Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION PF OLANZAPINE FORM I

Abstract This invention provides an improved process for the preparation of Olanzapine Form I. Olanzapine, which is 2-methyl-4-( 4-methyl-l-piperazinyl)-1 DH-thieno[2,3-b] [1,5] benzodiazapine has the formula I given below. More specially, the invention provides insitu improved process for the direct preparation of crystalline form of Olanzapine Form-I. The present invention also provides high pure Olanzapine Form I with single individual impurity less than 0.l % by HPLC.
Full Text

FIELD OF THE INVENTION
This invention provides an improved process for the preparation of Olanzapine Form I. Olanzapine Form I, which is 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b] [1,5] benzodiazapine Form-I has the formula I given below More specially, the invention provides an improved process for the direct preparation of crystalline form of Olanzapine Form-I.

Olanzapine Form I of the Formula I is a pharmaceutical compound useful as a typical
antipsychotic drug.
BACK GROUND OF THE INVENTION / PRIOR ART
The Olanzapine was first disclosed in US Patent No. 5, 229, 382 .The process disclosed
in the said patent includes, condensing propanaldehyde with malanonitrile and sulphur
in the presence of N,N-Dimethylformamide and triethylamine to give 2-amino-5-methyl
thiophene-3-carbonitrile, which on condensation with 2-fluoronitro benzene gave 2-(2-
nitro anilino)-5-methyl thiophene-3-carbonitrile, which on reduction and cyclization with
stannous chloride gave 4-AminO"2-methyl-10H-thieno[2,3-b][l,5] benzodiazepine
hydrochloride. The 4-Amino-2-methyl-10H-thieno[2,3-b] [ 1,5]benzodiazepine
hydrochloride salt was condensed with N-Methylpiperazine in toluene and dimethyl sulphoxide to give Olanzapine which on crystallization in Acetonitrile to give Olanzapine (Pure).

The crystal form of Olanzapine has disclosed in the US Patent No. 5, 736., 541. As described in US Patent No. 5, 736, 541, the synthesis of Olanzapine according to the methods described in US Patent No. 5, 229, 382 produces a met stable, dull colored product referred to in the 5, 736, 541 Patent as Form-I and not well suited for commercial use in pharmaceutical formulations.
The US patent no 5, 736, 541 discloses and claims a more stable polymorphic form of Olanzapine, designated as Form-II, a method to produce Form-II Olanzapine and pharmaceutical compositions containing Form-II.
Olanzapine. Form-I and Form-II are characterized in the US patent no 5, 736, 541 by powder X-ray diffraction. The inter planar spacings (d-spacings) and typical relative intensities (I / Ii) are reported.
As per the US patent no 5, 736, 541, a typical example of an X-ray diffraction pattern for Olanzapine Form I and Form II is as follows wherein d represents the pattern planner spacing and I/Ii reports the typical relative intensities.



us Patent No. 5, 703, 232 claims lower alcohol solvates of Olanzapine referred to in this patent as Form - I and methods for their preparation. The polymorph designated as Form I in this patent has the same characteristics inter planar spacing by X-ray diffraction as Form II disclosed in the above mentioned US patent no 5, 736, 541 and should therefore be considered as Form II . In the US patent no 5, 703, 232 the Form prepared has the same characteristic inter planar spacing by X-ray diffraction as the polymorph

designated as Form-II in the US Patent no 5, 736, 541 and therefore should thus be considered same polymorph,
US patent no 5, 637, 584 provides a methylene chloride crystalline solvate of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno [2,3-b][l,5]benzodiazepine (Olanzapine) and also provides a process for preparing anhydrous Form I using a methylene chloride solvate comprising drying such methylene chloride solvate and crystallizing the dried material in a solvate selected from the group consisting of aromatic hydrocarbons, C3-C9 ketones, C3-C9 branched alcohols, C3-C9 esters, C3-C9 hydrocarbons, C3-C9 ethers and cyclic ethers in the presence of Form I 2-methyl"4-(4-methyl-l-piperazinyl)-10H-thieno [2,3-b][l,5] benzodiazepine.
US patent no 3, 631, 250 discloses a compound selected from the group consisting of a methanol, ethanol, 1-propanol crystalline solvates of 2-methyl-4(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5] benzodiazepine (Olanzapine) and provides a process for preparing anhydrous Form I comprising contesting a lower alcohol solvate with a solvent selected from the group consisting of ethyl acetate, acetone, 2-propanol, t-butanol, tetrahydrofuran, and toluene and also provides a new method for preparing a lower alcohol solvate of Olanzapine,
WO Patent WO 02/18390A1 describes a method for the preparation of hydrates of Olanzapine and its conversion into a pure crystalline form of Olanzapine Form-I and also describes a method of converting Olanzapine Fort-II to From-I using methylene chloride as a solvent.
Objective of the Present Invention:
The main objective of the present invention is to provide an improved, direct and simple process for the preparation of Olanzapine Form I, which is a typical antipsychotic drug overcoming the disadvantages of the prior art.

Another objective of the present invention is to provide an improved process for the preparation of Olanzapine Form I by inset process.
According to the present invention, there is provided an improved process for the preparation of Olanzapine Form I which comprises :
i) Refluxing a mixture of 4-Amino-2-methyl-l 0H-thieno[2,3-b][l ,5] benzo
diazepine hydrochloride, N-methyl piperazine, dimethyl sulphoxide and toluene under inert atmosphere for a period in the range of 5-25 hours preferably by 15-20 hours at a temperature in the range of 110-130°C. preferably in the range of
122-125°C.
ii) Cooling the resulting reaction mixture to a temperature in the range of 20-90°C. iii) Adding demineralized water to the cooled mixture.
iv) Cooling the resulting mixture to a temperature in the range of - 10 to 30°C preferably 0-5 °C and stirring for a period in the range of 2 - 10 hours.
v) Filtering the mixture and sucking dry for a period in the range of 0.5-2 hours.
vi) Slurring the resulting wet cake with DM water at a temperature in the range of 50-90°C preferably at 60-65*^C for a period in the range of 20 min to 3 hours preferably for 45 min. to 2 hours.
vii) Filtering the material and sucking dry for a period in the range of 0.5 to 2 hours.
viii) Repeating the steps (vi) to (vii) till the traces of dimethyl sulphoxide and its odour are removed . The traces of dimethyl sulphoxide and its odour are removed by repeating the slurry of wet cake in water at 50-90^C for 3 to 4 times is necessary. If the dimethyl sulfoxide odour is not removed totally, it will lead to failure in the formation of Olanzapine Form I.

ix) Dissolving the resulting wet cake in a chlorinated solvent preferably methylene chloride at a temperature in the range of 25-30°C.
x) Separating the aqueous layer, if any.
xi) Stirring the organic layer i.e. methylene chloride layer with anhydrous sodium sulfate or anhydrous magnesium sulfate for a period in the range of 20 min. to 2 hours .
xii) Filtering and washing with methylene chloride.
xiii) Repeating the steps & (xii) till the moisture content is less than 0.1%. The methylene chloride layer should be dried repeatedly with anhydrous magnesium sulfate upto the moisture content below 0.1% at 25-30°C is necessary. If the moisture content of methylene chloride layer is in between 0.1% to 0.15%, results in the failure of the formation of Olanzapine Form-I
xiv) Purging dry ammonia gas in methylene chloride layer (step No. xiii) upto saturation at a temperature in the range of 25-3 0°C in the presence of the anhydrous magnesium sulfate for getting the consistent polymorphic form of Olanzapine Form I.
xv) Removing the magnesium sulphate salts from reaction mixture and washing the salts with methylene chloride.
xvi) Refluxing the methylene chloride layer for a period in the range of 30 min to
2 hours,
xvii) Concentrating the reaction mixture under vacuum (600-650 mm/Hg) upto product isolation takes place. Distillation of methylene chloride under vacuum also have a key role for impurity profile while preparation of Olanzapine Form I. Impurity formation is observed when the methylene chloride is distilled atmospherically

at 45-50°C whereas methylene chloride is distilled under vacuum (600-650 mm/Hg) below 30°C gave HPLC purity 99.92% with single individual impurity less than 0.1 %.
Cooling the reaction mixture to a temperature in the range of - 10 to 25°C preferably 0 - 2°C.
Stirring the material for a period in the range of 30 min. to 5 hours preferably 1-2 hours at a temperature in the range of 0-5°C

Air drying the material at a temperature in the range of 25-30°C for a period in the range of 10-15 hours and
Continuously maintaining a vacuum (600-650 mm/Hg) at a temperature in the range of 60-70°C for a period in the range of 12-72 hours without breaking the vacuum. The Continuously keeping the material under vacuum in step (x’i) may be done for a period preferably ranging from 36-60 hours more preferably 45-50 hours without breaking the vacuum (600-650 mm/Hg) to avoid the impurity formation of impurity in Olanzapine Form I.
The details of the invention are given in the Examples given below which are provided solely to illustrate the present invention, therefore they should not be construed to limit the scope of the invention . Many other specific embodiments of the present invention which will be obvious and apparent to one skilled in the art from the foregoing disclosure are also fall with in the scope of the present invention.

EXAMPLE 1
A mixture of 4-Amino-2"methyl-10H-thieno-[2,3-b] [1,5] benzodiazepine hydrochloride (100 g), N-Methyl piperazine (312.76 g), dimethyl sulfoxide (460 ml) and toluene (460 ml) are heated to reflux. The reaction mixture is maintained at reflux for 20 hours. Completion of the reaction is monitored by Thin layer chromatography (TLC) and then cooled to 40-50°C. Water (460 ml) added to the reaction mixture and further cooled to 0-5°C. The reaction mixture is maintained at 0-5°C for 2 hours and filtered. Yield :127 g (wet). Water (600 ml), wet material are stirred at 60-65°C for 45 min. and filtered. Water (600 ml) and wet material are stirred at 60-65°C and repeated three to four times to remove the traces of dimethyl sulfoxide and its odour. Yield: 119 g (wet). Wet material is dissolved in methylene chloride (3000 ml) and water is separated. The methylene chloride (organic) layer is dried with anhydrous magnesium sulfate repeatedly (100 g each time) upto moisture content of organic layer is below 0.1%. Dry ammonia gas is purged into the organic layer while stirring with anhydrous magnesium sulfate (50 g) at 25-30°C upto saturation. The magnesium sulfate salts are filtered and washed with methylene chloride (100 ml). The organic layers are mixed and refluxed for 30 min. The organic layer is concentrated under vacuum (600-650mm/Hg) upto product isolation is started. The reaction mixture is cooled to 0-5°C and maintained for 1 hr, at 0-5°C. Product is filtrated and washed with chilled methylene chloride (50 ml) Yield: 93.0 g. The product is air dried for 12 hours. Yield: 72.0 g. The air dried product is further dried under vacuum (600-650 mm/Hg) at 60-70°C for 48 hours continuously gave 99.92% pure Olanzapine Form I. Yield: 61.5 g. The inter planer spacing (d-spacings) and typical relative intensities (I/Ii) of powder X-ray diffraction are as follows.

d-value I/Ii
9.92608 100.0
8.52807 2'9.5
8.19986 18.2



EXAMPLE 2
A mixture of 4-Amino-2-methyl-10H-thieno-[2,3-b] [1,5] benzodiazepine hydrochloride (25 g), N-Methyl piperazine. (78.19 g), dimethyl sulfoxide (115 ml) and toluene (115 ml) are heated to reflux. The reaction mixture is maintained at reflux for 20 hours completion of the reaction is monitored by Thin layer chromatography (TLC) and then cooled to 40-50°C. Water (115 ml) added to the reaction mixture and further cooled to 0-5°C. The reaction mixture is maintained at 0-5°C for 2 hours and filtered. Yield: 32.0 g (wet). Wet material is charged 150 ml water and stirred at 60-65°C for 45 min. followed by filtration. Wet material and water (150 ml) are stirred at 60-65°C and repeated three to four times to remove the traces of dimethyl sulfoxide and its odour. Yield: 31.3 g (wet). Wet material is dissolved in chloroform (750 ml) and water is separated. The chloroform (organic) layer is dried over anhydrous magnesium sulfate repeatedly (25 g each time) till the moisture content of organic layer is below 0.1%. Dry ammonia gas is purged into the organic layer while stirring with anhydrous magnesium sulfate (12.5 g) at 25-30°C upto saturation. The magnesium sulfate salts are filtered and washed with chloroform (25 ml). The organic layers are combined and refluxed for 30 min. The organic layer is concentrated under vacuum (600-650 mm/Hg) upto product isolation is started. The reaction mixture is cooled to 0-5°C and maintained for 1 hour at 0-5°C. Product is filtered and washed with chilled chloroform (12.5 ml) Yield: 11.6 g (wet). The product is air dried for 12 hours. Yield: 10.0 g. The air dried product is further dried under vacuum (600-650 mm/Hg) at 60-70°C for 48 hours continuously gave 99.50% pure Olanzapine Form I. Yield: 8.5 g. The inter planer spacing (d-spacings) and typical relative intensities (I/Ii) of powder X-ray diffraction are as follows.



The aforementioned crystalline forms prepared by the process described in the Examples 1 to 2 have been examined for their structural and analytical data viz., powder X-ray diffraction (XRD) and Infrared absorption spectroscopy (IR). The results obtained are
discussed and the respective drawings attached (Fig. 1-4).
The X-ray diffraction pattern setout herein for examples 1 to 2 were obtained using X-ray diffractrometer having a copper anode, radiation source of wave length I -= 1.5406A°. The samples were scanned between 2.000° to 50.000° of 2-theta scale. In the drawings
Fig -1 is a characteristic X-ray powder diffraction pattern of Olanzapine Form I obtained by the process described in the Example - 1 (vertical axis : Lin (counts); Horizontal axis : 2-theta scale).
Fig -2 is a characteristic infrared as absorption spectrum in potassium bromide of Olanzapine Form I obtained by the process described in the Example - 1 (vertical axis, remissions (%); Horizontal axis : wave number (cm'*)).
Fig -3 is a characteristic X-ray powder diffraction pattern of Olanzapine obtained by the process described in the Example ~ 2 (vertical axis : Lin (counts) ; Horizontal axis : 2-theta scale).
Fig -4 is a characteristic infrared as absorption spectrum in potassium bromide of Olanzapine obtained by the process described in the Example - 2. (vertical axis, remission (%); Horizontal axis : wave number (cm**)).

Advantages of the Invention:
1. The present invention is simple and inset process for direct preparation of
Olanzapine Form I.
The novel feature of the present invention are three critical parameters (as described as 2, 3 and 4) and has been ascertained for getting consistently Olanzapine Form I.
2. Removal of dimethyl sulphoxide by repeated hot water treatment, otherwise product having odour of dimethyl sulphoxide. If the dimethyl sulfoxide odour is not removed totally, it will lead to failure in the formation of Form I.
3. Removal of moisture with anhydrous magnesium sulfate from organic layer. The organic layer should be dried repeatedly with anhydrous magnesium sulfate upto the moisture content below 0.1% at 25-30°C is necessary. Even though the moisture content of organic layer is in between 0.1% to 0.15% also results in the failure in formation of Form I.
4. Purging of dry ammonia gas for getting consistent polymorphic Form I.
The other novel feature of the present invention is to get high purity Olanzapine Form I with single individual impurity less than 0.1% as described below in point no. 5 and 6,
5. Concentrating the reaction mixture under vacuum (600-650 mm/Hg) upto
material separation takes place. Distillation of methylene chloride also have a key
role for impurity profile while preparation of Olanzapine Form I. Impurity
formation is observed when the methylene chloride is distilled atmospherically at
45-50°C. where as methylene chloride is distilled under reduced pressure below
30°C gave HPLC purity 99.92% with single individual impurity less than 0.1% is
obtained.

6. Air drying at 25"30°C for 12 hours, and continuous drying the material under vacuum at 60-70'^C for 48 hours without breaking the vacuum to avoid impurity formation in API.
The process of the invention is simple and safe and can be employed for commercial production.




We Claim:
1. An improved process for the preparation of Olanzapine Form I, which comprises:
i) Refluxing a mixture of 4-Amino-2-methyl-10H4hieno [2,3-b][l,5] benzo
diazepine hydrochloride, N-methyl piperazine, dimethyl sulphoxide and toluene under nitrogen atmosphere for a period in the range of 5-25 hours at a temperature in the range of 110-130°C.
ii) Cooling the mixture to 20-90°C.
iii) Adding water.
iv) Cooling the mixture to - 10 to 30°C and stirring for 2 - 10 hours.
v) Filtering the mixture and sucking dry for 0.5 - 2 hours.
vi) Slurrying the wet cake with water at 50-90°C for 20 min to 3 hours.
vii) Filtering the material and sucking dry for 30 min.
viii) Repeating the steps (vi) to (vii) till the traces of dimethyl sulphoxide and its odour are removed .
ix) Dissolving the wet cake in chlorinated solvent preferably methylene chloride at 25-30°C,
x) Separating the aqueous layer if any.

xi) Stirring Methylene chloride layer with magnesium sulfate for 20 min, to 2 hours.
xii) Filtering the anhydrous magnesium sulfate and washing with methylene
chloride.
xiii) Repeating the steps (xi) & (xii) till the moisture content is less than 0.1%
at 25-30°C.
xiv) Purging dry ammonia gas in methylene chloride organic layer upto saturation at 25-30°C in the presence of the anhydrous magnesium sulfate.
xv) Filtering the methylene chloride layer and washing the salts with methylene chloride.
xvi) Refluxing the methylene chloride layer for 30 min to 2 hours.
Distilling off the methylene chloride under vacuum (600-650 mm/Hg) upto product isolation started.
Cooling the material to - 10 to 25°C.
Stirring the material for 30 min. to 5 hours at 0-5°C
Filtering the material and washing with chilled methylene chloride.
Air drying the material at 25-30°C for 10-15 hours and
Continuously maintaining a vacuum (600-650 mm/Hg) at 60-70°C for 12-72 hours without breaking the vacuum (600-650 mm/Hg).
2. An improved process as claimed in claim 1 wherein the slurring of wet cake with water in step (vi) is effected at a temperature in the range of 70 deg C preferably at a temperature in the range of 60-65 °C for a period in the range of 45 min. to 2 hours.

3. An improved process as claimed in claims 1 & 2 wherein the repeated slurring the wet cake with water is effected till the traces of dimethyl sulphoxide and its odour are removed.
4. An improved process as claimed in claims 1 to 3 wherein the chlorinated solvents used for dissolving in step (ix) are methylene chloride and chloroform preferably methylene chloride.
5. An improved process as claimed in claims 1 to 3 wherein the stirring of the Methylene chloride layer with anhydrous magnesium sulfate in step (xi) is effected for a period in the range of 30 min. to 1 hr and repeating the anhydrous magnesium sulfate treatment upto methylene chloride layer's moisture content is below 0.1%.
6. An improved process as claimed in claims 1 to 4 wherein the Methylene chloride layer is saturated with ammonia by purging dry ammonia gas in the presence of anhydrous magnesium sulfate.
7. An improved process as claimed in claims 1 to 5 wherein the methylene chloride is distilled under vacuum (600-650 mm/Hg) below 30°C upto product isolation started.
8. An improved process as claimed in claims 1 to 6 wherein the cooling of the material in step is effected at a temperature in the range of - 5 to 15°C , preferably at 0-2°C.
9. An improved process as claimed in claims 1 to 7 wherein the stirring of the material In step is effected for a period in the range of 1- 2 hours at a temperature in the range of 0-5°C

10. An improved process as claimed in claims 1 to 8 wherein the continuously
keeping the material under vacuum is effected for a period ranging from 36-60
hours preferably 45-50 hours without breaking the vacuum to avoid thp formation
of API impurity in Olanzapine Form I.
11. An improved process for the preparation of Olanzapine Form I substantially as
herein described with reference to the Examples


Documents:

128-che-2004-abstract.pdf

128-che-2004-claims filed.pdf

128-che-2004-claims granted.pdf

128-che-2004-correspondnece-others.pdf

128-che-2004-correspondnece-po.pdf

128-che-2004-description(complete) filed.pdf

128-che-2004-description(complete) granted.pdf

128-che-2004-description(provisional).pdf

128-che-2004-drawings.pdf

128-che-2004-form 1.pdf

128-che-2004-form 19.pdf

128-che-2004-form 26.pdf

128-che-2004-form 5.pdf

abs-128-che-2004.jpg


Patent Number 202029
Indian Patent Application Number 128/CHE/2004
PG Journal Number 05/2007
Publication Date 02-Feb-2007
Grant Date 05-Sep-2006
Date of Filing 19-Feb-2004
Name of Patentee NEULAND LABORATORIES LTD
Applicant Address NO 204, MERIDIAN PLAZA, 6-3-853/1, AMEERPET, HYDERABAD 500 016,
Inventors:
# Inventor's Name Inventor's Address
1 SHRI PRAKASH DHAR DWIVEDI NEULAND LABORATORIES LTD, NO 204, MERIDIAN PLAZA, 6-3-853/1, AMEERPET, HYDERABAD 500 016,
2 PAMUJULA SREENVASULU NEULAND LABORATORIES LTD, NO 204, MERIDIAN PLAZA, 6-3-853/1, AMEERPET, HYDERABAD 500 016,
3 SURAPANENI SASI KIRAN NEULAND LABORATORIES LTD, NO 204, MERIDIAN PLAZA, 6-3-853/1, AMEERPET, HYDERABAD 500 016,
4 DAVULURI RAMMOHAN RAO NEULAND LABORATORIES LTD, NO 204, MERIDIAN PLAZA, 6-3-853/1, AMEERPET, HYDERABAD 500 016,
PCT International Classification Number C07D495/04
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA