SK51022005A3 - Method for the preparation of 5,6-dimethoxy-2-(4pyridyl)methyl-1- indanon and 5,6-dimethoxy-2-piperidine-4-ylmethyl-1-1-one, intermediate products in preparation of pharmaceutical substance of donepezil - Google Patents

Abstract

describes the way preparation 5,6-dimethoxy-2- (4-pyridyl) methylene butyl-l-indanone and 5,6-dimethoxy-2-piperidin-4-ylmethyl-l-one, which ones serve than intermediates at training substances to- ncpczil.

Description

Technical field.

The invention relates to a process for the preparation of 5,6-dimethoxy-2- (4-pyridyl) methyl-1-indanone and 5,6-dimethoxy-2-piperidin-4-ylmethyl-1-one, which are used as intermediates in the preparation of the pharmaceutical substance donepezia .

BACKGROUND OF THE INVENTION.

Reference is made in the literature to the preparation of 5,6-dimethoxy-2- (4-pyridyl) methyl-lindanone in U.S. Pat. EP-1047674, which is used in the synthesis of a pharmaceutical substance donepezil. This preparation method is shown in Scheme 1. The starting materials for the preparation of 5,6-dimethoxy-2- (4-pyridyl) methyl-1-indanone (IV) in said patent is 5,6-dimethoxy-2-ethoxycarbonyl-1-indanone ( I) and 4-pyridylmethyl chloride (4-picolyl chloride) (II), from which 5,6-dimethoxy-1-oxo-2-pyridin-4-ylmethyl-indane-2-carboxylic acid ethyl ester is prepared under basic conditions in a first step of acid (III) in a yield of 90%. In the second step, in the potassium hydroxide medium, the carboxyl group is cleaved from 5,6-dimethoxy-oxo-2-pyridin-4-ylmethyl-indane-2-carboxylic acid ethyl ester (III) to give 5,6-dimethoxy-2 ( 4-pyridyl) methyl-1-indanone (IV) in 95% yield. Subsequently, the substance donepezil is prepared from 5,6-dimethoxy-2- (4-pyridyl) methyl-1-indanone (IV) by two steps. First, the pyridinium salt of benzyl bromide in acetonitrile is prepared from 5,6-dimethoxy-2- (4-pyridyl) methyl-1-indanone (IV), which is then reduced with hydrogen to catalyze platinum oxide. Scheme 1.

Donepezil (IV)

The preparation of the second intermediate 5,6-dimethoxy-2-piperidin-4-ylmethyl-1-one is described in U.S. Pat. WO 9722584 (Scheme 2). The starting material in this case is 4- [3- (3,4-dimethoxyphenyl) -3-oxopropyl] piperidine-1-carboxylic acid methyl ester (V), which was prepared by Friedel-Crafts acylation of methyl 4- (2-chlorocarbonylethyl) of piperidine-1-carboxylate with 1,2-dimethoxybenzene in an aluminum chloride environment in a yield of 95%. In the next step, in a yield of 92%, 4- [2- (3,4-dimethoxybenzoyl) allyl] piperidine-1-carboxylic acid methyl ester (VI) was prepared in acetic anhydride and tetramethydiaminoethane from 4- [3- (3,4- dimethoxyphenyl) -3-oxopropyl] piperidine-1-carboxylic acid (V). Subsequent intra-molecular cyclization of intermediate (VI) in sulfuric acid afforded 4- (5,6-dimethoxy-1-oxoindan-2-ylmethyl) piperidine-1-carboxylic acid methyl ester (VII) in a yield of 94%. Intermediate (VII) in potassium hydroxide gave 5,6-dimethoxy-2-piperidin-4-ylmethyl-1-one (VIII) in 79% yield, from which alkylation with benzyl chloride gave donepezil in 61% yield.

donepezil

-3 Summary of the Invention.

The invention relates to a process for the preparation of 5,6-dimethoxy-2- (4-pyridyl) methyl-1-indanone of formula (IV) and 5,6-dimethoxy-2-piperidin-4-ylmethyl-1-one of formula (VIII) ), which serve as intermediates in the preparation of the substance donepezil of general formula (XIII).

Said compounds are prepared by the following sequence of reactions according to Scheme 3: The starting material for compounds (IV) and (VIII) is 5,6-dimethoxy-2- (pyridin-4-yl) methylene-indan-1-one (XI), which prepared by the azeotropic condensation reaction of 5,6-dimethoxy-1-indanone (IX) with 4-pyridinecarbaldehyde (X), which is described in U.S. Pat. EP 711756.

Subsequent catalytic reduction of 5,6-dimethoxy-2- (pyridin-4-yl) methylene-indan-1-one (XI) with hydrogen in the first step produces 5,6-dimethoxy-2- (4-pyridyl) methyl-1- indanone (IV) in quantitative yield and purity above 99%.

In the catalytic reduction, a catalyst of 1 to 10% palladium on carbon, 0.5 to 10% palladium on alumina, 1 to 10% platinum on carbon and 0.5 to 5% platinum on alumina is used in an amount of 1 to 20% by weight, preferably 5% % palladium on carbon in an amount of 5% by weight.

The reaction time depends on the reaction temperature and pressure, and may vary from 2 to 24 hours, with an optimum reaction time of 8 hours for the most suitable temperatures of the solvents used. In the reduction, methanol, ethanol, propanol, 2-propanol, acetic acid and tetrahydrofuran are used as solvents, preferably tetrahydrofuran. The reduction is carried out at temperatures of from 20 to 100 ° C and pressures of from 1 to 10 bar, preferably 25 ° C and 1 bar.

In the second step, catalytic reduction of 5,6-dimethoxy-2- (4-pyridyl) methyl-1-indanone (IV) with hydrogen in acetic or formic acid using a platinum or radio catalyst is again utilized to give 5,6-dimethoxy-2. -piperidin-4-ylmethyl-1-one (VIII).

The product (VIII) is produced in a yield of from 68 to 95% depending on the temperature and pressure used. The catalyst used is 1 to 10% platinum on carbon, 0.5 to 5% platinum on alumina, 1 to 5% rhodium on carbon, and 0.5 to 5% radium on alumina in an amount of 1 to 20% by weight, preferably 5% platinum on carbon in an amount of 5% by weight.

Scheme 3.

about

(IX)

(X)

PTSA

Toluene

ABOUT

(XI)

THF

IN

Pd / C

H ₂

Donepezil where R is Me, phenyl, 4-nitrophenyl, 4-methylphenyl, 4-bromophenyl and 4-chlorophenyl

The reaction time depends on the reaction temperature and pressure, and may range from 5 to 30 hours, with a reaction time of 15 hours being optimal for the most suitable temperatures of the solvents used. Acetic acid or formic acid, preferably acetic acid, are used as solvents in the reduction. The reduction is carried out at temperatures from 30 to 100 ° C and pressures from 1 to 30 bar, preferably 50 ° C and 3 bar.

The preparation of donepezil alone from 5,6-dimethoxy-2- (4-pyridyl) methyl-1-indanone (IV) is carried out first by preparing the pyridinium salt, which is subsequently reduced with hydrogen to catalize platinum oxide (WO 9936405).

From 5,6-dimethoxy-2-piperidin-4-ylmethyl-1-one (VIII), donepezil of formula (XIII),

prepared by substitution nucleophilic reaction with benzyl ester of various sulfonic acids of general formula (XII),

wherein R is Me, phenyl, 4-nitrophenyl, 4-methylphenyl, 4-bromophenyl and 4-chlorophenyl.

The product (XIII) is produced in a yield of 53 to 86% depending on the temperature used. The bases used are: potassium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, sodium methoxide and potassium tert-butoxide, sodium hydride.

The reaction time depends on the reaction temperature and the base used, and may range from 5 to 15 hours, for the most suitable temperatures of the solvents used, the optimal reaction time is 10 hours. Solvents such as methanol, ethanol, propanol, 2-propanol, dimethylformamide, tetrahydrofuran, acetone, methyl ethyl ketone and dimethyl sulfoxide are used in the reaction, preferably

-6dimetylformamid. The preparation of Donepezil is carried out at temperatures from 0 to 150 ° C, depending on the base used.

DETAILED DESCRIPTION OF THE INVENTION.

Example 1.

Preparation of 5,6-dimethoxy-2- (4-pyridyl) methyl-1-indanone

10 g (3.6 mmol) of 5,6-dimethoxy-2 (pyridin-4-yl) methylen-indan-1-one are stirred in 100 ml of tetrahydrofuran in an autoclave with 1 g of 5% palladium on carbon under a hydrogen atmosphere at atmospheric pressure. and room temperature for 7 hours. Subsequently, the solution is filtered through filter paper and the filtrate is concentrated and recrystallized from ethanol. 8.6 g (85%) of a white crystalline solid are obtained, m.p. 191-192 ° C.

1 H-NMR (200MHz, CDCl ₃ ) δ (ppm): 2.6-2.9 (3H, m), 3.05-3.4 (2H, m), 3.9 (3H, s), 3.95 (3H, s), 6.8 (1H (s), 7.2 (2H, d, J = 6 Hz), 7.2 (1H, s), 8.5 (2H, d, J = 6 Hz)

MS: m / e = 284 (M + 1) < ^{+ &gt};.

Example 2.

Preparation of 5,6-dimethoxy-2- (4-pyridyl) methyl-1-indanone

50 g (17.7 mmol) of 5,6-dimethoxy-2- (pyridin-4-yl) methylene-indan-1-one are mixed in an autoclave in 100 ml of ethanol with 3 g of 10% palladium on carbon under a hydrogen atmosphere at 3 bar. bar and 50 ° C for 4 hours. Subsequently, the solution is filtered through filter paper and the filtrate is concentrated and recrystallized from ethanol. 49.5 g (98%) of a white crystalline solid are obtained, m.p. 190-192 ° C.

1 H-NMR (200MHz, CDCl 3) δ (ppm): 2.6-2.9 (3H, m), 3.05-3.4 (2H, m), 3.9 (3H, s), 3.95 (3H, s), 6.8 (1H, s), 7.2 (2H, d, J = 6 Hz). 7.2 (1 H, s), 8.5 (2 H, d, J = 6 Hz)

MS: m / e = 284 (M + 1) < ⁺ > ^.

Example 3.

Preparation of 5,6-dimethoxy-2- (4-pyridyl) methyl-1-indanone

10 g (3.6 mmol) of 5,6-dimethoxy-2 (pyridin-4-yl) methylene-indan-1-one are stirred in 100 ml of tetrahydrofuran in an autoclave with 1 g of 5% platinum on carbon under a hydrogen atmosphere at atmospheric pressure. and a temperature of 70 ° C for 5 hours. Subsequently, the solution is filtered through

The filter paper and filtrate are concentrated and recrystallized from ethanol. 9.2 g (92%) of a white crystalline solid are obtained, m.p. 192-193 ° C.

1 H-NMR (200MHz, CDCl ₃ ) δ (ppm): 2.6-2.9 (3H, m), 3.05-3.4 (2H, m), 3.9 (3H, s), 3.95 (3H, s), 6.8 (1H (s), 7.2 (2H, d, J = 6 Hz), 7.2 (1H, s), 8.5 (2H, d, J = 6 Hz)

MS: m / e = 284 (M + 1) < ⁺ > ^.

Example 4.

Preparation of 5,6-dimethoxy-2-piperidin-4-ylmethyl-1-one

10 g (3.5 mmol) of 5,6-dimethoxy-2- (4-pyridyl) methyl-1-indanone are mixed in 200 ml of acetic acid in an autoclave with 2 g of 5% platinum on carbon under a hydrogen atmosphere at 3 bar and temperature. 50 ° C for 10 hours. Subsequently, the solution is filtered through filter paper and the filtrate is concentrated. The crude product was dissolved in 100 mL of dichloromethane, extracted with 10% sodium bicarbonate solution, dried over sodium sulfate and concentrated. 7.5 g (74%) of an oily substance are obtained.

1 H-NMR (200MHz, CDCl ₃ ) δ (ppm): 1.05-1.3 (3H, m), 1.5-1.9 (4H, m), 2.5-2.8 (4H, m), 33.2 (3H, m), 3.85 (3H, s), 3.9 (3H, s), 6.8 (1H, s), 7.2 (1H, s)

MS: m / e = 290 (M + 1) < ⁺ > ^.

Example 5.

Preparation of 5,6-dimethoxy-2-piperidin-4-ylmethyl-1-one

10 g (3,5 mmol) of 5,6-dimethoxy-2- (4-pyridyl) methyl-1-indanone are stirred in 200 ml of acetic acid in an autoclave with 2 g of 5% carbon on carbon under a hydrogen pressure of 3 bar and 80 ° C. C. The solution was filtered through filter paper and the filtrate was concentrated.The crude product was dissolved in 100 mL of dichloromethane, extracted with 10% sodium bicarbonate solution, dried over sodium sulfate and concentrated to give 6.9 g (68%) oil. fabric.

1 H-NMR (200MHz, CDCl 3) δ (ppm): 1.05-1.3 (3H, m), 1.5-1.9 (4H, m), 2.5-2.8 (4H, m), 33.2 (3H, m), 3.85 ( 3H, s (H), 3.9 (3H, s), 6.8 (1H, s), 7.2 (III, s)

MS: m / e = 290 (M + 1)

Example 6.

Preparation of 5,6-dimeloxy-2-piperidin-4-yimethyl-1-one

5 g (1.76 mmol) of 5,6-dimethoxy-2- (4-pyridyl) methyl-1-indanone are stirred in 100 ml of acetic acid in an autoclave with 1 g of 5% platinum on carbon under a hydrogen atmosphere at 2 bar.

-8 and 50 ° C for 8 hours. Subsequently, the solution is filtered through filter paper and the filtrate is concentrated. The crude product was dissolved in 100 mL of dichloromethane, extracted with 10% sodium bicarbonate solution, dried over sodium sulfate and concentrated. 4 g (78%) of an oil are obtained.

1 H-NMR (200MHz, CDCl ₃ ) δ (ppm): 1.05-1.3 (3H, m), 1.5-1.8 (4H, m), 2.5-2.8 (4H, m), 33.2 (3H, m) ), 3.85 (3H, s), 3.9 (3H, s), 6.8 (1H, s), 7.2 (1H, s)

MS: m / e = 290 (M + 1) < ⁺ > ^.

Example 7.

Preparation of 2- (1-benzyl-piperidin-4-ylmethyl) -5,6-dimethoxy-indan-1-one (donepezil)

5 g (17.2 mmol) is stirred in 80 ml of anhydrous dimethylformamide at 80 ° C.

5,6-dimethoxy-2-piperidin-4-ylmethyl-1-one, 2.6 g (18.9 mmol) of potassium carbonate and 3.4 g (18.1 mmol) of methanesulfonic acid benzyl ester over 12 hours. Subsequently, the mixture was cooled to room temperature and poured into 200 ml of water, and the precipitated product was extracted with 3 x 70 ml of dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated. The crude product is dissolved in 150 ml of anhydrous isopropanol and then 1 g of hydrogen chloride is blown into the solution after cooling to 5 ° C. The solution is allowed to stir for 5 hours at 5 ° C and then the precipitated product is filtered off with suction. 5.3 g (74%) of a white crystalline solid are obtained, m.p. 211-212 ° C.

1 H-NMR (200MHz, CDCl ₃ ) δ (ppm): 1.39-1.43 (2H, m), 1.78 (1H, m), 1.98-2.07 (4H, m),

2.52-3.26 (3 H, m), 3.4 (4 H, m), 3.8 (3 H, s), 3.87 (3 H, s), 4.15 (2H, s), 6.76 (1H, s), 7.02 (1H, s) 7.33-7.61 (5H, m)

MS: m / e = 380 (M + 1) < ⁺ > ^.

Example 8.

Preparation of 2- (1-benzyl-piperidin-4-ylmethyl) -5,6-dimethoxy-indan-1-one (Donepezil)

5 g (17.2 mmol) was stirred in 100 ml of anhydrous dimethylformamide at 100 ° C.

5,6-dimethoxy-2-piperidin-4-ylmethyl-1-one, 0.8 g (18.9 mmol) sodium hydroxide and 4.7 g (18.1 mmol) 4-toluenesulfonic acid benzyl ester over 6 hours. Subsequently, the mixture was cooled to room temperature and poured into 200 ml of water, and the precipitated product was extracted with 3 x 70 ml of dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated. The crude product is dissolved in 150 ml of anhydrous isopropanol and then 1 g of hydrogen chloride is blown into the solution after cooling to 5 ° C. The solution is allowed to stir for 5 hours at 5 ° C and subsequently

-9 the dropped product is aspirated. 4.8 g (67%) of a white crystalline solid are obtained, m.p. 210-211 ° C.

1 H-NMR (200MHz, CDCl ₃ ) δ (ppm): 1.39-1.43 (2H, m), 1.78 (1H, m), 1.98-2.07 (4H, m),

2.52-3.26 (3 H, m), 3.4 (4 H, m), 3.8 (3 H, s), 3.87 (3 H, s), 4.15 (2H, s), 6.76 (1H, s), 7.02 (1H, s) 7.33-7.61 (5H, m)

MS: m / e = 380 (M + 1) < ⁺ > ^.

Example 9.

Preparation of 2- (1-benzyl-piperidin-4-ylmethyl) -5,6-dimethoxy-indan-1-one (Donepezil)

5 g (17.2 mmol) of 5,6-dimethoxy-2-piperidin-4-ylmethyl-1-one, 2.6 g (18.9 mmol) of potassium carbonate and 4.7 g are stirred in 100 ml of anhydrous acetone at 60 ° C. g (18.1 mmol) of 4-toluenesulfonic acid benzyl ester over 6 hours. Subsequently, the mixture was cooled to room temperature and poured into 200 ml of water, and the precipitated product was extracted with 3 x 70 ml of dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated. The crude product is dissolved in 150 ml of anhydrous isopropanol and then 1 g of hydrogen chloride is blown into the solution after cooling to 5 ° C. The solution is allowed to stir for 5 hours at 5 ° C and then the precipitated product is filtered off with suction. 3.1 g (43%) of a white crystalline solid are obtained, m.p. 209-210 ° C.

1 H-NMR (200MHz, CDCl ₃ ) δ (ppm): 1.39-1.43 (2H, m), 1.78 (1H, m), 1.98-2.07 (4H, m),

2.52-3.26 (3 H, m), 3.4 (4 H, m), 3.8 (3 H, s), 3.87 (3 H, s), 4.15 (2H, s), 6.76 (1H, s), 7.02 (1H, s) 7.33-7.61 (5H, m)

MS: m / e = 380 (M + 1) < ⁺ > ^.

Example 10.

Preparation of 2- (1-benzyl-piperidin-4-ylmethyl) -5,6-dimethoxy-indan-1-one (donepezil)

To a mixture of 5 g (17.2 mmol) of 5,6-dimethoxy-2-piperidin-4-ylmethyl-1-one in 100 ml of anhydrous tetrahydrofuran at 0 ° C was added 0.7 g (17.4 mmol) of 60% hydride. solution. Stir the mixture at 0 ° C for 1 hour. Subsequently, 4.7 g (18.1 mmol) of 4-toluenesulfonic acid benzyl ester in 30 ml of dried tetrahydrofuran was added dropwise over 10 minutes. Subsequently, the mixture is cooled to room temperature and poured into 300 ml of water and the product is extracted with 3 x 80 ml of dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated. The crude product is dissolved in 150 ml of anhydrous isopropanol and then 1 g of hydrogen chloride is blown into the solution after cooling to 5 ° C. Allow the solution to stir for 5 hours

- 10 hours at 5 ° C and then the precipitated product is aspirated. 3.7 g (52%) of a white crystalline solid are obtained, m.p. 209-210 ° C.

1 H-NMR (200MHz, CDCl ₃ ) δ (ppm): 1.39-1.43 (2H, m), 1.78 (1H, m), 1.98-2.07 (4H, m),

2.52-3.26 (3 H, m), 3.4 (4 H, m), 3.8 (3 H, s), 3.87 (3 H, s), 4.15 (2H, s), 6.76 (1H, s), 7.02 (1H, s) 7.33-7.61 (5H, m)

MS: m / e = 380 (M + 1) < ⁺ > ^.

Industrial usability.

The invention is industrially applicable in the manufacture of the pharmaceutical substance donepezil.

Claims (10)

Patent claims. A process for the preparation of 5,6-dimethoxy-2- (4-pyridyl) methyl-1-indanone of the general formula (IV), characterized in that 5,6-dimethoxy-2- (pyridin-4-yl) methylene-indane- 1-one of formula (XI). HjCO H ₃ CO (xi) is catalytically reduced in the presence of solvents at a temperature of 20 to 100 ° C and a pressure of 1 to 10 bar. 2. A process for the preparation of 5,6-dimethoxy-2-piperidin-4-ylmethyl-1-one of formula (VIII): (VIII) - 12, characterized in that compound (VIII) is prepared by reduction of 5,6-dimethoxy-2- (4-pyridyl) methyl-1-indanone of formula (IV) by catalytic reduction in the presence of solvents at temperatures ranging from 20 to 100 ° C and pressures from 1 to 30 bar. The method of claim 1, wherein the reduction is a catalytic reduction in the presence of palladium on carbon, palladium on alumina, platinum on carbon, platinum on alumina, ruthenium on carbon, or ruthenium on alumina. Process according to claims 1 and 3, characterized in that the reduction is carried out in the presence of solvents preferably such as methanol, ethanol, propanol, 2-propanol, acetic acid, dioxane and tetrahydrofuran. A process according to claim 2, wherein the reduction is a catalytic reduction in the presence of platinum on carbon, platinum on alumina, ruthenium on carbon or ruthenium on alumina. Process according to claims 2 and 5, characterized in that the reduction is carried out in the presence of solvents such as acetic acid or formic acid. A process for the preparation of donepezil of formula (XIII), (XIII), characterized in that a 5,6-dimethoxy-2-piperidin-4-ylmethyl-1-one of formula (VIII) is treated with a nucleophilic reagent of formula (XII). XII), o n (ΧΠ) wherein R is Me, phenyl, 4-nitrophenyl, 4-methylphenyl, 4-bromophenyl and 4-chlorophenyl. in the presence of a base and protic and / or aprotic solvents. The process according to claim 7, wherein the reaction is carried out in the presence of a base: potassium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, sodium methoxide and potassium tert-butoxide. The process according to claims 7 and 8, wherein the preparation is carried out in the presence of solvents such as methanol, ethanol, propanol, 2-propanol, dimethylformamide, tetrahydrofuran, acetone, methyl ethyl ketone and dimethylsulfoxide. Preparation process according to claims 7, 8 and 9, characterized in that the reduction is carried out at temperatures in the range of 0 to 150 ° C.