CZ2006102A3 - Process for preparing 1-benzyl-4-(5,6-dimethoxyindan-1-on-2-yl)methylpiperidine (donepezil free base) of high purity - Google Patents

Abstract

Process for preparing 1-benzyl-4- (5,6-dimethoxyindan-1-on-2-yl) methylpiperidine (donepezil free base) of formula I by hydrogenation of 1-benzyl-4 - [(5,6-dimethoxy-1-indanone) ) -2-ylidene] methylpyridinium bromide of formula IV in the presence of a platinum-on-charcoal catalyst. 1-Benzyl-4- (5,6-dimethoxyindan-1-on-2-yl) -methylpiperidine (donepezil free base) of Formula I is liberated to give 1-benzyl-4- (5,6-dimethoxyindan-1-one) -2-yl) -methylpiperidine hydrobromide (donepezil hydrobromide) of formula (V) by treatment with aqueous ammonia.

Description

Process for preparing 1-benzyl-4- (5,6-dimethoxyindan-1-one-2-yl) -methylpiperidine (donepezil free base) of high purity

Technical field:

The invention relates to a process for the preparation of 1-benzyl-4- (5,6-dinethoxymdan-1-one-2-yl) methylpiperidine (donepezil free base) of formula (I) of high purity. Donepezil is a reversible, non-competitive inhibitor of acetylcholinesterase with a high degree of selectivity for the central form of the enzyme and low affinity for peripheral forms of acetylcholinesterase.

BACKGROUND OF THE INVENTION:

German patent document DE 4439822 (US 5606064) describes the preparation of donepezil starting from 5,6-dimethoxy-1-indanone of formula (II)

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MeO.

(Π) and its reaction with pyridine-4-carbaldehyde to prepare 5,6-dimethoxy-2- (4-pyridyl) methylene-1-indanone of formula (III),

subsequent reaction with benzyl bromide to prepare 1-benzyl-4 - [(5,6-dimethoxy-lindanone) -2-ylidene] methylpyridinium bromide of formula (IV),

which, by hydrogenation with 10% by weight of Adams catalyst (pure PtO ₂ ), gives the free base of donepezil. Although the entire range of hydrogenation catalysts is mentioned in the claims, only the Adams catalyst used in a relatively large amount of 10% is mentioned in the examples. The overall yield of the hydrogenator thus described is 58% th.

A similar preparation of donepezil is described in WO 99/36405, where only the preparation of 5,6-dimethoxy-2- (4-pyridyl) methylene-lindanone (III) is different. Adams catalyst in an amount of 10% by weight is also used for the hydrogenation. The total yield described is 77% th.

The use of an Adams catalyst for hydrogenation results in admixtures of hardly removable by-products. When using an Adams catalyst to a certain degree of hydrogenation, pure product is formed, but hydrogenation is not possible until complete conversion (only 50-60%) and the non-hydrogenated starting material and the mixture of non-hydrogenated intermediates are difficult to remove by conventional methods. When the hydrogenation is carried out to complete conversion using the Adams catalyst, other by-products are formed which, like the non-hydrogenated products, cannot be easily removed by conventional techniques.

A disadvantage of these processes is therefore the use of a large amount of catalyst and the formation of a wide range of by-products which are difficult to remove in order to obtain a product suitable for use in pharmaceutical preparations.

SUMMARY OF THE INVENTION

These disadvantages are overcome by the process according to the invention, which is a process for the preparation of 1-benzyl-4- (5,6-dimethoxyindan-1-one-2-yl) methylpiperidine (donepezil free base) of formula (I)

hydrogenation of 1-benzyl-4 - [(5,6-dimethoxy-1-indanone) -2-ylidene] methyl-pyridinium bromide of formula (IV),

It is an object of the invention that the hydrogenation is carried out in the presence of a platinum-on-carbon catalyst.

The platinum on activated carbon catalyst for hydrogenation is used with a platinum content of 0.1 to 10% by weight in the dry or wet state and the amount of catalyst used is 0.1 to 5% by weight.

The hydrogenation is divided into two phases, the first of which is methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, t-butanol and the second phase a solvent mixture the corresponding alcohol (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, t-butanol) and water, with a water content of between 5 and 50% by volume, but usually between 10 and 20%.

The hydrogenation is carried out at a hydrogen pressure in the range from 1 to 10 bar, but usually from 0.2 to 4 bar.

The hydrogenation is carried out at a temperature in the range of 20 to 80 ° C, but usually in the range of 50 to 60 ° C.

• * 4

-benzyl-4- (5,6-dimethoxyindan-1-one-2-yl) -methylpiperidine (donepezil free base) of formula (I) is liberated from the resulting 1-benzyl-4- (5,6-dimethoxyindan-1-one); on-2-yl) -methylpiperidine hydrobromide (donepezil hydrobromide) of formula (V)

by treatment with aqueous ammonia in ethanol, which subsequently crystallizes from ethanol-water.

The advantages of the proposed method according to the present invention are as follows:

- the platinum on activated carbon catalyst used in an amount of 0.1 to 5% by weight is considerably more advantageous compared to the prior art (for example, I compare 10 g of Adams catalyst with 8.59 g platinum, for the same amount of 10 g platinum on activated carbon catalyst) (5% platinum, 50% water) contains 0.25 g platinum);

possibility to use the platinum catalyst on activated carbon repeatedly;

the platinum-on-carbon catalyst, in combination with the solvent mixture used in the hydrogenation, results in a pure product with no admixtures of difficult-to-remove hydrogenation by-products, and at the same time the reaction can be conducted up to 100% conversion;

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the yield of the pure product is considerably higher compared to the prior art.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a process for the preparation of 1-benzyl-4- (5,6-dimethoxyindan-1-one-2-yl) methylpiperidine (donepezil free base) of formula (I) of high purity.

The feedstock for the hydrogenation of 1-benzyl-4 - [(5,6-dimethoxy-1-indanone) -2-ylidene] methylpyridinium bromide of formula (IV) is prepared by standard two-step synthesis from 5,6-dimethoxy-1-indanone of formula (II) by condensation with 4-pyridine-carbaldehyde to give 5,6-dimethoxy-2- (4-pyridyl) methylene-lindanone of formula (III) followed by reaction with benzyl bromide.

The resulting 1-benzy 1-4 - ((5,6-dimethoxy-1-indanone) -2-ylidene) methylpyridinium bromide of formula (TV) is hydrogenated with hydrogen in the presence of a platinum catalyst (platinum content 0.1 to 10%) to activated carbon in an amount of 0.1 to 5% by weight, in the first phase in an alcohol suspension (from a series of alcohols methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, t-butanol) at hydrogen pressure 0 After this initial hydrogenation phase, water is added to the reaction mixture to dissolve the formed precipitated product and allow subsequent hydrogenation to be completed under the same conditions, after concentration and crystallization to obtain pure 1-benzyl. -4- (5,6-Dimethoxyindan-1-one-2-yl) -methylpiperidine hydrobromide (donepezil hydrobromide) of formula (V) in high yield.

The resulting 1-benzyl-4- (5,6-dimethoxy indan-1-one-2-yl) -methylpiperidine hydrobromide (donepezil hydrobromide) of formula (V) is suspended in ethanol and sequentially. · AAA

AA AA 44 AAAA 44 4 The addition of aqueous ammonia liberates 1-benzyl-4- (5,6-dimethoxyindan-1-one-2-yl) methylpiperidine (donepezil free base) of formula (I), which crystallizes from the reaction mixture.

The thus prepared 1-benzyl-4- (5,6-dimethoxyindan-1-one-2-yl) methylpiperidine (donepezil free base) of formula (I) is of high purity and is suitable for the preparation of donepezil hydrochloride useful in pharmaceutical preparations.

· · «·» · »·» · Φ · φ · · Φ · · · · ·

Preparation of 1-benzyl-4- (5,6-dimethoxyindan-1-one-2-yl) methylpiperidine (donepezil free base)

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Examples:

The principles of the process according to the invention are illustrated in more detail in the following examples. These examples are illustrative only and in no way limit the scope of the invention.

Example 1

Preparation of 5,6-dimethoxy-2- (4-pyridyl) methylene-1-indanone of formula IIH

Method:

Dissolve 5,6-Dimethoxy-1-indanone of formula (II) (4.0 kg) in toluene (621), add p-toluenesulfonic acid monohydrate (4.16 kg) and add 4-pyridinecarboxaldehyde (2.34) kg). The resulting mixture is heated to quark and the reaction water is removed from the azeotropic cap (approx. 6 hours).

The reaction mixture was cooled to 15-20 ° C and basified with a solution of sodium hydroxide (0.9 kg) in water (70 L). The resulting dense, light yellow mixture was cooled to 10-15 ° C and stirred for one hour. The product is filtered off with suction, washed with water (101) and dried to constant weight.

Yield: 5.8 kg, i.e. 99% th. (calculated on the starting 5,6-dimethoxy-1-indanone) • ··· • · · · · φφφφφφφφφφφ

Example 2

Preparation of 1-Benzyl-4- (6,6-dimethoxy-1-indanone) -4-ylidenemethylpyridinium bromide of formula (IV)

Method:

5,6-Dimethoxy-2- (4-pyridyl) methylene-1-indanone of formula (III) (5.0 kg) is suspended in acetonitrile (801) and the suspension is heated to reflux. Benzyl bromide (3.19 kg) was added dropwise. The reaction mixture was refluxed for 4 hours.

After 4 hours, the mixture was cooled to 15-20 ° C and stirred for 1 hour.

The product was filtered off with suction and washed with cooled acetonitrile (20 L). The yellow product was dried to constant weight.

Yield: 7.88 kg, i.e. 98% th. (calculated from the starting 5,6-dimethoxy-2- (4-pyridyl) methylene-1-indanone)

Example 3.

Preparation of 1-Benzyl-4- (5,6-dimethoxyindan-1-one-2-yl) -methylpiperidine (donepezil free base) of formula (I)

Method:

1-Benzyl-4 - [(5,6-dimethoxy-1-indanone) -2-ylidene] methylpyridinium bromide of formula (IV) (5.0 kg) was charged into the autoclave and ethanol (2001) was added. After stirring, the platinum-on-carbon catalyst (0.05 kg, -5% Pt, water content 50%, 1.25 g 100% Pt) is suspended in the autoclave mixture. The mixture in the autoclave is heated to about 60 ° C. After closing, the autoclave was purged three times with nitrogen and three times with hydrogen and pressurized to 50 psi with hydrogen. Hydrogenation is carried out at a pressure of 0.26 to 0.36 MPa at 60 ° C for 5 hours.

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4 4 · 4 · · · 4

44 * 4 4 4 4 4

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A suspension begins to form and must be dissolved with water to complete the hydrogenation.

The hydrogenation was discontinued, the autoclave was vented and purged with nitrogen and water (20 L) was added for hydrogenation. The autoclave is closed again, purged three times with nitrogen and three times with hydrogen, and pressurized with hydrogen to a pressure of 0.5 bar. Hydrogenation sp is further carried out at a pressure of 0.20 to 0.30 MPa at 60 ° C for 8 hours.

The reaction mixture from the autoclave was filtered from the catalyst and washed with ethanol (321). The filtrate was concentrated in vacuo to a residue.

The resulting 1-Benzyl-4- (5,6-dimethoxyindan-1-one-2-yl) methylpiperidine hydrobromide (donepezil hydrobromide) was suspended in ethanol (601) and ammonia (0.61) was added dropwise with stirring. The product was concentrated and recrystallized from ethanol-water.

The crystal is filtered off with suction and washed with 0-5 ° C ethanol-water (101) and dried at 50 ° C.

Yield 3.77 kg, i.e. 94% th.

Example 4

Preparation of 1-Benzyl-4- (5,6-dimethoxyindan-1-one-2-yl) -methylpiperidine (donepezil free base) of formula (I)

The procedure of Example 3, but using methanol instead of the ethanol solvent.

Yield: 84% th.

Example 5

Preparation of 1-Benzyl-4- (5,6-dimethoxyindan-1-one-2-yl) methylpiperidine (donepezil free base) of formula (I).

The procedure of Example 3, but 1-propanol was used in place of the ethanol solvent. Yield: 70% th.

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4 ··· · 4 4 4 · · 4 4 4 · 4

4 · 4 4 4

444 ·· 44 4443 * 4 »4

Example 6

Preparation of 1-Benzyl-4- (5,6-dimethoxyindan-1-one-2-yl) -methylpiperidine (donepezil free base) of formula (I).

The procedure of Example 3 was followed but using 2-propanol instead of the ethanol solvent. Yield: 79% th.

Example 7

Preparation of 1-Benzyl-4- (5,6-dimethoxyindan-1-one-2-yl) methylpiperidine (donepezil free base) of formula (II).

The procedure of Example 3, but 1-butanol was used instead of ethanol solvent. Yield: 59% th.

Example 8

Preparation of 1-Benzyl-4- (5,6-dimethoxyindan-1-one-2-yl) -methylpiperidine fdonepezil free base) of formula (I).

The procedure of Example 3, but using 2-butanol instead of the ethanol solvent. Yield: 72% th.

Example 9

Preparation of 1-Benzyl-4- (5,6-dimethoxyindan-1-one-2-yl) methylpiperidine (donepezil free base) of formula (I)

The procedure of Example 3 was followed, but instead of ethanol solvent, t-butanol was used. Yield: 65% th.

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Example 10

Preparation of 1-Benzyl-4- (5,6-dimethoxyindan-1-one-2-yl) methylpiperidine hydrochloride (donepezil)

Method:

-Benzy 1-4- (5,6-dimethoxyindan-1-one-2-yl) -methylpiperidine (donepezil free base) of formula (I) (3.3 kg) was suspended in ethanol (42 L) and stirred with stirring. The mixture was heated to 50-60 ° C and stirred until the suspension was dissolved. Activated carbon (0.15 kg) was added to the solution, which was filtered and washed with methanol (4.01) after stirring warm.

The filtrate was cooled to 20-25 ° C and an ethanolic hydrogen chloride solution was added dropwise to pH 4-5 and the mixture was stirred for one hour to form a crystal. The resulting crystalline suspension was cooled to 0-5 ° C and stirred for two hours. The crystal was filtered off with suction and washed with ethanol (6.61) at 0-5 ° C and dried at 60 ° C.

Yield: 3.3 kg, i.e. 91% th. HPLC purity 99.83 area%. The purity of donepezil prepared subsequently from Examples 4 to 9 was above 99.5 area%.

Industrial applicability

The process for the preparation of 1-benzyl-4- (5,6-dimethoxyindan-1-one-2-yl) -methylpiperidine (donepezil free base) of formula (I) can be applied under favorable technical-economic conditions using a small amount of catalyst, maintaining a sufficiently high yield with high purity under mild reaction conditions.

Claims (10)

A process for the preparation of 1-benzy 1-4- (5,6-dimethoxymdan-1-one-2-yl) methylpiperidine (donepezil free base) of formula (I) by hydrogenation of 1-benzyl-4 - [(5, 6-dimethoxy-1-indanone-2-ylidene] methylpyridinimine bromide of formula (IV); characterized in that the hydrogenation is carried out in the presence of a platinum-on-carbon catalyst. Process according to claim 1, characterized in that the catalyst used for the hydrogenation is platinum on activated carbon with a platinum content of 0.1 to 10% by weight in the dry or wet state and the amount of catalyst used is 0.1 to 5% by weight. Method according to claims 1 and 2, characterized in that the hydrogenation is divided into two phases, wherein in the first phase an alcohol from the series methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2- butanol, t-butanol and ·. φ φ φ φ φ »» »» »Φ Φ Φ Φ Φ Φ «in the second phase, a mixture of the appropriate alcohol (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, t-butanol) and water is used as solvent. Process according to claims 1 to 3, characterized in that in the second stage of the hydrogenation a mixture of the corresponding alcohol and water with a water content in the range of 5 to 50% is used. Process according to claims 1 to 3, characterized in that in the second stage of the hydrogenation a mixture of the corresponding alcohol and water with a water content in the range of 10 to 20% is used. Process according to either of Claims 4 and 5, characterized in that the hydrogenation is carried out at a hydrogen pressure of from 1 to 10 bar. Process according to either of Claims 4 and 5, characterized in that the hydrogenation is carried out at a hydrogen pressure of from 0.2 to 0.4 MPa. Process according to either of Claims 6 and 7, characterized in that the hydrogenation is carried out at a temperature of 20 to 80 ° C. Process according to either of Claims 6 and 7, characterized in that the hydrogenation is carried out at a temperature of 50 to 60 ° C. Process according to either of Claims 8 and 9, characterized in that 1-benzyl-4- (5,6-dimethoxyindan-1-one-2-yl) -methyl-piperidine (donepezil free base) of formula (I) is released from the resulting 1-benzyl-4- (5,6-dimethoxyindan-1-one-2-yl) methylpiperidine hydrobromide (donepezil hydrobromide) of formula (V) by treatment with aqueous ammonia.