FIELD OF THE INVENTION

This invention relates to the field of organic chemistry and more particularly to synthetic process for the preparation of N-benzyl-4-formylpiperidine, a key intermediate which is useful in the synthesis of Donepezil.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,895,841 discloses donepezil hydrochloride, chemically known as (±) -2,3-dihydro-5,6-dimethoxy-2-[( 1 -(phenylmethyl)-4-piperidinyl]methyl]-1 H-inden-1 -one hydrochloride, as cyclic amine compounds. Donepezil hydrochloride 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-formly piperdine(VIII) is a key intermediate in the synthesis of donepezil.

The intermediate (VIII) can be obtained by Wittig reaction by using (methoxymethyl)triphenyl phosphonium chloride as a reagent as disclosed in EP0206560 or US 5,100,90. However, this reaction is not only very expensive, but requires the reaction to take place under cryogenic conditions. Another method, such as disclosed in U.S. Pat. No. 4895,841, employs pyridine-4-aldeyde in the synthesis of intermediate (VIII), which is followed by reduction of aromatic ring at last stage also involves very harsh reaction conditions. Another method is based on the partial reduction of N-benzyl-4-ethoxycarbonylpiperidine with diisobutylalminium hydride (DIBAL-H) at -78°C (Chen Y.L., EP 441517 A2). Similarly, in yet another method, trimethyl silydiazomethane is condensed with N-benzyl-4-piperidone to get enamine, followed by hydrolysis so give the final product (Synlett 1994, 2,109). In another synthesis route is based on the partial reduction of N-benzyl-4-ethoxycarbonylpiperidine with sodium bis(2-methoxyethoxy)aluminum hydride (SMEAH) in the presence of N-methyl piperazine or pyrrolidine (Synthesis 1976, 8, 526-27 ; Tetrahedron 2001, 57, 2701-2710). In another route, N-Benzyl-4-piperidone was reacted with dimethyloxosulfonium methyl iodide to get epoxide, followed by rearrangement in the presence of magnesium bromide etherate (Syn.comm. 2004, 34, 3529-33). There is another process known in art to prepare this intermediate, which was exemplified in patent US 2009/0187020 Al. All these methods commonly require expensive reagents, low temperatures and tedious procedures, thus we report here an improved reproducible process and that is amenable to scale-up.

Hence, there is still a need for an improved process for preparing N-benzyl-4-formylpiperidine that can take care of prior art disadvantages. This invention provides a simple and industrially viable process for the synthesis of N-benzyl-4-formylpiperidine which may be more conveniently prepared and enables the synthesis of donepezil to be carried out in a cost effective manner and avoiding unfavorable reaction.

SUMMARY OF THE INVENTION

In one aspect the invention provides a process for the synthesis of N-benzyl-4-formylpiperidine, a key intermediate used in the synthesis Donepezil. The said process comprises of decomposition of compound of formula VII in the presence of base.

In another aspect the invention provides a process for preparing a compound of formula VII, said method comprises of reacting N-Benzyl-4-hydroxymethylpiperidine with dimethylsulfide and N-chlorosuccinamide; or dimethylsulfide and N-bromosuccinamide; or dimethylsulfide and chlorine gas; or thioanisole and N-chlorosuccinamide; or thioanisole and N-bromosuccinamide in a suitable organic solvent or mixture thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method for producing N-benzyl-4-formyIpiperidine (VIII), a key intermediate used in the synthesis of Donepezil.

One embodiment of this invention is directed to a method of producing N-benzyl-4-formylpiperidine (VIII). The said method comprises of decomposition of compound of formula VII in the presence of base. The base used in the reaction with the compound of formula (VII) is an alkali metal alkoxide, or an alkali metal hydroxide or alkylamines. The alkoxide is preferably a C1 -C6 alkoxide, more preferably a Cl-C4 alkoxide, and most preferably a methoxide or ethoxide. The alkali metal is preferably lithium, sodium or potassium. The reaction temperature is suitably in the range from about -25°C to about 10 C°.

In another embodiment this invention provides a process of synthesis of compound d of formula VII (sulfoxonium complex) said method comprising of reacting N-Benzyl -4-hdroxymethylpiperidine with dimethylsulfide and N-chlorosuccinamide; or dimethylsulfide and N-bromosuccinamide; or dimethylsulfide and chlorine gas; or thioanisole and N-chloro succinamide; or thioanisole and N-bromosuccinamide in a suitable organic solvent. The solvent used in the reaction of compound of formula VII is benzene, toluene, xylene, dioxane, tetrahydrofuan, chlorinated solvents or a mixture thereof. The reaction temperature is suitably in the range from about -25°C to about10°C.
This invention provides a process for the oxidation of N-Benzyl-4-hydroxymethylpiperidine (IV) to N-Benzyl-4-formylpiperidine (VIII), which is operationally simple, highly selective, and efficient. This process would effectively allow an overall transformation such as: RR'CHOH + C12 —->RR'CO + 2HC1, which is mediated by a sulfide. The operability of this scheme has now been demonstrated. For example, treatment of dimethyl sulfide in carbon tetrachloride at 0°C with 1 equiv of chlorine in carbon tetrachloride at 0°C results in rapid formation of the partially insoluble complex V, which when cooled to -20 °C and treated with N-Benzyl-4-hydroxymethylpiperidine (IV) for 2 hr at -20°C with stirring is converted to the sulfoxonium complex VII. Addition of 2 equiv of triethylamine removal of the cooling bath, and isolation after 5 min afford pure N-Benzyl-4-formylpiperidine (VIII) in ca.80% yield after distillation.

The oxidation of N-benzyl-4-hydroxymethylpiperidine (IV) can be effected even more cleanly and efficiently (85 % yield) using the reported complex VI from dimethyl sulfide and N-chlorosuccinimide under carefully controlled conditions.

Hereinafter the invention is explained more specifically referring to the working examples, it being understood that the examples incur no restricting effect on the invention.

Example 1
Preparation of N-Benzyl 4-formylpiperidine
To a solution of N-Benzyl-4-hydroxymethylpiperidine (100 g, 0.4878 mol) in toluene (2 L) at -10°C to -15°C, dimethyl sulfide (30 g, 0.4828 mol) and triethyl amine (62g, 0.6127 mol) were added in a single lot under argon and stirred for 15-30 min. N-Chlorosuccinamide (180 g, 1.3480 mol) was added lot wise over lhr while maintaining the internal temperature at -10°C to -15°C. The reaction mixture was stirred for 3 hr at -10°C to -15°C. Completion of reaction was monitored by Gas Chromatography (GC) or Thin layer chromatography (TLC). After completion of reaction, dilute Sodium hydroxide solution (40 g in 1200 mL of water) was added slowly at temperature less than -5°C. After the addition, the mixture was warmed to 20°C and stirred for 1 hr at 20°C. The aqueous and organic layers were separated and the product from organic layer was extracted with sodium bisulphite solution (140 g in 1100 mL of water). The product layer was washed with dichloromethane (200 mL). Sodium carbonate solution (25% in water) was added to product aqueous layer to adjust pH to 9.5 to 9.8. The product was extracted with dichloromethane and concentrated to give crude product which on high vacuum distillation at 0.1 mm gave N-Benzyl-4-formylpiperidine as a color less oil (84 g, 85% yield).

Example-2
Preparation of N-Benzyl-4-formylpiperidine

To a stirred solution of N-Benzyl-4-hydroxymethylpiperidine (10 g, 0.0488 mol) in dichloromethane, thioanisole (11.3 g, 0.09 mol) and triethyl amine (18.5 g, 0.09 mol) were added at 0°C in a single lot under argon. The solution was cooled to -10°C to -15°C. N-Chlorosuccinamide (12.2 g, 0.091mol) was added lot wise over 1 hr to the reaction mixture while maintaining the internal temperature at -10°C to -15°C. The reaction mixture was stirred for 3 hr at -10°C to -15°C. Completion of reaction was monitored by Gas Chromatography (GC) or thin layer chromatography (TLC). After completion of reaction, dilute sodium hydroxide solution (4 g in 120 mL of water) was slowly added below -5°C. After the addition, the reaction mixture was warmed to 20°C and stirred for 1 hr. The aqueous and organic layers were separated. The product from organic layer was extracted with sodium bisulphite solution (14 g in 110 mL of water). The aqueous product layer was washed with dichloromethane. The aqueous layer was collected and pH was adjusted to 9.5 to 9.8 with sodium carbonate solution (25% in water). The product was extracted with dichloromethane. Organic layer was concentrated and the product distilled under high vacuum at 0.1 ppm to give N-Benzyl 4-formyl piperidine as colorless oil (4.5 g, 45% yield).

Example-3

To a Stirred solution of N-Benzyl-4-hydroxymethylpiperidine (10 g, 0.0488 mol) of in toluene (200 ml), N-tert-butylbenzenesulfenamide (8.8 g, 0.0488 mol) and triethyl amine (6.2 g, 0.06lmol) were added at 0°C in a single lot under argon. The solution was cooled to -10°C to -15°C. N-Chlorosuccinamide (18 g, 0.13480 mol) was added lot wise over 1 hr while maintaining the temperature -10°C to -15°C. The reaction mixture was stirred for 3 hr at -10°C to -15°C. Completion of reaction was monitored by Gas Chromatography (GC) or thin layer chromatography (TLC). After completion of reaction, dilute sodium hydroxide solution (4 g in 120 mL of water) was slowly added below -5°C. After the addition, the reaction mixture was warmed to 20°C and stirred for 1 hr. The aqueous and organic layers were separated. The product from organic layer was extracted with sodium bisulphite solution (14 g in 110 mL of water). The product layer was washed with dichloromethane. The aqueous layer was collected and pH was adjusted to 9.5 to 9.8 with sodium carbonate solution (25% in water). The product was extracted into dichlormethane and concentrated and distilled under high vacuum to afford N-Benzyl-4-formylpiperidine as colorless oil (6 g, 60% yield).

Example-4
To a solution of chlorine (3.2 g, 0.045 mol) in carbon tetrachloride at -10°C, a solution of thioanisole (5.6 g, 0.045 mol) of in dichloromethane was added under argon. A white precipitate appeared immediately after addition of the sulfide. The mixture was cooled to -20°C, and a solution of N-Benzyl-4-hydroxymethylpiperidine (5 g, 0.025 mol) in dichloromethane was added dropwise. Stirring was continued for 90 min at -20°C, and then a solution of triethylamine (4.9 g, 0.05 mol) in dichloromethane was added dropwise. The cooling bath was removed, and after 5 min ether was added. The product from organic layer was extracted with sodium bisulphite solution (7 g in 60 mL of water). The product layer was washed with dichloromethane. The aqueous layer pH was adjusted to 9.5 to 9.8 with sodium carbonate solution (20% in water) and then extracted with dichloromethane. The organic layer was concentrated and distilled under high vacuum (0.1 mm) to give N-Benzyl-4-formylpiperidine as colorless oil (2.5g, 50% yield).

We Claim

1. A method for preparing a compound of formula (VIII):

said method comprises of decomposition of compound of formula VII in the presence of abase.

2. The process according to claim 1, wherein the said compound of formula VII
is formed by reacting N-Benzyl -4-hydroxymethylpiperidine with
- dimethylsulfide and N-chlorosuccinamide; or
- dimethylsulfide and N-bromosuccinamide; or
- dimethylsulfide and chlorine gas; or
- thioanisole and N-chlorosuccinamide; or
- thioanisole and N-bromosuccinamide; or
- thioanisole and chlorine gas; or
- N-tert-Butylbenzenesulfenamide and N-chlorosuccinimide; or
- N-tert-Butylbenzenesulfenamide and N-bromosuccinimide; or
- N-tert-Butylbenzenesulfenamide and chlorine gas.

3. The process according to claim 2, wherein said reaction is carried out in the presence of a solvent.

4. The process according to claim 3, wherein the said solvent is benzene, toluene, xylene, dioxene, THF, or chlorinated solvents or a mixture thereof.

5. The process according to claim 2, wherein the reaction is carried out at a temperature in the range from about -25°C to about 10°C.

6. The process according to claim 1, wherein said base is an alkali metal alkoxide, or an alkali metal hydroxide or alkylamines.

7. The process according to claim 6, wherein said alkali metal is Lithium, Sodium or Potassium.

8. The process according to claim 1, wherein the reaction with the compound of formula VII is carried out at a temperature in the range from about -25°C to about 20 C°.