FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of (1-methyl-piperidin-4yl)-acetaldehyde, a key intermediate for the synthesis of Naratriptan.

BACK GROUND OF THE INVENTION:
Naratriptan is a serotonin receptor agonist and its pharmaceutical salts are widely used as anit-migrane agents and also for cluster headaches. Naratriptan of formula I is chemically known as N-methyl-3-(1 -methyl-4-piperidinyl)-1 H-indole-5-ethanesulphonamide and is being sold as hydrochloride salt under the trade name AMERGE.

Formula
Naratriptan and its pharmaceutically acceptable salts as well as its related compounds useful in the treatment of migraine are reported in GB 2208646 and its equivalents US4997841 and EP303507. These patents disclose several processes for preparing Naratriptan and related compounds. According to one process 4-hydrazino-N-methyl-benzene-ethanesulphonamide of formula Ill is. reacted with 1-methyl-4-piperidineacetaldehyde of formula II under Fischer indolization conditions to get Naratriptan of formula I, a hydrazone intermediate is formed insitu in the reaction. The stepwise process is as shown in scheme-I.

US 5554629 discloses a process for preparing (1-methyl-piperidin-4yl)-acetaldehyde of formula II by reducing (1-methyl-piperidin-4-yl)-aceticacid methylester of formula IV to 2-(1-methy!-piperidin-4-yl)-ethanol of formula V in the presence of diisobutylaluminium hydride (DIBALH) and converting the compound of formula V to {1-methy!-piperidin^yl)-acetaldehyde of formula II by swern oxidation. The schematic descnptlon is as shown in the scheme-II given below;

The main drawbacks associated with the prior art processes are that the preparation of aldehyde intermediate of formula II requires more steps and the overall yield is very low; use of column chromatography in the isolation of Naratriptan, which is unpractical on commercial scale; yield of Naratriptan produced using the processes is less than 10%; and use of diisobutylaluminium hydride for the reduction which is not only difficult to handle but also hazardous and not feasible on the industrial scale.

Keeping in view of the difficulties in commercialization of the above mentioned processes for the preparation of {1-methyl-piperidin-4yl)-acetaldehyde of formula II, there still remains a need to develop an industrially viable and improved method for synthesizing (1-methyl-piperidin-4yl)-acetaldehyde of formula II and its further use in the preparation of Naratriptan.

Thus, the present invention meets the need in the art to avoid the usage of costly and hazardous reagents.

OBJECT OF THE INVENTION:

The main objective of the present invention is to provide an improved and industrially advantageous process for the preparation of (1-methyl-piperidin-4yl)-acetaldehyde, which is a key intermediate for the synthesis of Naratriptan.

SUMMARY OF THE INVENTION

The present invention relates to an improved and efficient process for the preparation of (1-
methy!-piperidin-4yl)-acetaldehyde of formula II, which is a key intermediate for the synthesis of

Naratriptan of formula I. ;

One aspect of the present invention provides an improved process for the preparation of {1-methyl-piperidin-4yl)-acetaidehyde of formula II comprises, reacting 1-methyl-piperidin-4-one of formula VI v^^lth phosphorous diester of formula VII to form (1-methyl-1,2,3,6-tetrahydro-pyridin-4yl)-acetic acid alkyl ester of formula VIM, hydrogenating the pyridinyl double bond of compound of formula VIII to (1-methyl-piperidin-4-yl)-acetic acid alkyl ester of formula IVa follovi/ed by reduction of ester compound of formula IVa to 2-(1-methyl-piperidin-4-yl)-ethanol of formula V and finally converting the compound of formula V to (1-methyl-plperidin-4yl)-acetaldehyde of formula II. The schematic process is shown in scheme-Ill given below:

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved, efficient and industrially viable process for the preparation of {1-methyl-piperidin-4yl)-acetaldehyde of formula II, which is a key intermediate for the synthesis of Naratriptan of formula I.

One embodiment of the present invention provides an improved process for preparing (1-methyl-piperidin-4yl)-acetaldehyde of formula 11, which comprises:

a) reacting 1 -methyl-piperidin-4-one of formula VI with phosphorous diester of formula VII in the presence of a base and a solvent to form (1-methyl-1,2,3,6-tetrahydro-pyridin-4yl)-acetic acid alkyl ester of formula VIII,

b) hydrogenating the pyridinyl double bond of compound of formula VIM using a metal catalyst in the presence of a solvent under hydrogen pressure to get (1-methyl-piperldin-4-yl)-acetic acid alkyl ester of formula IVa,

c) reducing ester compound of formula IVa to 2-(1-methyl-piperidin-4-yl)-ethanol of formula V in the presence of a reducing agent in a suitable solvent and
d) converting the compound of formula V to (1 -methyl-piperidin-4yl)-acetaldehyde of formula II in the presence of an oxidizing agent.

According to the present invention 1-methyl-piperidin-4-one of formula VI is reacted with phosphorous diester of formula VII in the presence of a strong base selected from metal hydrides such as sodium hydride, potassium hydride, metal alkoxide such as sodiummethoxide, potassium tertiary butoxide and metal hydroxides such as sodium

hydroxide or potassium hydroxide to give (1-methyl-1,2,3,6-tetrahydro-pyridin-4yl)-acetic acid alkyl ester of formula VIII. Solvent used in this reaction is selected from tetrahydrofuran, dioxane, dimethylformamide or dimethyl sulfoxide.
Hydrogenating (1-methyl-1,2,3,6-tetrahydro-pyridin-4yl)-acetic acid alkyl ester of formula VIM, is carried out in the presence of a metai catalyst selected from the group consisting of palladium, palladium hydroxide, palladium on activated carbon, palladium on alumina, platinum, platinum dioxide, platinum on activated carbon or raney nickel to give (1-methyl-piperidin-4-yl)-acetic acid alkylester of formula IVa. Solvent used for hydrogenation is selected from polar solvents such as C1-C4 aliphatic alcohols like methanol, ethanol or isopropanol under the hydrogen gas pressure.

Reduction of (1-methyl-piperidin-4-yl)-acetic acid alkylester of formula IVa to 2-(1-methyl-piperidin-4-yl)-ethanol of formula V is carried out in the presence of a reducing agent selected from vitride, lithium aluminium hydride, diisobutyl aluminium hydride or sodium borohydride. The reduction is performed in a suitable inert solvent selected from tetrahydrofuran, toluene, methyl tert-butyl ether or isopropyl ether.

2-(1-methyl-piperidin-4-yi)-ethanol of formula V is oxidized to {1-methyl-plperidin-4yl)-acetaldehyde of formula II by using any of the reagents selected from pyridinium dichromate, pyridinium chlorochromate, jones reagent, 1,2,2,6,6- tetramethyl-1-piperidinyloxy catalyzed sodium hypochlorite, tetrapropyl ammonium perruthenate with N-methylmorpholine N-oxide, swern oxidation (oxalyl chloride, dimethylsulfoxide, triethylamine) or manganese dioxide. Solvents used in the reaction are selected from toluene, tetrahydrofuran, acetonitrile or dichloromethane.

Another embodiment of the present invention is to provide an improved process for the preparation of 2-(1-methyl-piperidin-4-yl)-ethanol of compound of formula V, which comprises, reducing ester compound of formula IVa to 2-(1-methyi-piperidin-4-yl)-ethanol of formula V in the presence of a reducing agent in a suitable solvent.
Reduction of (1-methy|-piperidin-4-y!)-acetic acid alkylester of formula IVa to 2-(1-methyl-piperidin-4-yl)-ethanol of formula V is carried out in the presence of a reducing agent selected from vitride, lithium aluminium hydride, diisobutyl aluminium hydride or sodium borohydride. The reduction is performed in a suitable inert solvent selected from tetrahydrofuran, toluene, methyl tert-butyl ether or isopropyl ether.

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.
Exannple-1: (1-methyl-1, 2, 3, 6-tetrahydro-pyridin-4yl)-acetic acid methyl ester.
Mixture of tetrahydrofuran {300ml), sodium hydride {17.7g) was cooled to -5°C and diethyl phosphino acetic acid methyl ester (102.5g) was added. Slowly raised the temperature of the reaction mass to about -5-10°C and stirred for about 30 min. N-methyl piperidone (50g) was added to the reaction mass at this temperature of -5-10°C and maintained the reaction mass at this temperature for about 3 hours. Cooled the reaction mass to 65-10°C and methanol (50ml) was added at 10-20°C. DM water (500mI) was slowly added to the reaction mass and dichloromethane (300m) was added. Extracted the aqueous layer with dichloromethane (200ml), combined the dichloromethane layers and washed with DM water (2X250ml) and distilled the solvent under vacuum to get 65-70g of the title compound.

Example-2: (1-methyl-piperidin-4-yl)-acetlc acid methyl ester.
Methanol (500mI) was taken in the hydrogenator under the nitrogen atmosphere and 5% Pd/C (16g) was added. (1-methyi-1,2,3,6-tetrahydro-pyridrn-4yl}-acetic acid methyl ester (SOg) obtained in example-1 was added to the reaction mass, nitrogen gas (IKg) was applied and flushed out. Hydrogen gas (2Kg) was applied for about 8 hours. Released the hydrogen gas, filtered the reaction mass on hyflovi/ bed and washed with methanol {80ml). Distill out the solvent completely under vacuum to give 70-75g of the title compound.

Example-3: 2(1 -methyl-piperidin-4-yl-ethanol).
Mixture of tetrahydrofuran (50ml) and vitride (28.6g) was cooled to -10°C and (1-methyl-piperidin-4-yl)-acetic acid methyl ester (lOg) obtained in example-2 was added to the reaction mass for about 45 min. Stirred the reaction mass for about 30 min and 5% NaOH (100ml) was added to the reaction mass. Slowly raised the temperature to about 25°C and stirred the reaction for about 30 min. Separated the upper layer and extracted the aqueous layer with tetrahydrofuran and toluene {35+15ml). Combined the organic layers and distilled out the solvent completely under vacuum to get 7.5-8.5 gm of the title compound.

Example-4: (1 -methyl-piperidin-4-yl)-acetaldehyde.
Cooled the mixture of dichloromethane (100ml) and dimethylsulphoxide (12g) to about -70 to -80°C and oxalyl chloride {9.9g) was added to the reaction mass for about 30-60 min. 2(1-methyl-plperidin-4-yl-ethanol) (10g) was added to the reaction mass for about 30-60 min at -70 to -80°C and maintained at the same temperature for about 15-30 min. Triethylamine (35.5g) was added slowly to the reaction mass for about 30 min and slowly raised the temperature of the reaction mixture to about 25-30°C. DM water (100ml) was added to the reaction mass and separated the layers. Extracted the aqueous layer with dichloromethane (60ml), combined the dichloromethane layers and washed with brine solution (2X100ml). Washed the dichloromethane layer with water {12ml) and distilled out completely under vacuum to yield 5.5-6.5 g of the title compound.

ExampIe-5: Naratriptan hydrochloride.
To a mixture of 4-hydrazino-N-methyl benzene ethanesulfonamide hydrochloride {20g) and DM water {200ml) was added IN HCI {30ml) at 25-30°C and stirred the suspension for about 5-10 min. Slowly added 1-methyl piperidin-4yl-acetaldehyde (12.5g in 100ml DM water) and adjusted the pH of the reaction mass to 1.5-2.0 using 2N HCI or liq. ammonia solution. Stirred the reaction mass for about 100-120 min and adjusted the pH to 9.0-9.5 with liq ammonia solution. Dichloromethane (140ml) was added to the reaction mass and separated the layers. Combined the organic layers and anhydrous sodium sulphate (20g) was added. Stirred the reaction mixture for about 15-20 min, filtered the reaction mass over hyflo bed and washed the bed with dichloromethane {20ml). Mixture of polyphosphoric acid (140g) and dichloromethane {300ml) were heated to about 35-37°C and added to the above organic layer. Stirred the reaction mass for about 90-120 min and cooled to 25-25°C. DM water (400ml) was added to the reaction mass and separated the layers. Cooled the aqueous layer to 0-5°C and adjusted the pH of the reaction mass to 9.5-10.0 using saturated sodium carbonate solution. Ethylacetate {200ml) was added to the reaction mass and separated the layers. Again added ethylacetate {200ml) to the reaction mass and separated the layers. Combined all the organic layers and distilled out the ethylacetate completely under vacuum. Ethanol (200ml) was added to the residue and heated the reaction mass to 35-40*'C. 17% IPA HCI (15ml) was added to the reaction mass, stirred the mass for about 25-30°C and cooled to about 25-30°C. Stirred the slurry for about 24 hours at 25-30°C, filtered the solid, washed with ethanol (20ml) and dried the solid under vacuum to get 6.0-8.0 g of the title compound.

We Claim:

1.An improved process for the preparation of (1-methyl-piperidin-4yl)-acetaldehyde of
formula

a key intermediate for the synthesis of Naratriptn of formula I,

which comprises,

a) reacting 1 -methyl-piperidin-4-one of formula VI with phosphorous diester of formula VII in the presence of a base and a solvent to form (1-methyl-1,2,3,6-tetrahydro-pyridin-4yl)- acetic acid alkyl ester of formula VIII,

b) hydrogenating the pyridinyl double bond of compound of formula VIII using a metal catalyst in the presence of a solvent under hydrogen gas to get the hydrogenated
compound, (1-methyl-piperidin-4-yl)-aceticacid alkyl ester of formula IVa,

c) reducing ester compound of formula IVa to 2-(1-methyl-piperidin-4-yl)-ethanol of formula V in the presence of a reducing agent in an inert solvent and

d) converting the compound of formula V to (1-methyl-piperidin-4yl)-acetaldehyde of fornnula II in the presence of an oxidizing agent in a suitable solvent.

2. A process for the preparation of compound of formula II as claimed in claim 1, wherein the base used in step a) is selected from metal hydrides such as sodium hydride, potassium hydride, metal alkoxide such as sodium methoxide, potassium tertiary butoxide and metal hydroxides such as sodium hydroxide or potassium hydroxide.

3. A process for the preparation of compound of formula II as claimed in claim 1, wherein the solvent used in step a) is selected from tetrahydrofuran, dioxane, dimethylformamide or dimethyl sulfoxide.

4. A process for the preparation of compound of formula II as claimed in claim 1, wherein the hydrogenation in step b) is carried out in the presence of a metal catalyst selected from the group consisting of palladium, palladium hydroxide, palladium on carbon, palladium on alumina, platinum, platinum dioxide, platinum on carbon or raney nickel.

5. A process for the preparation of compound of formula II as claimed In claim 1, wherein the solvent used for hydrogenation in step b) is selected from polar solvents such as C1-C4 aliphatic alcohols like methanol, ethanol or isopropanol.

6. A process for the preparation of compound of formula II as claimed in claim 1, wherein the reducing agent used In step c) is selected from vitride, lithium aluminium hydride or sodium borohydride.

7. A process for the preparation of compound of formula II as claimed in claim 1, wherein the solvent used for reduction in step c) is selected from tetrahydrofuran, toluene, methyl tert-butyl ether or isopropyl ether.

8. A process for the preparation of compound of formula II as claimed in claim 1, wherein the oxidation is step d) is carried out In the presence of the reagents selected pyridlnium dichromate, pyridinium chlorochromate, jones reagent 1,2,2,6,6- tetramethyl-1-piperidinyloxy catalyzed sodium hypochlorite, tetrapropyl ammonium perruthenate with N-methylmorphollne N-oxide, swern oxidation (oxalyl chloride, dimethylsulfoxide, friethylamrne) or manganese dioxide.

9. An Improved process for the preparation of 2-(1-methyl-plperidin-4-yl)-ethanol of compound of formula V which comprises:

a) reducing ester compound of formula IVa to 2-{1-methyl-piperidin-4-yl)-ethanol of formula V in the presence of vitride in an inert solvent.

10. A process for the preparation of compound of formula V as claimed in claim 9, wherein the inert solvent is selected from tetrahydrofuran, toluene, methyl tert-butyl ether or isopropyl ether.