FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Bromo formyl Nornarwedine of Formula I.

The compound of formula-I is the key precursor in the preparation of Galantamine of formula II.

BACKGROUND OF THE INVENTION

Galantamine is chemically known as [4aS,6R,8aS]-4a,5,9,10,ll,12-Hexahydro-3-methoxy-ll-methyl-6H-benzofuro[3a,3,2-ef]-[2]benzazepin-6-ol (II). Galantamine is a competitive and reversible acetyl cholinesterase inhibitor, which is approved for the treatment of mild to moderate Alzheimer's disease and is under development for other indications such as Vascular Dementia, Alzheimer's disease with cerebrovascular disease, mild cognitive impairment, schizophrenia, Parkinson's disease and other diseases wherein cognition is impaired. Galantamine (I) is commercially available as Razadyne®.

Galantamine is a tertiary alkaloid, usually isolated from plants belonging to Amaryllidaceae family, for example, from galanthus species, such as the Daffodil, Narcissus pseudomarcissus and snowdrop or Leucojum aestivum. These plants are having Galantamine in concentrations of up to 0.3% with only small amounts of companion alkaloids, so that the extraction method can be used. This process of extraction is expensive and time consuming, hence not feasible for industrial scale operations.
Journal of Heterocyclic Chemistry (1995), 32, 195-199 reported a process for the preparation of bromo formyl Nornarwedine (I), by reacting Bromo formyl norbelladine (III) with potassium ferricyanide and sodium bicarbonate in chloroform to produce Dibromo formyl Nornarwedine (IV), which is further treated with Zinc in ethanol to produce bromo formyl Nornarwedine (I). The process is as shown in Scheme -I below:

US 6,043,359 of Sanochemia, also discloses a process for the preparation of bromo formyl Nornarwedine (I), by reacting Bromo formyl norbelladine (III) with potassium ferricyanide, potassium carbonate in toluene to produce bromo formyl Nornarwedine (I).

The process is as shown in Scheme -II below:

The major disadvantage with above processes is that the oxidative cyclization reaction is carried out at higher temperatures, which produces unwanted impurities and the removal of these impurities is difficult and required repeated crystallizations, which reduces the yield of Bromo formyl Nornarwedine (I). Further, it was observed difficulties in isolation of Bromo formyl Nornarwedine (I) from the reaction mass due to formation of emulsion.

Hence, there is a need to develop a process, which reduces the unwanted impurities to a pharmaceutical acceptable limit, which in turn provides Bromo formyl Nornarwedine (I) of high purity and improved yield.

The inventors found during the optimization, the use of phase transfer catalyst (PTC) provides the advantage of completion of oxidative cyclization reaction at low temperatures and easy layer separation in the isolation of Dibromo formyl Nornarwedine (IV).

The present invention is specifically directed towards the oxidative cyclization Bromo formyl norbelladine (III) using an oxidizing agent and a base in the presence of a phase transfer catalyst to produce Bromo formyl Nornarwedine (I).

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a simple and cost effective process for the preparation of Bromo formyl Nornarwedine of formula (I) with high purity and good yield on a commercial scale.

SUMMARY OF THE INVENTION

The present invention provides an improved process for the preparation of Bromo formyl Nornarwedine of Formula (I), which comprises:

(i) oxidative cyclization of compound of Formula (III); with an oxidizing agent and a base in the presence of a phase transfer catalyst in a solvent to produce Dibromo formyl Nornarwedine of Formula (IV);

(ii) reacting the compound of formula (IV) with metal in a solvent to produce Bromo formyl Nornarwedine of Formula (I).

In another embodiment of the present invention the Bromo formyl Nornarwedine of Formula (I) prepared by the above process is converted to Galantamine of Formula (II).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for the preparation of Bromo formyl Nornarwedine of Formula (I).

The process comprises oxidative cyclization of Bromo formyl norbelladine (III) with an oxidizing agent and a base in the presence of a phase transfer catalyst in a solvent to produce Dibromo formyl Nornarwedine (IV).

The oxidizing agent used in the above reaction is selected from potassium permanganate, lead tetraacetate, potassium dichromate, ferric chloride, potassium ferricyanide, hydrogen peroxide or mixture thereof; the base is selected from sodium carbonate, sodium hydroxide, potassium bicarbonate, potassium carbonate, potassium hydroxide, calcium bicarbonate, calcium hydroxide, calcium carbonate, magnesium hydroxide, magnesium carbonate, magnesium bicarbonate or mixture thereof.

The phase transfer catalyst (PTC) used in the above reaction is selected from crown ethers such as 18-crown-6 ether, 12-crown-4 ether, 15-crown-5 ether, dibenzo-18-crown-6 ether and diaza-18-crown-6 ether or mixture thereof.

The solvent used in the above reaction is selected from esters such as ethyl acetate, isopropyl acetate; hydrocarbon solvents such as heptane, hexane, benzene, toluene, xylene, cyclopentane, cyclooctane; chlorinated hydrocarbon solvents such as dichloromethane, chloroform. The reaction is performed at a temperature below 40°C for about 1 hour to about 8 hours. After completion of the reaction, the organic layer is separated and distilled off solvent to produce Dibromo formyl Nornarwedine (IV).

The Dibromo formyl Nornarwedine (IV) obtained by the above process is reduced with a metal in a solvent to produce Bromo formyl Nornarwedine of Formula (I).

The metal used in the above reaction is selected from iron (Fe), tin (Sn), Zinc (Zn) or mixture thereof. The solvent is selected from alcohol solvents such as methanol, ethanol, propanol, butanol or mixture thereof. The reaction is performed at a temperature below 100°C for about 8 hrs. After completion of the reaction, the reaction mass is filtered, followed by removal of organic layer to produce Bromo formyl Nornarwedine of Formula (I), which is further purified by conventional means such as crystallization or slurry process.

In the preferred embodiment of the present invention, the process comprises oxidative cyclization of Bromo formyl norbelladine (III) with an oxidizing agent selected from potassium ferricyanide and a base selected from potassium carbonate in the presence of a phase transfer catalyst selected from 18-crown-6 ether in a solvent selected from toluene to produce Dibromo formyl Nornarwedine (IV), which is further reduced with metal selected from Zn in alcohol selected from ethanol to produce Bromo formyl Nornarwedine (I).

Bromo formyl Nornarwedine of Formula (I) prepared by the above process is converted to Galantamine by reacting with NaBH4/CeCl3a in THF solvent to produce mixture of (±)-Bromo formyl Galantamine and (±)-Bromo formyl Epigalantamine, which is further reacted with

LiAlH4 in THF solvent to produce mixture of (±)-Galantamine and (±)-Epigalantamine. Oxidation of Mixture of (±)-Galantamine and (±)-Epigalantamine is carried out in the presence of Mn02 in acetone to produce (±)-Narwedine, which is further treated with triethyl amine and seeded with (-)-Narwedine in ethanol to produce (-)-Narwedine. Stereoselective reduction of (-)-Narwedine is carried out in the presence of L-selectride in THF solvent to produce (-)-Galantamine, which is further reacted with aqueous hydrobromide acid in THF to produce Galantamine hydrobromide.

The compound of Formula (III) used in the above process is prepared by condensation of Isovallin with Tyramine in the presence of boric acid and sodium borohydride in methanol to produce Norbelladine. N-formylation of Norbelladine is carried out in the presence of formic acid and ethylformate in DMF to produce N-Formyl Norbelladine. Further, Bromination of N-Formyl Norbelladine is carried out in the presence of bromine in dichloromethane and methanol to produce Bromo formyl norbelladine (III).

It has been observed that the use of phase transfer catalyst (PTC) selected from crown ethers in the above reaction, resulted oxidative cyclization reaction at a temperature below 40°C and easy layer separation (no emulsion formation) in the isolation of Dibromo formyl Nornarwedine (IV). Further, resulted Bromo formyl Nornarwedine (I) with increased in yield by 25%.

The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.

EXAMPLE-1; PREPARATION OF BROMO FORMYL NORNARWEDINE.

Bromo formyl norbelladine (35.0 g) was suspended in toluene (1.75 L) and cooled to 10-15°C. Potassium ferricyanide (152.25 g), 10% aq w/w potassium carbonate solution (0.7 L) and 18-Crown-6 (0.2 g) were added to above suspension and stirred for 1 hour 30 minutes at 10-15°C. After completion of the reaction, solid obtained (weight; 13.2g) was separated from toluene layer (volume-1250 ml) by distillation. Solid was dissolved in ethanol (583 ml). Zinc was added to this solution and stirred for 8 hours at 78-80°C for the conversion of Dibromo formyl

Nornarwedine to Bromo formyl Nomarwedine. Reaction mass was filtered under heating and completely solid obtained (weight; 12g) was separated from ethanol by distillation. Water (30 ml) was added to solid and stirred for 1 hour at 25-30°C. The product was filtered and dried. Yield of Bromo formyl Nornarwedine was 8.9 g. Chromatographic purity (BY HPLC): 99.58%, Formyl Nornarwedine: 0.33%, Assay (BY HPLC): 98.0%

EXAMPLE-2: PREPARATION OF BROMO FORMYL NORNARWEDINE.

Bromo formyl norbelladine (35.0 g) was suspended in toluene (1.75 L) at 25-40°C. Potassium ferricyanide (152.25 g), 10% aq w/w potassium carbonate solution (0.7 L) and 18-Crown-6 (0.2 g) were added to above suspension and stirred for 1 hour 30 minutes at 25-40°C. After completion of the reaction, solid obtained (weight; 13.5g) was separated from toluene layer (volume-1265 ml) by distillation. Solid was dissolved in ethanol (583 ml). Zinc was added to this solution and stirred for 8 hours at 78-80°C for the conversion of Dibromo formyl Nornarwedine to Bromo formyl Nornarwedine. Reaction mass was filtered under heating and completely solid obtained (weight; 12.2g) was separated from ethanol by distillation. Water (30 ml) was added to solid and stirred for 1 hour at 25-30°C. The product was filtered and dried. Yield of Bromo formyl Nornarwedine was 9.1 g. Chromatographic purity (BY HPLC):99.7%, Formyl Nornarwedine: 0.17%, Assay (BY HPLC): 97.9%

EXAMPLE-3: PREPARATION OF BROMO FORMYL NORNARWEDINE.

Bromo formyl norbelladine (35.0 g) was suspended in toluene (1.75 L) at 25-40°C. Potassium ferricyanide (152.25 g), 10% aq w/w potassium carbonate solution (0.7 L) and 18-Crown-6 (1.75 g) were added to above suspension and stirred for 1 hour 30 minutes at 25-40°C. After completion of the reaction, solid obtained (weight; 13.6g) was separated from toluene layer (volume-1260 ml) by distillation. Solid was dissolved in ethanol (583 ml). Zinc was added to this solution and stirred for 8 hours 78-80°C for the conversion of Dibromo formyl Nornarwedine to Bromo formyl Nornarwedine. Reaction mass was filtered under heating and completely solid obtained (weight; 12.2g) was separated from ethanol by distillation. Water (30 ml) was added to solid and stirred for 1 hour at 25-30°C. The product was filtered and dried. Yield of Bromo formyl Nornarwedine was 9.1 g. Chromatographic purity (BY HPLC):99.74%, Assay (BY HPLC): 97.4%.

WE CLAIM

1. A process for the preparation of Bromo formyl Nornarwedine of Formula (I), which comprises:

(i) oxidative cyclization of compound of Formula (III);
with an oxidizing agent and a base in the presence of a phase transfer catalyst in a solvent to produce Dibromo formyl Nornarwedine of Formula (IV);


(ii) reacting the compound of formula (IV) with a metal in a solvent to produce Bromo formyl Nornarwedine of Formula (I).

2. The process according to claim 1, wherein the oxidizing agent used in step (i) is selected from potassium permanganate, lead tetraacetate, potassium dichromate, ferric chloride, potassium ferricyanide, hydrogen peroxide or mixture thereof.

3. The process according to claim 1, wherein the base used in step (i) is selected from sodium carbonate, sodium hydroxide, potassium bicarbonate, potassium carbonate, potassium hydroxide, calcium bicarbonate, calcium hydroxide, calcium carbonate, magnesium hydroxide, magnesium carbonate, magnesium bicarbonate or mixture thereof.

4. The process according to claim 1, wherein the phase transfer catalyst (PTC) used in step (i) is selected from crown ethers such as 18-crown-6 ether, 12-crown-4 ether, 15-crown-5 ether, dibenzo-18-crown-6 ether and diaza-18-crown-6 ether or mixture thereof.

5. The process according to claim 1, wherein the solvent used in step (i) is selected from esters such as ethyl acetate, isopropyl acetate; hydrocarbon solvents such as heptane, hexane, benzene, toluene, xylene, cyclopentane, cyclooctane; chlorinated hydrocarbon solvents such as dichloromethane, chloroform.

6. The process according to claim 1, wherein the metal used in step (ii) is selected from iron (Fe), tin (Sn), Zinc (Zn) or mixture thereof.

7. The process according to claim 1, wherein the solvent used in step (ii) is selected from alcohol solvents such as methanol, ethanol, propanol, butanol or mixture thereof.

8. The process according to claim 1, wherein the Bromo formyl Nornarwedine of Formula (I) is converted to Galantamine of Formula (II).