DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE PREPARATION OF INTERMEDIATES USED IN THE PREPARATION OF REVEFENACIN

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.
FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of intermediates and their conversion to Revefenacin.

BACKGROUND OF THE INVENTION

Revefenacin having a chemical name of 1-(2-{4-[(4-carbamoylpiperidin-1-yl)methyl]-Nmethylbenzamido}ethyl)piperidin-4-yl-N-({1,1’-biphenyl}-2-yl) carbamate (formula I):

Revefenacin is an anticholinergic and indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). Revefenacin is available as inhalation solution (175 mcg/ 3 mL) and being marketed in United States with brand name YUPELRI®.

EP0747355A1 of Yamanouchi Pharma discloses biphenyl piperidine carbamate process as shown in below scheme I:

The drawback of the said process is in the use of DPPA, which is highly toxic and a potential explosive like most other azide compounds. In the reaction, acyl azide compounds are formed as intermediate compounds and these compounds undergo degradation to give impurities. Further, DPPA is highly expensive reagent. The reaction also involves heating wherein acyl azide/DPPA can be potential explosive.

US 7,288,657 of Theravance Biopharma discloses Revefenacin and a process for the preparation thereof as shown in scheme II:

The said process is not suitable for industrial scale up as SO3.pyridine complex is extremely hygroscopic, and it degrades in the presence of moisture. Moreover, the obtained oxidized product, N-benzyl-N-methylamino aldehyde via oxidation of N-benzyl-N-methyl ethanolamine is not stable. This procedure may be feasible on a small scale but not suitable for industrial scale, due to the low purity of the final compound.

US 8,754,225 of Theravance Biopharma discloses a process for the preparation of Revefenacin, which involves preparation of biphenyl piperidine N-(methylamino)ethyl carbamate and its conversion to Revefenacin. The process of biphenyl piperidine N-(methylamino)ethyl carbamate is schematically represented in Scheme III:

This prior art process also involves reduction of aldehyde compound and lengthy process to prepare intermediate.

The inventors of the present invention observed that the prior art processes end up with one or the other problems, for example, high levels of impurities and low yields, when they have conducted experiments.

Therefore, there is a need to develop an improved process for the preparation of Revefenacin, which is simple, cost-effective, high purity, high yield at commercial scale.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is an improved process for the intermediates and their conversion to Revefenacin (I).

SUMMARY OF THE INVENTION

In an embodiment, the present invention is to provide an improved process for the preparation of Biphenyl piperidine carbamate of formula (V) used in the preparation of Revefenacin (I):

which comprises:
(a) reaction of biphenyl-2-isocynate of formula (III)

with 4-hydroxy piperidine compound of formula (IIIa),

in presence of base to obtain N-protected biphenyl piperidine carbamate of formula (IV);

wherein R is a leaving group;

(b) deprotection of N-protected biphenyl piperidine carbamate of formula (IV) with reducing agent to obtain biphenyl piperidine carbamate of formula (V).

In another embodiment, the present invention is to provide an improved process for the preparation of Revefenacin (I):

(a) reacting biphenyl piperidine carbamate of formula (V) with N-benzyl-N-methylamine of formula (III) or its salt thereof wherein X is a leaving group,

to obtain biphenyl piperidine N-benzyl-N-methyl carbamate of formula (VI);

(b) debenzylation of biphenyl piperidine-N-benzyl-N-methyl carbamate of formula (VI) to obtain biphenyl piperidine N-(methylamino) ethyl carbamate (VII); and

(c) converting biphenyl piperidine N-(methylamino)ethyl carbamate (VII) to Revefenacin (I).

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment, the present invention is to provide an improved process for the preparation of Biphenyl piperidine carbamate of formula (V):

The step (a) of the present invention comprises reacting biphenyl-2-isocynate compound of formula (III):

with 4-hydroxy piperidine of formula (IIIa):

wherein ‘R’ is a leaving group comprises tert-butoxycarbonyl (Boc), Benzyl (Bn), benzyloxycarbonyl (Cbz) and the reaction is carried between 20-120°C in presence of a base comprises triethylamine, diethylamine, N,N-dimethylaniline, N,N-diisopropyoethylamine or 4-dimethylaminopyridine; in presence of a solvent comprises toluene, tetrahydrofuran, acetone, butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, methyl acetate, methylene chloride, water or mixture thereof to obtain N-protected biphenyl piperidine carbamate compound of formula (IV).

The biphenyl-2-isocynate compound of formula (III) is obtained by reacting 2-aminobiphenyl with triphosgene at a reflux temperature in a solvent. The solvent comprises acetone, butanone, methyl isobutyl ketone, methylene chloride, ethyl acetate, hydrocarbon such as toluene or mixture thereof to obtain biphenyl-2-isocynate. The compound of biphenyl-2-isocynate may be isolated or obtained as in-situ compound.

In another embodiment, Biphenyl piperidine carbamate of formula (V) of the present invention comprises reacting biphenyl-2-isocynate compound of formula (III) with 4-hydroxy N-benzyl piperidine in presence of diisopropylethylamine.

After completion of the reaction, N-protected biphenyl piperidine carbamate compound of formula (IV) is extracted by using a solvent comprises toluene, methylene chloride, methyl isobutyl ketone, isopropanol, ethyl acetate, isopropyl acetate, mixture thereof.

Step (b) of the present invention comprises deprotection of N-protected biphenyl piperidine carbamate of formula (IV) by using a reducing agent to obtain biphenyl piperidine carbamate of formula (V). The reducing agent comprises acetyl chloride or trifluoroacetic acid or catalyst 10% Palladium on carbon or Nb2O5 on carbon at 30-70°C in presence or absence of solvent. The solvent comprises tert-butanol, methanol, ethanol, acetone, toluene, methylene chloride, methyl isobutyl ketone, propanol, isopropanol, ethyl acetate, isopropyl acetate, water or mixture thereof. After completion of the reaction, the catalyst is removed by filtration and the solution obtained is concentrated and/or subjected for isolation, which involves combining the concentrated mass in a solvent, treatment with base, extraction into suitable solvent and crystallization of the solid by recrystallization. The solvent comprises toluene, methylene chloride, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, or mixture thereof and the base comprises sodium hydroxide and potassium hydroxide.

In another embodiment, the present invention is to provide an improved process for the preparation of Revefenacin of formula (I):

In the process of Revefenacin, the step (a) comprises converting N-benzyl-N-methyl ethanolamine to N-benzyl-N-methyl ethylamine derivative of formula (III) or its salt thereof by adding thionyl chloride or para-toluenesulfonate to N-benzyl-N-methyl ethanolamine at a temperature of below 10°C in a solvent. The solvent comprises toluene, methylene chloride, methyl isobutyl ketone, methyl tert-butyl ether (MTBE), methanol, ethanol, isopropanol, ethyl acetate, or isopropyl acetate.

wherein X is a leaving group comprises halogen (-Cl, -Br, and -I) and tosylate and the reaction is carried out at 20-40°C. After completion of reaction, solvent is removed and isolated by using solvent selected from methyl isobutyl ketone, methyl tert-butyl ether, dichloromethane to obtain N-benzyl-N-methylamine of formula (III) or its salt. The obtained compound of formula (III) or its salt is dissolved in water under nitrogen atmosphere in presence of a base. The base is selected from sodium carbonate, sodium bicarbonate, potassium bicarbonate, and potassium carbonate. The reaction mixture is heated between 40-80°C to obtain a clear solution. To this solution, solution of biphenyl piperidine carbamate compound of formula (V) is added slowly at 40-80°C and stirred at 50-100°C under reflux till the completion of reaction. The reaction mass is concentrated and extracted by using solvent, which is selected from acetone, toluene, methylene chloride, methyl isobutyl ketone, methyl tert-butyl ether (MTBE), ethyl acetate and isopropyl acetate, to obtain biphenyl piperidine-N-benzyl-N-methyl carbamate compound of formula (VI).

The solution of biphenyl piperidine carbamate compound of formula (V) is obtained by dissolving in a solvent comprises acetone, toluene, methylene chloride, methyl isobutyl ketone, methyl tert-butyl ether (MTBE), methanol, tetrahydrofuran, ethanol, tert-butanol, isopropanol, ethyl acetate, isopropyl acetate at temperature of about 40-80°C while stirring for 5 min to 1h.
In the process of Revefenacin, step (b) comprises debenzylation of biphenyl piperidine-N-benzyl-N-methyl carbamate compound of formula (VI) by treating with a reducing agent. The reducing agent comprises Palladium-Carbon (Pd-C), supported palladium catalysts, in a solvent comprises water, C1-4 alcohol such as methanol, ethanol, isopropyl alcohol, tert-butanol, n-butanol, and/or mixtures thereof. The reduction is carried out in an autoclave at 35-40°C under nitrogen atmosphere till the completion of the reaction that monitored by qualitative HPLC analysis. After the completion of the reaction, the catalyst is removed by filtration. The filtrate is concentrated and extracted biphenyl piperidine N-(methylamino)ethyl carbamate (VII) by using a solvent comprises acetone, toluene, methylene chloride, methyl isobutyl ketone, methyl tert-butyl ether (MTBE), isopropyl acetate, and filtered. The filtered product is kept under suction to remove the solvent completely and dried to obtain biphenyl piperidine N-(methylamino)ethyl carbamate compound of formula (VII).

In another embodiment, the present invention provides a process for debenzylation of biphenyl piperidine-N-benzyl-N-methyl carbamate compound of formula (VI) by treating with a reducing agent that comprises Pd-C in presence of tert-butanol. The inventors of the present inventors found that the process of prior art, which involves use of ethanol, methanol leads to the formation of impurities such as secondary amine compounds. Thus, an improved process for debenzylation is developed to avoid/reduce the formation of impurities.

In the process of Revefenacin of the present invention, the step (c) comprises reacting biphenyl piperidine N-(methylamino)ethyl carbamate (VII) with 4-carboxybezaldehyde in presence of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC. HCl), N,N-diisopropylethylamine and hydroxybenzotriazole (HOBT) at 20-30°C while stirring till the completion of reaction. Water is added to the reaction mass and the organic layer is separated followed by treating the organic layer with aqueous acid such as hydrochloride and aqueous base such as sodium hydroxide. The organic layer is concentrated at a temperature below 45°C till no more solvent distils to obtain biphenyl piperidine N-methyl benzaldehyde. This compound is dissolved in methylene chloride while stirring for 2 h± 15 min to obtain a clear solution. To this solution, isonipecotamide solution is added. The reaction mass is cooled at 0-5°C followed by sodium triacetoxyborohydride is added slowly to the reaction mass at a temperature below 10°C. The temperature of the reaction is allowed to reach 20-30°C and stirred till the completion of reaction. The reaction mass is concentrated at below 45°C under reduced pressure, cooled to 20-30°C and treated with aqueous acid and aqueous base. Methylene chloride is added to reaction mass, organic layer is separated and concentrated, and Revefenacin is isolated as a wet filtered mass using solvents methanol and water.

The resultant wet mass of Revefenacin is purified. The purification process involves dissolution of the wet mass in methanol, treatment with carbon enoanticromos, addition of water slowly to the above filtrate at a temperature below 30°C and stirred for a period of 1-20 hours to complete the crystallization of Revefenacin. The resultant solid is filtered and washed with mixture of methanol and purified water. The obtained solid is kept under suction and dried to get Revefenacin in pure form.

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

EXAMPLES

Example 1: Preparation of Biphenyl-2-isocyanate (III):

2-Aminobiphenyl (II) (100 g) was dissolved in toluene (1000 ml) at 20-30°C and triphosgene (87.70 g) was added slowly at temperature 20-40°C. The contents were heated at temperature 105-115°C under reflux till the completion of the reaction monitored by qualitative HPLC analysis. The reaction mass is distilled and taken forward for next step.

Example 2: Preparation of Biphenyl piperidine carbamate using Boc-4-hydroxy piperidine (IV):

Methylene chloride (50 ml) was added to suspension of biphenyl-2-isocyanate (50 g), boc-4-hydroxy piperidine (51.5 g) and triethyl amine (51.8g) and stirred for 4 h at 25-30°C under nitrogen atmosphere. Ethyl acetate (500 ml) and DM Water (250 ml) were added to the reaction mass and stirred for 10 min. The layers were separated, and the organic layer was washed with sodium chloride solution (500 ml). The organic layer was concentrated under vacuum at 40-45°C to obtain a thick oily mass. Methanol (500 ml) was added to concentrated mass at 10 - 15°C followed by acetyl chloride (120.6 g) was added slowly at a temperature below 15°C in 1 h and stirred for 12 h at 20 - 30°C. The reaction mass was concentrated under vacuum at 40-45°C to obtain a thick residue. Methylene chloride was added to the residue and washed with 1N hydrochloric acid (250 ml). The layers were separated, and pH of the aqueous layer was adjusted to 12 with 50% sodium hydroxide (150 ml) followed by methylene chloride (500 ml) was added. The organic layer was separated and concentrated under vacuum at 40-45°C to obtain a thick oily mass. Ethyl acetate (500 ml) was added to the concentrated mass and heated to 50 - 55°C followed by cooling to 20 - 25°C. The reaction mass was stirred for 4 h at 20 - 25°C. The solid obtained was filtered and purified by column chromatography (30% ethyl acetate in hexane to ethyl acetate in 10% methanol) to get Biphenyl piperidine carbamate (21 g).

Example 3: Preparation of Biphenyl piperidine carbamate using 4-hydroxy-N-benzylpiperidine (IV):
Step-a: Preparation of biphenyl-2-isocyanate:

2-Aminobiphenyl (II) (100 g) was dissolved in toluene (1000 ml) at 20-30°C and triphosgene (87.70 g) was added slowly at a temperature of about 20-40°C. The contents were heated to the temperature of 105-115°C under reflux till the completion of the reaction monitored by qualitative HPLC analysis. The reaction mass was distilled and taken forward for the next step.

Step-b: Preparation of Benzyl protected Biphenyl piperidine carbamate:

Toluene (500 ml) was added to 4-hydroxy-N-benzylpiperidine (IIIa) (158 g) at 20-30°C and suspension was heated to 50-60°C under stirring. N,N-diisopropyoethylamine (15.25 g) was added to the solution at 50-60°C. This solution was added slowly to the solution of biphenyl-2-isocyanate (~1100 ml) at temperature of about 90-100°C and heated to 105-115°C under reflux for ~12 h. The reaction mass was cooled to 20-30°C and purified water (500 ml) was added and stirred at 20-30°C for 15±5 min. The layers were allowed to settle at 20-30°C for 15±5 min and upper organic layer (~1600 ml) was separated at 20-30°C. Toluene (200 ml) was added to the aqueous layer and stirred for 15±5 min. The layers were separated, and all the organic layers were combined. The combined organic layer (~1800 ml) was concentrated completely at a temperature below 60°C under reduced pressure to obtain Benzyl protected Biphenyl piperidine carbamate (IV) as thick oily material. The reaction mass was taken forward for the next step without further purification.

Step-c: Preparation of Biphenyl piperidine carbamate (V):

Benzyl protected biphenyl piperidine carbamate (IV) obtained as thick oily material (250 ml) was dissolved in ethanol (1000 ml). 5M aqueous HCl (150 ml) and ammonium formate (93 g) were added to this solution at 20-30°C. The above reaction mass was deoxygenated by purging nitrogen gas at 20-30°C for 15±5 minutes followed by 10% Palladium on carbon paste was added and heated the reaction to 45-55°C till the completion of the reaction monitored by qualitative HPLC analysis. The reaction mass was cooled to 20-30°C and Palladium catalyst was removed by filtration through a hyflo pad and the residue was washed with ethanol (200 ml) at 20-30°C under nitrogen atmosphere. The filtrate (~1400 ml) was concentrated at below 40°C under reduced pressure (400-20 mm Hg) till no more solvent was distils to obtain concentrated mass as an oily material. The contents were cooled to 20-30°C followed by purified water (500 ml) and methylene chloride (500 ml) were added at 20-30°C and pH of the reaction mass was adjusted to 12.0-13.0 by adding ~20% w/w aqueous sodium hydroxide (~230 ml) at 20-30°C for 15±5 min and stirred at 20-30°C for 15±5 min. The layers were allowed to settle at 20-30°C for 15±5 min and the lower organic layer (~500 ml) was separated at 20-30°C. Methylene chloride (200 ml) was added to aqueous layer at 20-30°C and stirred for 15±5 min. The layers were allowed to settle at 20-30°C for 15±5 min. The lower organic layer (~200 ml) was separated at 20-30°C and all the organic layers were combined. Purified water (500 ml) was added to the combined organic extract and stirred at 20-30°C for 15±5 min. The organic layer (~650 ml) was separated and concentrated at a temperature below 40°C under reduced pressure (500-20 mm Hg) till no more methylene chloride distils to obtain concentrated mass as a pale-yellow solid. Ethyl acetate (100 ml) was added to the concentrated mass and distilled completely at a temperature below 40°C under reduced pressure (200-20 mm Hg) to obtain concentrated mass as a pale-yellow solid. Ethyl acetate (1200 ml) was added to the above concentrated mass at 20-40°C and heated at 70-80°C under reflux and stirred to form a solution. The reaction mass was slowly cooled to 20-30°C and stirred 2 h±10 min. The contents were cooled to 0-5°C and stirred for 1h±10 min to precipitate the product. The product was filtered and washed with pre-cooled ethyl acetate (100 ml). The product was kept under suction and dried under reduced pressure for 2 h ± 15 min to obtain biphenyl piperidine carbamate (V) (105.0 g). (Yield: 65%, Purity: ~99% by HPLC).

Example 4: Preparation of N-benzyl N-methyl-2-chloroethylamine hydrochloride (III):

N-benzyl N-methylethanolamine (NBMEA, 125 g) was dissolved in methylene chloride (625ml) at 20-30°C and cooled to 0-5°C. Thionyl chloride (180.3 g) was added slowly at a temperature below 10°C. The temperature of the reaction was raised to 20-30°C and stirred for ~5 h. The reaction mass was concentrated under reduced pressure (400-20 mm of Hg) at a temperature below 40°C till no more solvent distils to obtain concentrated mass as a thick oily residue. Methylene chloride (250 ml) was added to concentrated reaction mass and continued distillation at a temperature below 40°C under reduced pressure (400-20 mm of Hg). The temperature of the reaction was adjusted to 20-30°C and methylene chloride (250 ml) was added and stirred for ~15 min to obtain a slurry. Methyl tert-butyl ether (875 ml) was added slowly to the slurry at 20-30°C and stirred at 20-30°C for 1 h±10 min to complete precipitation of N-benzyl-N-methyl-2-chloroethylamine hydrochloride. The obtained product was filtered and washed with methyl tert-butyl ether (MTBE, 375 ml) at 20-30°C under nitrogen atmosphere. The wet filtered mass (190 g) was dried under reduced pressure (100-20 mm Hg) for 2 h ± 15 min to obtain N-benzyl N-methyl-2-chloroethylamine hydrochloride (III) (165.0 g). (Yield: 85%, Purity: >99% by HPLC).

Example 5: Preparation of Biphenyl piperidine N-benzyl-N-methyl ethyl carbamate (VI):

Step a: Biphenyl piperidine carbamate (V) (125 gm) was dissolved in tetrahydrofuran (875 ml) at 20-30°C to obtain a suspension and heated at 50-60°C under stirring for ~15 min to obtain a clear solution.

N-benzyl N-methyl-2-chloroethylamine hydrochloride (III) (130 g) was dissolved in purified water (375 ml) under nitrogen atmosphere at 20-30°C and sodium carbonate (179 g) was added slowly and heated at 50-60°C. To this solution, Biphenyl piperidine carbamate solution (Step a) was added slowly at 50-60°C. The reaction mass was heated to 65-70°C under reflux and stirred till the completion of reaction monitored by qualitative HPLC analysis. The reaction mass (~1450 ml) was concentrated to a volume of ~800 ml at a temperature below 45°C under reduced pressure and the temperature was allowed to reach 25±5°C. Purified water (375 ml) and methylene chloride (875 ml) were added to the concentrated mass at 20-30°C and the layers were separated. Methylene chloride (375 ml) was added to the aqueous layer and the layers were separated, and all the organic layers were combined and washed with 30% w/w aqueous sodium chloride solution (675 ml). The organic layer was concentrated completely at a temperature below 40°C under reduced pressure. Isopropyl alcohol (250 ml) was added to the concentrated mass and distilled completely. Isopropyl alcohol (875 ml) was added to the concentrated mass and the contents were heated to 40-45°C and stirred for ~30 min. The reaction mass was cooled to 20-30°C and stirred for 4 h±15 min. Thereafter, the slurry was cooled to 0-5°C and stirred for 2h±10 min. The obtained product was filtered at 0-5°C and washed with pre-cooled isopropyl alcohol (250 ml) to obtain Biphenyl piperidine N-benzyl-N-methyl carbamate (VI) as a wet mass (~140 g) (Purity: 99% by HPLC).

Step-B: Preparation of Biphenyl piperidine N-(methylamino)ethyl carbamate (VII):

Tert-butanol (250 ml) was added to biphenyl piperidine N-benzyl-N-methyl carbamate (VI) (wet filtered mass, ~140 g as obtained in Example 5) and solution was concentrated at a temperature below 50°C under reduced pressure (400-20 mm Hg) till no more solvent distilled off. Tert-butanol (1250 ml) was added to the concentrated mass and temperature was adjusted to 35-45°C and the solution was transferred into an autoclave at 35-40°C. The slurry of 10% Palladium on carbon paste (37.5 g) in tert-butanol (250 ml) was added to the solution in autoclave under nitrogen atmosphere at 35-40°C. The autoclave was evacuated, and hydrogen was applied at pressure 50-60 psi (3.5-4.5 kg/cm2). The temperature of the reaction mass was lowered to 35-45°C and hydrogenation was continued by maintaining the hydrogen pressure at 50-60 psi (3.5-4.5 Kg/cm2) till the completion of the hydrogenation monitored by qualitative HPLC analysis. In the autoclave, hydrogen was replaced with nitrogen at 35-45°C, catalyst was removed by filtration through hyflo bed, and the residue was washed with preheated tert-butanol (250 ml,) under nitrogen atmosphere at 30-40°C. The concentrated mass was filtered at a temperature below 45°C under reduced pressure and concentrated mass was kept at 40-45°C under reduced pressure (<100 mm Hg) for ~30 min. Methylene chloride (250 ml) was added to the concentrated mass and distilled completely. Again, methylene chloride (188 ml) was added to the concentrated mass and heated to 30-40°C under stirring for ~15 min to form a solution. Isopropyl acetate (1250 ml) was added to the solution at 25-40°C slowly and the suspension was stirred for 4 h ± 15 min. The reaction mass cooled to 0-5°C and stirred for 2 h±10 min to precipitate the product. The product was filtered at 0-5°C and washed with pre-cooled isopropyl acetate (250 ml). The filtered product was kept under suction and further dried under reduced pressure for 2 h ± 15 min to obtain Biphenyl piperidine N-(methylamino)ethyl carbamate (VII) (87 g). (Yield: 65%, Purity: >99% by HPLC).

Example 6: Part-A: Preparation of Biphenyl piperidine N-methyl benzaldehyde:

Methylene chloride (1000 ml) was added to N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC. HCl, 65.0 g) at 20-30°C followed by N,N-Diisopropylethylamine (91.4 g), 4-Formylbenzoic acid (4-Carboxybenzaldehyde) (46.72 g) were added to above a solution under nitrogen atmosphere and stirred for 10±5 min. 1-Hydroxybenzotriazole (HOBT, 45.9 g) was added to the reaction mass at 20-30°C while stirring for 10±5 min. This solution was added to a solution of Biphenyl piperidine N-(methylamino)ethyl carbamate (Example-6, 100 g) prepared by dissolving in methylene chloride (500 ml) at 20-30°C over a period of 15±5 min. and stirred till the completion of reaction monitored by qualitative HPLC analysis. Purified water (1000 ml) was added to the reaction mass at 20-30°C and the contents were stirred for 15±5 min. The layers were separated, and aqueous 1N hydrochloride solution (800 ml) was added to the lower organic layer and stirred. The layers were allowed to settle and the lower organic layer (~1500 ml) was separated and repeated the same two times. The organic layer was treated with 1N aqueous sodium hydroxide solution (1000 mL) followed by with 10% w/w aqueous sodium chloride solution (1000 ml) and then concentrated completely at a temperature below 45°C under reduced pressure to obtain biphenyl piperidine N-methyl benzaldehyde (VIII) as oily mass (~150 g). (Purity: >95%). The resultant reaction mass was taken forward to the next step without further purification.

Part-B: Preparation of Revefenacin Technical:

Isonipecotamide (108.78 g) was suspended in isopropyl alcohol (3.5 lit) followed by acetic acid (34 g) and anhydrous sodium sulphate (80.40 g) were added at 20-30°C under nitrogen atmosphere to obtain a solution. To this solution, solution of biphenyl piperidine N-methyl benzaldehyde (~150 g) dissolved in methylene chloride (400 ml) was added at 20-30°C and stirred at 20-30°C for 2 h± 15 min. The reaction mass was cooled to 0-5°C and sodium triacetoxyborohydride (180 g) was added to the reaction mass in small lots at a temperature below 10°C. The temperature of the reaction mass was adjusted to 20-30°C and stirred till the completion of reaction monitored by qualitative HPLC analysis. The reaction mass was concentrated completely at below 45°C under reduced pressure (400-20 mm Hg) to obtain semi solid / thick oil(~ 680 g). The concentrated mass was cooled at 20-30°C and purified water (5 lit) was added to get a clear solution. The pH of the reaction mass was adjusted to 3.2 to 3.7 using conc. hydrochloric acid (~130 ml) at 20-30°C and 2-Methyl tetrahydrofuran (1.5 lit) was added to the solution and then the layers were separated. The aqueous layer was washed with methylene chloride (2 lit), cooled the aqueous layer to 2-10°C and the pH of the reaction mass was adjusted to 9.5 - 10.5 by adding ~30% w/w aqueous solution of sodium hydroxide (~280 ml). The temperature of the reaction mass was allowed to reach 20-30°C. These steps i.e. addition of MDC, separation layers, treating the organic layers with aqueous NaOH were repeated once again and then the organic layer was treated with 30% w/v sodium chloride solution and then concentrated completely at below 30°C under reduced pressure. Methanol (100 ml) was added to the concentrate and distilled the solvent completely. Methanol (100 ml) was added to the concentrated mass at 20-30°C and stirred for 15±5 min to obtain a clear solution. Purified water (1400 ml) was added slowly to the reaction mass and stirred for 18 h to complete the crystallization of the product. The product was filtered and washed with a mixture of methanol and purified water (1: 2 ratio; 300 ml) to obtain Revefenacin as a wet mass (~230 g), (Purity: 99.5%).

Part-C: Purification of Revefenacin (I):

Methanol (600 ml) was added to Revefenacin wet filtered mass (~230 g) at 20-30°C and stirred for 30±5 min. to obtain a clear solution. Carbon enoanticromos (5 g) was added to the solution and stirred for 1 h. The reaction mass was filtered through hyflo bed, and the residue was washed with methanol (150 ml) under nitrogen atmosphere. The reaction mass was filtered through micron filter and washed with methanol (50 ml). DM water (1600 ml) was added slowly to the above filtrate and stirred for 18 h to complete the crystallization of the product. The product was filtered and washed with a mixture of methanol and purified water (1:2; 300 ml). Further, the product was washed with purified water (2 x 100 ml) and dried under reduced pressure (100-20 mm Hg) for 2 h ± 15 min to get Revefenacin in pure form (Yield: 75%, Purity: >99.5%). ,CLAIMS:WE CLAIM:

1. A process for the preparation of Biphenyl piperidine carbamate of formula (V):

which comprises:
(a) reaction of biphenyl-2-isocynate of formula (III)

with 4-hydroxy piperidine compound of formula (IIIa),

in presence of a base to obtain N-protected biphenyl piperidine carbamate of formula (IV);

wherein R is a leaving group;

(b) deprotection of N-protected biphenyl piperidine carbamate of formula (IV) with reducing agent to obtain biphenyl piperidine carbamate of formula (V).

2. The process as claimed in claim 1, wherein the base comprises potassium carbonate, lithium carbonate, sodium carbonate, sodium ethoxide, sodium bicarbonate, potassium bicarbonate, potassium acetate, sodium acetate, diisopropylamine, diisopropylethylamine, triethylamine, dimethylamine and trimethyl amine.

3. The process as claimed in claim 1, wherein reducing agent comprises acetyl chloride or trifluoroacetic acid or Palladium on carbon or Nb2O5 on carbon.

4. The process as claimed in claim 1, wherein the leaving group is selected from tert-butoxycarbonyl (Boc), Benzyl (Bn) and benzyloxycarbonyl (Cbz).

5. The process as claimed in claim 1, wherein the compound of Formula (IIIa) is 4-hydroxy N-benzyl piperidine and the base is diisopropylethylamine.

6. A process for the preparation of Revefenacin (I), which comprises:
(a) reacting biphenyl piperidine carbamate of formula (V) with N-benzyl-N-methylamine of formula (III) or its salt thereof,

wherein X is selected from halogen and tosyl
to obtain biphenyl piperidine N-benzyl-N-methyl carbamate of formula (VI);

(b) debenzylation of biphenyl piperidine-N-benzyl-N-methyl carbamate of formula (VI) to obtain biphenyl piperidine N-(methylamino) ethyl carbamate (VII);

(c) converting biphenyl piperidine N-(methylamino)ethyl carbamate (VII) to Revefenacin (I).

7. The process as claimed in claim 6, wherein the Formula (III) is N-benzyl N-methyl-2-chloroethylamine or salt thereof.

8. The process as claimed in claim 6, wherein the debenzylation is carried out using the reducing agent comprises Pd-C, Fe, Sn, Zn in acidic media, and/or in combination with hydrogen.

9. The process as claimed in claim 6, wherein the debenzylation is carried out in presence of tert-butanol.