WO2007096895A1 - Preparation of anhydrous olanzapine of form-1 - Google Patents
Preparation of anhydrous olanzapine of form-1 Download PDFInfo
- Publication number
- WO2007096895A1 WO2007096895A1 PCT/IN2006/000130 IN2006000130W WO2007096895A1 WO 2007096895 A1 WO2007096895 A1 WO 2007096895A1 IN 2006000130 W IN2006000130 W IN 2006000130W WO 2007096895 A1 WO2007096895 A1 WO 2007096895A1
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- WIPO (PCT)
- Prior art keywords
- olanzapine
- methyl
- anhydrous
- amino
- preparation
- Prior art date
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- ZTTWQKYKGNLCCA-UHFFFAOYSA-N Cc1cc(C(N)=Nc(cccc2)c2N2)c2[s]1 Chemical compound Cc1cc(C(N)=Nc(cccc2)c2N2)c2[s]1 ZTTWQKYKGNLCCA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- Figure 1 depicts the IR Spectrum for anhydrous olanzapine form - 1 showing wave number horizontally and % transmittance vertically and values are noted herein;
- FIG. 1 depicts the XRD pattern for anhydrous olanzapine form-1 showing 2 ⁇ values horizontally and intensity values vertically and the values are noted in the description.
Abstract
A product of anhydrous Olanzapine of Form I as characterized and described by a study of XRD, IR, 1H NMR, 13C NMR data.
Description
TITLE:
PREPARATION OF ANHYDROUS OLANZAPINE OF FORM-1
FIELD OF INVENTION:
The invention pertains to the product of obtaining OLANZAPINE of Form-I, in anhydrous form.
BACKGROUND OF THE INVENTION:
OLANZAPINE is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno [2,3-b][1 ,5] benzodiazepine.
Currently there are many drugs available for the treatment of disorders of the central nervous system. Amongst these drugs is a category known as antipsychotic for treating serious mental conditions such as schizophrenia and schizophreniform illnesses.
The great majority of drugs available for treatment of schizophrenia are prone to produce extra pyramidal side effects when used at dosages that yield a beneficial effect on the symptoms of the disease. The severity of adverse events and/or lack of efficacy in a considerable number of patients frequently results in poor compliance or termination of treatment.
Olanzapine, 2-methyl-4-(4-methyl-l-piperazinyl)-IOH-thieno-[2,3b] [1 ,5] benzo diazepine is a potent antipsychotic agent. Olanzapine or its acid addition salt is an active ingredient of pharmaceutical preparations used in the treatment of disorders of the central nervous system.
PRIOR ART:
Olanzapine was described for the first time in the European Patent EP 0454436BI. One of the methods for preparation of Olanzapine is based on condensation of 4-amine-2-methyl-10H- thieno [2,3-b][1, 5] benzodiazepine
with N-methylpiperazine carried out in dimethyl sulfoxide and toluene. At the final stage of the reaction water is added in order to isolate the product. The crude product thus obtained is crystallized from acetonitrile.
In the second method Olanzapine is obtained by cyclization of l-{[2- aminoaniline)-5- methylthiophen-3-yl] carbonyl}-4-methylpiperazine carried out in N-methylpiperazine and anisole. The crude Olanzapine is isolated by treating the reaction mixture with ammonia, isopropanol and ethyl acetate and finally purified. Purification is performed by column chromatography with the use of Florisil eluted with ethyl acetate and the product is further crystallized from acetonitrile. Both methods claimed in EP 0454436BI lead to obtain Olanzapine in a pure crystalline form which is identified by the same melting point, NMR spectrum (1 H and 13C) and mass spectrum.
In US 5229382 invention describes the preparation of Olanzapine and does not describe or mention any of the Forms. It only relates to another property of the Compound and the formulations corresponding to it.
In the patent EP 07336335 B1 , it has been said that the first form of Olanzapine herein after referred to as Form I in US 5229382 is metastable and not suitable for commercial use in pharmaceutical formulations such as tablets due to its color.which changes over time on exposure to air and a more stable second polymorph of Olanzapine is claimed. Olanzapine polymorphic Form Il is obtained by suspending crude Olanzapine in ethyl acetate in anhydrous conditions and crystallization from this solution. The existence of two different polymorphs has been confirmed by X-ray powder diffraction patterns characterized by different interplanar spacing d and relative intensities l/lo.
The drawback of the methods described above is that they require the use of different solvents at the subsequent steps of isolation and purification of technical grade Olanzapine. Moreover, these methods are rather difficult to repeat and often do not lead to obtaining the required polymorphic form.
For example, following the procedure of Preparation 1 of European Patent EP 0828494, comprising suspending the crude Olanzapine in a very small amount of Methylene chloride, filtration off the precipitate, then its maceration with Methylene chloride and drying, the obtaining of crystalline Form Il solvate with Methylene chloride is declared in the said patent. However, the X- ray powder diffraction pattern of the product matches with that of Olanzapine Form Il as claimed in EP 733635BI.
On the other hand, in EP 0828494, preparation methods were given for a polymorph defined by the Applicant as Olanzapine Form I, by crystallization of crude Olanzapine from acetone (Preparation 5), tetrahydrofuran (Preparation 6), ethyl acetate (Preparation 7), t-butanol (Preparation 8) and by transforming Form Il in toluene to Form I.
In WO03097650 it is described that the use of any solvent such as acetonitrile, tetrahydrofuran, acetone, toluene or ethyl acetate for crystallization of crude Olanzapine always results in crystalline Form II, identified by X-ray powder diffraction patterns described in EP 0733635. The only one solvent enabling to obtain polymorphic Form I of Olanzapine by crystallization of crude Olanzapine or of its crystalline Form Il is Methylene chloride.
Independently, the use of Methylene chloride to crystallize Olanzapine Form I as mono- and dihydrate has been described in International Patent Application WO 02/18390.
Moreover, the attempts to reproduce the methods known from the art for isolation and purification of Olanzapine obtained by the reaction of a molar excess of N-methyl piperazine and 4-amine-2-methyl-IOH-thieno [2,3- b] [1 , 5] benzodiazepine in organic solvent, e.g. dimethyl sulphoxide, and subsequent addition of water and alcohol, show that the obtained product contains usually 10-15% of impurities. Triple crystallization from different solvents is required to
remove these impurities and to obtain Olanzapine of pharmaceutical grade which is again hydrate.
In US 6251895 the invention describes the novel Dihydrate D of 2- Methyl thieno benzodiazepine and a formulation thereafter. Applicants claim that 2- methyl - 4-(4-methyl-1-piperazinyl)-10H-thieno[2,3 b]-[1 ,5]-benzodiazepine exists as 2 different dehydrate forms, which are distinguishable by XRD
Thus, according to all of the teachings of the above mentioned and many others patents and patent applications, the typical methods for preparation of Olanzapine of technical grade comprise the condensation of N-methyl piperazine with 4-amino-2-methyl-10H-thieno- [2, 3-b] [I, 5] benzodiazepine in an organic solvent, e. g. dimethyl sulphoxide, to which alcohol and excess of water is added after the reaction is completed, to remove unreacted substrates and impurities. The product is separated in a form of solvate with alcohol. Depending on the method used for the purification of technical grade Olanzapine, pharmaceutical grade of OLANZAPINE is obtained. Using different methods of crystallization, OLANZAPINE Form I in hydrated form is described.
OBJECTS OF THE INVENTION:
The above-described patents in Prior Art have not claimed anhydrous form of Olanzapine Form I.
The primary objective of this invention is to develop ANHYDROUS OLANZAPINE of Form -1 on commercial scale. .
Further objective of the invention is to develop a stable compound of OLANZAPINE Form -1 in ANHYDROUS FORM.
The above and other objects and advantages will be clear from the following description of the preferred embodiment.
Since the polymorphic Form 1 of OLANZAPINE is reported in hydrated form only, a need is felt to produce an anhydrous material of Form I. This aim was accomplished according to the present invention by developing a method for preparation of essentially pure Olanzapine polymorphic Form I, in which the Olanzapine thus obtained is anhydrous.
The foregoing description is outlined rather broadly preferred and alternatively featured of the present invention so that those skilled in the art may better understand the detailed description of the invention that follows. Additional features of the invention will be described hereinafter that form the subject of claims of the invention. Those skilled in the art should appreciate that they can readily use the disclosed concept and specific embodiment as a basis for carrying out the same purposes of the present invention. Those skilled in the art should realize such equivalent conception do not depart from the spirit and scope of the invention in its broadest sense.
SUMMARY OF THE INVENTION:
The brief summary of the invention can be described in stage wise which results in preparation of anhydrous OLANZAPINE of Form- 1.
Stage-I: 5-amino-4-cyano-2-methyl thiophene
Malononitrile is reacted with Propionaldehyde in presence of Sulphur Powder and Triethylamine in N,N-dimethlyformamide to give 5-Amino- 4-Cyano-2-Methyl Thiophene
Stage-ll: 4-Cyano-2-methyl-1-(2-Nitro phenyl amino) Thiophene
2-fluoronitrobenzene is condensed with 5-Amino-4-Cyano-2-Methyl Thiophene in lsopropyl alcohol and Potassium Hydroxide powder give 4-cyano-2-methyl-1-(2-nitrophenyl amino) Thiophene.
Stage-Ill: 4-amino-2-methyl-1 OH-Thieno [2,3-b][1 ,5] Benzodiazepine
Reduction of 4-cyano-2-methyl-1-(2-nitrophenyl amino) Thiophene with Stannous Chloride and Hydrochloric acid in lsopropyl Alcohol and followed by cyclization to get 4-Amino-2-Methyl-1 OH-Thieno [2,3,- b][1 , 5] Benzodiazepine .
Stage-IV: Olanzapine Technical grade
Condensation of 4-amino-2-methyl-10H-Thieno[2,3,-b][1 ,5] Benzo diazepine and N-methyl Piperazine in presence of Dimethyl Sulfoxide and Toluene gives Olanzapine Technical grade in anhydrous form.
Stage-V: Olanzapine Form-I
Recrystallisation of Technical grade anhydrous Olanzapine in
Dichloromethane gives Olanzapine Form-I.
DESCRIPTION OF DRAWINGS:
Figure 1 depicts the IR Spectrum for anhydrous olanzapine form - 1 showing wave number horizontally and % transmittance vertically and values are noted herein;
758.14 cm'1; 846.05 cm"1; 971.72 cm'1; 1005.84 cm"1; 1145.13 cm'1; 1189.11 cm"1; 1221.69 cm"1; 1285.76 cm"1; 1346.43 cm"1; 1422.58 cm'1;
1463.26 cm"1; 1590.12 cm"1; 2802.07 cm"1; 2847.88 cm"1; 2930.80 cm"1; 3239.46 cm"1
Figure 2 depicts the XRD pattern for anhydrous olanzapine form-1 showing 2 ø values horizontally and intensity values vertically and the values are noted in the description.
DESCRIPTION OF THE INVENTION
Now the invention will describe in detail with reference to the chemical drawings herein provided for easy reference, an improved method for the preparation of Anhydrous OLANZAPINE of Form I
Reaction of Malononitrile with Propionaldehyde in presence of Sulphur Powder and Triethylamine in N, N-dimethlyformamide gives 5-Amino- 4-Cyano-2- Methyl Thiophene as per the procedure described in EP 0454436A1
CN
DMF
CH3 — CH2 — CHO + CH2 + S
Propionaldehyde Triethyl amine
Sulphur
Melanonitrile
5-amino-4-cyano- 2-methyl thiophene
2-fluoronitrobenzene is condensed with 5-Amino-4-Cyano-2-Methyl Thiophene in lsopropyl alcohol and Potassium Hydroxide powder to get 4- cyano - 2- methyl-1-(2-nitrophenyl amino) Thiophene.
5-amino-4-cyano- lsopropyi alcohol
4-cyano-2-methyl-1-(2-Nitrophenylamino) 2-methyl thiophene Thiophene.
Reduction of 4-cyano-2-methyl-l-(2-nitrophenyl amino) Thiophene with Stannous Chloride and Hydrochloric acid in lsopropyi Alcohol and followed by cyclization to get 4-Amino-2-Methyl- 10H-Thieno [2,3,-b][l,5] Benzodiazepine using the same procedure as described in EP 0454436Al but using lsopropyi alcohol in place of Ethanol
Stannous chloride
lsopropyi alcohol
4-cyano-2-methyl-1-(2-Nitrophenylamino) Hydrochloric acid Thiophene.
4-amino-2-methyl-1 OH-Thieno [2,3-b][1 ,5] Benzodiazepine
Condensation of 4-amino-2-methyl-1 OH-Thieno [2,3,-b][1 ,5] Benzodiazepine and N-methyl Piperazine in presence of Dimethyl Sulfoxide and Toluene gives Olanzapine Technical grade by following same procedure as described in EP 0454436A1.
N-Methyl piperazine Toluene
Dimethyl sulfoxide
DM water
4-amino-2-methyl-1 OH-Thieno [2,3-b][1 ,5] Benzodiazepine
And further the inventor has adopted a novel step in the process by isolating technical grade olanzapine by treatment with methanol and drying to obtain anhydrous form.
DESCRIPTION OF THE PREFERRED EMBODIMENT:
Recrystallisation of Technical grade anhydrous Olanzapine in dichloromethane gives anhydrous Olanzapine Form I. It is carried out according to the procedure described below.
Anhydrous OLANZAPINE (Technical grade) is dissolved in Methylene chloride at reflux temperature. The resultant clear solution is then treated with activated carbon and stirred for 1 hour at reflux temperature. It is then filtered and the clear filtrate is collected into a separate vessel. It is then slowly cooled to ambient temperature. The mass is stirred for 1 hour at room temperature and then further cooled to 0° C. it is kept under stirring at 0° C for 3 hours. The separated solid is filtered and washed with chilled methylene chloride. The product obtained is dried at 40° C till constant weight. The material thus obtained is taken back into the vessel and treated with methanol to make slurry. The slurry was stirred for 30 minutes and filtered. The solid is washed with methanol and the product is dried at 60° C till constant weight.
It will be understood that the aforesaid description is only illustrative of the present invention and is not intended that the present invention is limited thereto. Many other specific embodiments of the present invention will be
apparent to. one skilled in the art from the foregoing disclosure. Any substitution, alteration or modifications of the present invention, which come within the scope of claims, are to which the present invention is readily susceptible without departing from the spirit of invention.
Characterization of the Olanzapine as prepared aforesaid is done by Infrared absorption spectrophotometer, Proton nuclear magnetic resonance spectrometer, Carbon magnetic resonance spectrometer and mass spectrometer.
The XRD pattern for the Anhydrous Olanzapine Form I is given below.
The IR Spectrum shows the following pattern:
758.14 cm'1; 846.05 cm"1; 971.72 cm"1; 1005.84 cm"1; 1145.13 cm"1; 1189.11 cm"1; 1221.69 cm"1; 1285.76 cm"1; 1346.43 cm"1; 1422.58 cm"1; 1463.26 cm"1; 1590.12 cm"1; 2802.07 cm"1; 2847.88 cm"1; 2930.80 cm"1;
3239.46 cm -1
Claims
CLAIMS,
1. A product of ANHYDROUS Olanzapine of Form - 1 as characterized and described by a study of XRD, IR, 1H NMR, 13 C NMR data having the chemical structure;
2. A product of ANHYDROUS Olanzapine of Form - 1 as claimed in claim 1 , where in the IR pattern of anhydrous Olanzapine Form I is as below.
758.14 cm'1; 846.05 cm"1; 971.72 cm"1; 1005.84 cm'1; 1145.13 cm"1; 1189.11 cm'1; 1221.69 cm'1; 1285.76 cm'1; 1346.43 cm"1; 1422.58 cm"1; 1463.26 cm"1; 1590.12 cm'1; 2802.07 cm'1; 2847.88 cm"1; 2930.80 cm'1; 3239.46 cm"1
3. A product of ANHYDROUS Olanzapine of Form - 1 as claimed in claim 1 , where in the XRD pattern of anhydrous Olanzapine Form I is as below.
4. A product of ANHYDROUS Olanzapine of Form - 1 as claimed in claim 1 , where in the 1 H NMR pattern of anhydrous Olanzapine Form I is as below.
1.9-2.4 (bcm, 4H) 2.65 (s, 3H) 4.12-4.16 (bcm, 1H) 4.4 (bm, 1H) 6.74-6.76(m, 1H) 7.26-7.30 (m, 2H) 7.31-7.32 (m, 1 H) 7.34 (d, 1H) 7.58-7.60 (d,1 H) 7.61-7.65 (m, 1H) 9.29 (bs, 1H)
A product of ANHYDROUS Olanzapine of Form - 1 as claimed in claim 1, where in the 13 C NMR pattern of anhydrous Olanzapine Form I is as below.
15.24; 45.98; 46.61 ; 54.96; 118.81; 119.40; 122.81; 123.53; 124.36; 127.97; 128.72; 140.93; 142.45; 151.74; 157.46
6. A product of ANHYDROUS Olanzapine of Form - 1 as claimed in claim 1 , where the product as resulted through the process claimed and described in the present invention and obtained as anhydrous OLANZAPINE Form I.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN328CH2006 | 2006-02-27 | ||
| IN328/CHE/2006 | 2006-02-27 |
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| WO2007096895A1 true WO2007096895A1 (en) | 2007-08-30 |
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| PCT/IN2006/000130 WO2007096895A1 (en) | 2006-02-27 | 2006-04-17 | Preparation of anhydrous olanzapine of form-1 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005008401A2 (en) * | 2003-07-12 | 2005-01-27 | Advanced Phase Separation, Llc | Multi-phase separation system |
| WO2005070937A1 (en) * | 2004-01-27 | 2005-08-04 | Synthon B.V. | A process for making olanzapine in a polymorph form i |
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2006
- 2006-04-17 WO PCT/IN2006/000130 patent/WO2007096895A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005008401A2 (en) * | 2003-07-12 | 2005-01-27 | Advanced Phase Separation, Llc | Multi-phase separation system |
| WO2005070937A1 (en) * | 2004-01-27 | 2005-08-04 | Synthon B.V. | A process for making olanzapine in a polymorph form i |
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