|Title of Invention||
PROCESS AND INTERMEDIATES FOR PREPARATION OF DONEPEZIL HYDROCHLORIDE
|Abstract||The invention discloses new compounds of formula (III): wherein R is a C1-4 liner or branched alkyl group. The invention also discloses new compounds of formula (IV) where M is a metal. The invention further discloses methods of making compounds of formulas (III) and (IV) and methods of making donepezil and pharmaceutically acceptable salts thereof, such as donepezil hydrochloride, using these compounds.|
|Full Text||FORM 2
THE PATENT ACT 1970
(39 of 1970)
The Patents Rules, 2003
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"Process and intermediate for preparation of Donepezil hydrochloride"
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956 (c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008,
3.PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention.
Technical Field of the Invention
The present invention relates to new processs for the synthesis of acetylcholinesterase inhibitors. The invention additionally relates to novel synthetic intermediate used in this process and preparation thereof.
Background of the Invention
US Patent No. 4895841 discloses Donepezil hydrochloride (I), chemically known as (±)-2, 3-dihydro-5, 6-dimethoxy-2-[[l-(phenylmethyl)-4-piperdinyl] methyl] -lH-inden-1-one hydrochloride, as cyclic amine compounds.
Donepezil hydrochloride (I) is a reversible inhibitor of the enzyme acetylcholinesterase useful in the treatment of mild to moderate dementia of the Alzheimer's type disease. N-benzyl 4-formyl piperidine (II) is a key intermediate in the synthesis of donepezil.
Above intermediate (II) can be obtained by using (methoxymethyl) triphenyl phosphonium chloride as a reagent as disclosed in EP0206560 which is not only very
expensive but also reaction requires high cryogenic conditions. Another method such as disclosed in US Patent No. 4895841 employs pyridine-4-aldehyde in the synthesis of intermediate (II), which is followed by reduction of aromatic ring at last stage also involves very harsh reaction conditions.
There are many processes known in the art to prepare donepezil hydrochloride which are exemplified in patent applications such as WO2005076749; EP1531151 and WO2005003092.
No known references teaches or enables the process of the present invention involving use of novel synthetic intermediate for the synthesis of donepezil avoiding expensive cost and unfavorable reaction conditions; nor do the published references alone or in combination suggest these processes.
The present invention is novel and relates to synthesis of donepezil hydrochloride using a novel synthetic intermediate. Thus, the object of the present invention is to provide a simple and industrially viable process for the synthesis of donepezil hydrochloride using a novel intermediate.
Brief Description of the Invention
The present invention relates to a process for preparing Donepezil hydrochloride (I) using a novel intermediate.
In one aspect, the present invention provides a new process for the synthesis of Donepezil hydrochloride (I), which is synthesized through a key intermediate N-benzyl 4-formyl piperidine (II) which is further prepared via novel intermediate of formula (III)
where R = C1-C4 alkyl chain, liner or branched. The process involves use of cheaper and readily available commercial reagents which makes the process industrially economical with high yield and purity of Donepezil hydrochloride (I).
In another aspect, the present invention provides a new and efficient process for synthesizing N-benzyl 4-formyl piperidine (II) using a novel intermediate of formula (III).
In yet another aspect, the present invention provides a novel synthetic intermediate, glycidic esters of the Formula (III) and process for preparation thereof. The process involves reaction of N-benzyl 4-piperidone with X-CH2COOR1 where X = chloro, bromo, iodo and R = C1-C4 alkyl chain, linear or branched, in a suitable solvent and in presence of base. The base is selected from a group comprising sodium methoxide, sodium ethoxide, sodium amide, n-butyl Lithium, lithium di-isopropyl amide (LDA) etc. or mixtures thereof. The solvent employed for this reaction is selected from benzene, toluene, xylenes, dioxane or THF or mixtures thereof.
The glycidic ester is further converted into the metal salt, preferably sodium, of glycidic acid (IV) in a suitable organic solvent, in presence of a base.
The sodium salt of the glycidic acid (IV) is then converted into the N-benzyl 4-formyl piperidine (II) in the presence of any aqueous acid at a temperature range of about 25 -
90° C, which is further reacted with 5, 6-dimethoxy indanone. The resulted product is reduced with palladium on carbon to get Donepezil hydrochloride (I).
The following examples illustrate specific aspects of the present invention. The examples are not intended to limit the scope of the invention in any of the aspects.
Preparation of l-Benzvl-5 epoxy-5-q- carbethoxy piperidine.
To a 500 ml flask fitted with a nitrogen inlet and CaC12 guard tube, 300 ml of dry toluene was added. To this, was added a mixture of 100 g (0.529 mol) N-benzyl 4-piperidone and 65.0 g (0.53 mol) ethyl chloroacetate. The contents were chilled to 10° C and sodium amide 31.0 g (0.793 mol) was added in lots over a period of 2h with the temperature maintained between 10 -15°C. Once the addition was over, the contents were warmed to room temperature (22°C) and stirred for 2h. The reaction mass was slowly poured into a beaker filled with crushed ice and extracted into 500 ml ethyl acetate. The organic layer was washed with 3 portions of 400 ml water with the last portion containing 6 ml acetic acid. The organic layer was dried over anhydrous sodium sulphate and then concentrated under vacuum to yield 102.0 g of the crude glycidic ester (70% yield), which was used as such for further step without any purification.
Preparation of sodium salt of l-benzyl-5 epoxy piperidine 5- carboxylic acid. The glycidic ester from Example 1 was slowly poured into a 15° C solution of sodium methoxide in alcohol and then warmed to room temperature (22°C) and stirred overnight to obtain a solid. The solid was filtered off under vacuum and washed with 50 ml ethanol, followed by 50 ml diethyl ether. The off-white solid weighed 88.0 g (85%).
Preparation of N-benzyl 4-formyl piperidine
The sodium salt from example 2 was dissolved in 250 ml water containing 50 ml HC1 and
heated to reflux temperature (95° C) and maintained for 2 hours. The reaction mass was
then cooled to 15° C with the aid of ice - water and liquor ammonia slowly added to the solution to render the pH alkaline. The contents were extracted into 300 ml dichloro methane, washed with water and dried over anhydrous sodium sulphate. The organic layer was concentrated under vacuum to yield yellow coloured oil. 45 g (68% yield).
Preparation of 1-Benzyl -4- [(5, 6 dimethoxy-l-indanon)-2-ylidenylmethyl piperidine To a solution of l.Og of 5, 6 dimethoxy indanone dissolved in 25ml THF, 0.562 g of sodium methoxide was added. The reaction contents were heated to 60°C and maintained for 30 min before cooling to 10°C. A solution of 1.1 g of N-benzyl 4-formyl piperidine dissolved in 25ml THF was then added drop-wise over a period of 30 min keeping the temperature less than 10°C. After complete addition, the reaction was slowly warmed to 25-30°C and stirred for 3h. The reaction mass was quenched in cold water and extracted with 100ml of ethyl acetate. The organic layer was washed with 2 X 100ml water and 100ml of sodium chloride solution and dried over anhydrous sodium sulphate. The organic layer was concentrated under vacuum to obtain an off-white solid (1.4g, 71% yield).
Preparation of 1-Benzyl -4- [(5, 6 dimethoxy-1-indanoyl)-2-yl) methyl -piperidine l. 0g of 1-Benzyl -4- [(5, 6 dimethoxy-1-indanon)-2-ylidenylmethyl piperidine was dissolved in 50 ml of ethanol and 100 mg of 10% palladium on carbon added to it. The reaction mass was subjected to l0 psi hydrogen pressure for lh. The catalyst was then filtered off and the filtrate was concentrated to residue, which was dissolved in 100ml of ethyl acetate and cooled to 15°C further 10ml conc. HCl was added and the resulting solid filtered, washed with diethyl ether and dried under vacuum. The solid weighed 0.9g ( 81% yield)
Preparation of 1-Benzyl -4- [(5, 6 dimethoxy-1-indanoyl)-2- yl) methyl -piperidine hydrochloride (Donepezil hydrochloride)
Step-a - 1 -Benzyl 4-epoxy-4-a-carboxyethyl piperidine
A solution of 1kg of N-benzyl 4-piperidone and 648g of ethyl chloro acetate in 3L of toluene were cooled to 10°C and 310g of sodamide was added portionwise over a period of 1.5h. After completion of addition the reaction mass was warmed to 25-30°C and stirred for 3hrs. The reaction mass was poured into a beaker containing crushed ice and extracted into 5L of ethyl acetate. The ethyl acetate layer was washed with 3X2. 5L of water containing 60ml of acetic acid. The organic layer is then washed with 2.5L of brine solution and dried over anhydrous sodium sulphate. The organic layer was concentrated under vacuum to yield a yellow colored oil weighed 1 kg.
Step-b - Sodium salt of 1-Benzyl 4-epoxy-4-a-carboxyethyl piperidine 1 kg of step-a product was dissolved in 500ml of 95% ethanol and slowly added to a cold solution of 235g of sodium methoxide in 500ml of 95% ethanol. After the addition, the solution was warmed to 25-30 °C and stirred overnight to obtain a white solid which was filtered and suck-dried. Yield 785g.
Step-c - N-benzyl 4-formyl piperidine
785g of step-b product was dissolved in 2.3L of water and 418ml of conc.HCl added to it slowly. The mixture was refluxed for 1.5h and then cooled to 15 °C and liq.NH3 added to it till pH=8.5-9.0. The contents were extracted into 2.5L of chloroform and washed with water and brine. The organic layer was dried over sodium sulphate and concentrated to obtain light yellow oil (88.5gm)
Step-d - 1-Benzyl -4- [(5, 6 dimethoxy-l-indanon)-2- ylidenylmethyl piperidine 78.5g of 5,6 dimethoxy indanone was dissolved in 500ml of THF and 66g of sodium methoxide added to it. The mixture was heated to 60°C and kept for 30-45min before cooling to 5°C. 88.5g of step-d product was dissolved in 500ml of THF and added drop-wise over a period of 30 min with temperature maintained 5-10°C. Once the addition was over, the reaction mixture was warmed to room temperature and stirred for 3h. The reaction mass was poured into cold water and extracted into 2.5L of ethyl acetate, washed
with water and then with brine The organic layer was dried with sodium sulphate and concentrated to obtain a solid (109g)
Step-e - 1-Benzyl -4- [(5, 6 dimethoxy-l-indanoyl)-2- yl] methyl -piperidine hydrochloride
109g of Step-d product was dissolved in 95% ethanol and 11g of 10% palladium on carbon added to it. The mixture was hydrogenated at l0 psi for lh. The catalyst was then filtered off and the filtrate concentrated to residue, the residue was dissolved in 500ml of ethyl acetate and cooled to 10°C. Conc.HCl was then added to precipitate a solid. The resulting solid was filtered and dried to get l00g of 1-Benzyl -4- [(5, 6 dimethoxy-1-indanoyl)-2- yl] methyl -piperidine hydrochloride.
Having described the objects of the invention with reference to the examples it is to be understood that the examples and descriptions herein are proffered by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof. Any person skilled in the art could effect various changes and modifications without departing from the spirit or scope of the present invention.
Dr. Gopakumar G. Nair Agent for the Applicant
Dated this 4th day of January 2006
|Indian Patent Application Number||17/MUM/2006|
|PG Journal Number||10/2013|
|Date of Filing||04-Jan-2006|
|Name of Patentee||CIPLA LIMITED|
|Applicant Address||289, BELLASIS ROAD, MUMBAI CENTRAL, MUMBAI-400 008|
|PCT International Classification Number||C07D211/32|
|PCT International Application Number||N/A|
|PCT International Filing date|