PROCESS FOR THE PREPARATION OF DEXLANSOPRAZOLE
Field of the Invention
The present invention relates to a process for the preparation of crystalline
dexlansoprazole.
Background of the Invention
Dexlansoprazole is chemically described as 2-[(R)-{[3-methyl-4-(2,2,2-
trifluoroethoxy)pyridin-2-yl] methyl }sulfinyl]-lH-benzimidazole as represented by Formula I.
FORMULA I
Dexlansoprazole is reportedly useful for healing of all grades of erosive esophagitis
(EE) for up to 8 weeks, to maintain healing of EE for up to 6 months and for the treatment of
heartburn associated with non-erosive gastroesophageal reflux disease (GERD) for 4 weeks.
U.S. Patent Nos. 6,462,058 and 7,285,668 and U.S. Publication No. 2007/0004779
describe processes for preparing crystalline forms of dexlansoprazole and its hydrates. PCT
Publication No. WO 2009/1 17489 describes processes for the preparation of amorphous
dexlansoprazole.
U.S. Patent No. 7,271,182 discloses the formation of alkali and alkaline earth metal
salts - such as sodium, magnesium, lithium, potassium, calcium, and barium - of
dexlansoprazole, by reacting dexlansoprazole with a metal hydroxide, a metal alkoxide or a
metal amide.
Summary of the Invention
The present inventors have found that certain salts of dexlansoprazole can be
converted into crystalline dexlansoprazole. By employing the present invention, crystalline
dexlansoprazole can also be obtained as a 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 crystalline dexlansoprazole.
Brief Description of the Drawings
Figure 1 depicts the X-ray powder diffraction pattern (XRPD) of crystalline
dexlansoprazole obtained according to Example 1.
Figure 1A provides the peak values for the XRPD pattern depicted in Figure 1.
Figure 2 depicts the X-ray powder diffraction pattern (XRPD) of crystalline
dexlansoprazole obtained according to Example 2.
Figure 2A provides the peak values for the XRPD pattern depicted in Figure 2.
Figure 3 depicts the X-ray powder diffraction pattern (XRPD) of crystalline
dexlansoprazole obtained according to Example 3.
Figure 3A provides the peak values for the XRPD pattern depicted in Figure 3.
Detailed Description of the Invention
One aspect of the present invention provides a process for the preparation of
crystalline dexlansoprazole, which comprises the steps of:
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 a solvent selected from the
group consisting of water, halogenated hydrocarbon, Ci_3 alkanol, ether and a
mixture thereof; and
c) isolating crystalline dexlansoprazole from the mixture.
The salt of dexlansoprazole used as a starting material may be in any form and
prepared according to the methods described in U.S. Patent No. 7,271,182. The salt may be
for example, alkali metal salt or alkaline earth metal salt, 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 amine salt, for example, ammonium halide, or a
hydrogen sulfate, for example, sodium or potassium hydrogen sulfate, or both. The solvent
may be a water miscible solvent, for example, acetone, C1-3 alkanol, dioxane, tetrahydrofuran,
dimethylformamide, acetonitrile, dimethylsulfoxide 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 in the
presence of a ketone solvent, for example, acetone to remove 2-({ [3-methyl-4-(2,2,2-
trifluoroethoxy)pyridin-2-yl]methyl}sulfonyl)-l H-benzimidazole impurity (sulfone
impurity). The dexlansoprazole obtained as a free base may optionally be isolated by solvent
removal. The dexlansoprazole is treated with a solvent selected from the group consisting of
water, halogenated hydrocarbon, C1-3 alkanol, ether, and a mixture thereof. The solvent may
be, for example, dichloromethane, 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 crystalline dexlansoprazole
may be isolated by filtration, distillation, decantation, vacuum drying, evaporation, or a
combination thereof.
Crystalline dexlansoprazole prepared by the present invention has a purity of more
than about 99.0%, for example more than about 99.4% and chiral purity of more than about
99.9% and is substantially free from sulfone impurity. For example, the crystalline
dexlansoprazole has a sulfone impurity not more than about 0.1%.
XRPD of the samples were determined by using Panalytical X'Pert Pro X-Ray Powder
Diffractometer in the range 3-40 degree 2 theta and under tube voltage and current of 45 Kv
and 40 mA respectively. Copper radiation of wavelength 1.54 angstrom and Xceletor detector
was used.
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 Crystalline Dexlansoprazole
A mixture of acetone (30 mL) and dexlasoprazole sodium (10 g; sulfone impurity
content: 6%) was stirred at 20°C to 25°C and filtered through 0.45m filter. De-ionized water
(10 mL) was added to the filtered solution at 20°C to 25°C, followed by addition of aqueous
sodium hydrogen sulfate (2.5 g of sodium hydrogen sulfate in 7 mL of water) drop-wise till
pH 7.3 was reached. The mixture was stirred for 10 to 15 minutes, followed by the addition
of de-ionized water (50 mL) and stirred for further 1 hour at 20°C to 25°C. The mixture was
filtered under vacuum, washed with de-ionized water (10 mL), followed by addition of
acetone (30 mL) and 6% aqueous ammonia solution (0.5 mL; 6%) to attain a pH of 9.5. Deionized
water (60 mL) was added to the mixture, stirred for 1 hour at 20°C to 25°C, filtered
under vacuum and washed with de-ionized water (10 mL), followed by the addition of deionized
water (30 mL) and dichloromethane (60 mL). The mixture was stirred and then
allowed to settle, and the organic layer was separated. Dichloromethane was recovered under
vacuum at 35°C to 40°C to obtain 10 to 15 mL of reaction mixture. Diisopropyl ether (150
mL) was added drop-wise to the reaction mixture, stirred for 1 hour at 20°C to 25°C, filtered
under vacuum, washed with diisopropyl ether (10 mL) and dried under vacuum at 20°C to
25°C for 8 hours to 10 hours to obtain the title compound.
Yield: 71.27%
Chiral purity: 99.9%
Chromatographic purity: 99.78%
Sulfone impurity content: not detectable
Moisture content: 0.12%
Example 2 : Preparation of Crystalline Dexlansoprazole
A mixture of acetone (100 mL) and dexlasoprazole sodium (20 g) was stirred at 20°C
to 30°C and filtered through 0.45m filter. Ammonium chloride solution (40 g of ammonium
chloride in 120 mL of water) was added to the filtered solution at 20°C to 25°C accompanied
by stirring, followed by addition of 5% aqueous potassium hydrogen sulfate drop-wise to
attain a pH of 6.99. The mixture was stirred for 45 minutes and filtered under vacuum. Water
(180 mL) was added slowly to the filtrate at 20°C to 25°C and stirred for 45 minutes. 6%
Aqueous ammonia solution (0.5 mL; 6%) was added drop-wise to attain a pH of 9, filtered
under vacuum and washed with acetone/de-ionized water (1/2, 150 mL) and dried under
vacuum in air for 2 hours. 8.5 g of the solid was stirred with dichloromethane (100 mL) and
de-ionized water (75 mL), and the organic layer was separated. The solvent was recovered
under vacuum at 35°Cto 40°C to obtain 10 to 15 mL of reaction mixture. Methanol (25 mL)
was added to the reaction mixture and the solvent was evaporated under vacuum at 35°C to
40°C to obtain 10 to 15 mL of reaction mixture. Diisopropyl ether (125 mL) was added to the
reaction mixture drop-wise at 20°C to 25°C, stirred for 1 hour at 20°C to 25°C, filtered under
vacuum. The solid was washed with diisopropyl ether (25 mL) and dried under vacuum at
30°C to 35°C for 4 hours using calcium chloride as a drying agent to obtain the title
compound.
Yield: 6.5 g
Chiral purity: 100%
Chromatographic purity: 99.45%
Sulfone impurity content: not detectable
Moisture content: 0.1%
Example 3 : Preparation of Crystalline Dexlansoprazole
A mixture of acetone (100 mL) and dexlasoprazole sodium (20 g) was stirred at 20°C
to 30°C and filtered through 0.45m filter. Ammonium chloride solution (40 g of ammonium
chloride in 120 mL of water) was added to the filtered solution at 20°C to 25°C accompanied
by stirring, followed by addition of 5% aqueous potassium hydrogen sulfate drop-wise to
attain a pH of 6.99. The mixture was stirred for 45 minutes and filtered under vacuum. Water
(180 mL) was added slowly to the filtrate at 20°C to 25°C and stirred for 45 minutes. 6 %
Aqueous ammonia solution (0.5 mL; 6%) was added drop-wise to attain a pH of 9, filtered
under vacuum and washed with acetone/de-ionized water (1/2, 150 mL) and dried under
vacuum in air for 2 hours. 7.5 g of the solid was stirred with dichloromethane (100 mL) and
de-ionized water (75 mL) and the organic layer was separated. The solvent was recovered
under vacuum at 35°C to 40°C to obtain 8 to 12 mL of reaction mixture. Methyl t-butyl ether
(110 mL) was added drop-wise to the reaction mixture at 20°C to 25°C, stirred for 1 hour at
20°C to 25°C and filtered under vacuum. The solid was washed with diisopropyl ether (20
mL) and dried under vacuum at 30°C to 35°C for 4 hours using calcium chloride as a drying
agent to obtain the title compound.
Yield: 4 g
Chiral purity: 100%
Chromatographic purity: 99.4%
Sulfone impurity content: not detectable
Moisture content: 0.1%

We claim:
1. A process for the preparation of crystalline dexlansoprazole, the process comprising
the steps of:
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 a solvent selected from the
group consisting of water, halogenated hydrocarbon, C1-3 alkanol, ether and a
mixture thereof; and
c) isolating crystalline dexlansoprazole from the mixture thereof.
2. A process according to claim 1, wherein the agent capable of liberating
dexlansoprazole is amine salt or hydrogen sulfate.
3. A process according to claim 2, wherein the hydrogen sulfate is sodium hydrogen
sulfate, potassium hydrogen sulfate or both.
4. A process according to claim 1, wherein the salt of dexlansoprazole is alkali metal salt
or alkaline earth metal salt.
5. A process according to claim 4, wherein the alkali metal salt of dexlansoprazole is
sodium salt.
6. A process according to claim 1, wherein the solvent used in step a) is a water miscible
solvent.
7. A process according to claim 6, wherein the water miscible solvent is acetone, C1-3
alkanol, dioxane, tetrahydrofuran, dimethylformamide, acetonitrile, dimethylsulfoxide or a
mixture thereof.
8. A process according to claim 1, wherein the halogenated hydrocarbon solvent used in
step b) is dichloromethane.
9. A process according to claim 1, wherein the C1-3 alkanol solvent used in step b) is
methanol.
10. A process according to claim 1, wherein the ether solvent used in step b) is methyl tbutyl
ether, diisopropyl ether or a mixture thereof.
11. Crystalline dexlansoprazole which has a chromatographic purity of at least 99%,
prepared by using a process according to claim 1.
12. Crystalline dexlansoprazole according to claim 11, wherein the sulfone impurity is not
more than 0.1%.
13. Crystalline dexlansoprazole according to claim 11, wherein the water content is not
more than 0.2%.
14. Crystalline dexlansoprazole according to claim 11, wherein the sulfone impurity is not
more than 0.1% and the water content is not more than 0.2%.