SK2502003A3 - Process for preparation of hydrates of olanzapine and their conversion into crystalline forms of olanzapine - Google Patents

Abstract

The present invention relates to a method for the preparation of hydrates of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine (hereinafter referred to as Olanzapine). The present invention also relates to a process for conversion of these hydrates into a pure crystalline form of olanzapine referred to as form-I. The present invention also relates to a method of converting Olanzapine Form-2 to Form-1.

Description

The present invention relates to a process for the preparation of 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine hydrates (hereinafter referred to as olanzapine) hydrates. The present invention also relates to a process for converting these hydrates into a pure crystalline form of olanzapine, referred to as Form-1. The present invention also relates to a process for converting Form-2 of olanzapine to Form-1.

In particular, the present invention relates to a process for the preparation of olanzapine hydrates and their conversion to Olanzapine Form -1 by recrystallization from a solvent. Olanzapine can be represented by the following structural formula.

BACKGROUND OF THE INVENTION

Olanzapine is useful for the treatment of psychotic patients and mild anxiety. The preparation of olanzapine and its acid salts exhibiting pharmaceutical properties, particularly in the treatment of central nervous system disorders, is discussed in U.S. Pat. 5,229,382.

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U.S. Pat. No. 5,229,382 does not refer to any specific polymorphic crystalline form of olanzapine. Description of European patent no. 733635A1 claims olanzapine Form-2. The process of this patent describes the preparation of Form-2 from ethyl acetate. This patent also determines the product obtained according to the method described in US patent no. 5,229,382 as a form-1.

Further, EP733635A1 discloses d values for Form-1 and Form-2 based on the results of X-ray diffraction analysis.

These values are:

value d value d forma -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

082 / B

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 noteworthy that EP 0 831 098 A2 describes the preparation of a number of olanzapine dihydrates, in particular dihydrate B, dihydrate D and dihydrate E. EP-D 831 098 A2 describes the d-values of the X-ray diffractograms for these forms.

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SUMMARY OF THE INVENTION

The present inventors carried out experiments aimed at obtaining olanzapine Form 1 by recrystallizing olanzapine from acetonitrile as described in Example 1, Sub-Example 4 of US Patent No. 5,201,549. This method is described herein for reference: a mixture of 4-amino 2-methyl-10H-thieno- [2,3-b] [1,5] benzodiazepine hydrochloride (100 g), N methylpiperazine (350 mL) dimethyl sulfoxide (465 mL) and toluene (465 mL) were heated to reflux. The reaction mixture is refluxed for 15 h and then cooled to 50 ° C and water is added. The mixture is cooled to 0-10 ° C and stirred at the same temperature for 6 h. The separated crude olanzapine was filtered off and dried in an oven to constant weight (76.5 g). The crude compound was added to acetonitrile (750 mL) at boiling point. The mixture is boiled for an additional 5 min. The mixture was filtered to remove undissolved solid. The filtrate is adjusted to a minimum volume by distillation, cooled to 0-5 ° C and held at this temperature for 1.0 h and then filtered. Dry the compound to constant weight in an oven (51.6 g).

The polymorphic form obtained from these experiments is characterized by powder X-ray diffraction on a Rigaku D / Max 2200. It is evident that the d-values of this product (Figure 1) correspond to the values of olanzapine Form-2 claimed in EP 733635A1. Therefore, it can be concluded that recrystallization of olanzapine in acetonitrile provides Form-2 rather than Form -1.

Accordingly, the present invention also provides a novel process for the preparation of olanzapine hydrate, which is different from those described in the literature. These hydrates are for practical purposes called olanzapine monohydrate I and olanzapine dihydrate I.

082 / B

Accordingly, the present invention also provides a novel process for preparing olanzapine Form 1 by recrystallizing olanzapine or its hydrates in dichloromethane.

The present invention also provides a novel method for converting form-2 olanzapine to form-1 olanzapine.

According to the present invention, the process for preparing olanzapine monohydrate-1 comprises the following steps:

(a) refluxing a mixture of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine, N-methyl-piperazine, dimethylsulfoxide (DMSO) and toluene hydrochloride for 5 to 20 h.

b) cooling the mixture to a temperature of 20 to 90 ° C,

(c) addition of water;

d) cooling the mixture to -5 to 25 ° C and stirring for 2 to 10 h,

(e) filtering the mixture and washing with water; and

f) drying at 30 to 50 ° C to constant weight.

According to the invention, the process for preparing olanzapine-I dihydrate comprises the following steps:

(a) refluxing a mixture of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine, N-methyl-piperazine, dimethylsulfoxide (DMSO) and toluene for 5 to 20 h.

b) cooling the mixture to a temperature of 20 to 90 ° C,

(c) addition of water;

d) cooling the mixture to -5 to 25 ° C and stirring for 2 to 10 h,

(e) filtering the mixture and washing with water; and

f) drying at ambient temperature to constant weight.

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Preferred ratio of 4-amino-2-methyl-10H-thieno hydrochloride [2,

3-b] [1,5] benzodiazepine, N-methylpiperazine, dimethylsulfoxide (DMSO) and toluene used to prepare the monohydrate and dihydrate are as follows:

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

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

Toluene (3 to 8 times the volume relative to 1.0 mole of 4-amino-2-methyl-10H-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, wherein the amount of dichloromethane used is 4.5-13 volume / weight of olanzapine to obtain a clear solution. The resulting solution is then treated with charcoal followed by filtration. At the end of this step, the filtrate is cooled to 0-5 ° C and stirred at the same temperature for 60-90 min. The collected solid was filtered off and rinsed with dichloromethane. The product obtained by drying in an oven at 60-70 ° C to constant weight is Form-1 olanzapine.

The process described in US patent 5 229 382 is used to prepare crude olanzapine and the process described in EP 733 635 A1 is used to prepare olanzapine form-2. However, other methods for preparing crude olanzapine and form-2 olanzapine and any other methods that can be used to prepare crude olanzapine and form-2 olanzapine in the methods of the invention may also be used.

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DETAILED DESCRIPTION OF THE INVENTION

The following examples are provided by way of illustration and are not intended to limit the scope of the invention.

Preparation of olanzapine monohydrate - 1

Example 1

A mixture of 4-amino-2-methyl-10H-thieno- [2,3-b] [1,5] benzodiazepine hydrochloride (20 kg), N-methylpiperazine (42 liters), diemtylsulfoxide (40 liters) and toluene (95 liters) ) is refluxed. The reaction mixture is refluxed for 17 h and 15 min. and then cooled to 40-50 ° C. Water (95 L) is slowly added at 40-50 ° C. The mixture was cooled to -0.6 to 1.2 ° C and stirred at this temperature for 6 h. The crude olanzapine was collected and filtered and rinsed with water (10 L). The product is dried at 30.5 to 31.8 ° C for 10 h and 50 min. The yield is 20 kg. A 20 g sample of this material after further heating for an additional 72 h provides a product with a moisture content of 5.22%.

Preparation of olanzapine-I dihydrate

Example 2

A mixture of 4-amino-2-methyl-10H-thieno- [2,3-b] [1,5] benzodiazepine hydrochloride (200 g), N-methylpiperazine (420 ml), dimethylsulfoxide (200 ml) and toluene (940 ml) ) is refluxed. The reaction mixture was refluxed for 12 h and then cooled to 40 ° C. Water (940 mL) was slowly added at 40-44 ° C.

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The reaction mixture is cooled to 0-5 ° C and stirred at this temperature for 5 h. The crude separated olanzapine was filtered and rinsed with water (100 mL).

The resulting solid was dried in air (25-35 ° C) for 24 h (yield 241)

g).

Preparation of the mold - 1

Example 3

The crude 2-methyl- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine (35.0 g) was suspended in dichloromethane (160.0 mL). The suspension is refluxed to obtain a clear solution. The resulting solution was then treated with charcoal (3.5 g) followed by filtration. Upon completion of this step, the filtrate is cooled to 0-5 ° C and stirred at this temperature for 1 h. The collected solid was filtered and rinsed with cold dichloromethane (10.0 mL). The product obtained by drying in an oven at a temperature of 65-70 ° C to a constant weight yielded form-1 of olanzapine (yield 22.0 g).

Convert mold - 2 to mold - 1

Example 4

A mixed suspension of pure form - 2 2-methyl-4- (4-methyl-1 piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine (20.0 g) in dichloromethane (90.0 mL) ) is refluxed to obtain a clear solution. The clear solution was filtered and the filtrate was then cooled to 3-5 ° C and stirred at this temperature for 1 h. The separated crystalline solid was filtered and rinsed with dichloromethane (4.0 mL). Subsequent drying at 60-70 ° C to constant weight yields form-1 of olanzapine (yield 12.7 g).

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Preparation of Olanzapine-I Monohydrate-I Form

Example 5

- 12-Methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine monohydrate (25.0 g) prepared according to Example 1 was suspended in dichloromethane (325 , 0 g). The suspension is refluxed to obtain a clear solution. The resulting solution was then treated with activated carbon (2.5 g) followed by filtration. Upon completion of this step, the filtrate is distilled to a minimum volume and then cooled to 2-4 ° C and stirred at this temperature for 90 min. The separated product was filtered and rinsed with cold dichloromethane (10 mL). The product obtained by drying in an oven at a temperature of 60-70 ° C to a constant weight yielded form-1 of olanzapine (yield 16.5 g).

Preparation of olanzapine-I dihydrate-1 form

Example 6

2-Methyl-4- (4-methyl-1-piperazinyl) -10H-thieno dihydrate [2,

3-b] [1,5] Benzodiazepine (40.0 g) prepared according to Example 2 was suspended in dichloromethane (520.0 mL). The suspension is refluxed to obtain a clear solution. The resulting solution was then treated with charcoal (4.0 g) followed by filtration. After completion of this step, the filtrate is adjusted to a minimum volume by distillation and the remaining mixture is cooled to 0-2 ° C and stirred at this temperature for 1 h. The collected solid was filtered and rinsed with dichloromethane (10.0 mL). The product obtained by drying in an oven at 65-70 ° C to a constant weight is olanzapine form-1 (yield 26.0 g).

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The crystalline forms described in Examples 1 to 6 above were investigated for their structural and analytical data by powder X-ray diffraction, differential scanning calorimetry, and infrared absorption spectroscopy. The results obtained are discussed and associated drawings are presented (Figures 2 to 19).

The X-ray diffractograms obtained for Examples 1 to 6 are obtained on a Rigaku D / Max-2200 powder diffractometer with a copper radiation source K at a wavelength of lambda = 0.154 nm. Samples are taken between 3 and 45 degrees 2teta.

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

value d I / 1 o 10, 0176 100 6, 8995 7 6, 3567 12 6, 1714 11 4, 8756 51 4, 7262 22 4, 5904 34 4, 4937 7 4, 4315 13 4, 3414 10 4, 1411 6 3, 9174 9 3, 8669 23

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3, 7857 26 3, 6480 9 3, 5701 15 3, 4451 3 3, 2500 4 3, 2065 4 2, 9646 5 2, 8715 3 2, 8572 2

The d-values for dihydrate-1 in Example 2 are provided (Figure 5).

value d I / 1 o 9, 9949 100 9, 6887 7 7, 0418 2 6, 4117 2 6, 2495 7 6, 1205 6 5, 4534 6 5, 2358 2 4, 8230 33 4, 7162 9

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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

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The X-ray diffractograms obtained for the products of Examples 3 to 6 are identical to those described in EP 733 635 A1.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a characteristic powder X-ray diffraction pattern of Form-2 obtained by recrystallization with acetonitrile (vertical axis-intensity (pulses per second), horizontal axis-two aunt (degrees)).

Figure 2 is a characteristic powder X-ray diffraction pattern of olanzapine monohydrate-I (vertical axis-intensity (pulses per second), horizontal axis-two aunt (degrees)).

Figure 3 is a characteristic infrared absorption spectrum of olanzapine monohydrate-I in potassium bromide (vertical axis - transmission (%), horizontal axis - wavelength (cm ^-1 )).

Figure 4 is a characteristic differential scanning calorimetry thermogram of olanzapine monohydrate-I (elevated -mW axis, horizontal axis temperature (° C)).

Figure 5 is a characteristic X-ray powder pattern of olanzapine-I dihydrate (vertical axis-intensity (pulses per second), horizontal axis-two aunt (degrees)).

Figure 6 is a characteristic infrared absorption spectrum of olanzapine-I dihydrate-I in potassium bromide (vertical axis - transmission (%), horizontal axis - wavelength (cm ^-1 )).

Figure 7 is a characteristic differential scanning calorimetry thermogram of olanzapine dihydrate-I (vertical axis - mW, horizontal axis - temperature (° C)).

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Figure 8 is a characteristic powder diffractogram of Form -1 obtained by recrystallization of crude olanzapine from dichloromethane (vertical axis - intensity (pulses per second), horizontal axis - two aunt (degrees)).

Figure 9 is a characteristic infrared absorption spectrum of Form 1 obtained by recrystallization of crude olanzapine from dichloromethane in potassium bromide (vertical axis - transmission (%), horizontal axis - wavelength (cm ^-1 )).

Figure 10 is a characteristic differential scanning calorimetry thermogram of Form-1 obtained by recrystallization of crude olanzapine from dichloromethane (vertical axis - mW, horizontal axis - temperature (° C)).

Figure 11 is a characteristic X-ray powder diffraction pattern of Form 1 obtained by converting Form-2 to Form-1 of olanzapine in dichloromethane (vertical axis-intensity (pulses per second), horizontal axis-two aunt (degrees)).

Figure 12 is a characteristic infrared absorption spectrum of Form 1 obtained by converting Form-2 to Form-1 of olanzapine in dichloromethane in potassium bromide (vertical axis - transmission (%), horizontal axis wavelength (cm ^-1 )).

Figure 13 is a characteristic differential scanning calorimetry thermogram of Form-1 obtained by converting Form-2 to Form-1 of olanzapine in dichloromethane (vertical axis-nW, horizontal axis-temperature (° C)).

Figure 14 is a characteristic X-ray powder pattern of Form-1 obtained by converting olanzapine-I monohydrate to Form-1 olanzapine in dichloromethane (vertical axis-intensity (pulses per second), horizontal axis-two aunt (degrees)).

Figure 15 is a characteristic infrared absorption spectrum of Form 1 obtained by converting olanzapine-I monohydrate to olanzapine Form-1 in dichloromethane in potassium bromide (vertical axis-transmission (%), horizontal axis-wavelength (cm ^-1 )).

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Figure 16 is a characteristic differential scanning calorimetry thermogram of Form-1 obtained by converting olanzapine-I monohydrate to Form-1 olanzapine in dichloromethane (vertical axis - mW, horizontal axis - temperature (° C)).

Figure 17 is a characteristic X-ray powder diffraction pattern of Form 1 obtained by converting Olanzapine-I dihydrate to Olanzapine Form-1 in dichloromethane (vertical axis-intensity (pulses per second), horizontal axis-two aunt (degrees)).

18 is a characteristic infrared absorption spectrum of Form 1 obtained on conversion of the dihydrate - I of olanzapine form - 1 Olanzapine in dichloromethane in potassium bromide (Vertical axis - Transmission (%); Horizontal axis: - wavenumber (cm ^_1)).

Figure 19 is a characteristic differential scanning calorimetry thermogram of Form-1 obtained by converting olanzapine-I dihydrate-I to olanzapine Form 1 in dichloromethane (vertical axis - mW, horizontal axis - temperature (° C)).

Claims (21)

A compound which is -1 olanzapine monohydrate. A compound which is olanzapine-I dihydrate. 3. A compound which is olanzapine-I monohydrate, giving a powder X-ray diffraction pattern having the following values: value d I / 1 o 10, 0176 100 6, 8995 7 6, 3567 12 6, 1714 11 4, 8756 51 4, 7262 22 4, 5905 34 4, 4937 7 4, 4315 13 4, 3414 10 4, 1411 6 3, 9174 9 3, 8669 23 3, 7857 26 3, 6480 9 3, 5701 15 32,082 / B 3, 4451 3 3, 2500 4 3, 2065 4 2, 9646 5 2, 8715 3 2, 8572 3 2, 6868 3 2, 6743 3 4. A compound which is olanzapine-I dihydrate to provide a powder X-ray diffraction pattern having the following values: value d I / 1 o 9, 9949 100 9, 6887 7 7, 0418 2 6.4117 2 6, 2495 7 6, 1205 6 5, 4534 6 5, 2358 2 4, 8230 33 4, 7162 9 4, 5717 15 32,082 / B 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 32 082 / 5. A process for the preparation of olanzapine monohydrate-I, comprising the steps of: (a) refluxing a mixture of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine, N-methylpiperazine, dimethylsulfoxide (DMSO) and toluene hydrochloride for 5 to 20 h. b) cooling the mixture to a temperature of 20 to 90 ° C, (c) addition of water; d) cooling the mixture to -5 to 25 ° C and stirring for 2 to 10 h, (e) filtering the mixture and rinsing with water; and f) drying at 30 to 50 ° C to constant weight. The process of claim 5, wherein the amounts of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride and N-methylpiperazine hydrochloride are in a ratio of 1: 2.0 to 8.4. The process of claim 5, wherein the volume of dimethylsulfoxide is two to eight times the number of moles of 4-amino-2-methyl-10H-thieno- [2,3-b] [1,5] benzodiazepine hydrochloride, The process of claim 5, wherein the volume of toluene is 3 to 8 times the number of moles of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride and dimethylsulfoxide hydrochloride. 9. A process for the preparation of olanzapine-I dihydrate comprising the steps of: 32,082 / B (a) refluxing a mixture of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride, N-methylpiperazine, dimethylsulfoxide (DMSO) and toluene for 5 to 20 h. b) cooling the mixture to a temperature of 20 to 90 ° C, (c) addition of water; d) cooling the mixture to -5 to 25 ° C and stirring for 2 to 10 h. e) filtering the mixture and rinsing with water and drying at ambient temperature to constant weight. The method of claim 9, wherein the amounts of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride and N-methylpiperazine hydrochloride are in a ratio of 1: 2.0 to 8.4. The process of claim 9, wherein the volume of dimethylsulfoxide is two to eight times the number of moles of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride, The method of claim 9, wherein the volume of toluene is three to eight times the number of moles of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride and dimethylsulfoxide, 13. A process for the preparation of olanzapine Form -1 from olanzapine dihydrate-I, comprising the steps of: a) stirring 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine (olanzapine monohydrate-I) in dichloromethane under reflux to obtain clear solution, 32,082 / B (b) treatment of the solution with activated carbon; c) filtration of the solution to obtain a filtrate, d) cooling the filtrate to 0-5 ° C; e) stirring for 60 to 90 min. f) filtration to obtain a solid, rinsing and drying at 60-70 ° C to constant weight. 14. The process of claim 13 wherein in step f) the solid is washed with dichloromethane. The process according to claim 13, wherein the amount of dichloromethane used in step a) is 4.5 to 13 volume / weight of 2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride. 16. A process for the preparation of olanzapine Form -1 from olanzapine monohydrate-I, comprising the steps of: (a) stirring 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2, 3-b] [1,5] benzodiazepine (olanzapine-I monohydrate) in dichloromethane under reflux to obtain a clear solution, (b) treatment of the solution with activated carbon; c) filtration of the solution to obtain a filtrate, d) cooling the filtrate to 0-5 ° C; e) stirring for 60 to 90 min. f) separating the solid, rinsing and drying at 60-70 ° C to constant weight. 32,082 / B The process according to claim 16, wherein the amount of dichloromethane used is 4.5-13 volume / weight of 2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride. The method of claim 16, wherein in step f) the solid is rinsed with dichloromethane. 19. A process for preparing olanzapine Form-1 from olanzapine Form-2, comprising the steps of: (a) stirring 2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine (form - 2 olanzapine) hydrochloride in dichloromethane under reflux to obtain a clear solution, b) filtration and cooling the filtrate to 0-5 ° C; c) stirring for 60 to 90 min. d) filtration to obtain a solid, rinsing and drying at 60-70 ° C to constant weight, The process according to claim 19, wherein the amount of dichloromethane used is 4.5 to 13 volume / weight of 2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride. 21. The process of claim 19 wherein in step d) the solid is rinsed with dichloromethane.