WO2009084030A2 - Improved process for the preparation of (1-benzyl-4-(5,6,- dimethoxyind anone-2-yl)methylpiperidine) hydrochloride-form iii - Google Patents
Improved process for the preparation of (1-benzyl-4-(5,6,- dimethoxyind anone-2-yl)methylpiperidine) hydrochloride-form iii Download PDFInfo
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- WO2009084030A2 WO2009084030A2 PCT/IN2008/000805 IN2008000805W WO2009084030A2 WO 2009084030 A2 WO2009084030 A2 WO 2009084030A2 IN 2008000805 W IN2008000805 W IN 2008000805W WO 2009084030 A2 WO2009084030 A2 WO 2009084030A2
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- benzyl
- indanone
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- hydrochloride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
Definitions
- US2004229914 discloses polymorphic form VI of donepezil hydrochloride and process for preparation thereof which comprises of dissolving donepezil free base obtained form patent 1847/CHE/2007 under process at the patent office in suitable alcoholic solvent at 60-65 0 C and treated with hydrochloric acid or hydrogen chloride at 25-3O 0 C to form crystalline form VI which is further treated with etheral solvent at 25-3O 0 C for 5-10 hr s to give Form VI.
- FIGURE I XRD for anhydrous Donepezil hydrochloride Form III
- FIGURE II DSC for anhydrous Donepezil hydrochlonde Form III
- FIGURE III IR Spectrum for anhydrous Donepezil hydrochloride Form III
- the condensation is carried out in organic solvent, selected from a group of halogenated organic solvent such as methylene chloride, ethylene chloride or chloroform; most preferably methylene chloride.
- organic solvent selected from a group of halogenated organic solvent such as methylene chloride, ethylene chloride or chloroform; most preferably methylene chloride.
- the ketonic organic solvent used is selected from acetone, methyl ethyl ketone, most preferably acetone.
Abstract
The present invention is directed to an improved industrially viable, cost effective process for manufacturing pure racemic crystalline anhydrous form of (1-benzyl-4-(5,6,- dimethoxyindanone-2yl)methylpiperidine) hydrochloride Form III commonly known as Donepezil hydrochloride with a purity level of greater than 99.9%.
Description
IMPROVED PROCESS FOR THE PREPARATION OF (l-BENZYL-4-(5,6,- DIMETHOXYIND ANONE-2- YL)METHYLPIPERIDINE) HYDROCHLORIDE-FORM III
Technical field of invention
The present invention is directed to an improved industrially viable, cost effective process for manufacturing pure racemic crystalline anhydrous form of (l-benzyl-4-(5,6,- dimethoxyindanone-2-yl)methylpiperidine) hydrochloride Form III commonly known as Donepezil hydrochloride with a purity level of greater than 99.9%.
Background of invention
Donepezil hydrochloride (1 -Benzyl-4-(5,6,-dimethoxyindanone-2-yl-)-methylpiperidine) hydrochloride of Formula-I
Formula-I belongs to a group of selective acetylcholine esterase inhibitor used for the treatment of mild to moderate Alzheimer's disease. Donepezil hydrochloride is a white crystalline powder. It is freely soluble in chloroform, water, glacial acetic acid, slightly soluble in ethanol, acetonitrile and insoluble in ethyl acetate and n-hexane.
US 5985864 disclose polymorphic form II, IV and V of donepezil hydrochloride and process of preparation thereof which comprises recrystallising donepezil hydrochloride in suitable solvent. The desired form can also be obtained by dissolving donepezil hydrochloride in suitable solvent and precipitating the desired form by addition of an antisolvent alternatively donepezil free base is dissolved in suitable solvent and treated with hydrochloric acid or hydrogen chloride or by humidifi cation of any form to give the desired form.
US6140321 discloses polymorphic form III of donepezil hydrochloride and process for preparation thereof which comprises of recrystallizing donepezil hydrochloride Form I or by dissolving donepezil hydrochloride form II in suitable solvent and precipitating the desired form by
addition of an antisolvent. Alternatively donepezil free base is dissolved in suitable solvent and treated with hydrochloric acid or hydrogen chloride or by humidification of any form to give desired form III.
US2004229914 discloses polymorphic form VI of donepezil hydrochloride and process for preparation thereof which comprises of dissolving donepezil free base obtained form patent 1847/CHE/2007 under process at the patent office in suitable alcoholic solvent at 60-650C and treated with hydrochloric acid or hydrogen chloride at 25-3O0C to form crystalline form VI which is further treated with etheral solvent at 25-3O0C for 5-10 hr s to give Form VI.
WO2002026709 discloses polymorphic form III of donepezil HCl by dissolving donepezil in ethanol and adding hydrochloric acid to get the desired form.
WO2004092137 discloses the polymorphic crystalline form Hl, H2 monohydrate and amorphous form thereof.
Its apparent from most of the prior art that, the preparation of donepezil has certain disadvantages such as the use of hazardous raw materials like lithium diisopropyl amine and n- butyllithium, costly raw materials like platinum oxide, unviable reaction conditions like temperature below -800C and low yields i.e. 62%. Therefore, there is a continuing need for developing a new process for the manufacturing of racemic donepezil and salt thereof which is cost effective and industrially viable.
Summary of the invention
The present invention describes an industrially viable process for manufacturing substantially pure racemic mixture of (l-benzyl-4-(5,6,-dimethoxyindanone-2-yl-)- methylρiperidine)hydrochloride Form III from donepezil free base form D, with a purity level of greater than 99.9% .
The process comprises of reacting 5, 6-dimethoxy-l-indanone with l-benzyl-4-piperidine carboxaldehyde followed by reduction to give solid crystalline Form D of Donepezil which is further converted to racemic crystalline form of Donepezil hydrochloride form III (Scheme VII).
Scheme VII
5,6-Dιmethoxy-1 -indanone 1 -Benzylpipeπdine-4 1-Benzyl-4-(5,6-dιmetrioxy-1-ιndanon)-2-
-carboxaldehyde ylidenyl methyl pipeπdine hydrochlonde
reduction
Racemic free base- Donepezil Donepezil Hydrochlonde Form D
Racemic Donepezil Hydrochlonde Form III
Another aspect of the present invention is to provide a racemic, crystalline, substantially pure form of donepezil hydrochlonde form III with a HPLC purity level of greater than 99.9% with impurity level of less than 0.1%.
Description of the figures
FIGURE I: XRD for anhydrous Donepezil hydrochloride Form III FIGURE II: DSC for anhydrous Donepezil hydrochlonde Form III FIGURE III: IR Spectrum for anhydrous Donepezil hydrochloride Form III
Detailed description of the invention
The present invention provides an improved process for the preparation of l-Benzyl-4-(5, 6 dimethoxy-l-indaiione)-2-yl-) methylpiperidine hydrochlonde Fonn III, which comprises of following steps:
a) Condensation of 5, 6-dimethoxy-l-indanone with l-benzyl-4-piperidine carboxaldehyde using a base selected from a group consisting of metal hydroxide like sodium hydroxide, potassium hydroxide; metal carbonates like potassium carbonate, sodium bicarbonate or metal alkoxide like sodium methoxide, sodium ethoxide, potassium sec-butoxide or potassium ter. butoxide b) addition of water after reaction completion followed by neutralization with suitable acid c) separation of the organic layer and treatment with activated carbon d) acidification of the organic layer with isopropanolic hydrogen chloride and removal of solvent by distillation e) dissolving the residue in a suitable alcoholic solvent and addition of suitable ketonic solvent to precipitate crystalline solid form of l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-ylidinyl) methyl piperidine hydrochloride f) reduction of the compound obtained from the step e above with suitable metal catalyst under pressure below 3 kg/cm2 in a suitable organic solvent/s, filtration of the residue and removal of the solvent by distillation g) dissolving the residue in a suitable halogenated organic solvent followed by neutralization with a suitable base, separation of the organic layer and treatment with activated carbon h) acidification of the organic layer with isopropanolic hydrogen chloride and removal of solvent by distillation i) dissolving the residue in a suitable alcoholic solvent and suitable ketonic organic solvent to precipitate crude donepezil hydrochloride j) dissolving donepezil hydrochloride, obtained form above in a mixture of purified water and an organic solvent, adjusting the pH to basic with a suitable base, isolation of compound, washing with water and drying to obtain racemic l-Benzyl-4-(5, 6 dimethoxy-1-indanone)-
2-yl) methyl piperidine, donepezil form D k) dissolving crystalline donepezil form D obtained from the step j above in a suitable organic solvent and treatment with activated carbon 1) Acidification of the organic layer with isopropanolic hydrogen chloride and removal of solvent by distillation followed by swapping with a suitable alcoholic solvent.
m) Isolating racemic l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-yl) methyl piperidine hydrochloride (Donepezil hydrochloride Form III) by addition of suitable ketonic solvent in the solvent layer obtained from the step I above.
Or
a. Dissolving donepezil form D obtained as per the procedure given in 1847/CHE/2007 in a suitable organic solvent and treatment with activated carbon b. Acidification of the organic layer with isopropanolic hydrogen chloride and removal of solvent by distillation followed by swapping with a suitable alcoholic solvent. c. Isolating racemic l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2~yl) methyl piperidine hydrochloride (Donepezil hydrochloride form III) by addition of suitable ketonic solvent in the solvent layer obtained from the step b above.
The base used for condensation was dissolved in a suitable alcoholic solvent such as methanol, ethanol or isopropanol; most preferably methanol.
The condensation is carried out in organic solvent, selected from a group of halogenated organic solvent such as methylene chloride, ethylene chloride or chloroform; most preferably methylene chloride.
The neutralization of the reaction mixture as in step b is carried using hydrochloric acid.
The alcoholic solvent used in the step e is selected from methanol, ethanol and isopropanol; most preferably methanol.
The ketonic organic solvent used is selected from acetone, methyl ethyl ketone; most preferably acetone.
The reduction of l-benzyl-4(5,6-dimethoxy-l-indanone)-2-ylidene methyl piperidine hydrochloride is carried out in the presence of Raney nickel or palladium on carbon in an organic solvent or mixture thereof at different ratios in suitable solvent selected from ethanol, methanol and isopropanol, acetic acid or mixture thereof; most preferably mixture at acetic acid and methanol at various ratios
The organic solvent used for reduction is selected from methanol, ethanol, isopropanol or acetic acid or mixture thereof, most preferably mixture of acetic acid with methanol in 1 : 1 ratio.
The reduction is carried under pressure below 3kg/cm ; most preferably 1.5 to 2kg/cm .
The neutralization of the reduced compound as in step g, is carried out in the presence of suitable base selected from sodium bicarbonate, potassium bicarbonate and like.
The basification of the compound as in stepj is carried out in the presence of suitable aqueous base selected from sodium hydroxide, potassium hydroxide and like.
The organic solvent used in step k is selected from a group consisting of halogenated organic solvent such as methylene chloride, ethylene chloride or chloroform most preferably methylene chloride.
The alcoholic solvents used in the stepj is selected from methanol, ethanol and isopropanol; most preferably methanol.
The ketonic organic solvent used is selected from acetone, methyl ethyl ketone, most preferably acetone.
The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.
Examples
Step 1: Preparation of l-Benzyl-4-(5, 6 Dimethoxy-l-indanone)-2-ylidinyl) methyl piperidine hydrochloride.
To 5,6-dimethoxy-l- indanone (10Og) in methylene chloride (1000ml) was added 1-benzyl piperidine-4-carboxaldehyde (150.0 g) and the reaction mixture was stirred for 15 minutes at 25- 30°C for dissolution. The reaction mixture was cooled to 0-50C and to it was added potassium hydroxide dissolved in methanol solution (48.0 g in 200 ml methanol) in a period of 30-60 minutes and stirred for 30 minutes at 0-50C. The temperature of the reaction mass was raised to 25-300C and the stirring continued for 2 hours. The reaction was monitored by thin layer chromatography for absence of 5, 6-dimethoxy-l -indanone. After the completion of the reaction purified water (30OmL) was added and the mixture was stirred for 15 minutes. The pH of the reaction mass was adjusted to 6.5-7.5 with concentrated hydrochloric acid at 25-300C and stirred for 30 minutes. The
layers were separated and the organic layer was extracted with methylene chloride. The methylene chloride layer was washed with purified water, treated with activated carbon (5g) and filtered. The pH of the filtrate was acidified to <2.0 with isopropanolic hydrochloride. The organic layer was distilled under vacuum, methanol (200.OmL) was added to the residue and stirred for 15 minutes followed by the addition of acetone (100OmL) and the stirring was continued for 3 hours at 25- 30°C. The compound was filtered and washed with acetone, to the wet cake was added methanol (200.OmL) and the mixture was stirred for 15 minutes followed by the addition of acetone (600.OmL) and stirring was continued for 3 hours. The mixture was filtered, washed with acetone (200.OmL) and dried at 60-650C to obtain the title compound, f Dry weight: 195.g)(% Yield: 91.3%)
Step 2: Preparation ofracenήc mixture of substantially pure crystalline solid form of Donepezil. l-Benzyl-4-(5, 6 Dimethoxy-l-indanone)-2-ylidinyl) methyl piperidine hydrochloride (50.0g) obtained form the step 1 above was taken in a mixture of acetic acid (650.0ml) and methanol (650.0 ml) and stirred at 25-30°C for 15 minutes. The reaction content was heated to 40-450C for complete dissolution cooled to 25-30°C and to it was added 5% Pd-C(50% wet) (2.5g) and was hydrogenated under 1.5-2.0 Kg/cm2 pressure. The reaction mixture was filtered and the solvent was distilled under vacuum below 600C, cooled to 25-300C. The residue was taken in methylene chloride (50OmL) and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution (50g Na2CO3 in 500 mL of purified water), the organic layer was separated and the aqueous layer was extracted with methylene chloride, both the methylene chloride layers were combined, washed with water, treated with activated carbon(5.0g) and filtered. The pH of the filtrate was acidified to <2.0 with isopropanolic hydrochloride at 25-30°C. The solvent was distilled under vacuum below 400C and cooled to 25-300C, methanol (55OmL) was added to the residue, stirred for 10 minutes followed by the addition of acetone (25OmL) and the stirring was continued for 3 hours at 25-30°C, the compound was filtered and washed with acetone. To the wet compound was added purified water (8OmL) and methanol (24OmL) and content was stirred at 25-300C for 15 minutes for complete dissolution. The pH is adjusted to 12.5-13 with 20% sodium hydroxide solution (20.OmL) and stirred for 5 minutes at 25-300C followed by further addition of purified water (60OmL) and the stirring was continued for 2 hrs at 25-300C. The compound was filtered, washed with purified water (5OmL) and dried for 30 minutes to yield crystalline racemic donepezil free base. (Dry weight: 37 g, HPLC: 99.5 %, % Yield: 80%)
Step 3: Preparation ofracemic mixture of substantially pure crystalline solid of Donepezil Hydrochloride Form III
Donepezil(35g) free base obtained from the step 2 above was taken in methylene chloride (35OmL) and stirred for complete dissolution and was treated with activated carbon(1.75g) and filtered, the pH of the filtrate was adjusted to <2.0 with isopropanolic hydrochloride at 25-30°C and the organic layer was distilled and swapped with methanol (175mL). The residue was dissolved in methanol (35OmL) and to it was added acetone (700ml) to crystallize Form III of Donepezil hydrochloride, the crystals were filtered and washed with acetone (7OmL) and dried to get hydrochloride salt of Donepezil Form III. (Dry weight: 32g, HPLC: 99.9 %, % Yield: 85%)
Claims
1. An improved process for industrial manufacture of l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2- ylidinyl)methyl piperidine hydrochloride or Donepezil Hydrochloride form III comprising of :
a. Condensation of 5,6-dimethoxy-l-indanone with l-benzyl-4-piperidine carboxaldehyde using a base selected from a group consisting of metal hydroxide like sodium hydroxide, potassium hydroxide; metal carbonates like potassium carbonate, sodium bicarbonate or metal alkoxide like sodium methoxide, sodium ethoxide, potassium sec-butoxide or potassium ter. butoxide dissolves in methanol, ethanol or isopropanol carried out in halogenated organic solvent selected from group comprising of methylene chloride, ethylene chloride or chloroform most preferably methylene chloride. b. Addition of water after reaction completion followed by neutralization with suitable acid, most preferably using hydrochloric acid c. Separation of the organic layer and treatment with activated carbon d. Acidification of the organic layer with isopropanolic hydrogen chloride and removal of solvent by distillation e. Dissolving the residue in a suitable alcoholic solvent selected from a group comprising of methanol, ethanol and isopropanol and addition of suitable ketonic solvent to precipitate crystalline solid form of l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-ylidinyl) methyl piperidine hydrochloride f. Reduction of the compound obtained from the step e above with suitable metal catalyst under pressure below 3kg/cm2 in a suitable organic solvent/s, filtration of the reaction completion and removal of the solvent by distillation g. Dissolving the residue in a suitable halogenated solvent selected from a group comprising of methylene chloride, ethylene chloride or chloroform most preferably methylene chloride, followed by neutralization with a suitable base selected from group comprising of sodium hydroxide, potassium hydroxide, sodium bicarbonate and potassium bicarbonate and separation of the organic layer and treatment with activated carbon h. Acidification of the organic layer with isopropanolic hydrogen chloride and removal of solvent by distillation
i. Dissolving the residue in a suitable alcoholic solvent elected from a group comprising of methanol, ethanol and isopropanol and suitable ketonic organic solvent to precipitate the solid j. Dissolving the compound obtained form the step i above in a mixture of purified water and an organic solvent, adjusting the pH to basic with a suitable base, isolation of compound, washing with water and drying to obtain racemic l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-yl) methyl piperidine(donepezil free base) in a substantially pure form. k. Dissolving donepezil free base in a suitable organic solvent and treatment with activated carbon
1. Acidification of the organic layer with isopropanolic hydrogen chloride and removal of solvent by distillation followed by swapping with a suitable alcoholic solvent m. Isolating racemic l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-yl) methyl piperidine hydrochloride (Donepezil hydrochloride) by addition of suitable ketonic solvent in the solvent layer obtained form the step I above.
2. An improved process for industrial manufacture of l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2- ylidinyl) methyl piperidine i.e. hydrochloride form III comprising: a) dissolving donepezil form D obtained as per the procedure given in 1847/CHE/2007 in a suitable organic solvent and treatment with activated carbon b) acidification of the organic layer with isopropanolic hydrogen chloride and removal of solvent by distillation followed by swapping with a suitable alcoholic solvent. c) isolating racemic l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-yl) methyl piperidine hydrochloride (Donepezil hydrochloride) by addition of suitable ketonic solvent in the solvent layer obtained form the step b above.
3. The process for industrial manufacture of l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-ylidinyl) methyl piperidine according to claim 1 and 2, wherein the reduction of 1 -benzyl -4(5,6- dimethoxy-l-indanone)-2-ylidene methyl piperidine hydrochloride is carried out in the presence of Raney nickel or palladium on carbon in an organic solvent selected from a group comprising of ethanol, methanol and isopropanol, acetic acid or mixture thereof; most preferably mixture at acetic acid and methanol at various ratios most preferably methanol: acetic acid in 1:1 ratio
4. The process for industrial manufacture of 1 -Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-ylidinyl) methyl piperidine according to claim 1 and 2, wherein the reduction is carried out under pressure below 3 Kg/cm2, preferably between 1.5 to 2 Kg/cm2.
5. The process for industrial manufacture of l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-ylidinyl) methyl piperidine according to claim 1 and 2, wherein the solvent used for dissolving donepezil is selected from a group comprising of halogenated organic solvent such as methylene chloride, ethylene chloride or chloroform most preferably methylene chloride.
6. The process for industrial manufacture of l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-ylidinyl) methyl piperidine according to claim 1 and 2, wherein solvent used for swapping is solvent selected from a group comprising of ethanol, methanol and isopropanol most preferably methanol.
7. The process for industrial manufacture of l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-ylidinyl) methyl piperidine according to claim 1 and 2, wherein ketonic solvent used is selected from acetone, methyl ethyl ketone, most preferably acetone.
8. Substantially pure anhydrous crystalline racemic form III of l-Benzyl-4-(5, 6 dimethoxy-1- indanone)-2-ylidinyl) methyl piperidine hydrochloride with a purity level of greater than 99.9%.
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| Application Number | Priority Date | Filing Date | Title |
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| IN2863CH2007 | 2007-12-03 | ||
| IN2863/CHE/2007 | 2007-12-03 |
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| WO2009084030A2 true WO2009084030A2 (en) | 2009-07-09 |
| WO2009084030A3 WO2009084030A3 (en) | 2011-03-17 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011061591A1 (en) | 2009-11-18 | 2011-05-26 | Jubilant Life Sciences Limited | Improved process for the preparation of 1-benzyl-4-(5,6-dimethoxy-1-indanone)-2-yl)methyl piperidine hydrochloride form-iii |
| US7994328B2 (en) | 2006-02-16 | 2011-08-09 | Aurobindo Pharma Ltd. | Process for the preparation of donepezil hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997046526A1 (en) * | 1996-06-07 | 1997-12-11 | Eisai Co., Ltd. | Stable polymorphs of donepezil (1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine) hydrochloride and process for production |
| EP1323712A1 (en) * | 2000-09-25 | 2003-07-02 | Eisai Co., Ltd. | Process for producing multiform crystal of donepezil hydrochloride |
-
2008
- 2008-12-02 WO PCT/IN2008/000805 patent/WO2009084030A2/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997046526A1 (en) * | 1996-06-07 | 1997-12-11 | Eisai Co., Ltd. | Stable polymorphs of donepezil (1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine) hydrochloride and process for production |
| EP1323712A1 (en) * | 2000-09-25 | 2003-07-02 | Eisai Co., Ltd. | Process for producing multiform crystal of donepezil hydrochloride |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7994328B2 (en) | 2006-02-16 | 2011-08-09 | Aurobindo Pharma Ltd. | Process for the preparation of donepezil hydrochloride |
| WO2011061591A1 (en) | 2009-11-18 | 2011-05-26 | Jubilant Life Sciences Limited | Improved process for the preparation of 1-benzyl-4-(5,6-dimethoxy-1-indanone)-2-yl)methyl piperidine hydrochloride form-iii |
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| WO2009084030A3 (en) | 2011-03-17 |
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