PROCESS FOR THE PREPARATION OF DEXLANSOPRAZOLE
Field of the Invention
The present invention relates to a process for the preparation of
dexlansoprazole.xH 20 , wherein x is about 0.0 to about 0.1.
Background of the Invention
Dexlansoprazole is chemically 2-[(R)-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-
2-yl]methyl}sulfinyl]-lH-benzimidazole as represented by Formula I.
FORMULA I
U.S. Patent Nos. 6,462,058, and 7,285,668 and US Patent Application No.
2007/0004779 describe processes for preparing crystalline forms of dexlansoprazole and
its hydrates. PCT Publication No. WO 2009/1 17489 describes a process for the
preparation of amorphous dexlansoprazole.
U.S. Patent No. 7,271,182 describes sodium salt, magnesium salt, lithium salt,
potassium salt, calcium salt, or barium salt of dexlansoprazole and their preparation
method.
U.S. Patent No. 7,169,799 describes processes for preparing crystal of (R)-2-[[[3-
methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole-n'H 20 (wherein
n' is about 0 to about 0.1) or a salt thereof by crystallization from an organic solvent
solution or suspension in which (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-
pyridyl]methyl]sulfmyl]benzimidazole-nH 20 (wherein n is about 0.1 to about 1.0) or a salt
thereof has been dissolved or suspended.
Summary of the Invention
The present inventors have found that the dexlansoprazole.xH 20 , wherein x is
about 2.6 to about 50 can be converted into dexlansoprazole.xH20 , wherein x is about 0.0
to about 0.1. By employing the present invention, dexlansoprazole.xH20 , wherein x is
about 0.0 to about 0.1, can also be obtained as chirally and chemically pure material in a
consistent manner. Thus, the present invention provides a simple, efficient and
industrially preferable process for the preparation of dexlansoprazole.xH 0 , wherein x is
about 0.0 to about 0.1 .
Detailed Description of the Invention
One aspect of the present invention provides a process for the preparation of
dexlansoprazole.xH20 , wherein x is about 2.6 to about 50, which comprises:
a) treating a salt of dexlansoprazole with an agent capable of liberating
dexlansoprazole as a free base in the presence of a solvent;
b) treating the dexlansoprazole obtained in step a) with water and a solvent
selected from the group consisting of halogenated hydrocarbon, ketone, C1.3
alkanol, ether and a mixture thereof; and
c) isolating dexlansoprazole.xH20 , wherein x is about 2.6 to about 50 from the
mixture thereof.
The salt of dexlansoprazole used as a starting material may be in any solid form
and prepared according to the methods described in U.S. Patent No. 7,271,182. The salt
may be, for example, sodium salt of dexlansoprazole. The salt of dexlansoprazole is
treated with an agent capable of liberating dexlansoprazole as a free base in the presence
of a solvent. The agent capable of liberating dexlansoprazole as a free base may be an
acid, for example, hydrochloric acid, amine salt, for example, ammonium halide, or a
hydrogen sulfate, for example, sodium or potassium hydrogen sulfate. The solvent used in
step a) or step b) may be water, water-miscible solvent, for example, acetone, .3alkanol,
dioxane, tetrahydrofuran, dimethylformamide, acetonitrile, dimethylsulfoxide or water
immiscible solvent, for example, halogenated hydrocarbon, dichloromethane, or a mixture
thereof.
The reaction mixture obtained in step a) or step b) may preferably be treated with
water, dichloromethane, acetone, or a mixture thereof. The liberation of dexlansoprazole
as a free base may be effected by stirring the reaction mixture. The reaction mixture may
be treated with ammonia, for example, aqueous ammonia or an alkyl amine, for example,
diisopropylethylamine in the presence of a ketone solvent, for example, acetone. The
dexlansoprazole.xH20 , wherein x is about 2.6 to about 50 obtained as a free base may
optionally be isolated by solvent removal.
Another aspect of the present invention provides a process for the preparation of
dexlansoprazole.xH20 , wherein x is about 0.0 to about 0.1, which comprises:
a) treating a salt of dexlansoprazole with an agent capable of liberating
dexlansoprazole as a free base in the presence of a solvent;
b) treating the dexlansoprazole obtained in step a) with water and a solvent
selected from the group consisting of C4.8 hydrocarbon, halogenated
hydrocarbon, ketone, C1.3 alkanol, ether and a mixture thereof;
c) isolating dexlansoprazole.xH 0 , wherein x is about 2.6 to about 50 from the
mixture thereof; and
d) isolating dexlansoprazole.xH 0 , wherein x is about 0.0 to about 0.1 by
crystallization from solvent, solution or suspensions in which
dexlansoprazole.xEbO, wherein x is about 2.6 to about 50, has been dissolved
or suspended.
The salt of dexlansoprazole used as a starting material may be in any solid form
and prepared according to the methods described in U.S. Patent No. 7,271,182. The salt
may be, for example, sodium salt of dexlansoprazole. The salt of dexlansoprazole is
treated with an agent capable of liberating dexlansoprazole as a free base in the presence
of a solvent. The agent capable of liberating dexlansoprazole as a free base may be an
acid, for example, hydrochloric acid, amine salt, for example, ammonium halide, or a
hydrogen sulfate, for example, sodium or potassium hydrogen sulfate. The solvent used in
step a) or step b) may be water, water miscible solvent, for example, acetone, C1-3 alkanol,
dioxane, tetrahydrofuran, dimethylformamide, acetonitrile, dimethylsulfoxide or water
immiscible solvent, for example, halogenated hydrocarbon, dichloromethane, or a mixture
thereof.
The reaction mixture obtained in step a) or step b) may preferably be treated with
water, dichloromethane, acetone or a mixture thereof. The liberation of dexlansoprazole
as a free base may be effected by stirring the reaction mixture. The reaction mixture may
be treated with ammonia, for example, aqueous ammonia or an alkyl amine, for example,
diisopropylethylamine in the presence of a ketone solvent, for example, acetone. The
dexlansoprazole.xH 0 , wherein x is about 2.6 to about 50 obtained as a free base may
optionally be isolated by solvent removal.
The dexlansoprazole.xH 20 , wherein x is about 2.6 to about 50 isolated in step c)
may be treated with a solvent. The solvent used in step d) may be selected from the group
consisting of water, d^alkanol, halogenated hydrocarbon, ketone, aliphatic hydrocarbon,
cyclic aliphatic hydrocarbon, ether and a mixture thereof. The solvent may be, for
example, n-butanol, tertiary-butanol, cyclohexane, dichloromethane, acetone, heptane,
methanol, methyl t-butyl ether, diisopropyl ether or a mixture thereof. The treatment with
the solvent may be carried out at a temperature of about -30°C to about 60°C, for example,
about 15°C to about 45°C. The dexlansoprazole.xH 20 , wherein x is about 0.0 to about
0.1, may be isolated by filtration, distillation, decantation, vacuum drying, evaporation, or
a combination thereof.
Another aspect of the present invention provides a process for the preparation of
dexlansoprazole.xH 20 , wherein x is about 0.0 to about 0.1, which comprises:
a) treating dexlansoprazole.xH 0 , wherein x is about 2.6 to about 50, with a
solvent selected from the group consisting of water, C -7 alkanol, aliphatic
hydrocarbon, cyclic aliphatic hydrocarbon, halogenated hydrocarbon, ketone,
ether and a mixture thereof; and
b) isolating dexlansoprazole.xH 0 , wherein x is about 0.0 to about 0.1 from the
mixture thereof.
The dexlansoprazole.xH 0 , wherein x is about 2.6 to about 50, is treated with a
solvent selected from the group consisting of water, Cj.yalkanol, halogenated
hydrocarbon, ketone, aliphatic hydrocarbon, cyclic aliphatic hydrocarbon, ketone, ether,
and a mixture thereof. The solvent may be, for example, n-butanol, tertiary-butanol,
cyclohexane, dichloromethane, acetone, heptane, methanol, methyl t-butyl ether,
diisopropyl ether, or a mixture thereof. The treatment with the solvent may be carried out
at a temperature of about -30°C to about 60°C, for example, about 15°C to about 45°C.
The dexlansoprazole.xH 20 , wherein x is about 0.0 to about 0.1 may be isolated by
filtration, distillation, decantation, vacuum drying, evaporation, or a combination thereof.
Another aspect of present invention provides dexlansoprazole.xEbO, wherein x is
about 2.6 to about 50.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those skilled in the
art and are intended to be included within the scope of the present invention.
EXAMPLES
Example 1: Preparation of Dexlansoprazole.xfibO, wherein x is about 27
Dexlansoprazole sodium (300 g) was dissolved in de-ionized water (15 L) at 26°C
to 30°C and the pH of the reaction mixture was adjusted to 12.4 to 12.6 using sodium
hydroxide (100 g). The reaction mixture was heated to 45°C to 50°C, stirred for 30
minutes and filtered through Celite-bed and filtrate was cooled to 35°C to 38°C. The
filtrate was extracted with dichloromethane ( 200 mL). The pH of the aqueous reaction
mixture was adjusted to 7.4 to 7.8 with dropwise addition of 2N hydrochloric acid (1485
mL). The reaction mixture was filtered, washed with water (1500 mL) and added to
acetone (900 mL). De-ionized water (300 mL) and aqueous ammonia (22.8 mL) were
added to this reaction mixture and heated to 35°C to 38°C. De-ionized water (4.8 L) was
added dropwise over a period of 45 minutes to 60 minutes. The reaction mixture was
stirred for 3 hours to 4 hours at 35°C to 38°C and the precipitate obtained was filtered and
washed with water (600 mL). The precipitate was again added to acetone (900 mL)
followed by addition of de-ionized water (300 mL) and aqueous ammonia (22.8 mL). The
reaction mixture was heated to 35°C to 38°C. De-ionized water (4.8 L) was added to the
reaction mixture drop-wise over a period of 45 minutes to 60 minutes. The reaction
mixture was stirred for 3 hours to 4 hours at 35°C to 38°C and the precipitate obtained was
filtered and washed with water (600 mL) to obtain the title product.
Yield: 402 g
Moisture: 57.0%
Example 2: Preparation of Dexlansoprazole. xH?0. wherein x is about 0.0 to about 0.1
Dexlansoprazole (402 g) prepared according to Example 1 was dissolved in
dichloromethane (1500 mL) and washed with 5% aqueous sodium chloride solution (1800
mL). Layers obtained were separated and washed with de-ionized water (1800 mL).
Organic layer was separated and filtered through Celite bed followed by washing with
dichloromethane (300 mL). Diisopropylethylamine (0.3 g) was added to the combined
dichloromethane layer (1800 mL). n-Butanol (360 mL) and activated carbon were added
to the reaction mixture and stirred for 30 minutes. The reaction mixture was filtered
through celite and a bed of molecular sieve (120 g) to get moisture of organic layer not
more than 0.25% w/w. Solvents were recovered completely under vacuum at less than
35°C to get the residue. Cyclohexane (2 x 360 mL) was added to the residue. The
cyclohexane was recovered completely from the reaction mixture under vacuum at less
than 35°C to get the residue. Cyclohexane (4300 mL) was added to the residue dropwise
and the solution was stirred for 4 hours at 25°C to 30°C. The reaction mixture was
filtered. Cyclohexane (600 mL) was added to the solid material and the reaction mixture
was stirred for 30 minutes at 25°C to 30°C, filtered under nitrogen atmosphere and dried
under vacuum at 35°C to 38°C for 10 hours to 12 hours to obtain the title compound.
Yield: 1 8 g
Moisture: 0.14%

WE CLAIM
1. A process for the preparation of dexlansoprazole.xfbO, wherein x is about 2.6 to
about 50, which comprises:
a) treating a salt of dexlansoprazole with an agent capable of liberating
dexlansoprazole as a free base in the presence of a solvent;
b) treating the dexlansoprazole obtained in step a) with water and a solvent
selected from the group consisting of halogenated hydrocarbon, ketone, .3
alkanol, ether and a mixture thereof; and
c) isolating dexlansoprazole.xH 20 , wherein x is about 2.6 to about 50 from the
mixture thereof.
2. A process for the preparation of dexlansoprazole.xH20 , wherein x is about 0.0 to
about 0.1, which comprises:
a) treating a salt of dexlansoprazole with an agent capable of liberating
dexlansoprazole as a free base in the presence of a solvent;
b) treating the dexlansoprazole obtained in step a) with water and a solvent
selected from the group consisting of C4.8 hydrocarbon, halogenated
hydrocarbon, ketone, C1.3 alkanol, ether and a mixture thereof;
c) isolating dexlansoprazole.xH 20 , wherein x is about 2.6 to about 50 from the
mixture thereof; and
d) isolating dexlansoprazole .xH20, wherein x is about 0.0 to about 0.1 by
crystallization from solvent, solution or suspensions in which
dexlansoprazole.xH 20 , wherein x is about 2.6 to about 50, has been dissolved
or suspended.
3. A process according to claim 1 or claim 2, wherein the salt of dexlansoprazole is
sodium salt.
4. A process according to claim 1 or claim 2, wherein the agent capable of liberating
dexlansoprazole as a free base is an acid, amine salt or hydrogen sulfate.
5. A process according to claim 4, wherein the agent capable of liberating
dexlansoprazole is hydrochloric acid.
6. A process according to claim 1 or claim 2, wherein the solvent used in step a) is
water, halogenated hydrocarbon, or a mixture thereof.
7. A process according to claim 6, wherein the halogenated hydrocarbon is
dichloromethane.
8. A process according to claim 1 or claim 2, wherein the halogenated hydrocarbon
used in step b) is dichloromethane.
9. A process according to claim 1 or claim 2, wherein the ketone used in step b) is
acetone.
10. A process according to claim 1 or claim 2, wherein the ether used in step b) is
tetrahydrofuran.
11. A process according to claim 2, wherein the solvent used in step d) is selected from
the group consisting of water, C1-7 alkanol, halogenated hydrocarbon, ketone, aliphatic
hydrocarbon, cyclic aliphatic hydrocarbon, ether, and a mixture thereof.
12. A process according to claim 11, wherein the solvent used in step d) is n-butanol,
tertiary-butanol, cyclohexane, dichloromethane, acetone, heptane, methanol, methyl tbutyl
ether, diisopropyl ether, or a mixture thereof.
13. A process for the preparation of dexlansoprazole.xH20 , wherein x is about 0.0 to
about 0.1, which comprises:
a) treating dexlansoprazole.xH20 , wherein x is about 2.6 to about 50, with solvent
selected from the group consisting of C1-7 alkanol, aliphatic hydrocarbon, cyclic
aliphatic hydrocarbon, halogenated hydrocarbon, ketone, ether, and a mixture
thereof; and
b) isolating dexlansoprazole.xH20 , wherein x is about 0.0 to about 0.1 from the
mixture thereof.
14. A process according to claim 13, wherein the solvent is n-butanol, tertiary-butanol,
cyclohexane, dichloromethane, acetone, heptane, methanol, methyl t-butyl ether,
diisopropyl ether, or a mixture thereof.
Dexlansoprazole.xH20, wherein x is about 2.6 to about 50.