Title of Invention

CRYSTALLINE ALKANOL SOLVATE FORM OF COMPOUND OF FORMULA (I) AND PROCESS FOR PREPARING THE SAME THEREOF

Abstract The invention provides methanol, ethanol, and 1-propanol solvates of olanzapine and a process for using such solvates.
Full Text FIELD OF THE INVENTION
The present invention relates to novel crystalline
alkanol solvates form of compound of formula (I) and a
novel process for preparing 2-methyl-4-(4-methyl-1-
piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine
(hereinafter referred to by its generic name
"olanzapine").
BACKGROUND AND PRIOR ART
Olanzapine has shown great promise in the treatment of
psychotic patients and is currently being evaluated for
that purpose. Unfortunately, the processes of recovery
of olanzapine known heretofore have not been entirely
satisfactory.
Thus, in the literature methods for preparing
olanzapine, such as contained in U.S. Patent
No.5,229,382, technical grade olanzapine was
precipitated by the addition of an excess of water to
the reaction mixture. Applicants have now discovered
that precipitation of technical grade olanzapine using
an alcohol solvate selected from the group consisting of
methanol, ethanol, and 1-propanol results in a
significantly purer technical grade olanzapine requiring
only one recrystallization.
STATEMENT OF INVENTION
The present invention related to a crystalline alkanol
solvate form of a compound of formula (I)
wherein the alkanol is selected from the group
consisting of methanol, ethanol, and 1-propanol.
Also, the present invention relates to a process for
preparing technical grade olanzapine comprising
crystallizing olanzapine from a reaction mixture using a
lower alcohol selected from the group consisting
methanol, ethanol, and 1-propanol to provide the
corresponding alcohol solvate of olanzapine; and drying
the resulting solvate.
SUMMARY OF THE INVENTION
Thus, applicants have now prepared and characterized
three stable olanzapine solvates selected from the group
consisting of ethanol, methanol, and 1-propanol (herein
referred to as "lower alcohol solvates") each of which
are particularly useful for preparing the technical
grade olanzapine.
Surprisingly, the use of the lower alcohol solvates
provides greater yields of the desired technical grade
olanzapine, eliminates tedious separation steps, and
provides a technical grade material that is easy to
handle for production purposes.
DETAILED DESCRIPTION
The present invention provides a compound selected from
the group consisting of a methanol, ethanol, and 1-
propanol crystalline solvates of 2-methyl-4-(4-methyl-1-
piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine
(olanzapine).
Further, this invention provides a process for
preparing technical grade olanzapine comprising
crystallizing olanzapine from a reaction mixture
using a lower alcohol selected from the group consisting
of methanol, ethanol, and 1-propanol to provide the
corresponding alcohol solvate of olanzapine; and drying
the resulting solvate.
As used herein, the term "technical grade 2-methyl-4-(4-
methyl-1-piperazinyl)-10H-thieno[2,3-
b] [1,5]benzodiazepine" shall refer to 2-methyl-4-(4-
methyl-1-piperazinyl)-10H-thieno[2,3-
b] [1,5] benzodiazepine product which contains less than
about 5% undesired related substances and preferably
less than 1% undesired related substances.
As used herein, the term "solvate" shall refer to a true
solvate of olanzapine, wherein the solvent molecule is
held within the crystalline lattice.
Form II olanzapine polymorph having a typical x-ray
powder diffraction pattern as follows, using a Siemens
D5000 x-ray powder diffractometer wherein d represents
the interplanar spacing:
A preferred embodiment of the invention is the
crystalline mono(methanol) solvate of 2-methyl-4-(4-methyl-1-
piperazinyl) -10H-thieno [2 , 3-b] [1, 5] benzodiazepine having a
typical x-ray powder diffraction pattern of Table 1:
The x-ray powder diffraction pattern in Table I and
for Form II was obtained with a copper Ka of wavelength ? =
1.54184A. The interplanar spacings are in the column marked
"d" are in Angstroms. The typical relative intensities are
in the column marked "I/I1".
Another preferred embodiment of the present
invention is the crystalline mono(ethanol)solvate of 2-
methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-
b][1,5]benzodiazepine exhibiting a typical x-ray powder
diffraction pattern of Table 2:
Another preferred embodiment of the invention is
the crystalline mono(1-propanol)solvate of 2-methyl-4-(4-
methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine
exhibiting a typical x-ray diffraction pattern of Table 3:
The x-ray powder diffraction data in Tables 2 and 3
was collected employing an Enraf-Nonius CAD4 kappa axis
diffractometer. The diffraction pattern was obtained with a
copper k of wavelength = 1.542A. The interplanar spacings in
the column marked "d" are expressed in Angstroms. The
typical relative intensities are in the column marked "I/I1".
The compounds and processes of the present
invention are useful for preparing olanzapine. Certain
compounds and conditions within the scope of this invention
are preferred. The following conditions, invention
embodiments, and compound characteristics listed in tabular
form may be independently combined to produce a variety of
preferred compounds and process conditions. The following
list of embodiments of this invention is not intended to
limit the scope of this invention in any way.
Some prefered characteristics of this invention
include the following:
A) A mono (ethanol) solvate of 2-methyl-4-(4-
methyl-1-piperazinyl)-10H-thieno[2,3-
b][1,5]benzodiazepine
B) Substantially pure refers to = 5% undesired
polymorph;
C) Substantially pure refers to = 2% undesired
polymorph;
D) A mono (methanol) solvate of olanzapine;
E) A mono (1-propanol) solvate of olanzapine;
F) A substantially pure solvate of olanzapine
selected from the group consisting of mono
(methanol), mono (ethanol), and mono (1-
propanol).
The formation of solvates is known to be an
individualistic effect. The ability of a given compound to
form a solvate is not predictable, to Applicant's knowledge.
Further, the beneficial utility of such solvates is
particularly surprising. The present invention provides
three crystalline solvates of 2-methyl-4-(4-methyl-1-
piperazinyl) -10H-thieno [2 , 3-b] [1, 5] benzodiazepine which have
been verified using x-ray crystal techniques. The solvates
of this invention may be prepared by suspending 2-methyl-4-
(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine
in warm solvent corresponding to the desired solvate. Most
preferably the solvent temperature is from about 0°C to
100°C, although other reaction temperatures can be effective
with alteration of the reaction conditions using known
techniques. A preferred temperature is from about 25 °C to
about 50°C. The mixture is most desirably stirred for about
3 0 minutes or more. The reaction time will vary with the
temperature of the reaction, pressure, and with the
completion of reaction desired.
The present invention provides a new method for
preparing material which applicants have identified herein as
"technical grade olanzapine". The process provides greater
yields of the desired material, eleminates tedious separation
steps, and provides a technical grade olanzapine that is easy
to handle for production purposes.
The most preferred alcohols for forming an
olanzapine solvate are methanol and ethanol. A particularly
preferred alcohol is methanol. The improved features include
fewer recrystallizations, improved throughput, and enhanced
environmental safety.
The solvate may be isolated by cooling the mixture
to ambient temperature or through the use of an antisolvent.
However, the most preferred isolation method is the lower
alcohol process described supra.
As used herein the term "drying" the solvates shall
mean that the solvates are dried or azeotroped under ambient
conditions or at a temperature less than about 50°C. The
drying may be completed in vacuo if the temperature and
pressure are carefully monitored using techniques known to
the artisan.
The term "crystallized" as used herein refers to
any conventional process including, for example, seeding,
chilling, scratching the glass of the reaction vessel, and
other such common techniques familiar to the skilled artisan.
Compound characterization methods include, for
example, x-ray powder pattern analysis, thermogravimetric
analysis (TGA), differential scanning calorimetery (DSC),
titrametric analysis for water, and H1-3NMR analysis for
solvent content.
The following examples are provided for purposes of
illustration and are not to be construed as limiting the
scope of the claimed invention. As used in the following
examples, the term "technical grade 2-methyl-4-(4-methyl-1-
piperazinyl) -10H-thieno [2, 3-b] [1, 5] benzodiazepine " shall
refer to 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3 -
b][1,5]benzodiazepine dried solvate product.
The following examples are provided for purposes of
illustration and are not to be construed as limiting the
scope of the claimed invention.
In a suitable three neck flask the following was added:
Dimethylsulfoxide (analytical): 6 volumes
Intermediate 1 : 75 g
N-Methylpiperazine (reagent) : 6 equivalents
Intermediate 1 can be prepared using methods known to the
skilled artisan. For example, the preparation of the
Intermediate 1 is taught in the '382 patent.
A sub-surface nitrogen sparge line was added to remove the
ammonia formed during the reaction. The reaction was heated
to 120°C and maintained at that temperature throughout the
duration of the reaction. The reactions were followed by
HPLC until = 5% of the intermediate 1 was left unreacted.
After the reaction was complete, the mixture was allowed to
cool slowly to 20°C (about 2 hours). Each reaction mixture
was then transferred to an appropriate three neck round
bottom flask and water bath. To this solution with agitation
was added 10 volumes reagent grade methanol and the reaction
was stirred at 20°C for 3 0 minutes. Three volumes of water
was added slowly over about 30 minutes. The reaction slurry
was cooled to zero to 5°C and stirred for 3 0 minutes. The
product was filtered and the wet cake was washed with chilled
methanol. The wet cake was dried in vacuo at 45°C overnight.
The product was identified as technical olanzapine.
Yield: 76.7%; Potency: 98.1%
Example 2
Methanol solvate
A 20 g sample of 2-methyl-4-(4-methyl-1-
piperazinyl) -10H-thieno [2 , 3-b] [1,5]benzodiazepine was
contacted with a 1:1 (vol) mixture of methanol and water.
The mixture was heated to about 78°C and maintained at about
78°C for about 30 minutes. The resulting mixture was allowed
to cool to about 3 0°C. The resulting product was isolated by
vacuum filtration and dried for about 3 0 minutes. The sample
was studied using x-ray powder analysis and identified as the
methanol solvate of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-
thieno[2,3-b][1,5]benzodiazepine . The thermogravimetric
mass loss was 10.1%. Differential Scanning Calorimetry
produced an endotherm at 129.7, 133.3, and 195.8 °C.
Example 3
Preparation of Technical Grade
The methanol solvate prepared as described supra, was dried
in a vacuum oven at about 50°C under about 100-300mm vacuum
for a period of about 27 hours. The resulting material was
identified as technical grade 2-methyl-4-(4-methyl-1-
piperazinyl) -10H-thieno [2, 3-b] [1, 5] benzodiazepine using x-ray
powder diffraction, DSC, and NMR.
Example 4
1-propano1 so1vate
A 2.0 g sample of 2-methyl-4-(4-methyl-1-
piperazinyl) -10H-thieno[2,3-b][1,5]benzodiazepine was
suspended in about 30 g of 1-propanol. The mixture was
stirred at about 70°C and maintained at about 70°C for about
30 minutes. The resulting mixture was cooled to about 25°C.
The solid product was isolated using vacuum filtration. The
wet cake was dried under ambient conditions. Yield: 1.3 g.
X-ray powder analysis demonstrated that the product was 1-
propanol solvate of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-
thieno[2,3-b][1,5]benzodiazepine. Differential Scanning
Calorimetry produced endotherms at 84.4 to 96.9, 129.1 to
147.4, and 195.8°C.
Example 5
Ethanol solvate
A 2.0 g sample of 2-methyl-4-(4-methyl-1-
piperazinyl) -10H-thieno [2 , 3-b] [1,5]benzodiazepine was
suspended in absolute ethanol. The stirred suspension was
heated to 60°C and maintained at about 60°C for about 30
minutes. The mixture was allowed to cool to about 25°C. The
solid product was isolated by vacuum filtration. The wet
cake was allowed to dry at about 25°C. The product was
identified as the ethanol solvate of 2-methyl-4-(4-methyl-1-
piperazinyl) -10H-thieno[2,3-b][1,5]benzodiazepine using x-ray
powder analysis. The thermogravimetric mass loss was 12.7%.
Differential Scanning Calorimetry produced an endotherm at
114. 8°C and 196.6°C.
Yield: 1.3 g
We Claim;
1. A crystalline alkanol solvate form of a compound of
Formula I:
wherein the alkanol is selected from the group
consisting of methanol, ethanol, 1-propanol.
2. A compound as claimed by claim 1,wherein the alkanol
is methanol and the crystalline mono methanol solvate
form having typical X-ray powder diffraction pattern
as represented by the following interplanar spacings:
3. A compound as claimed by Claim 2 wherein the compound
is substantially pure mono methanol solvate.
4. A compound as claimed in claim 1, wherein the alkanol
is ethanol and the crystalline mono ethanol solvate
form having typical X-ray powder diffraction pattern
as represented by the following interplanar spacings:
5. A compound as claimed by Claim 4 wherein the compound
is substantially pure mono ethanol solvate.
6. A compound as claimed in claim 1, wherein the alkanol
is 1-propanol and the crystalline mono 1-propanol
solvate form having typical X-ray powder diffraction
pattern as represented by the following interplanar
spacings:
7. A compound as claimed by Claim 6, wherein the compound
is substantially pure mono 1-propanol solvate.
8. A process for preparing technical grade olanzapine
comprising, crystallizing olanzapine from a reaction
mixture using a lower alcohol selected from the group
consisting of methanol, ethanol, and 1-propanol to
provide the corresponding alcohol solvate of
olanzapine; and
drying the resulting solvate.
9. A process as claimed in claim 8, wherein the lower
alcohol is methanol.
10. Technical grade olanzapine whenever prepared by the
process as claimed in claim 10 to 11.

The invention provides methanol, ethanol, and 1-propanol solvates of olanzapine and a process for using such solvates.

Documents:

516 CAL-1996-CORRESPONDENCE 1.2.pdf

516 CAL-1996-FORM 1 1.1.pdf

516 CAL-1996-OTHERS 1.1.pdf

516-CAL-1996-(29-03-2012)-CORRESPONDENCE.pdf

516-CAL-1996-(29-03-2012)-FORM-27.pdf

516-CAL-1996-ABSTRACT-1.1.pdf

516-cal-1996-abstract.pdf

516-CAL-1996-CLAIMS-1.1.pdf

516-cal-1996-claims.pdf

516-CAL-1996-CORRESPONDENCE 1.1.pdf

516-CAL-1996-CORRESPONDENCE 1.3.pdf

516-CAL-1996-CORRESPONDENCE-1.1.pdf

516-CAL-1996-CORRESPONDENCE.pdf

516-CAL-1996-DESCRIPTION (COMPLETE)-1.1.pdf

516-cal-1996-description (complete).pdf

516-cal-1996-examination report.pdf

516-CAL-1996-FORM 1-1.1.pdf

516-cal-1996-form 1.pdf

516-cal-1996-form 13.pdf

516-cal-1996-form 18.pdf

516-CAL-1996-FORM 2-1.1.pdf

516-cal-1996-form 2.pdf

516-cal-1996-form 26.pdf

516-CAL-1996-FORM 27 1.1.pdf

516-CAL-1996-FORM 27.pdf

516-CAL-1996-FORM 3-1.1.pdf

516-cal-1996-form 3.pdf

516-CAL-1996-FORM 5-1.1.pdf

516-cal-1996-form 5.pdf

516-cal-1996-gpa.pdf

516-cal-1996-reply to examination report.pdf

516-cal-1996-specification.pdf

516-cal-1996-translated copy of priority document.pdf


Patent Number 242869
Indian Patent Application Number 516/CAL/1996
PG Journal Number 38/2010
Publication Date 17-Sep-2010
Grant Date 16-Sep-2010
Date of Filing 22-Mar-1996
Name of Patentee ELI LILLY AND COMPANY
Applicant Address LILLY CORPORATE CENTER, INDIANAPOLIS, IN 46285
Inventors:
# Inventor's Name Inventor's Address
1 CHARLES ARTHUR BUNNELL 3114 THOMAS DRIVE, LAFAYETT, INDIANA 47905
2 BARRY ARNOLD HENDRIKSEN CASTLEWELLAN, 71, WALTHAM AVENUE, GUILDFORD, SURREY, GU2 6QE
3 TERRENCE MICHAEL HOTTEN 134 WEST HEATH ROAD, COVE, FARNBOROUGH, HAMPSHIRE
4 DAVID EDWARD TUPPER 8 MILDENHALL CLOSE, LOWER EARLY, READING, BERKSHIRE
5 SAMUEL DEAN LARSEN 3088 HAMILTON, WEST LAFAYETTE, INDIANA 47906
PCT International Classification Number C07D 495/04
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 08/409,566 1995-03-24 U.S.A.
2 08/410,474 1995-03-24 U.S.A.