AN IMPROVED INDUSTRIAL PROCESS FOR THE SYNTHESIS OF A KEY INTERMEDIATE OF DONEPEZIL

The present invention relates to an improved, highly economical and environment-friendly process and protocol for the industrial manufacture of 5,6-dimethoxy-indan-l-one of formula (III), a key intermediate required for the preparation of l-benzyl-4-[(5,6-dimethoxyindan-l-on-2-yl)methyl] piperidine (formula I), also known as Donepezil. In view of the

(RS)-2-[(l-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-l-one

(RS)-2-[(l-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-l-one

5,6 dimthoxy-1-indenone N-benzyl-4-formy;-piperidine

highly favorable and growing clinical acceptance of Donepezil for the treatment and management of Alzheimer's disease, it is imperative there should be robust, scalable and cost-effective methods to build the key synthons (III) and (IV).

Donepezil was first disclosed by Eisai, Japan, in EP 296560 and US 4895841. Its synthesis, as taught by the patent is shown in Scheme 1 and may be termed as the most widely used synthetic technology for donepezil. The intermediates III and IV are coupled through base mediated aldolization, subsequent dehydration and finally controlled hydrogenation of the enone moiety II to furnish donepezil (III).

The innovator's patent mentions the synthon III is commercially available and is prepared by following the reaction sequence described in Scheme 2.

Specifically, it is made by a five stage reaction sequence comprising of the following steps (1) conversion of vanillin to veratraldehyde (2) aldolization and dehydration to afford the unsaturated acid VI (3) hydrogenation to give rise to 3-(3,4-dimethoxyphenyl)-propionic acid (V) and finally (4) conversion of the acid to acid chloride and then subjecting this acid chloride to aluminum chloride mediated intramolecular Friedel Craft acylation which furnishes the bi cyclic 1-indanone.

In all available prior art, the formation of the C-C bond has been accomplished by Knovenagel reaction of veratraldehyde with malonic acid and a base. This is a rather expensive proposition for industrial scale, since malonic acid is costly and there are inconvenient operational issues involved. The Friedel Craft reaction requiring hazardous materials like thionyl chloride and aluminum chloride is also complicated a phenomenon and can be best avoided if it can be. In all it can be said the prior art methods reported to prepare synthon I are tedious and low yielding ones.

In sharp contrast much work has gone into developing facile methods for preparation of the other synthon IV. This may perhaps be due to the difficulty associated with coexistence of the formyl function and nitrogen hetero atom. However this does not imply efforts in this direction be to the neglect of formation of the formula (III) through a sequence of reactions that is economical, scalable and environmentally benign..

Although 3,4-dimethoxy cinnamic acid is well known in literature, no single method or protocol is found which will be appropriate for making a structure of formula (III), the key intermediate for preparing donepezil. Preparation of 3,4-dimethoxycinnamic acid by treatment of veratraldehyde with ethyl acetate over P205 is described by H.J, Harwood et.al.in J. Am. Chem. Soc., 1933, 55 (6), 2555-2559. Use of sodium methoxide to effect the aldol reaction of ethyl acetate enolate with veratraldehyde has also been mentioned in US4618698. and in Org. Synthesis, Collective Volume I,p 252,1941, wherein the authors used metallic sodium and ethanol to get 3,4-dimethoxycinnamic acid ethyl ester. However in most cases complete information on quality and yield is not clearly mentioned.

SUMMARY OF THE PRESENT INVENTION

The present invention describes one of probably the very best sequence of three reactions starting from veratraldehyde and the corresponding protocol wherein each step is not only economical and scalable to any extent but is also highly environment friendly. Scheme 3 shows the complete sequence as achieved in laboratory and commercial scale.

Use of polyphosphoric acid (PPA) for Friedel Craft acylation, in particular intra molecular one, is well known, however so far we could not come across any reference where this reagent has been used for the final cyclization to furnish structure of formula (III). Only one Chinese reference of April 2010 could be extracted wherein the authors have reportedly used PPA in the last step, e.g., GUANGZHOU CHEMICAL INDUSTRY. Years, the volume (of): 201 038 (4), Chemical Industry Author: Lin Yu Peg Xinsheng Bishop Hall, Author: Guangdong Medical College, Department of Medicinal Chemistry and Drug points, Guangdong, Dongguan, 523808. However in this route the authors use NaBH4 + 10% HCl for reducing the double bond of 3, 4-dimethoxy cinnamic acid and they have given a cautionary note against the high risk involved.

The route of synthesis described in Scheme -III is possibility the most cost effective, operationally easy, very less hazardous one which can be scaled up to ton quantity. The polyphosphoric acid can be used in ratios of 5 to 10 % (w/w) and the mixture is freely strirrable in SS reactors using overhead agitators having fixed anchor blades at 72 -90 rpm.

EXAMPLES

The examples mentioned below are indicative of the results we got in carrying out the reactions sequence and the scope there of, but they are in no way limited to the specific examples described herein.

Example 1

Preparation of 3,4-dimethoxycinnamic acid

Under a nitrogen blanket, sodium metal (23g, 1.00 mole) in pieces, were taken in 210 ml of dry methanol in a 2 liter four necked round bottom flask fitted with a mechanical stirrer, thermometer pocket, dropping funnel and reflux condenser and the mixture was then stirred at 55C for 30 minutes. A mixture of veratraldehyde (100g,0.60 mole) and ethyl acetate (716.Ig, 8.18 mole) was added drop wise at 60-62C over a period of Ih. The mixture was stirred for six hours and excess ethyl acetate and was distilled off together with methanol up to an overhead temperature of 65C. Water (448 ml) was added and the mixture was again distilled up to an overhead temperature of 91C. Subsequently KOH (549.42g,1.76 moles, 18% in water) was added drop wise at a bottom temperature of 90-95C and the mixture was refluxed for 6h. The mixture was treated with 2.50g of activated carbon, filtered, pH brought to 3.0 by 48% sulfuric acid at 70C when the cinnamic acid precipitated out. The product was filtered under suction at 20C, washed with 3 X 210 ml of water and dried. 5,6-Dimethoxy cinnamic acid was obtained (120g, 96% yield, melting range 177 - 180°C.

Example 2

Preparation of 3,4-dimethoxycinnamic acid from veratraldehyde

Sodium methoxide (120g, 30% solution in methanol) was taken in a 2 liter round bottom flask equipped as in Example 1 under a stream of nitrogen. A mixture of veratraldehyde (lOOg, 0.6 mole) and ethyl acetate (7.72 mole, 680g) was added drop wise at 35 -40C over a period of Ih. The mixture was stirred at 60C for 6h, The excess ethyl acetate and methanol were distilled off maintaining an overhead temperature of 60C, 286 ml of water was added and the mixture was distilled again with an overhead temperature of 90C. The rest of the process was same as described in Example 1 following which was obtained 5,6-dimethoxycinnamic acid (117g, 93% yield, melting range 178 - 180C).

Example 3

Preparation of 3-(3,4-dimethoxyphenyl)-propionic acid

The acid (40kg, 192.3 moles) and 400 liters of ethyl acetate were placed in a hydrogenator and the mixture was stirred. Moist palladium on carbon (5% mounted) was added (2kg, @5% w/w of the acid) and stirring of the mixture was started under 1.5 atmosphere at 150 rpm with slow increase of the temperature to 50C. After the hydrogenation was completed as revealed by in-process TLC analysis, the catalyst was filtered off on plate filtering the liquors in a reactor and the ethyl acetate was evaporated under reduced pressure. The product was filtered under suction at 20C, washed with 2 x 50 liters of n-hexane and dried. 3-(3,4-dimethoxyphenyl)-propionic acid was obtained (39.0Kg, 97% yield ,melting range 96-98°C).

Example 4

Preparation of 5,6-Dimethoxy-indan-l-one

The acid (100 g, 0.476 moles) and of polyphosphoric acid(500 g) were taken in a 2 liter four necked round bottom flask equipped as in Example 1 and the mixture was then stirred at 70-90°C for 60 minutes. Reaction was completed as revealed by in-process TLC analysis and quenched with ice. The product was isolated by extraction with 3 x 0,5 liters of ethyl acetate, and the combined the organic layer was washed with saturated sodium bicarbonate and filtered under reduced pressure at 20°C, Subsequent washing with 0.2 liter of n-hexane and drying furnished 5,6-Dimethoxy- indan-l-one (80 g, 97% yield ,melting range 118-120°C).

CLAIMS

1. We are claiming an extremely efficient, less hazardous and economic way of making the structure having formula (III), a key intermediate for the preparation of donepezil.

2. The said process comprises a protocol of converting veratraldehyde into 3,4- dimethoxy cinnamic acid using ethyl acetate sodium enolate to furnish 3,4-dimethoxy cinnamic acid (IV).

3. The compound of structure (IV) is subjected to catalytic hydrogenation under very mild conditions to afford the 3-(3,4- dimethoxyphenyl)-propionic acid.(structure of formula V).

4. The structure V thus obtained is subjected to intramolecular acylation using just polyphosphoric acid and the said reaction furnishes the structure having formula (III), a key intermediate for making donepezil.

5. We also claim such a sequence of reactions has not so far been performed in the art of organic synthesis to synthesize 5,6-dimethoxy indan-l-one.