Description:FIELD OF THE INVENTION
The present invention relates to process for the preparation of tert-Butyl ((1R,2S,5S)-2-amino-5- (dimethyl carbamoyl) cyclohexyl) carbamate of Formula - I.

BACKGROUND OF THE INVENTION
Tert-Butyl ((1R,2S,5S)-2-amino-5- (dimethyl carbamoyl) cyclohexyl) carbamate is one of the key intermediate can be used in manufacturing of many Compounds. It is also used in the preparation of Edoxaban

Edoxaban chemical name is N 1 -(5-chloropyridin-2-yl) -N 2 -((1 S ,2 R ,4 S ) -4- [(Dimethyl amino) carbonyl] -2- [(5-methyl- 4,5,6,7- tetrahydro thiazolo [5,4-c] pyridin-2-yl) carbonyl] amino cyclohexyl) ethane diamide.

Edoxaban is an oral anticoagulant that inhibits activated blood coagulation factor X (also referred to as activating factor X or FXa) and is used as a preventive and/or therapeutic agent for thrombotic diseases that inhibit blood clotting, specifically nonvalvular It reduces the risk of embolism in which blood vessels are blocked by thrombus in diseases prone to thrombus formation, such as atrial fibrillation and deep vein thrombosis.

However, methods for preparing Edoxaban have significant disadvantages in terms of production efficiency and production cost.

It is well known fact that, the active pharmaceutical ingredients (APIs) are clearly dependents of the intermediates compounds which are used in the reaction and always leads to provide better productivity in the final stage. The use of economically produced intermediates will result in the production of API at an economically affordable condition.

Several processes for the preparation of tert-Butyl ((1R,2S,5S)-2-amino-5-(dimethyl carbamoyl) cyclohexyl) carbamate of Formula-I are disclosed in WO2014081047, IN266530, JP5548129, IN406262, US8686189 and US20050245565.

The process disclosed in prior art failed to provide efficient methods for obtaining tert-Butyl ((1R,2S,5S)-2-amino-5- (dimethyl carbamoyl) cyclohexyl) carbamate in high purity and high yields. The lack of efficient manufacturing processes increases the cost of the Edoxaban and the pharmaceutical compositions containing it, which has already resulted in expensive medications.

Therefore, it would be desirable and of paramount importance to have a process for the preparation of process for the preparation of tert-Butyl ((1R,2S,5S)-2-amino-5-(dimethyl carbamoyl) cyclohexyl) carbamate of Formula (I), by employing inexpensive, readily available, easy to handle reagents. It would also be desirable to have a process with high purity and high yield that can be readily scaled up and which does not require a special purification step, thereby making it more suitable for industrial scale preparation.

SUMMARY OF THE INVENTION
The present invention provides a cost effective, novel and an efficient process for the preparation of tert-Butyl ((1R,2S,5S)-2-amino-5- (dimethyl carbamoyl) cyclohexyl) carbamate of Formula (I) with higher yields and purity.

In one aspect, the present invention provides process for the preparation of tert-Butyl ((1R,2S,5S)-2-amino-5- (dimethyl carbamoyl) cyclohexyl) carbamate of Formula (I).

which comprises:

1) brominating the compound of Formula X

in presence of brominating agent, base and solvent to obtain compound of Formula IX;

2) hydrolysis of the compound of Formula IX with a hydrolysing agent in solvent to obtain compound of Formula VIII.

3) insitu reacting compound of Formula VIII with ammonium hydroxide to obtain compound of Formula-VII.

4) insitu reacting compound of Formula VII with base to obtain compound of Formula-VI.

5) protecting the compound of Formula VI with di-tert-butyl dicarbonate and base to obtain compound of Formula V.

6) mesylation of the compound of Formula V with mesylating agent, base and solvent to obtain compound of Formula IV.

7) insitu azidification of the compound of Formula IV with organosilane agent, alkali metal azide and base in solvent to obtain compound of Formula III.

8) insitu reduction of the compound of Formula III with reducing metalic agent, base in solvent, further with (+)-O, O’-Di-p-toluoyl-D-tartaric Acid or Maleic acid in presence of a solvent to obtain compound of Formula II.

9) reacting of the compound of Formula II with a base in presence of a solvent to obtain compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION
Base used in the reaction is selected from the group consisting of sodium methoxide, sodium carbonate, sodium bicarbonate, potassium methoxide, sodium hydroxide or potassium hydroxide, triethylamine, aq. ammonia and the like. Preferably using sodium hydroxide.

Solvent used in the reaction is selected from the group consisting of methylene dichloride, acetonitrile, acetone, methyl isobutyl ketone, methyl ethyl ketone, methyl tert-butyl ether, diisopropyl ethter, water, methanol, diisopropyl ether, toluene, n-methyl-2-pyrrolidone, dimethyl formamide, tetra hydro furan, ethyl acetate, hexane, isopropyl alcohol, ethanol, propanol and the like. Preferably using methanol and isopropyl alcohol.

The reagents used in the reaction is selected from the group consisting of n-bromosuccinimide, dibromo dimethyl hydantoin, di-tert-butyl decarbonate anhydride, 40% aq. N,N-Dimethyl amine, 25% aq. ammonia, Methane sulphonyl chloride, sodium azide and Trimethyl silyl azide, Raney Ni, 80% Hydrazine hydrate, D(+)-p-tolulyl tartaric acid, Maleic acid. Preferably using n-bromosuccinimide, Raney Ni, Trimethyl silyl azide and D(+)-p-tolulyl tartaric acid.

Metalic agent used in the reaction is selected from the group consisting of Sodium thiosulphate, ammonium chloride, Sodium chloride, Dodecyl pyridinium chloride. Preferably using Raney Ni.

Accordingly, the present invention provides processes for the preparation of tert-Butyl ((1R,2S,5S)-2-amino-5- (dimethyl carbamoyl) cyclohexyl) carbamate of Formula (I) as shown in the Scheme-I given below.

In one embodiment, the present invention provides process for the preparation of tert-Butyl ((1R,2S,5S)-2-amino-5- (dimethyl carbamoyl) cyclohexyl) carbamate of Formula (I).

In stage-1, brominating the compound of Formula X

in presence of brominating agent, base and solvent to obtain compound of Formula IX;

The reaction temperature may range from -5 to 25 °C and preferably at a temperature in the range from 5 to 15 °C. The duration of the stirring may range from 0 to 6 hours, preferably for a period of 2 to 4 hours.

In stage-2, hydrolysis of the compound of Formula IX with a hydrolysing agent in solvent to obtain compound of Formula VIII.

The reaction temperature may range from 5 to 35 °C and preferably at a temperature in the range from 10 to 15 °C. The duration of the stirring may range from 10 to 24 hours, preferably for a period of 14 to 15 hours.

In stage-3, insitu reacting compound of Formula VIII with ammonium hydroxide to obtain compound of Formula-VII.

The reaction temperature may range from 25 to 50 °C and preferably at a temperature in the range from 40 to 45 °C. The duration of the stirring may range from 5 to 10 hours, preferably for a period of 7 to 8 hours.

In stage-4, insitu reacting compound of Formula VII with base to obtain compound of Formula-VI.

The reaction temperature may range from 5 to 45 °C and preferably at a temperature in the range from 25 to 35 °C. The duration of the stirring may range from 10 to 24 hours, preferably for a period of 14 to 15 hours.

In stage-5, protecting the compound of Formula VI with di-tert-butyl decarbonate and base to obtain compound of Formula V.

The reaction temperature may range from 25 to 50 °C and preferably at a temperature in the range from 40 to 45 °C. The duration of the stirring may range from 2 to 10 hours, preferably for a period of 3 to 4 hours.

In stage-6, mesylation of the compound of Formula V with mesylating agent, base and solvent to obtain compound of Formula IV.

The reaction temperature may range from 0 to 25 °C and preferably at a temperature in the range from 5 to 15 °C. The duration of the stirring may range from 0 to 5 hours, preferably for a period of 2 to 3 hours.

In stage-7, insitu azidification of the compound of Formula IV with organosilane agent, alkali metal azide and base in solvent to obtain compound of Formula III.

The reaction temperature may range from 50 to 90 °C and preferably at a temperature in the range from 70 to 75 °C. The duration of the stirring may range from 24 to 72 hours, preferably for a period of 30 to 40 hours.

In stage-8, insitu reduction of the compound of Formula III with reducing metalic agent, base in solvent, further with (+)-O, O’-Di-p-toluoyl-D-tartaric Acid in presence of a solvent to obtain compound of Formula II.

The reaction temperature may range from 50 to 85 °C and preferably at a temperature in the range from 70 to 75 °C. The duration of the stirring may range from 5 to 25 hours, preferably for a period of 12 to 18 hours.

In stage-9, reacting of the compound of Formula II with a base in presence of a solvent to obtain compound of Formula I.

The reaction temperature may range from 15 to 45 °C and preferably at a temperature in the range from 25 to 35 °C. The duration of the stirring may range from 0 to 5 hours, preferably for a period of 0 to 1 hours.

EXPERIMENTAL SECTION
The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.

Example-1: Process for preparation of tert-Butyl ((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate

Stage-1: Process for the preparation of (1S,4S,5S)-4-Bromo-6-oxabicyclo[3.2.1]octan-7-one
To a solution of (I S)-3-cyclohexene-1-carboxylic acid (400.0 grams, 3.1708 mmol) in dichloromethane (2000 mL) was charged sodium bicarbonate (279.97 grams, 3.329 mmol), and the reaction mixture was cooled to 0-5° C. N-bromosuccinimide (592.5 grams, 3.329 mmol) was added in four portions (over 60 minutes) while maintaining the temperature 10±5° C . The yellow to white suspension was warmed to room temperature and stirring continued for 3 hours until completion of the reaction as measured by TLC (thin-layer chromatography). The reaction mixture was first treated with 10% aqueous sodium thiosulfate solution (2 x 2000 mL). After separation of the aqueous and organic phases, the organic phase was extracted with 10% ammonium chloride solution (2 x 2000 mL) and the organic phase was concentrated in vacuo then co-distilled with acetone (200 mL) at 45-50 ? to afford crude product which was further purified by acetone (400 mL) slurry at 55±5 ? then cooled to 0-5 ?, maintained for 3 h at same temperature. Reaction mixture was filtered through Buckner funnel and washed the wet cake with acetone (150 mL) afford (lS,4S,5S)-4-bromo-6-oxa-bicyclo [3.2.1]octan-7-one as a white solid (502 grams, 77% yield).

Stage-2: Process for the preparation of tert-Butyl ((1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl)carbamate
Compound obtained in Stage-1 (500 grams, 2.438 mol) was mixed by addition of acetonitrile (3125 mL) and an aqueous solution of dimethyl amine (40%, 1240 mL, 2.48 V). The reaction mixture was stirred at 10-15 °C for 15 hours and then concentrated under reduced pressure maintaining the temperature below 40°C. An aqueous ammonia solution (25%, 3.9 L, 51.52 mol) was added, and the mixture was stirred at 40-45 °C for 8-9 hours and then temperature cool to 25-35 ?, maintain for 14-15 hours then concentrated under reduced pressure, co-distilled with water (575 mL). Deionized water (2200 mL), di-tert-butyl dicarbonate (798 grams, 0.146 mol), and 48% NaOH aqueous solution (507.5 grams, 1.01 w/w) were added and stirred for 2 hours at 40-45°C. After reaction completion, sodium chloride (250 grams) and methylene dichloride (2000 mL) were added, and the layers were separated. The organic layer was washed with saturated sodium chloride solution (1000 mL) and the organic layer was concentrated under reduced pressure to afford crude which was purified by methyl tert butyl ether (1500 mL) slurry at 50-55 ? for 1h and then cool to 25-35 ?. The cake was filtered and washed with methyl tert butyl ether (250 mL) and dried under vacuum at 50-55 ? to give tert-Butyl ((1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl)carbamate as a white solid (447 g, 64% yield)

Stage-3: Process for the preparation of 3-3(1R,2R,4S)-2-((tert-Butoxycarbonyl)amino)-4-(dimethylcarbamoyl)cyclohexyl methanesulfonate
To a solution of compound obtainted in stage-2 (400 grams, 1.397 mol) in methylene dichloride (4000 mL), methane sulfonyl chloride (320.1 grams, 2.794 mol) and triethyl amine (367.6 grams, 3.632 mol) were added to the solution at 15±5?. The reaction mixture was stirred for 2 hours at 15±5°C. Methanol (1000 mL) and water (800 mL) were added to the mixture, and stirring was continued for 15 min, separated the layers and the organic layer was washed with 5% sodium bicarbonate aqueous solution (800 mL), and the separated organic phase was concentrated under reduced pressure at to afford crude which was purified by slurry with methyl tert butyl ether (1000 mL), isolated by filtration and wet cake washed with methyl tert butyl ether and dried under vacuum at 50-55 ? to give (1R,2R,4S)-2-((tert-Butoxycarbonyl)amino)-4-(dimethylcarbamoyl)cyclohexyl methanesulfonate as off-white solid. (444.0 grams, 87% yield).

Stage-4: Process for the preparation of tert-Butyl ((1R,2S,5S)-2-azido-5-(dimethyl carbamoyl) cyclohexyl) carbamate
26.8 grams of Sodium azide was charged into a solution of (1R,2R,4S)-2-((tert-Butoxycarbonyl)amino)-4-(dimethylcarbamoyl)cyclohexyl methanesulfonate (50 grams, 0.137 mol, obtained in stage-3) in 250 mL of Dimethyl formamide in a round bottomed flask at 25-35 ?. It was heated at 70-75 ? and maintained for 24 h. Cooled to 25-35 ? and charged solution of 10 grams sodium carbonate in 300 mL of water. Cooled to 0-5 ? and maintained for 2 hours at same temperature and solid product separated by filtration. The wet material slurry with water (150 mL) followed by methyl tert butyl ether (150 mL) then filtered and dried obtained solid under vacuum at 50-55 ? for 12 hours afford tert-Butyl ((1R,2S,5S)-2-azido-5-(dimethyl carbamoyl)cyclohexyl)carbamate as an off-white solid. (31 grams, 72.5% yield)

Stage-5: Process for the preparation of tert-Butyl{(1R,2S,5S)-2-amino-5-[(dimethylamino)-carbonyl] cyclohexyl} carbamate -p-toluoyl-D-tartarate
To a solution of tert-Butyl ((1R,2S,5S)-2-azido-5-(dimethyl carbamoyl) cyclohexyl) carbamate (10 grams, 0.032 mol, obtained in stage-4) in water (60 mL) added hydrazine hydrate (80%, 10.04 grams, 0.1605 mol) and Raney Ni (3.0 grams) at 25-35? and the reaction was stirred at 70-75 °C for 16 hours and then filtrated. The filtrate was extracted with methylene dichloride (80 mL) then organic layer was concentrated under reduced pressure to crude residue and ethyl acetate (150 mL) and (+)-O, O’-Di-p-toluoyl-D-tartaric Acid (12.4 grams) were added to the residue at 25-35 ?. Reaction mixture was stirred at 50 °C for 3 hours. The resulting slurry was filtrated at 30 °C. The wet crystalline mass washed with ethyl acetate (10 mL) and the wet material dried under vacuum at 50-55? to give tert-Butyl{(1R,2S,5S)-2-amino-5-[(dimethyl amino)-carbonyl]cyclohexyl}carbamate p-toluoyl-D-tartarate as an white solid (19.5 grams, 90% yield).

Stage-6: Process for the preparation of tert-Butyl ((1R,2S,5S)-2-amino-5-(dimethyl carbamoyl) cyclohexyl) carbamate.
To a solution of tert-Butyl ((1R,2S,5S) -2- amino -5-(dimethyl carbamoyl) cyclohexyl) carbamate-p-toluoyl-D-tartarate (10 grams, 0.015 mol, obtained in stage-5) in water (50 mL), reaction mixture pH was adjusted to 12 with 20% aqueous NaOH solution (30 mL) at 25-35 ? and stirred for one hour. Reaction mixture was extracted with methylene dichloride (80 mL), layers separated, organic layer was concentrated under reduced pressure to afford crude which was leached with 1:2 ratio mixture of toluene and hexane at 25-35 ? then maintain for one hour. The product was isolated by filtration and wet cake was washed with hexane (10 mL). The wet material dried under vacuum at 50-55 ? to give tert-Butyl ((1R,2S,5S)-2-amino-5-(dimethyl carbamoyl) cyclohexyl) carbamate (3.6 grams, 85% yield).

, Claims:1) An improved process for the preparation of tert-butyl ((1r,2s,5s)-2-amino-5-(dimethylcarbamoyl) cyclohexyl) carbamate compound of Formula (I)

which comprises:
1) brominating the compound of Formula (X)

in presence of brominating agent, base and solvent to obtain compound of Formula (IX);

2) hydrolysis of the compound of Formula IX with a hydrolysing agent in solvent to obtain compound of Formula VIII;

3) insitu reacting compound of Formula VIII with ammonium hydroxide to obtain compound of Formula-VII;

4) insitu reacting compound of Formula VII with base to obtain compound of Formula-VI;

5) protecting the compound of Formula VI with di-tert-butyl dicarbonate and base to obtain compound of Formula V;

6) mesylation of the compound of Formula V with mesylating agent, base and solvent to obtain compound of Formula IV;

7) insitu azidification of the compound of Formula IV with organosilane agent, alkali metal azide and base in solvent to obtain compound of Formula III;

8) insitu reduction of the compound of Formula III with reducing metalic agent, base in solvent, further with (+)-O, O’-Di-p-toluoyl-D-tartaric Acid or Maleic acid in presence of a solvent to obtain compound of Formula II;

9) reacting of the compound of Formula II with a base in presence of a solvent to obtain compound of Formula I.

2) An improved process for the preparation of tert-butyl ((1r,2s,5s)-2-amino-5-(dimethylcarbamoyl) cyclohexyl) carbamate compound of Formula (I)

which comprises:
1) brominating the compound of Formula (X)

in presence of brominating agent, base and solvent to obtain compound of Formula (IX);

2) hydrolysis of the compound of Formula IX with a hydrolysing agent in solvent to obtain compound of Formula VIII;

3) insitu reacting compound of Formula VIII with ammonium hydroxide to obtain compound of Formula-VII;

4) insitu reacting compound of Formula VII with base to obtain compound of Formula-VI;

5) protecting the compound of Formula VI with di-tert-butyl dicarbonate and base to obtain compound of Formula V;

6) mesylation of the compound of Formula V with mesylating agent, base and solvent to obtain compound of Formula IV;

7) insitu azidification of the compound of Formula IV with organosilane agent, alkali metal azide and base in solvent to obtain compound of Formula III;

8) insitu reduction of the compound of Formula III with reducing metalic agent, base in solvent, further with (+)-O, O’-Di-p-toluoyl-D-tartaric Acid in presence of a solvent to obtain compound of Formula II;

9) reacting of the compound of Formula II with a base in presence of a solvent to obtain compound of Formula I.

3) A compound of Formula (II), and its process of preparation, which comprises:

insitu reduction of the compound of Formula III with reducing metalic agent, base in solvent, further with (+)-O, O’-Di-p-toluoyl-D-tartaric Acid in presence of a solvent to obtain compound of Formula II.

4) A process for the preparation of tert-butyl ((1r,2s,5s)-2-amino-5-(dimethylcarbamoyl) cyclohexyl) carbamate compound of Formula (I)

which comprises:
1) insitu reduction of the compound of Formula III with reducing metalic agent, base in solvent, further with (+)-O, O’-Di-p-toluoyl-D-tartaric Acid or Maleic acid in presence of a solvent to obtain compound of Formula II;

2) reacting of the compound of Formula II with a base in presence of a solvent to obtain compound of Formula I.

5) The process as claimed in claim 1, 2 and 4, wherein said solvent is selected from group consisting of methylene dichloride, acetonitrile, acetone, methyl isobutyl ketone, methyl ethyl ketone, methyl tert-butyl ether, diisopropyl ethter, water, methanol, diisopropyl ether, toluene, n-methyl-2-pyrrolidone, dimethyl formamide, tetra hydro furan, ethyl acetate or hexane.

6) The process as claimed in claim 1, 2 and 4, wherein said base is selected from group consisting of sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine or ammonia.

7) The process as claimed in claim 1, 2 and 4, wherein said reagent is selected from group consisting of n-bromosuccinimide, dibromo dimethyl hydantoin, di-tert-butyl decarbonate anhydride, 40% aq. N,N-Dimethyl amine, 25% aq. ammonia, Methane sulphonyl chloride, sodium azide and Trimethyl silyl azide, Raney Ni, 80% Hydrazine hydrate, D(+)-p-tolulyl tartaric acid or Maleic acid.

8) The process as claimed in claim 1, 2 and 4, wherein said salt is selected from group consisting of Sodium thiosulphate, ammonium chloride, Sodium chloride or Dodecyl pyridinium chloride.