thieno [2,3-b] 2.84832 2.87332 2.95693 2.99172 2.84832 2.87332 2.95693 2.99172 2. Compound, which is Olanzapine dihydrate-1, and its powder X-ray diffraction pattern can be described by the following: d value I/Io 9.9949 100 9.6887 7 7.0418 2 6.4117 2 6.1205 6 5.4534 6 5.2358 2 4.8230 33 4.7162 9 4.5717 15 4.4847 6 4.3924 8 4.3080 4 4.2070 3 4.0735 3 2.8572 2 2.8715 3 2.9646 5 2. Compound which is Olanzapine dihydrate-1. 3.12072 3.17732 3.42422 3.525611 3.60725 3.65094 3.68373 3.12072 3.1773 2 3.4242 2 3.5256 11 3.6072 5 3.6509 4 3.6837 3 3.7386 13 3.7699 9 3.8438 12 3.9242 9 3.9974 3 3.2065 4 3.2500 4 3.4451 3 3.5701 15 3.6480 9 3.7857 26 3.8669 23 3.8756 51 4.7262 22 4.5904 34 4.4937 7 4.4315 13 4.3414 10 4.1411 6 3. Compound, which is Olanzapine monohydrate-1, and its powder X-ray diffraction pattern can be described by the following: d value I/Io 10.0176 100 6.8995 7 6.3567 12 6.1714 11 4-1062 ¹ ','efon 461-1ÖÓ0 Rix: 46^099