PROCESS FOR THE PREPARATION OF ASENAPINE INTERMEDIATE
Field of the Invention
The present invention provides a process for the preparation of the asenapine
intermediate of Formula III using a magnesium-methanol-acetic acid mixture.
Background of the Invention
Asenapine and its pharmaceutically acceptable salts, including asenapine maleate, are
known from U.S. Patent No. 4,145,434. Asenapine maleate is chemically (3aRS,12bRS)-5-
Chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole (2Z)-2-
butenedioate (1:1), having the structure as represented in Formula I.
COOH
COOH
Formula I
Asenapine maleate is marketed in the United States under the brand name SAPHRIS®,
for the treatment of schizophrenia.
Processes for the preparation of asenapine maleate and intermediates thereof are
disclosed in U.S. Patent Nos. 4,145,434 and 7,872,147; PCT Publication Nos. WO 2009/008405,
WO 2008/081010 and WO 2009/087058; and in Organic Process Research and Development,
Vol. 12, p. 196-201 (2008), which are incorporated herein by reference.
U.S. Patent No. 4,145,434 describes a process for the preparation of asenapine maleate
which involves reducing the carbon-carbon double bond of the intermediate of Formula II
O' ^N'
1
CH3
11-chloro-2-methyl-2,3-dihydro-1/-/-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-1-one
Formula II
to obtain the intermediate of Formula III
1
CH3
(3aS,12bS)-re/-11-chloro-2-methyl-2,3,3a,12b-tetrahydro-1AV-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-1-
one
Formula III
by a process involving the addition of a solution of an intermediate of Formula II in toluene to a
suspension of magnesium in a mixture of toluene and methanol.
The magnesium-methanol process disclosed in U.S. Patent No. 4,145,434 for the
preparation of an intermediate of Formula III is not suitable for an industrial scale preparation
due to its poor product selectivity and the associated safety concerns as detailed below:
• Poor product selectivity as the desired /ra«5'-isomer and undesired cz5-isomer are
formed in an unfavorable ratio of about 1:4.
• Poor reaction control, because the reaction between magnesium and methanol is
heterogeneous and exothermic in nature. This limits the maximum scale at which
one can safely operate the process and results in the formation of a significant
amount of side products.
• The use of carcinogenic dibromomethane for the activation of magnesium metal
poses a health hazard.
3
Organic Process Research and Development, Vol. 12, p. 196-201 (2008), describes a
dose-controlled reverse addition process wherein instead of adding an intermediate of Formula II
to a suspension of magnesium in methanol and toluene, portions of the magnesium-methanol
suspension are added to a solution of the intermediate of Formula II. Although the dosecontrolled
reverse-addition process helped in overcoming the drawbacks associated with poor
reaction control, this process failed to provide any improvement in terms of product selectivity,
and the desired trans-isomer and undesired c/.s--isomer still being formed in an unfavorable ratio.
Organic Process Research and Development, Vol. 12, p. 196-201 (2008), further
describes that only magnesium in a combination with methanol was able to reduce the carboncarbon
double bond of the intermediate of Formula II. The carbon-carbon double bond of an
intermediate of Formula II cannot be reduced using catalytic hydrogenation with other metal
catalysts such as palladium, platinum, rhodium, ruthenium, iridium, zinc and lithium, using
magnesium in ethanol, using magnesium in propanol, or by a Birch reduction.
In view of the drawbacks associated with the prior art processes, especially poor product
selectivity and the inability of other metal catalysts and solvents or Birch reductions in reducing
the double bond of the intermediate of Formula II, there exists a need in the art for a process
which provides better product selectivity.
Summary of the Invention
The present inventors have developed an improved process for the preparation of the
/rara-intermediate of Formula III having better product selectivity. The process of the present
invention involves preparation of the intermediate of Formula III by carrying out the reduction
of the intermediate of Formula II using a magnesium-methanol-acetic acid mixture. The process
of the present invention provides the intermediate of Formula III in 1:1 cisJrans ratio.
A first aspect of the present invention provides a process for the preparation of an
intermediate of Formula III
Formula III
4
comprising reducing the intermediate of Formula II
O' ^N'
1
CH3
Formula II
using a magnesium-methanol-acetic acid mixture.
A second aspect of the present invention provides a process for the preparation of
asenapine maleate of Formula I
COOH
'COOH
Formula I
comprising the steps of:
i) reducing the intermediate of Formula II
using a magnesium-methanol-acetic acid mixture to obtain the intermediate of
Formula III;
Formula III
ii) reducing the carbonyl group of the intermediate of Formula III to obtain asenapine
of Formula IV; and
N
I
CH3
Formula IV
iii) converting asenapine of Formula IV to asenapine maleate of Formula I.
Other objects, features, advantages and aspects of the present invention will become
apparent to those of ordinary skill in the art from the detailed description provided below.
Detailed Description of the Invention
The term "ambient temperature", as used herein, includes temperature in the range of
about 20°C to about 35°C.
The intermediate of Formula II, to be used for the preparation of the intermediate of
Formula III, may be prepared by the process disclosed in U.S. Patent No. 4,145,434 which is
incorporated herein by reference.
The conversion of the intermediate of Formula II into the intermediate of Formula III
may be carried out by dissolving the intermediate of Formula II in a mixture of methanol and
acetic acid. The reaction mixture may be heated to about 40°C to 65 °C. Magnesium metal
turnings may be added portion-wise. The reaction mixture may be stirred for about 30 minutes
to about 5 hours. The magnesium salts formed during the reaction and the un-reacted
magnesium may be removed from the reaction mixture either by adding water and optionally
adjusting the pH of the reaction mixture to about 1 to 2 by adding concentrated hydrochloric
6
acid, or by filtration, followed by extraction with a solvent and removal of the solvent by
distillation under reduced pressure to obtain a mixture of diastereomers. In embodiments
involving removal of the magnesium salts and un-reacted magnesium by filtration, the resulting
solid material may be further extracted with a solvent to extract the mixture of diastereomers
from the solid material. The mixture of diastereomers may then be separated into cis- and transhomer?,
by silica gel column chromatography using an ethyl acetate:hexane (30:70) mixture as
the eluent.
The solvent to be used for carrying out the extraction may be selected from waterimmiscible
solvents selected from the group comprised of hydrocarbons, ethers, alkyl acetates or
chlorinated hydrocarbons. Examples of hydrocarbons may include toluene, benzene or xylene.
Examples of ethers may include diethyl ether, ethyl methyl ether or tetrahydrofuran. Examples
of alkyl acetates may include ethyl acetate or di-isopropyl acetate. Examples of chlorinated
hydrocarbons may include dichloromethane or chloroform.
The process of the present invention provides the intermediate of Formula III in a 1:1
cis.trans ratio.
The reduction of the carbonyl group of the intermediate of Formula III to obtain
asenapine of Formula IV may be carried out using complex metal hydrides such as diisobutylaluminum
hydride, lithium borohydride or sodium trimethoxyborohydride. The
reduction of the carbonyl group of the intermediate of Formula III may also be carried out using
borane dimethyl sulphide. The reduction of the carbonyl group of the intermediate of Formula
III may be carried out in an organic solvent selected from ethers or hydrocarbons. Examples of
ethers may include diethyl ether, ethyl methyl ether, di-isopropyl ether, tetrahydrofuran or 1,4-
dioxane. Examples of hydrocarbons may include benzene, toluene or xylenes.
In a preferred embodiment of the present invention, reduction of the carbonyl group may
be carried out by adding a solution of borane dimethyl sulphide in tetrahydrofuran to a preheated
solution of the intermediate of Formula III in tetrahydrofuran at a temperature of about
50°C to about 80°C in an inert atmosphere. The reaction mixture may be stirred for about 8
hours to about 16 hours. Dimethyl sulphide produced during the reaction may be slowly
distilled-off from the reaction mixture. Fresh tetrahydrofuran may be added to compensate for
the loss of tetrahydrofiiran during distillation. An additional amount of borane dimethyl
sulphide solution may be added and the reaction mixture may be stirred for about 1 hour to
about 6 hours for completion of the reaction. Alcohol selected from the group comprising
methanol, ethanol or propanol may be added. The contents may be stirred for about 5 to about
30 minutes followed by the addition of a mixture of sulphuric acid and water. The reaction
mixture may be stirred at about 60°C to about 90°C for about 4 hours to about 10 hours, cooled,
then extracted with a solvent selected from hydrocarbon solvents such as benzene, toluene,
xylenes, monochlorobenzene or 1,2-dichlorobenzene. Water may be added followed by the
slow addition of an ammonia solution in a period of about 5 to about 30 minutes. Asenapine of
Formula IV may be extracted from the reaction mixture by adding a solvent selected from
hydrocarbon solvents such as benzene, toluene, xylenes, monochlorobenzene or 1,2-
dichlorobenzene followed by drying.
Drying may be accomplished by any suitable method such as air drying, drying under
reduced pressure, vacuum tray drying or a combination thereof Drying may be carried out at
ambient temperature to a temperature of about 80°C.
Conversion of asenapine of Formula IV into asenapine maleate of Formula I may be
carried out by conventional methods such as the method described in U.S. Patent No. 4,145,434.
In the foregoing section, embodiments are described by way of examples to illustrate the
process of invention. However, these are not intended in any way to limit the scope of the
present invention. Variants of the examples evident to persons ordinarily skilled in the art are
within the scope of the present invention.
Examples
Comparative Example: Preparation of Traits-ll-Chloro-2-Methvl-2,3,3a, 12b-Tetrahvdro-lHDibenzor2.3:
6J10xepinor4.5-C1Pvrrol-l-One (Formula IIP
7g of 1 l-chloro-2-methyl-2,3-dihydro-lH-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-l-one
was suspended in methanol (50 mL). Magnesium metal turnings (10 g) were added. The
reaction mixture was slowly heated to reflux temperature. Brisk effervescence was observed.
The reaction mixture was cooled to control the reaction, again refluxed for about 2 hours under
controlled conditions, diluted with methanol (30 mL), further refluxed for about 30 minutes and
cooled to ambient temperature. Methanol (150 mL) was added. The pH was adjusted to about 1
to 2 by adding concentrated hydrochloric acid, and a clear solution was obtained. The solution
was extracted with ethyl acetate (3 x 100 mL) and the combined ethyl acetate layers were
washed with water (3 x 50 mL). Ethyl acetate was removed by distillation under reduced
pressure to obtain a mixture of two isomers as a brown oil (4.6 g). The mixture of isomers was
separated into cis- and ^ran^'-isomers using silica gel column chromatography eluting with ethyl
acetate: hexane.
8
trans-isomer: 0.65 mg
c/5-isomer: 3.5 g
Working Examples
Example 1: Preparation of ^rfln5-ll-Chloro-2-Methvl-2,3,3a,l2b-Tetrahvdro-lHDibenzo^
23:6J^Oxepinol4.5-C1Pvrrol-l-One rFormula III)
2 g of ll-chloro-2-methyl-2,3-dihydro-lH-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-l-one
was dissolved in a mixture of methanol (60 mL) and acetic acid (20 mL). The reaction mixture
was heated to about 53°C. Magnesium metal turnings (2.0 g) were added portion-wise. The
reaction mixture was stirred for about 1 hour, filtered and washed with methanol (100 mL).
Methanol was removed by distillation from the filtrate to obtain a white solid (16 g). The white
solid was dissolved in dichloromethane (200 mL) and washed with water (2 x 500 mL). The
solid obtained during filtration was also dissolved in water (100 mL) and the aqueous layer was
extracted with dichloromethane (50 mL). The two dichloromethane solutions were combined.
Dichloromethane was removed by distillation under reduced pressure to obtain a mixture of two
isomers as £in oily brown compound (2 g). The mixture of isomers was separated into cis- and
/ra«5-isomers using silica gel column chromatography eluting with ethyl acetate:hexane (30:70)
mixture.
trans-isomer: 0.7 g
d5-isomer: 0.7 g
Example 2: Preparation of rrg/zj'-l l-Chloro-2-Methvl-2,3,3a,12b-Tetrahvdro-lHDibenzor2.3:
6.710xepinor4.5-C1Pvrrol-l-One (Formula IIP
2 g of ll-chloro-2-methyl-2,3-dihydro-lH-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-l-one
was dissolved in a mixture of methanol (60 mL) and acetic acid (20 mL). The reaction mixture
was heated to about 50°C. Magnesium metal turnings (2.38 g) were added portion-wise at about
45°C to about 65°C. The reaction mixture was stirred at ambient temperature for about 2 hours.
Water (80 mL) was added. The pH of the reaction mixture was adjusted to 1 by adding
concentrated hydrochloric acid. The reaction mixture was extracted with ethyl acetate (150 mL)
and washed with water (3 x 200 mL). Ethyl acetate was distilled-off to obtain a mixture of two
isomers as an oily brown compound (2 g). The mixture of isomers was separated into cis- and
trans-isomers using silica gel column chromatography eluting with ethyl acetate:hexane (30:70)
mixture.
/ra«5-isomer: 0.7 g
cw-isomer: 0.8 g
Example 3: Preparation of Asenapine [Formula IV]
A 2M solution of borane dimethyl sulphide in tetrahydrofuran (128 mL) was added dropwise
to a pre-heated solution (heated to about 64°C) of /ra«5-(3a,12b)-ll-chloro-2-methyl-
2,3,3a,12b-tetrahydro-lH-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-l-one (30 g) in tetrahydrofuran
(300 mL) at about 64°C under nitrogen flow. The reaction was allowed to proceed for about 12
hours. Dimethyl sulphide produced during the reaction was slowly removed by distillation from
the reaction mixture and fresh tetrahydrofuran was added. Borane dimethylsulphide in
tetrahydrofuran 2M solution (24 mL) was added and the reaction mixture was stirred for about 3
hours. Tetrahydrofuran was distilled-off under reduced pressure. Methanol (250 mL) was
added to the residue and the reaction mixture was stirred for 15 minutes. A sulphuric acid:water
mixture (75 mL:500 mL) was added over about 5 minutes. The reaction mixture was stirred at
about 80°C for about 7 hours, cooled to about 50°C and washed with toluene (2 x 200mL). The
layers were separated. The aqueous layer was cooled to about 0°C to 5°C, and the crystallized
salt was filtered, washed with cold water (100 mL) and dried in air at about 45°C for about 15
hours.
29 g of the air-dried material was suspended in water (150 mL). An ammonia solution
was added slowly over about 10 minutes. Asenapine was extracted from the reaction mixture by
adding toluene (2 x 100 mL), washing with water (100 mL), then removing toluene by
distillation under reduced pressure.
Yield: 22.2 g
10

WE CLAIM:

1. A process for the preparation of the intermediate of Formula III

Formula III
comprising reducing the intermediate of Formula II
using a magnesium-methanol-acetic acid mixture.
A process for the preparation of asenapine maleate of Formula I
Formula I
comprising the steps of:
i) reducing the intermediate of Formula II
COOH
COOH
11
4.
O
Formula II
using a magnesium-methanol-acetic acid mixture to obtain the intermediate of
Formula III;
ii) reducing the carbonyl group of the intermediate of Formula III to obtain asenapine
of Formula IV; and
I
CH3
Formula IV
iii) converting asenapine of Formula IV to asenapine maleate of Formula I.
The process according to claim 1 or 2, wherein the reduction of the intermediate of
Formula II is carried out at a temperature of 40°C to 65°C.
The process according to claim 1 or 2, wherein the reduction of the intermediate of
Formula II is carried out in 30 minutes to 5 hours
The process according to claim 2, wherein the reduction of the carbonyl group of the
intermediate of Formula III is carried out using complex metal hydrides selected from diisobutylaluminum
hydride, lithium borohydride or sodium trimethoxyborohydride.
12
r*. V>V
0 \ ^ V \^ ** 04 95M$
6. The process according to claim 2, wherein the reduction of the carbonyl group of the
intermediate of Formula III is carried out using borane dimethyl sulphide.
7. The process according to claim 2, wherein the reduction of the carbonyl group of the
intermediate of Formula III is carried out in an organic solvent selected from ethers and
hydrocarbons.
8. The process according to claim 2, wherein the reduction of the carbonyl group of the
intermediate of Formula III is carried out at 50°C to 80°C
9. The process according to claim 2, wherein the reduction of the carbonyl group of the
intermediate of Formula III is carried out in 8 hours to 16 hours.
10. The process according to claim 1 or 2, wherein the intermediate of Formula III is
obtained in 1:1 cis:trans ratio.