WO2011004387A2 - Process for the preparation of dexlansoprazole polymorphic forms - Google Patents

Process for the preparation of dexlansoprazole polymorphic forms Download PDF

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WO2011004387A2
WO2011004387A2 PCT/IN2010/000415 IN2010000415W WO2011004387A2 WO 2011004387 A2 WO2011004387 A2 WO 2011004387A2 IN 2010000415 W IN2010000415 W IN 2010000415W WO 2011004387 A2 WO2011004387 A2 WO 2011004387A2
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dexlansoprazole
preparation
crystalline
anhydrous
amorphous
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PCT/IN2010/000415
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French (fr)
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WO2011004387A3 (en
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Ramakoteswara Rao Jetti
Neelima Bhagavatula
Saswata Lahiri
Lakshmana Rao Vadali
Swamy Saidugari
Veera Narayana Bandlamudi
Shankar Rama
Seshardi Rao Manukonda
Srinivasa Rao P. V.
Debashish Datta
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Matrix Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • the present invention relates to a novel process for the preparation of amorphous Dexlansoprazole from Dexlansoprazole solvate
  • the present invention also relates to novel processes for the preparation of polymorphic forms IV, Vl, amorphous, anhydrous and hemihydrate of dexlansoprazole BACKGROUND OF THE INVENTION
  • Benzimidazole compounds such as Lansoprazole, Omeprazole, Rabeprazole and the like have a proton pump inhibitor like activity such as gastric acid secretion suppressing effect and gastric mucosa defensive effect These compounds are used extensively as agents for the treatment of peptic ulcer
  • Lansoprazole chemically known as 2-[[[3-methyl-4- (2,2,2-t ⁇ fluoroethoxy)-2-pyr ⁇ d ⁇ nyl]methyl]sulf ⁇ nyl]-1 H-benz ⁇ m ⁇ dazole, is reported in Japanese Patent Application J P-A-61-50978, U S Pat No 4,628,098, JP-A-10-195068 and WO 98/21201 and has been recognized as the most potent antiulcer compound having superior activity It has more demand having world wide market
  • benzimidazole compounds mentioned herein have a sulfur atom which is asymmetrically substituted forming a chiral centre
  • WO92/8716 disclosed a pyr ⁇ dylmethylsulf ⁇ n ⁇ yl-1 H-benz ⁇ m ⁇ dazole compound which is enantiomerically pure, or a salt thereof and a process for producing the same WO 99/38513 disclosed a method of treating ulcers, etc which comprises administering an optically pure (R)-lansoprazole (herein after referred as 'Dexlansoprazole') or a pharmaceutically acceptable salt thereof
  • R optically pure
  • Dexlansoprazole represented by Formula (I)
  • Dexlansoprazole (R)-lansoprazole] or [(S)-lansoprazole] was disclosed in J P-A-11-508590 (WO 97/02261), US 7169799 and US 7285668.
  • US 6664276 disclosed the process for the preparation of amorphous Dexlansoprazole by dissolving racemic Lansoprazole in acetonitrile and fractionated by HPLC with the aid of a chiralcel column using mobile phase containing hexane/2-propanol/ethanol. The fractions of the optical isomers of shorter retention time were combined and concentrated. The individual lots were combined and dissolved in ethanol and filtered. Hexane is added and evaporated to dryness to yield amorphous Dexlansoprazole.
  • the US' 276 patent also disclosed the process for the preparation of Dexlansoprazole sesquihydrate by dissolving amorphous Dexlansoprazole in ethanol and water. The solution is seeded and allowed to stand at room temperature. Precipitated crystals were collected by filtration and dried to afford Dexlansoprazole sesquihydrate.
  • US 20060057195 disclosed the process for the preparation of amorphous Dexlansoprazole by keeping hydrated crystals of Dexlansoprazole at about 20° C to about 100° C.
  • US 7271182 disclosed crystalline sodium, lithium, potassium, magnesium, calcium and barium salts of Dexlansoprazole and processes for their preparation.
  • WO 2009088857 disclosed crystals of ethanol hydrate, isopropanol hydrate, hydrate, 1.0 hydrate, 1.5 hydrate, methanol solvate and ethanol solvate of Dexlansoprazole and processes for their preparation.
  • WO2009087672 disclosed stable amorphous Dexlansoprazole and a process for preparing the same by optically resolving racemic Lansoprazole by forming a reversible host-guest inclusion complex that includes a chiral guest molecule in the Lansoprazole lattice
  • WO2009113696 A1 disclosed anhydrous crystal of Dexlansoprazole and a process for preparing the same by heating amorphous Dexlansoprazole or solvate or hydrate crystal of Dexlansoprazole to not lower than about 71 0 C
  • the present invention relates to novel processes for preparation of amorphous and crystalline forms of Dexlansoprazole which are used in the pharmaceutical compositions
  • the present invention provides a novel process for the preparation of amorphous Dexlansoprazole by drying Dexlansoprazole solvate under reduced pressure at about 45°C
  • the present invention provides a process for the preparation of amorphous Dexlansoprazole by keeping crystalline Dexlansoprazole Form III or Form Vl in a desiccator in the presence of a dehydrating agent
  • the present invention provides a process for the preparation of amorphous Dexlansoprazole by keeping Dexlansoprazole Form Vl under reduced pressure
  • the present invention provides a novel process for the preparation of crystalline Dexlansoprazole Form IV comprising the steps of, a) dissolving Dexlansoprazole in isopropyl alcohol, b) adding an antisolvent, and c) isolating crystalline Dexlansoprazole Form IV
  • the present invention provides a novel process for the preparation of crystalline Dexlansoprazole Form Vl comprising the steps of; a) dissolving Dexlansoprazole in n-propanol, b) adding an antisolvent, and c) isolating crystalline Dexlansoprazole Form Vl.
  • the present invention provides a process for the preparation of anhydrous Dexlansoprazole by keeping crystalline Dexlanso
  • the present invention provides a process for the preparation of anhydrous Dexlansoprazole by keeping Dexlansoprazole Form IV under reduced pressure at a temperature of about 20-40° C for about 1 to 3 hours.
  • the present invention provides a novel process for the preparation of anhydrous Dexlansoprazole by removing water from Dexlansoprazole sesquihydrate.
  • the present invention provides a process for the preparation of Dexlansoprazole hemihydrate by keeping Dexlansoprazole sesquihydrate in a desiccator in the presence of a dehydrating agent.
  • the present invention relates to a novel process for the preparation of amorphous Dexlansoprazole from Dexlansoprazole solvate.
  • the present invention also relates to novel processes for the preparation of crystalline Dexlansoprazole Form IV and Form Vl.
  • the present invention further relates to novel processes for the preparation of amorphous, crystalline anhydrous and crystalline hemihydrate forms of Dexlansoprazole.
  • the present invention provides a process for the preparation of amorphous Dexlansoprazole comprising the steps of:
  • step b) drying the obtained compound in step b) under reduced pressure to get amorphous Dexlansoprazole.
  • crystalline Dexlansoprazole is dissolved in a mixture of alcohol and water, cooled to 5-1O 0 C for about an hour, the obtained solid is filtered to give crystalline Dexlansoprazole solvate
  • the obtained Dexlansoprazole solvate is dried at about 45 0 C under reduced pressure for 8-14 hrs to give amorphous Dexlansoprazole
  • the alcohol used for the dissolution of Dexlansoprazole is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol or terf-butanol, crystalline Dexlansoprazole solvate formed here is Dexlansoprazole alcohol hydrate and the Dexlansoprazole alcohol hydrate is Dexlansoprazole ethanol hydrate or Dexlansoprazole n- propanol hydrate or Dexlansoprazole methanol hydrate or Dexlansoprazole n-butanol hydrate or tert-butanol hydrate
  • the present invention provides a novel process for the preparation of amorphous Dexlansoprazole by drying Dexlansoprazole solvate under reduced pressure at about 45°C
  • Dexlansoprazole solvate is dried at about 45°C under reduced pressure for 8-14 hrs to give amorphous Dexlansoprazole
  • the present invention provides a process for the preparation of amorphous Dexlansoprazole by keeping crystalline Dexlansoprazole Form III or Form Vl in a desiccator in the presence of a dehydrating agent
  • amorphous Dexlansoprazole is prepared by keeping crystalline Dexlansoprazole Form III and Form Vl in a desiccator in the presence of a dehydrating agent at 25 to 35°C for about 5 days to about 24 hours respectively
  • the present invention provides a process for the preparation of amorphous Dexlansoprazole by keeping Dexlansoprazole Form Vl under reduced pressure
  • amorphous Dexlansoprazole is prepared by keeping Dexlansoprazole Form Vl for about 1 to 2 hours at 35 0 C under vacuum and slowly raised the temperature to 45 0 C and dried for about 1 to 3 hrs to give amorphous Dexlansoprazole
  • the present invention provides a process for the preparation of crystalline Dexlansoprazole Form IV comprising the steps of
  • Dexlansoprazole is dissolved in isopropyl alcohol To the clear solution is added to n-pentane and stirred for about an hour or two at room temperature The obtained solid is filtered and dried at ambient temperature to give crystalline Dexlansoprazole Form IV
  • the present invention provides a process for the preparation of novel crystalline Dexlansoprazole Form Vl comprising the steps of
  • Dexlansoprazole is dissolved in n-propanol and treated with carbon This solution is added to n-pentane which is pre-cooled to 0-5 0 C, stirred for about 1 hr at the same temperature, filtered and suck dried to give crystalline Dexlansoprazole Form Vl
  • the present invention provides a process for the preparation of anhydrous Dexlansoprazole by keeping crystalline Dexlansoprazole Form IV or Form V in a desiccator in the presence of a dehydrating agent
  • anhydrous Dexlansoprazole is prepared by keeping crystalline Dexlansoprazole Form IV or Form V in a desiccator in the presence of a dehydrating agent at 25 to 35°C for 15 hours to give anhydrous Dexlansoprazole
  • the present invention provides a process for the preparation of anhydrous Dexlansoprazole by keeping Dexlansoprazole Form IV under reduced pressure at a temperature of about 45° C for about 1 to 3 hours
  • the present invention provides a process for the preparation of anhydrous Dexlansoprazole by keeping Dexlansoprazole Form V under reduced pressure at a temperature of about 45°C for about 3 to 5 hours
  • anhydrous Dexlansoprazole is prepared by keeping Dexlansoprazole Form IV or Form V for about 1 to 2 hours at 35 0 C under vacuum and slowly raised the temperature to 45 0 C and dried for about 1 to 5 hrs to give anhydrous Dexlansoprazole
  • the present invention provides a process for the preparation of anhydrous Dexlansoprazole comprising the steps of,
  • Dexlansoprazole sesquihydrate is suspended in a solvent, stirred for about 5-15 mm, heated to reflux, azeotropic mixture is collected through dean-stark apparatus, reaction mass is cooled to room temperature, optionally added an antisolvent, the reaction mass is stirred for about 15-30 mm at the room temperature and the obtained solid is filtered to get anhydrous Dexlansoprazole
  • solvent used for the suspending Dexlansoprazole sesquihydrate is selected from dichloromethane, chloroform, hexane, heptane, cyclohexane, diethylether, dusopropylether or mixtures thereof and the antisolvent used is selected from hexane, heptane, cyclohexane, diethylether or dnsopropylether
  • suspend used herein may be dissolution, partially dissolution or undissolution
  • present invention provides a process for the preparation of anhydrous dexlansoprazole comprising the steps of,
  • Dexlansoprazole sesquihydrate is dissolved in a water miscible solvent, stirred for about 5-15 min, the solvent is removed to a minimal volume, preferably about 3 volumes of the solvent is removed by distillation under reduced pressure, the solution is cooled to room temperature, slowly added an antisolvent, the reaction mass is stirred for about 15-30 mm at room temperature, and the obtained solid is filtered to get crystalline anhydrous Dexlansoprazole
  • water miscible solvent is selected from acetonitrile, methanol, ethanol or isopropanol and the antisolvent is selected from diethyl ether, dnsopropylether, hexane, heptane or cyclohexane
  • the present invention provides a process for the preparation of Dexlansoprazole hemihydrate by keeping Dexlansoprazole sesquihydrate in a desiccator in the presence of a dehydrating agent
  • Dexlansoprazole sesquihydrate is kept in a desiccator in presence of a dehydrating agent at 25 to 35°C for 15 to 24 hours to give Dexlansoprazole hemihydrate
  • the dehydrating agent employed herein is selected from phosphorous pentoxide, manganese oxide, molecular sieves, calcium oxide, silica gel, anhydrous sodium hydroxide, calcium chloride, potassium carbonate and the like
  • Example 1 Preparation of amorphous Dexlansoprazole.
  • Dexlansoprazole (20Og) was dissolved in ethanol (385ml) and DM water (15ml) at 25-3O 0 C and heated to 40-45 0 C to get clear solution
  • the reaction mass was stirred at 40-45 0 C for about 10-15 mm and filtered the reaction mass through hi-flow bed
  • the filtrate thus obtained was cooled to 5-10° for about 45-60 mm, filtered the compound and spin dried at 25-3O 0 C for about 15-30 min to get Dexlansoprazole ethanol hydrate
  • the compound obtained was dried in vacuum oven at 4O 0 C for 12-14 hrs to obtain 135g of the title compound
  • Example 2 Preparation of amorphous Dexlansoprazole.
  • Dexlansoprazole (5Og) was dissolved in n-propanol (100ml) and DM water (3 7ml) at 25- 3O 0 C and heated to 40-45 0 C to get clear solution
  • the reaction mass was stirred at 40-45 0 C for about 10-15 mm and filtered the reaction mass through hi-flow bed
  • the filtrate thus obtained was cooled to 5-1O 0 C for about 45-60 mm, filtered the compound and spin dried at 25-3O 0 C for about 15-30 mm to get Dexlansoprazole propanol hydrate
  • the compound thus obtained was dried in vacuum oven at 4O 0 C for 12-14 hrs to obtain 18g of the title compound
  • Example 3 Preparation of amorphous Dexlansoprazole.
  • Dexlansoprazole Form III (5g) was kept in a desiccator for drying in presence of phosphorous pentoxide at 25 to 30°C for 5 days The resulted solid was identified as amorphous form of Dexlansoprazole
  • Example 4 Preparation of amorphous Dexlansoprazole.
  • Dexlansoprazole Form Vl (5g) was kept in a desiccator for drying in presence of phosphorous pentoxide at 25 to 30°C for 24 hours The resulted solid was identified as amorphous form of Dexlansoprazole
  • Example 5 Preparation of amorphous Dexlansoprazole.
  • Dexlansoprazole Form Vl (2 5g) was kept in a desiccator for drying in presence of 3A molecular sieve powder at 25 to 30 0 C for 16 hours under nitrogen atmosphere The resulted solid was identified as amorphous form of Dexlansoprazole (HPLC Purity > 99 95%)
  • Example 6 Preparation of amorphous Dexlansoprazole.
  • Dexlansoprazole Form Vl (2 5g) was kept in a desiccator for drying in presence of 4A molecular sieve powder at 25 to 30 0 C for 16 hours under nitrogen atmosphere The resulted solid was identified as amorphous form of Dexlansoprazole (HPLC Purity > 99 95%)
  • Example 7 Preparation of amorphous Dexlansoprazole.
  • Dexlansoprazole Form Vl (2Og) was dried for 1 to 2 hours at 30 0 C under vacuum and slowly the temperature was raised to 40 0 C and dried for 1 to 3 hours The solid was identified as amorphous form of Dexlansoprazole
  • Dexlansoprazole (1g) was dissolved in ethanol (5 ml) at 25-30°C The clear solution was added to heptane (50 ml) and maintained for 30-60 mm at 25-30°C with agitation The solid obtained was filtered and aerially dried at room temperature The product obtained was identified as Dexlansoprazole Form III
  • Dexlansoprazole (5g) was dissolved in isopropyl alcohol (20 ml) at 25 to 30°C The solution was filtered to remove the undissolved particulate material This clear solution was added to n-Pentane (200 ml) and stirred for 1 hour at 25 to 30 0 C The solid obtained was filtered and dried at ambient temperature The product was identified as Dexlansoprazole Form IV
  • Dexlansoprazole (2Og) was dissolved in n-propanol (80 ml) at 25 to 30 0 C 2g carbon was added to the above solution and stirred for 10 to 15 minutes at 25 to 30°C The solution was then filtered through hi-flow bed and washed with n-propanol (10 ml) In another flask, n- Pentane (900 ml) was cooled to 0 to 5°C The above reaction mixture was added to n- Pentane and stirred for 1hour at 0 to 5°C The solid obtained was filtered and suction dried The product was identified as Dexlansoprazole Form Vl Example 12: Preparation of anhydrous Dexlansoprazole.
  • Dexlansoprazole Form IV (2g) was kept in a desiccator for drying in presence of phosphorous pentoxide at 25 to 30 0 C for 15 hours. The resulted solid was identified as anhydrous form of Dexlansoprazole.
  • Dexlansoprazole Form IV (3g) was kept in oven at 40°C under vacuum for 1 to 3 hours. The resulting solid was identified as anhydrous Dexlansoprazole.
  • Example 14 Preparation of anhydrous Dexlansoprazole.
  • Dexlansoprazole Form V (3g) was kept in oven at 40°C under vacuum for 3 to 5 hours. The resulting solid was identified as anhydrous Dexlansoprazole.
  • Dexlansoprazole sesquihydrate (10g) was suspended in diisopropylether (300ml), stirred the reaction mass for about 10 min and heated the reaction mass to 70-75 0 C.
  • the azeotropic mixture (150ml) was collected by using dean stark apparatus.
  • the reaction mass was cooled to 25-3O 0 C and stirred for about 20 min at the same temperature, filtered the solid and washed with diisopropyl ether (10ml) to yield 8.8 g of the title compound.
  • Dexlansoprazole sesquihydrate (5Og) was suspended in cyclohexane (800ml) and dichloromethane (400ml), stirred the reaction mass for about 10 min and heated the reaction mass to 55-6O 0 C.
  • the azeotrope mixture (400ml) was collected by using dean stark apparatus.
  • the reaction mass was cooled to 25-3O 0 C and stirred for about 20 min at the same temperature. Filtered the solid and washed with cyclohexane (100ml) to yield 42 g of the title compound.
  • Example 17 Preparation of anhydrous Dexlansoprazole.
  • Dexlansoprazole sesquihydrate (10g) was suspended in dichloromethane (200ml), stirred the reaction mass for about 10 min and heated the reaction mass to 40-45 0 C.
  • the azeotrope mixture (180ml) was collected by using dean stark apparatus.
  • the reaction mass was cooled to 25-3O 0 C, cyclohexane (120ml) was added to the residue, stirred for about 20 min at the same temperature, filtered the solid and washed with cyclohexane (30ml) to yield 9 g of the title compound.
  • Dexlansoprazole sesquihydrate (5Og) was suspended in n-heptane (220ml), stirred the reaction mass for about 10 min and heated the reaction mass to 95-100 0 C.
  • the azeotrope mixture (50ml) was collected by using dean stark apparatus.
  • the reaction mass was cooled to 25-3O 0 C, stirred for about 20 min at the same temperature, filtered the solid and washed with n-heptane (20ml) to yield 9.1g of the title compound.
  • Dexlansoprazole sesquihydrate (10g) was suspended in n-heptane (180ml) and dichloromethane (20ml), stirred the reaction mass for about 10 min and heated the reaction mass to 65-7O 0 C.
  • the azeotrope mixture (20ml) was collected by using dean stark apparatus.
  • the reaction mass was cooled to 25-3O 0 C and stirred for about 20 min at the same temperature, filtered the solid and washed with n-heptane (20ml) to yield 9 g of the title compound.
  • Dexlansoprazole sesquihydrate (10g) was suspended in n-hexane (300ml), stirred the reaction mass for about 10 min and heated the reaction mass to 70-75 0 C.
  • the azeotrope mixture (150ml) was collected by using dean stark apparatus.
  • the reaction mass was cooled to 25-3O 0 C and stirred for about 20 min at the same temperature, filtered the solid and washed with n-hexane (10ml) to yield 9.0 g of the title compound.
  • Example 21 Preparation of anhydrous Dexlansoprazole.
  • Dexlansoprazole sesquihydrate (10g) was dissolved in acetonitrile (50ml) and stirred the reaction mass for about 10 min to get a clear solution.
  • the solvent was distilled off about 3 volumes under vacuum at 45 0 C.
  • the solution to was cooled to 20-25 0 C, diisopropylether (150ml) was added drop wise to the reaction mass and stirred for about 20 min at the same temperature, filtered the solid and washed with diisopropyl ether (10ml) to yield 8.5 g of the title compound.
  • Example 22 Preparation of Dexlansoprazole hemihydrate.
  • Dexlansoprazole sesquihydrate (2g) was kept in a desiccator for drying in presence of phosphorous pentoxide at 25 to 30 0 C for 15 to 24 hours.
  • the resulted solid was identified as Dexlansoprazole hemihydrate.
  • Example 23 Preparation of Dexlansoprazole hemihydrate.
  • Dexlansoprazole sesquihydrate (2g) was kept in a desiccator for drying in presence of 3A molecular sieve powder at 25 to 30°C for 16 hours under nitrogen atmosphere.
  • the resulted solid was identified as Dexlansoprazole hemihydrat ⁇ r
  • Example 24 Preparation of Dexlansoprazole hemihydrate.
  • Dexlansoprazole sesquihydrate (2g) was kept in a desiccator for drying in presence of 4A molecular sieve powder at 25 to 30 0 C for 16 hours under nitrogen atmosphere. The resulted solid was identified as Dexlansoprazole hemihydrate.

Abstract

The present invention relates to a novel process for the preparation of amorphous Dexlansoprazole formula (I): from Dexlansoprazole solvate. The present invention also relates to novel processes for the preparation of polymorphic forms IV, Vl, amorphous, anhydrous and hemihydrate forms of Dexlansoprazole.

Description

PROCESS FOR THE PREPARATION OF DEXLANSOPRAZOLE POLYMORPHIC FORMS
This Patent application claims priority from Indian Patent Applications 1436/CHE/2009 filed on Jun 18, 2009, 2408/CHE/2009 filed on Oct 5, 2009 and 359/CHE/2010 filed on Feb 15, 2010
FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of amorphous Dexlansoprazole from Dexlansoprazole solvate
The present invention also relates to novel processes for the preparation of polymorphic forms IV, Vl, amorphous, anhydrous and hemihydrate of dexlansoprazole BACKGROUND OF THE INVENTION
Benzimidazole compounds such as Lansoprazole, Omeprazole, Rabeprazole and the like have a proton pump inhibitor like activity such as gastric acid secretion suppressing effect and gastric mucosa defensive effect These compounds are used extensively as agents for the treatment of peptic ulcer
In the above mentioned benzimidazoles, Lansoprazole, chemically known as 2-[[[3-methyl-4- (2,2,2-tπfluoroethoxy)-2-pyrιdιnyl]methyl]sulfιnyl]-1 H-benzιmιdazole, is reported in Japanese Patent Application J P-A-61-50978, U S Pat No 4,628,098, JP-A-10-195068 and WO 98/21201 and has been recognized as the most potent antiulcer compound having superior activity It has more demand having world wide market
These benzimidazole compounds mentioned herein have a sulfur atom which is asymmetrically substituted forming a chiral centre WO92/8716 disclosed a pyrιdylmethylsulfιnιyl-1 H-benzιmιdazole compound which is enantiomerically pure, or a salt thereof and a process for producing the same WO 99/38513 disclosed a method of treating ulcers, etc which comprises administering an optically pure (R)-lansoprazole (herein after referred as 'Dexlansoprazole') or a pharmaceutically acceptable salt thereof Dexlansoprazole, represented by Formula (I), is less toxic and showed excellent antiulcer action, gastric acid secretion-inhibiting action, mucosa-protecting action, anti-Helicobacter pylori action, etc.,
Figure imgf000003_0001
Formula (I)
The method for producing Dexlansoprazole [(R)-lansoprazole] or [(S)-lansoprazole] was disclosed in J P-A-11-508590 (WO 97/02261), US 7169799 and US 7285668.
US 6664276 disclosed the process for the preparation of amorphous Dexlansoprazole by dissolving racemic Lansoprazole in acetonitrile and fractionated by HPLC with the aid of a chiralcel column using mobile phase containing hexane/2-propanol/ethanol. The fractions of the optical isomers of shorter retention time were combined and concentrated. The individual lots were combined and dissolved in ethanol and filtered. Hexane is added and evaporated to dryness to yield amorphous Dexlansoprazole.
The US' 276 patent also disclosed the process for the preparation of Dexlansoprazole sesquihydrate by dissolving amorphous Dexlansoprazole in ethanol and water. The solution is seeded and allowed to stand at room temperature. Precipitated crystals were collected by filtration and dried to afford Dexlansoprazole sesquihydrate.
US 20060057195 disclosed the process for the preparation of amorphous Dexlansoprazole by keeping hydrated crystals of Dexlansoprazole at about 20° C to about 100° C. US 7271182 disclosed crystalline sodium, lithium, potassium, magnesium, calcium and barium salts of Dexlansoprazole and processes for their preparation.
WO 2009088857 disclosed crystals of ethanol hydrate, isopropanol hydrate, hydrate, 1.0 hydrate, 1.5 hydrate, methanol solvate and ethanol solvate of Dexlansoprazole and processes for their preparation. WO2009087672 disclosed stable amorphous Dexlansoprazole and a process for preparing the same by optically resolving racemic Lansoprazole by forming a reversible host-guest inclusion complex that includes a chiral guest molecule in the Lansoprazole lattice WO2009113696 A1 disclosed anhydrous crystal of Dexlansoprazole and a process for preparing the same by heating amorphous Dexlansoprazole or solvate or hydrate crystal of Dexlansoprazole to not lower than about 710C
The above-mentioned conventional method for the production of Dexlansoprazole does not necessarily satisfy the purity, solubility, preservation stability and industrial viability
Moreover the prior art process involves heating upto 1000C wherein the possibility of forming impurities are more Thus there is a need for a better process for the preparation of
Dexlansoprazole having superior properties than the ones disclosed in the prior art Thus, the present invention relates to novel processes for preparation of amorphous and crystalline forms of Dexlansoprazole which are used in the pharmaceutical compositions
SUMMARY AND OBJECT OF THE INVENTION
In -one aspect, the present invention provides a novel process for the preparation of amorphous Dexlansoprazole by drying Dexlansoprazole solvate under reduced pressure at about 45°C
In another aspect, the present invention provides a process for the preparation of amorphous Dexlansoprazole by keeping crystalline Dexlansoprazole Form III or Form Vl in a desiccator in the presence of a dehydrating agent
In yet another aspect, the present invention provides a process for the preparation of amorphous Dexlansoprazole by keeping Dexlansoprazole Form Vl under reduced pressure In yet another aspect the present invention provides a novel process for the preparation of crystalline Dexlansoprazole Form IV comprising the steps of, a) dissolving Dexlansoprazole in isopropyl alcohol, b) adding an antisolvent, and c) isolating crystalline Dexlansoprazole Form IV In yet another aspect, the present invention provides a novel process for the preparation of crystalline Dexlansoprazole Form Vl comprising the steps of; a) dissolving Dexlansoprazole in n-propanol, b) adding an antisolvent, and c) isolating crystalline Dexlansoprazole Form Vl. In yet another aspect, the present invention provides a process for the preparation of anhydrous Dexlansoprazole by keeping crystalline Dexlansoprazole Form IV or Form V in a desiccator in the presence of a dehydrating agent.
In yet another embodiment, the present invention provides a process for the preparation of anhydrous Dexlansoprazole by keeping Dexlansoprazole Form IV under reduced pressure at a temperature of about 20-40° C for about 1 to 3 hours.
In yet another aspect, the present invention provides a novel process for the preparation of anhydrous Dexlansoprazole by removing water from Dexlansoprazole sesquihydrate.
In yet another embodiment, the present invention provides a process for the preparation of Dexlansoprazole hemihydrate by keeping Dexlansoprazole sesquihydrate in a desiccator in the presence of a dehydrating agent. DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel process for the preparation of amorphous Dexlansoprazole from Dexlansoprazole solvate. The present invention also relates to novel processes for the preparation of crystalline Dexlansoprazole Form IV and Form Vl. The present invention further relates to novel processes for the preparation of amorphous, crystalline anhydrous and crystalline hemihydrate forms of Dexlansoprazole.
In one embodiment, the present invention provides a process for the preparation of amorphous Dexlansoprazole comprising the steps of:
a) dissolving crystalline Dexlansoprazole in a mixture of alcohol and water,
b) cooling, isolating Dexlansoprazole solvate, and
c) drying the obtained compound in step b) under reduced pressure to get amorphous Dexlansoprazole. According to the present invention crystalline Dexlansoprazole is dissolved in a mixture of alcohol and water, cooled to 5-1O0C for about an hour, the obtained solid is filtered to give crystalline Dexlansoprazole solvate The obtained Dexlansoprazole solvate is dried at about 450C under reduced pressure for 8-14 hrs to give amorphous Dexlansoprazole
According to the present invention the alcohol used for the dissolution of Dexlansoprazole is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol or terf-butanol, crystalline Dexlansoprazole solvate formed here is Dexlansoprazole alcohol hydrate and the Dexlansoprazole alcohol hydrate is Dexlansoprazole ethanol hydrate or Dexlansoprazole n- propanol hydrate or Dexlansoprazole methanol hydrate or Dexlansoprazole n-butanol hydrate or tert-butanol hydrate
In another embodiment, the present invention provides a novel process for the preparation of amorphous Dexlansoprazole by drying Dexlansoprazole solvate under reduced pressure at about 45°C
According to the present invention, Dexlansoprazole solvate is dried at about 45°C under reduced pressure for 8-14 hrs to give amorphous Dexlansoprazole In yet another embodiment, the present invention provides a process for the preparation of amorphous Dexlansoprazole by keeping crystalline Dexlansoprazole Form III or Form Vl in a desiccator in the presence of a dehydrating agent
According to the present invention amorphous Dexlansoprazole is prepared by keeping crystalline Dexlansoprazole Form III and Form Vl in a desiccator in the presence of a dehydrating agent at 25 to 35°C for about 5 days to about 24 hours respectively
In yet another embodiment, the present invention provides a process for the preparation of amorphous Dexlansoprazole by keeping Dexlansoprazole Form Vl under reduced pressure
According to the present invention amorphous Dexlansoprazole is prepared by keeping Dexlansoprazole Form Vl for about 1 to 2 hours at 350C under vacuum and slowly raised the temperature to 450C and dried for about 1 to 3 hrs to give amorphous Dexlansoprazole In yet another embodiment, the present invention provides a process for the preparation of crystalline Dexlansoprazole Form IV comprising the steps of
a) dissolving Dexlansoprazole in isopropyl alcohol,
b) adding to an antisolvent, and
c) isolating crystalline Dexlansoprazole Form IV
According to the present invention Dexlansoprazole is dissolved in isopropyl alcohol To the clear solution is added to n-pentane and stirred for about an hour or two at room temperature The obtained solid is filtered and dried at ambient temperature to give crystalline Dexlansoprazole Form IV
In another embodiment, the present invention provides a process for the preparation of novel crystalline Dexlansoprazole Form Vl comprising the steps of
a) dissolving Dexlansoprazole in n-propanol,
b) adding to an antisolvent, and
c) isolating crystalline Dexlansoprazole Form Vl
According to the present invention Dexlansoprazole is dissolved in n-propanol and treated with carbon This solution is added to n-pentane which is pre-cooled to 0-50C, stirred for about 1 hr at the same temperature, filtered and suck dried to give crystalline Dexlansoprazole Form Vl
In yet another embodiment, the present invention provides a process for the preparation of anhydrous Dexlansoprazole by keeping crystalline Dexlansoprazole Form IV or Form V in a desiccator in the presence of a dehydrating agent
According to the present invention, anhydrous Dexlansoprazole is prepared by keeping crystalline Dexlansoprazole Form IV or Form V in a desiccator in the presence of a dehydrating agent at 25 to 35°C for 15 hours to give anhydrous Dexlansoprazole
In yet another embodiment, the present invention provides a process for the preparation of anhydrous Dexlansoprazole by keeping Dexlansoprazole Form IV under reduced pressure at a temperature of about 45° C for about 1 to 3 hours In yet another embodiment, the present invention provides a process for the preparation of anhydrous Dexlansoprazole by keeping Dexlansoprazole Form V under reduced pressure at a temperature of about 45°C for about 3 to 5 hours According to the present invention anhydrous Dexlansoprazole is prepared by keeping Dexlansoprazole Form IV or Form V for about 1 to 2 hours at 350C under vacuum and slowly raised the temperature to 450C and dried for about 1 to 5 hrs to give anhydrous Dexlansoprazole In yet another embodiment, the present invention provides a process for the preparation of anhydrous Dexlansoprazole comprising the steps of,
a) suspending Dexlansoprazole sesquihydrate in solvent,
b) removing water,
c) optionally adding an antisolvent, and
d) isolating anhydrous Dexlansoprazole
According to the present invention, Dexlansoprazole sesquihydrate is suspended in a solvent, stirred for about 5-15 mm, heated to reflux, azeotropic mixture is collected through dean-stark apparatus, reaction mass is cooled to room temperature, optionally added an antisolvent, the reaction mass is stirred for about 15-30 mm at the room temperature and the obtained solid is filtered to get anhydrous Dexlansoprazole
According to the present invention, solvent used for the suspending Dexlansoprazole sesquihydrate is selected from dichloromethane, chloroform, hexane, heptane, cyclohexane, diethylether, dusopropylether or mixtures thereof and the antisolvent used is selected from hexane, heptane, cyclohexane, diethylether or dnsopropylether
The term "suspend" used herein may be dissolution, partially dissolution or undissolution In yet another embodiment, the present invention provides a process for the preparation of anhydrous dexlansoprazole comprising the steps of,
a) dissolving Dexlansoprazole sesquihydrate in water miscible solvent,
b) removing water,
c) adding an antisolvent, and d) isolating crystalline anhydrous dexlansoprazole
According to the present invention, Dexlansoprazole sesquihydrate is dissolved in a water miscible solvent, stirred for about 5-15 min, the solvent is removed to a minimal volume, preferably about 3 volumes of the solvent is removed by distillation under reduced pressure, the solution is cooled to room temperature, slowly added an antisolvent, the reaction mass is stirred for about 15-30 mm at room temperature, and the obtained solid is filtered to get crystalline anhydrous Dexlansoprazole According to the present invention water miscible solvent is selected from acetonitrile, methanol, ethanol or isopropanol and the antisolvent is selected from diethyl ether, dnsopropylether, hexane, heptane or cyclohexane
In yet another embodiment, the present invention provides a process for the preparation of Dexlansoprazole hemihydrate by keeping Dexlansoprazole sesquihydrate in a desiccator in the presence of a dehydrating agent
According to the present invention, Dexlansoprazole sesquihydrate is kept in a desiccator in presence of a dehydrating agent at 25 to 35°C for 15 to 24 hours to give Dexlansoprazole hemihydrate
According to the present invention the dehydrating agent employed herein is selected from phosphorous pentoxide, manganese oxide, molecular sieves, calcium oxide, silica gel, anhydrous sodium hydroxide, calcium chloride, potassium carbonate and the like
The following examples are provided for illustrative purposes only and are not intended to limit the scope of the in any way
EXAMPLES
Example 1 : Preparation of amorphous Dexlansoprazole.
Dexlansoprazole (20Og) was dissolved in ethanol (385ml) and DM water (15ml) at 25-3O0C and heated to 40-450C to get clear solution The reaction mass was stirred at 40-450C for about 10-15 mm and filtered the reaction mass through hi-flow bed The filtrate thus obtained was cooled to 5-10° for about 45-60 mm, filtered the compound and spin dried at 25-3O0C for about 15-30 min to get Dexlansoprazole ethanol hydrate The compound obtained was dried in vacuum oven at 4O0C for 12-14 hrs to obtain 135g of the title compound
Example 2: Preparation of amorphous Dexlansoprazole.
Dexlansoprazole (5Og) was dissolved in n-propanol (100ml) and DM water (3 7ml) at 25- 3O0C and heated to 40-450C to get clear solution The reaction mass was stirred at 40-450C for about 10-15 mm and filtered the reaction mass through hi-flow bed The filtrate thus obtained was cooled to 5-1O0C for about 45-60 mm, filtered the compound and spin dried at 25-3O0C for about 15-30 mm to get Dexlansoprazole propanol hydrate The compound thus obtained was dried in vacuum oven at 4O0C for 12-14 hrs to obtain 18g of the title compound
Example 3: Preparation of amorphous Dexlansoprazole.
Dexlansoprazole Form III (5g) was kept in a desiccator for drying in presence of phosphorous pentoxide at 25 to 30°C for 5 days The resulted solid was identified as amorphous form of Dexlansoprazole
Example 4: Preparation of amorphous Dexlansoprazole.
Dexlansoprazole Form Vl (5g) was kept in a desiccator for drying in presence of phosphorous pentoxide at 25 to 30°C for 24 hours The resulted solid was identified as amorphous form of Dexlansoprazole
Example 5: Preparation of amorphous Dexlansoprazole.
Dexlansoprazole Form Vl (2 5g) was kept in a desiccator for drying in presence of 3A molecular sieve powder at 25 to 300C for 16 hours under nitrogen atmosphere The resulted solid was identified as amorphous form of Dexlansoprazole (HPLC Purity > 99 95%)
Example 6: Preparation of amorphous Dexlansoprazole.
Dexlansoprazole Form Vl (2 5g) was kept in a desiccator for drying in presence of 4A molecular sieve powder at 25 to 300C for 16 hours under nitrogen atmosphere The resulted solid was identified as amorphous form of Dexlansoprazole (HPLC Purity > 99 95%) Example 7: Preparation of amorphous Dexlansoprazole.
Dexlansoprazole Form Vl (2Og) was dried for 1 to 2 hours at 300C under vacuum and slowly the temperature was raised to 400C and dried for 1 to 3 hours The solid was identified as amorphous form of Dexlansoprazole
Example 8: Preparation of Dexlansoprazole Form III.
Dexlansoprazole (1g) was dissolved in ethanol (5 ml) at 25-30°C The clear solution was added to heptane (50 ml) and maintained for 30-60 mm at 25-30°C with agitation The solid obtained was filtered and aerially dried at room temperature The product obtained was identified as Dexlansoprazole Form III
Example 9: Preparation of Dexlansoprazole Form IV.
Dexlansoprazole (5g) was dissolved in isopropyl alcohol (20 ml) at 25 to 30°C The solution was filtered to remove the undissolved particulate material This clear solution was added to n-Pentane (200 ml) and stirred for 1 hour at 25 to 300C The solid obtained was filtered and dried at ambient temperature The product was identified as Dexlansoprazole Form IV
Example 10: Preparation of Dexlansoprazole Form V.
3g of Dexlansoprazole was suspended in pyridine (12 ml) at 25-300C and stirred for 15-20 mm to get the clear solution To this solution heptane (100 ml) added dropwise and maintained for 30-60 mm at 25-300C with agitation The solid obtained was filtered and washed with heptane (50 ml) The product obtained was identified as Dexlansoprazole Form V Example 11 : Preparation of Dexlansoprazole Form Vl.
Dexlansoprazole (2Og) was dissolved in n-propanol (80 ml) at 25 to 300C 2g carbon was added to the above solution and stirred for 10 to 15 minutes at 25 to 30°C The solution was then filtered through hi-flow bed and washed with n-propanol (10 ml) In another flask, n- Pentane (900 ml) was cooled to 0 to 5°C The above reaction mixture was added to n- Pentane and stirred for 1hour at 0 to 5°C The solid obtained was filtered and suction dried The product was identified as Dexlansoprazole Form Vl Example 12: Preparation of anhydrous Dexlansoprazole.
Dexlansoprazole Form IV (2g) was kept in a desiccator for drying in presence of phosphorous pentoxide at 25 to 300C for 15 hours. The resulted solid was identified as anhydrous form of Dexlansoprazole.
Example 13: Preparation of anhydrous Dexlansoprazole.
Dexlansoprazole Form IV (3g) was kept in oven at 40°C under vacuum for 1 to 3 hours. The resulting solid was identified as anhydrous Dexlansoprazole. Example 14: Preparation of anhydrous Dexlansoprazole.
Dexlansoprazole Form V (3g) was kept in oven at 40°C under vacuum for 3 to 5 hours. The resulting solid was identified as anhydrous Dexlansoprazole.
Example 15: Preparation of anhydrous Dexlansoprazole.
Dexlansoprazole sesquihydrate (10g) was suspended in diisopropylether (300ml), stirred the reaction mass for about 10 min and heated the reaction mass to 70-750C. The azeotropic mixture (150ml) was collected by using dean stark apparatus. The reaction mass was cooled to 25-3O0C and stirred for about 20 min at the same temperature, filtered the solid and washed with diisopropyl ether (10ml) to yield 8.8 g of the title compound.
Example 16: Preparation of anhydrous Dexlansoprazole.
Dexlansoprazole sesquihydrate (5Og) was suspended in cyclohexane (800ml) and dichloromethane (400ml), stirred the reaction mass for about 10 min and heated the reaction mass to 55-6O0C. The azeotrope mixture (400ml) was collected by using dean stark apparatus. The reaction mass was cooled to 25-3O0C and stirred for about 20 min at the same temperature. Filtered the solid and washed with cyclohexane (100ml) to yield 42 g of the title compound.
Example 17: Preparation of anhydrous Dexlansoprazole.
Dexlansoprazole sesquihydrate (10g) was suspended in dichloromethane (200ml), stirred the reaction mass for about 10 min and heated the reaction mass to 40-450C. The azeotrope mixture (180ml) was collected by using dean stark apparatus. The reaction mass was cooled to 25-3O0C, cyclohexane (120ml) was added to the residue, stirred for about 20 min at the same temperature, filtered the solid and washed with cyclohexane (30ml) to yield 9 g of the title compound.
Example 18: Preparation of anhydrous Dexlansoprazole.
Dexlansoprazole sesquihydrate (5Og) was suspended in n-heptane (220ml), stirred the reaction mass for about 10 min and heated the reaction mass to 95-1000C. The azeotrope mixture (50ml) was collected by using dean stark apparatus. The reaction mass was cooled to 25-3O0C, stirred for about 20 min at the same temperature, filtered the solid and washed with n-heptane (20ml) to yield 9.1g of the title compound.
Example 19: Preparation of anhydrous Dexlansoprazole.
Dexlansoprazole sesquihydrate (10g) was suspended in n-heptane (180ml) and dichloromethane (20ml), stirred the reaction mass for about 10 min and heated the reaction mass to 65-7O0C. The azeotrope mixture (20ml) was collected by using dean stark apparatus. The reaction mass was cooled to 25-3O0C and stirred for about 20 min at the same temperature, filtered the solid and washed with n-heptane (20ml) to yield 9 g of the title compound.
Example 20: Preparation of anhydrous Dexlansoprazole.
Dexlansoprazole sesquihydrate (10g) was suspended in n-hexane (300ml), stirred the reaction mass for about 10 min and heated the reaction mass to 70-750C. The azeotrope mixture (150ml) was collected by using dean stark apparatus. The reaction mass was cooled to 25-3O0C and stirred for about 20 min at the same temperature, filtered the solid and washed with n-hexane (10ml) to yield 9.0 g of the title compound.
Example 21 : Preparation of anhydrous Dexlansoprazole.
Dexlansoprazole sesquihydrate (10g) was dissolved in acetonitrile (50ml) and stirred the reaction mass for about 10 min to get a clear solution. The solvent was distilled off about 3 volumes under vacuum at 450C. The solution to was cooled to 20-250C, diisopropylether (150ml) was added drop wise to the reaction mass and stirred for about 20 min at the same temperature, filtered the solid and washed with diisopropyl ether (10ml) to yield 8.5 g of the title compound. Example 22: Preparation of Dexlansoprazole hemihydrate.
Dexlansoprazole sesquihydrate (2g) was kept in a desiccator for drying in presence of phosphorous pentoxide at 25 to 300C for 15 to 24 hours. The resulted solid was identified as Dexlansoprazole hemihydrate.
Example 23: Preparation of Dexlansoprazole hemihydrate.
Dexlansoprazole sesquihydrate (2g) was kept in a desiccator for drying in presence of 3A molecular sieve powder at 25 to 30°C for 16 hours under nitrogen atmosphere. The resulted solid was identified as Dexlansoprazole hemihydratβr
Example 24: Preparation of Dexlansoprazole hemihydrate.
Dexlansoprazole sesquihydrate (2g) was kept in a desiccator for drying in presence of 4A molecular sieve powder at 25 to 300C for 16 hours under nitrogen atmosphere. The resulted solid was identified as Dexlansoprazole hemihydrate.

Claims

WE CLAIM:
1. A process for the preparation of amorphous Dexlansoprazole comprising the steps of: a) dissolving Dexlansoprazole in a mixture of alcohol and water,
b) cooling, isolating Dexlansoprazole solvate, and
c) drying the obtained compound in step b) under reduced pressure to get amorphous Dexlansoprazole.
2. The process according to claim 1 , wherein said alcohol is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol or terf-butanol.
3. The process according to claim 1, wherein said Dexlansoprazole solvate is Dexlansoprazole alcohol hydrate.
4. The process according to claim 3, wherein said Dexlansoprazole alcohol hydrate is Dexlansoprazole ethanol hydrate, Dexlansoprazole n-propanol hydrate, Dexlansoprazole n-butanol hydrate, Dexlansoprazole isopropanol hydrate or Dexlansoprazole tert-butanol hydrate.
5. A process for the preparation of amorphous Dexlansoprazole comprises drying solvate crystals of Dexlansoprazole under reduced pressure.
6. The process according to claim 5, wherein said drying is carried out under vacuum at about 2O0C to about 450C.
7. A process for the preparation of amorphous Dexlansoprazole by keeping crystalline Dexlansoprazole in a desiccator in the presence of a dehydrating agent.
8. The process according to claim 7, wherein said crystalline Dexlansoprazole is crystalline Dexlansoprazole Form III or Form Vl.
9. A process for the preparation of amorphous Dexlansoprazole by keeping crystalline Dexlansoprazole Form Vl under reduced pressure at about 20-400C for about 1-3 hours.
10. A process for the preparation of crystalline Dexlansoprazole Form IV comprising the steps of:
a) dissolving Dexlansoprazole in isopropylalcohol,
b) adding to an antisolvent, and
c) isolating Dexlansoprazole Form IV.
11. A process for the preparation of crystalline Dexlansoprazole Form Vl comprising the steps of:
a) dissolving Dexlansoprazole in n-propanol,
b) adding to an antisolvent, and
c) isolating Dexlansoprazole Form Vl.
12. The process according to claim 10 and 11 , wherein said antisolvent is n-pentane or n- heptane.
13. A process for the preparation of anhydrous Dexlansoprazole by keeping crystalline Dexlansoprazole Form IV in a desiccator in presence of a dehydrating agent.
14. A process for the preparation of anhydrous Dexlansoprazole by keeping crystalline Dexlansoprazole Form IV or Form V under reduced pressure at about 20-400C.
15. A process for the preparation of anhydrous Dexlansoprazole comprising the steps of: a) suspending Dexlansoprazole sesquihydrate in solvent,
b) removing water,
c) optionally adding an antisolvent, and
d) isolating crystalline anhydrous Dexlansoprazole.
16. The process according to claim 15, wherein said solvent is selected from dichloromethane, chloroform, hexane, heptane, cyclohexane, diethylether, diisopropylether or mixtures thereof and the antisolvent is selected from hexane, heptane, cyclohexane, diethylether or diisopropylether.
17. The process according to claim 15, wherein water is removed by azeotropic mixture.
18. A process for the preparation of anhydrous Dexlansoprazole comprising the steps of: a) dissolving Dexlansoprazole sesquihydrate in a water miscible solvent,
b) removing water,
c) adding an antisolvent, and
d) isolating crystalline anhydrous Dexlansoprazole.
19. The process according to claim 18, wherein said water miscible solvent is selected from acetonitrile, methanol, ethanol or isopropanol and the antisolvent is selected from diethyl ether, diisopropylether, hexane, heptane or cyclohexane. -
20. The process according to claim 18, wherein water is removed by distillation under reducing pressure.
21. A process for the preparation of crystalline Dexlansoprazole hemihydrate by keeping Dexlansoprazole sesquihydrate in a desiccator in the presence of a dehydrating agent.
22. The process according to claims 7, 13 and 21 , wherein said dehydrating agent is selected from phosphorous pentoxide, manganese oxide, molecular sieves, calcium oxide, silica gel, anhydrous sodium hydroxide, calcium chloride or potassium carbonate.
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