WO2014157860A1

WO2014157860A1 - Process for the preparation of high purity olanzapine and crystalline form ii thereof

Info

Publication number: WO2014157860A1
Application number: PCT/KR2014/002137
Authority: WO
Inventors: Sang Guk Park; Hoo Sook KIM; Yong Jik Kim; Joong In Lim; Soon Hoe Kim
Original assignee: Dong-A St Co., Ltd
Priority date: 2013-03-28
Filing date: 2014-03-13
Publication date: 2014-10-02
Also published as: KR20140118154A; KR101489062B1

Abstract

The present invention provides a process for the preparation of high-purity olanzapine with high yield and a process for the preparation of olanzapine crystalline Form II, which are industrially applicable. The preparation processes according to the present invention are useful for the preparation of high-purity olanzapine and olanzapine crystalline Form II with high yield and thus can be effectively used for mass production.

Description

PROCESS FOR THE PREPARATION OF HIGH PURITY OLANZAPINE AND CRYSTALLINE FORM II THEREOF

The present invention relates to a process for the preparation of high-purity olanzapine. Moreover, the present invention relates to a process for the preparation of high-purity olanzapine crystalline Form II using high-purity olanzapine.

Olanzapine is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine having a structure of the following formula 1 that acts as an antagonist on receptors of dopamine D₁, D₂, D₃, D₄ and D₅; of serotonine 5-HT₂ and 5HT₃; alpha-1-adrenergics, collinergics and H₁ histaminergics:

[Formula 1]

Moreover, olanzapine is a powerful neuroleptic with neuroleptic properties, has anxiolytic or antiemetic properties, and is useful for the treatment of mental disorders such as schizophrenia, schizophreniform disorder, and acute mania, and is reported that it is used for the treatment of mild anxiety disorders with low dosages.

European Patent Publication No. EP 0454436 disclosed the olanzapine for the first time, in which processes for the preparation of olanzapine from various intermediates are described. One of the processes for the preparation of olanzapine comprises preparing 2-(2-nitroanilino)-5-methyl-thiophene-3-carbonitrile and stannous chloride (SnCl₂) by reduction and cyclization using hydrogen chloride in aqueous alcohol solution, reacting the resulting 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine with N-methylpiperazine in an organic solvent such as anisole, toluene, dimethylformamide (DMF) or dimethylsulfoxide (DMSO), preferably at a temperature range of 100 to 150°C for about 20 hours, and obtaining a solid product, followed by addition of alcohol and excess water. Meanwhile, the crude product is filtered and collected, and the crude olanzapine is crystallized in acetonitrile to obtain a crystalline form.

The reaction time of the above preparation process is 20 hours, and even after the completion of the reaction, the reaction is cooled to 50 °C, followed by addition of water, the mixture is cooled to 0 to 10 °C, and maintained at the same temperature for 6 hours, and then olanzapine is filtered. As a result, the production time is very long and the production cost increases, thus it is difficult to industrially use. Further, the above preparation process has prepared olanzapine using a mixed solvent of dimethylsulfoxide (DMSO) and toluene (weight ratio 1:1) as a reaction solvent, but the yield is low (75-84%), which is problematic for both economic and environmental reasons.

Meanwhile, it is described in European Patent Publication No. EP 0733635 that the crystalline form prepared by the preparation process according to European Patent Publication No. EP 0454436 is crystalline Form I, which is metastable and changes color over time.

However, it is described in the background art of Korean Patent Publication No. 2003-0038721 that the crystalline form prepared by preparing crude olanzapine using a mixture of 4-aminomethyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride (100 g), N-methylpiperazine (350 ml), DMSO (465 ml), and toluene (465 ml), filtering and drying the isolated crude olanzapine, adding acetonitrile (750 ml) at the boiling point of the crude olanzapine (the experiment for the preparation of olanzapine crystalline Form I by recrystallization of olanzapine from acetonitrile according to the preparation process described in Example 1-4 of European Patent Publication No. EP 0454436) coincides with olanzapine crystalline Form II described in European Patent Publication No. EP 0733635, and thus the olanzapine recrystallized from acetonitrile is not crystalline Form I stated in European Patent Publication No. EP 0733635, but is crystalline form II.

Meanwhile, European Patent Publication No. EP 0733635 discloses that high-purity olanzapine crystalline Form II can be prepared from anhydrous ethyl acetate. However, the olanzapine prepared by the above preparation process is a mixed crystalline form in which a small amount of crystalline Form I and crystalline Form II are mixed, not crystalline Form II proposed in the above literature, and the high-purity olanzapine crystalline Form II cannot be obtained.

International Patent Publication No. WO 2007/102167 discloses a process for the preparation of olanzapine crystalline Form II from anhydrous olanzapine using acetone and an anti-solvent, and International Patent Publication No. WO 2007/054750 discloses a process for the preparation of olanzapine using a solvent of toluene and dimethylimidazolidinone, and olanzapine hydrochloride trihydrate. However, the processes for the preparation of olanzapine and olanzapine crystalline forms according to these prior art patents provide low yields and produce low-purity products.

Therefore, a new process for the preparation of high-purity olanzapine and olanzapine crystalline Form II has been required. Particularly, in terms of International Standards such as ICH guideline that recommend that the impurity be 0.1% or less, a preparation process that yields olanzapine crystalline Form II as a final product with an ultrahigh purity of 99.9% or higher is required.

Thus, the present inventors have developed a novel process for the preparation of high-purity olanzapine and a process for the preparation of high-purity olanzapine crystalline Form II using high-purity olanzapine and solved the problems associated with the prior art such as low yield, long reaction time, etc. thus preparing high-purity olanzapine and crystalline Form II.

An object of the present invention is to provide a process for the preparation of olanzapine with high yield and high purity.

Another object of the present invention is to provide a process for the preparation of olanzapine crystalline Form II with high purity.

The present invention provides a process for the preparation of pharmaceutically useful high-purity olanzapine and olanzapine crystalline Form II.

Hereinafter, the present invention will be described in more detailed.

Preparation Process of Olanzapine

The present invention provides a process for the preparation of olanzapine, the process comprising condensing 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine or a salt thereof with N-methylpiperazine in the presence of a mixed solvent containing a first solvent of N-methyl-2-pyrrolidone (NMP) or dimethylsulfoxide (DMSO) and a second solvent of ethanol or 1-propanol.

The preparation process of the present invention may further comprise filtering and washing the product of the condensation.

4-Amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine used as a reactant in the condensation may be prepared by a known method disclosed in U.S. Patent No. 5,229,382 and U.S. Patent No. 6,008,216, a continuation-in-Part application thereof, and provided in the form of a salt, preferably in the form of hydrochloride.

The use of the mixed solvent of the first solvent and the second solvent in the condensation reduces the reaction time and give high-purity olanzapine with high yield, and ethanol may preferably be used as the second solvent.

Moreover, the volume ratio of the first solvent and the second solvent may preferably be 1:1 to 5:1, more preferably 2:1 to 4:1, most preferably, 3:1.

Furthermore, the condensation may be performed at about 100 to about 130 °C for about 3 to about 5 hours, which significant reduces the long reaction time of the prior art. Thus, the preparation process of the present invention is more suitable for mass production than the prior art.

The washing solvent used in the washing step may be a mixed solvent of the solvent used in the condensation and water, and a mixed solvent of ethanol and water may be used, for example.

The process for the preparation of olanzapine according to the present invention uses a novel solvent in a small amount, which makes it possible to reduce the production time and cost and shorten the reaction time, resulting in less side reactions, an increase in the purity to 99% or higher, and an improvement in the yield, and thus can be effectively used for mass production. Moreover, the decrease in the reaction time minimizes evaporation of harmful substances into the air, and thus it can be said that the preparation process of the present invention is a nature-friendly synthesis process.

Preparation Process of Olanzapine Crystalline Form II

The present invention provides a process for the preparation of olanzapine crystalline Form II, the processing comprising crystallizing the olanzapine prepared by the above preparation process with C₁-C₄ alcohol and water to give a crystalline product.

The preparation process of the present invention may further comprise filtering, washing, and drying the crystalline product.

The crystallization may be performed by dissolving the olanzapine prepared by the preparation process of the present invention in C₁-C₄ alcohol at about 40 to about 60 °C and adding water dropwise at about 15 to about 25 °C.

The C₁-C₄ alcohol used in the crystallization may preferably be 1-propanol or ethanol.

Moreover, the volume ratio of the C₁-C₄ alcohol and water may preferably be 1:0.5 to 1:2, more preferably 1:1.

The washing solvent used in the washing step may be a mixed solvent of the solvent used in the crystallization and water, and a mixed solvent of 1-propanol or ethanol and water may be used, for example.

According to the process for the preparation of olanzapine crystalline Form II of the preset invention, the reaction conditions are simple, the crystallization time is short, and the reaction yield is high, and thus the preparation process of the present invention is very commercially and economically useful for mass production.

Moreover, olanzapine crystalline Form II prepared by the preparation process according to the present invention does not contain olanzapine crystalline Form I and contains olanzapine impurities A, B, C, etc. in a total amount of 0.01% or less, which are represented by the following formulas A to C and specified in the United States Pharmacopeia (USP), thus yielding olanzapine crystalline Form II with an ultrahigh purity of 99.9% or higher:

[Formula A]

[Formula B]

[Formula C]

Moreover, the process for the preparation of olanzapine crystalline Form II according to the present invention can prepare olanzapine crystalline Form II with an ultrahigh purity of 99.9% or higher, in which the total impurities are 0.01% or less and olanzapine crystalline Form I is not contained.

FIG. 1 shows the results of X-ray powder diffraction (XRPD) of olanzapine crystalline Form II prepared in Example 3.

FIG. 2 shows the results of Fourier transform infrared spectroscopy (FT-IR) of olanzapine crystalline Form II prepared in Example 3.

FIG. 3 shows the results of differential scanning calorimetry (DSC) of olanzapine crystalline Form II prepared in Example 3.

FIG. 4 shows the results of X-ray powder diffraction (XRPD) of olanzapine crystalline Form II prepared in Example 4.

FIG. 5 shows the results of X-ray powder diffraction (XRPD) of olanzapine crystalline Form II prepared using acetonitrile in Comparative Example 4.

FIG. 6 shows the results of X-ray powder diffraction (XRPD) of olanzapine crystalline Form II prepared using anhydrous ethyl acetate in Comparative Example 5.

FIG. 7 shows the results of X-ray powder diffraction (XRPD) of olanzapine crystalline Form II prepared using acetone and water in Comparative Example 6.

The present invention will now be described in detail with reference to the following Examples. However, the Examples according to the present invention can be modified in various ways, and the scope of the present invention should not be interpreted as being limited to the following Examples. The Examples of the present invention are provided so that those skilled in the art can sufficiently understand the present invention.

Preparation Example: Preparation of 4-amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride

5M hydrochloric acid solution (34 L) was added to tin chloride (II) dihydrate (12.23 kg) and stirred for 10 minutes. 2-(2-Nitroanilino-5-methylthiophene-3-carbonitrile (3.5 kg) and ethanol (2 L) were added to the resulting suspension, and the mixture was heated and stirred at an internal temperature of 80 to 85 °C for about 2 hours. Upon completion of the reaction, activated carbon (250 g) was added and further stirred for 1 hour. The reaction solution was filtered under reduced pressure, cooled to 0 to 5 °C, and further stirred for 1 hour. The resulting crystals were filtered under reduced pressure and washed with ethanol. Dehydrated crystals were placed in a reactor, a mixed solvent of methylene chloride and ethanol (5:1, 35 L) was added to the reactor such that the crystals are suspended, and then 2N sodium hydroxide (35 L) was added and stirred for 10 minutes. The organic layer was extracted, washed with water and brine, dehydrated, filtered, and concentrated under reduced pressure. Concentrated hydrochloric acid (1.41 L) was added dropwise, cooled and stirred at 0 to 5 °C for 1 hour. The resulting crystals were filtered under reduced pressure, washed with cold ethanol, and dried to give a product 2.89 kg (yield 80%).

Purity (HPLC): 99.94 %

Examples 1 and 2: Preparation of olanzapine according to the present invention

Example 1: Preparation of olanzapine using DMSO and ethanol

4-Amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride (50 g) prepared in the Preparation Example was mixed with DMSO (300 ml) and ethanol (100 ml) and stirred in a mixture of N-methylpiperazine (320 ml) at an internal temperature of 100 to 130 °C for 3 to 5 hours. Upon completion of the reaction, the mixture was cooled to room temperature, ethanol (200 ml) was added, and then purified water (500 ml) was added. The mixture was stirred at 0 to 5 °C for 1 hour, and the resulting solids were filtered and washed with ethanol/water (1:1, x 10). The obtained solids were dried in a vacuum oven at 50 °C for 12 to 24 hours to give pale yellow olanzapine 54.6 g (yield 92.5 %).

Purity (HPLC): 99.26 %

¹H NMR(600MHz, CDCl₃): δ2.28(s,3H), δ2.32(s,3H), δ2.47(br t,1H,4H), δ3.50(br s,4H), δ5.00(s,1H), δ6.27(s,1H), δ6.57(d,1H), δ6.84(t,1H), δ6.94(t,1H), δ7.00(d,1H)

Example 2: Preparation of olanzapine using N-methyl-2-pyrrolidone and ethanol

4-Amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride (2.89 kg) prepared in the Preparation Example was mixed with N-methyl-2-pyrrolidone (17.3 L) and ethanol (5.8 L), and N-methylpiperazine (10.3 L) was added, and stirred under reflux at an internal temperature of 100 to 130 °C for 3 to 5 hours. The mixture was cooled to room temperature, ethanol (11.6 L) was added, and the mixture was cooled to 0 to 5 °C. Purified water (34.7 L) was added dropwise to the cooled reaction mixture, the mixture was stirred at 0 to 5 °C for 1 hour and filtered, and the resulting solids were washed with ethanol/water (1:1, x 10). The obtained solids were dried in a vacuum oven at 50 °C for 15 hours to give pale yellow olanzapine 3.04 kg (yield 89 %).

Purity (HPLC): 99.67 %

¹H NMR: the same as in Example 1

Examples 3 and 4: Preparation of olanzapine crystalline Form II

Example 3: Preparation of olanzapine crystalline Form II using 1-propanol and water

Olanzapine (1 g) prepared in Example 1 was completely dissolved in 1-propanol (20 ml) by heating (45 to 55 °C) and cooled to room temperature. Purified water (20 ml) was slowly added dropwise to the mixture to produce crystalline solids at room temperature for 1 hour. The resulting crystalline solids were filtered and dried in a vacuum oven at 60 °C for 48 hours to give pale yellow high-purity olanzapine crystalline Form II 0.83 g (yield 83 %).

Purity (HPLC): 99.99% (total impurities: 0.01% or less)

X-ray powder diffraction (XRPD): shown in FIG. 1 and Table 1

FT-IR: shown in FIG. 2

DSC: shown in FIG. 3

[Table 1]

Example 4: Preparation of olanzapine crystalline Form II using ethanol and water

Olanzapine (1 g) prepared in Example 1 was dissolved in ethanol (20 ml) by heating to an internal temperature of 45 °C and cooled to room temperature. Purified water (20 ml) was slowly added dropwise to the mixture for 1 hour to produce crystalline solids at room temperature for 1 hour. The resulting crystalline solids were filtered and dried in a convection oven at 60 °C for 48 hours to give pale yellow high-purity olanzapine crystalline Form II 0.85 g (yield 85 %).

Purity (HPLC): 99.99% (total impurities: 0.01% or less)

X-ray powder diffraction (XRPD): shown in FIG. 4

Comparative Examples 1 and 2: Preparation of olanzapine

Comparative Example 1: Preparation of olanzapine using DMSO and toluene

4-Amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride (50 g) prepared in the Preparation Example was stirred under reflux in a mixed solvent of N-methylpiperazine (35 ml), DMSO (177.3 ml), and toluene (233 ml) under nitrogen atmosphere for 20 hours. The mixture was cooled to about 50 °C and added with water (46.5 ml), and then the product was crystallized overnight at 5 °C. The product was filtered, washed with water, and dried to give the final product 54.6 g (yield 84.3%).

Purity (HPLC): 98.61%

¹H NMR: the same as in Example 1

Comparative Example 2: Preparation of olanzapine using toluene and dimethylimidazolidinone (1:1)

Toluene (50 ml), dimethylimidazolidinone (50 ml), and N-methylpiperazine (17.5 ml) were added to 4-amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride (5 g) prepared in the Preparation Example and stirred under reflux at 130 °C for 11 hours. The mixture was distilled under reduced pressure, cold water was added dropwise at 3 to 5 °C, and then the product was crystallized at 3 to 5 °C for 1 hour. The product was filtered, washed with water, and then recrystallized using acetonitrile to give olanzapine 3.4 g (yield 57.8%).

Purity (HPLC): 98.08%

¹H NMR: the same as in Example 1

Comparative Example 3: Preparation of olanzapine using toluene and dimethylimidazolidinone (3:1)

Toluene (50 ml), dimethylimidazolidinone (16 ml), and N-methylpiperazine (17.5 ml) were added to 4-amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine hydrochloride (5 g) prepared in the Preparation Example and stirred under reflux at 120 °C for 9 hours. The mixture was distilled under reduced pressure, cold water was added dropwise, and then the product was crystallized at 0 to 5 °C for 1 hour. The product was filtered, washed with water, and dried to give olanzapine 5.26 g (yield 89.1%).

Purity (HPLC): 95.7%

¹H NMR: the same as in Example 1

Comparative Examples 4 to 6: Preparation of olanzapine crystalline Form II

Comparative Example 4: Preparation of olanzapine crystalline Form II using acetonitrile

Olanzapine (10 g) prepared by the process of Comparative Example 1 was suspended in heated (50 to 55 °C) acetonitrile (70 ml). The mixture was further heated for 5 minutes and filtered, and undissolved solids were removed. The filtrate was treated with carbon and filtered. The filtrate was distilled to a minimum volume, cooled to 0 to 5 °C, stirred for 1 hour, and filtered. The resulting product was filtered under reduced pressure and dried at 50 °C under vacuum for 24 hours to give olanzapine crystalline Form II 6.7 g (yield 67%).

Purity (HPLC): 99.79%

X-ray powder diffraction (XRPD): shown in FIG. 5

Comparative Example 5: Preparation of olanzapine crystalline Form II using anhydrous ethyl acetate

Olanzapine (20 g) prepared by the process of Comparative Example 1 was suspended in anhydrous ethyl acetate (400 ml). The mixture was heated to 55 °C and maintained at 55 °C for 30 minutes. The mixture was cooled to 0 to 5 °C, and the resulting product was filtered under reduced pressure and dried at 50 °C under vacuum for 24 hours to give olanzapine crystalline Form II 12.7 g (yield 63.5%).

Purity (HPLC): 99.78%

X-ray powder diffraction (XRPD): shown in FIG. 6

Comparative Example 6: Preparation of olanzapine crystalline Form II using acetone and water

Olanzapine (20 g) prepared by the process of Comparative Example 1 was suspended in acetone (400 ml). The mixture was heated to 45 to 50 °C and completed dissolved. Then, the mixture was cooled to room temperature, and purified water (400 ml) was slowly added. The resulting product was filtered under reduced pressure and dried at 50 °C under vacuum for 24 hours to give a mixture of olanzapine crystalline Forms I and II 17.2 g (yield 86%).

Purity (HPLC): 99.89% (mixed crystalline Forms I and II)

X-ray powder diffraction (XRPD): shown in FIG. 7

The yields and purities of olanzapine prepared in Examples 1 and 2 and Comparative Examples 1 to 3 are shown in the following table 2. Moreover, the yields and purities of olanzapine crystalline Form II prepared in Examples 3 and 4 and Comparative Examples 4 to 6 are shown in the following table 3.

[Table 2] Yield and purity of olanzapine

[Table 3] Yield and purity of olanzapine crystalline Form II

Measurement Methods

(1) ¹H NMR

- Manufacturer: Varian

- Model: Oxford NMR 600 MHz model

- CDCl₃: Merck

(2) HPLC

- Manufacturer: Agilent Technologies

- Model: Agilent-1100 series

- Column: 4.6×250mm, 5 μm C₁₈ column

(3) XRPD

- Model: Bruker D8ADVAN

- Output: 40kv, 40mA

- Measurement angle: 3.5-40, 6 deg/min

(4) DSC

- Manufacturer: METTLER

- Model: DSC1 STAR System

- Heating rate: 10 °C/min

(5) FT-IR

- Manufacturer: JASCO

- Model: FT_IR 4100.Spectrum

The invention has been described in detail with reference to preferred embodiments thereof. However, it will be appreciated by those skilled in the art that changes may be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims

A process for the preparation of olanzapine, the process comprising condensing 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine or a salt thereof with N-methylpiperazine in the presence of a mixed solvent containing a first solvent of N-methyl-2-pyrrolidone (NMP) or dimethylsulfoxide (DMSO) and a second solvent of ethanol or 1-propanol.
The process of claim 1, further comprising filtering and washing the product of the condensation.
The process of claim 1, wherein the salt of 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine is 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride.
The process of claim 1, wherein the second solvent is ethanol.
The process of claim 1, wherein the volume ratio of the first solvent and the second solvent is 1:1 to 5:1.
The process of claim 1, wherein the condensation is performed at about 100 to about 130 °C for about 3 to about 5 hours.
The process of claim 1, wherein the purity of the prepared olanzapine is 99% or higher.
A process for the preparation of olanzapine crystalline Form II, the process comprising crystallizing the olanzapine prepared by the process of any one of claims 1 to 7 with C₁-C₄ alcohol and water to give a crystalline product.
The process of claim 8, further comprising filtering, washing, and drying the crystalline material.
The process of claim 8, wherein the crystallization is performed by dissolving olanzapine in C₁-C₄ alcohol at about 40 to about 60 °C and adding water dropwise at about 15 to about 25 °C.
The process of claim 8, wherein the C₁-C₄ alcohol is 1-propanol or ethanol.
The process of claim 8, wherein the volume ratio of the C₁-C₄ alcohol and water is 1:0.5 to 1:2.
The process of claim 8, wherein the purity of the prepared olanzapine crystalline Form II is 99.9% or higher.