The present invention reports improved process for preparation of Edoxaban Tosylate and its intermediates
BACKGROUND OF THE INVENTION:
Edoxaban (trade names Savaysa, Lixiana) is an oral anti-coagulant drug which acts as a direct factor Xa inhibitor. Compared to warfarin, it has fewer interactions with other medications.
It was developed by Daiichi Sankyo and approved in July 2011 in Japan for prevention of venous thromboembolisms (VTE) following lower-limb orthopedic surgery. It was also approved by the FDA in November 2015 for the prevention of stroke and non–central-nervous-system systemic embolism.
It is used for treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant and to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF).
Edoxaban inhibits free factor Xa and prothrombinase activity and inhibits thrombin-induced platelet aggregation. Inhibition of factor Xa in the coagulation cascade reduces thrombin generation and thrombus formation. Factor Xa (FXa) is an essential blood coagulation factor that is responsible for the initiation of the coagulation cascade. FXa cleaves prothrombin to its active form thrombin which then acts to convert soluble fibrinogen to insoluble fibrin and to activate platelets. Stabilization of the platelet aggregation by fibrin mesh ultimately leads to clot formation.
A number of anticoagulants inhibit the activity of Factor Xa. Unfractionated heparin (UFH), low molecular weight heparin (LMWH), and Fondaparinux inhibit the activity of factor Xa indirectly by binding to circulating Antithrombin (AT III). These agents must be injected. Warfarin, Phenprocoumon, and Acenocoumarol are orally active vitamin K antagonists (VKA) which decrease hepatic synthesis of a number of coagulation factors including Factor X. In recent years, a new series of oral, direct acting inhibitors of Factor Xa have entered clinical development. These include Rivaroxaban, Apixaban, Betrixaban, LY517717, Darexaban (YM150) and Edoxaban (DU-176b). Andexxa has been studied as a reversal agent for Edoxaban but has not received FDA approval so far.
Chemically, Edoxaban is N1-(5-chloropyridin-2-yl) -N2-((IS,2R/4S)-4- [(dimethylamino) carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino}eyelohexyl)ethanediamide, represented by the following formula (A) :

(A)
The p-toluenesulfonic acid monohydrate salt of compound A is represented by the following formula (B):

(B)
Several processes are known in the literature for preparing Edoxaban for example, US Patent No. 7365205; US Publication No. 20090105491.
Edoxaban (and salts/solvates thereof) may be prepared by a variety of methods. One such method involves use of an intermediate as depicted below, wherein PG is an amine protecting group (herein referred to as amine-protected (1S,2R,4S)-1,2-amino-N ,N-dimethylcyclohexane-4-carboxamide).

For example, US Patent No. 7,365,205 discloses Edoxaban, pharmaceutical acceptable salts thereof, as well as a process for the preparation of Edoxaban using this intermediate wherein the protecting group (PG) is Boc.
US20150239909A1 relates to an improved and industrially advantageous process for the preparation of (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one represented by the following formula (1):
which is a key intermediate in the synthesis of Edoxaban.
A method for the synthesis of the (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one (I) was reported in Tetrahedron Letters, 51, (2010) Pages 3433-3435 which involves the reaction of (1S)-cyclohex-3-ene-1-carboxylic acid represented by the following formula (II):

with N-bromosuccinimide in the presence of molecular sieves using dichloromethane as a solvent.
Example 45 of EP1405852B1 discloses the preparation of Edoxaban Tosylate monohydrate from Edoxaban free base dissolved in methylene chloride and p-toluensulfonic acid dissolved in ethanol. The solvent system is distilled off to change the solvent to ethanol/water and the product is crystallized from this mixture.
Reference Example 3 of US8686189B2 discloses the preparation of Edoxaban Tosylate monohydrate by reacting Edoxaban free base and p-toluensulfonic acid monohydrate in 30% hydrous ethanol. The product is crystallized from the reaction mixture after adding more ethanol.
Test Example 3 of EP2371830B1 discloses a preparation process of Edoxaban Tosylate monohydrate in ethanol/water with stable high yields based on the dissolution at a certain temperature of the Edoxaban free base and an amount of p-toluensulfonic acid monohydrate below the stoichiometric amount and adding an excess of p-toluensulfonic acid under low temperature. None of these documents disclose the purity obtained of the Edoxaban Tosylate monohydrate thus obtained.
WO2015129603A1 discloses a method of purification of Edoxaban Tosylate monohydrate from some process impurities using a mixture of ethanol/water based on dissolving the compound in a mixture of aqueous ethanol 70%v/v and adding more ethanol at a low temperature to crystallize the product. According to this document, the maximum content of any type of impurity following the purification method disclosed therein is 0.03%a/a and the total content of all impurities is 0.13%a/a or less by HPLC (detection wavelength 290nm) with respect to the HPLC area value of a free form of the Edoxaban. Taking into account that all the Examples were carried out from a starting material having a purity of 99.84% with all the impurities being in the amount of 0.03%a/a or less by HPLC and the total content of all impurities being 0.16%a/a or less by HPLC, and that the products obtained in Examples 1-3 have 99.87-99.88%a/a, the effect on the purification is not significant. Besides, this recrystallization process uses a huge amount of ethanol with respect to the amount of the starting material (21.6 volumes ethanol per weight starting material and 2.4 volumes water per weight of starting material) which is a drawback in terms of process economy.

Indian patent application 201641023903 relates generally to the synthesis of active pharmaceutical agents and more specifically to the preparation of an amine-protected (1S,2R,4S)-1,2-amino-N,N­ dimethylcyclohexane-4-carboxamide) camphor sulfonate, which may be an intermediate used in the synthesis of Edoxaban and pharmaceutically acceptable salts, solvates, or salt of solvates thereof. Further, the present invention provides methods for the synthesis of this intermediate with improved purity.
US Patent No. 8,686,189 discloses this Boc-protected intermediate as well along with acid addition salts thereof. Although the use of an azidation reagent (like ‘205 Patent) in this process has been reduced to one step, an azidation process is still required. Additionally, the required azidation step is lengthy, generally taking in excess of 70 hours to complete, which leads to a corresponding increase in product cycle times if the process is used commercially.
US Patent No. 8,357,808 discloses a process for the preparation of Edoxaban using an oxalate salt of the Boc-protected intermediate involving class II and costly solvent acetonitrile. It discloses conditions for preparation of Edoxaban intermediate. In this process, the generation of ‘Impurity X’ which is formed during the subsequent reaction of oxalate salt (X-A) is reportedly minimized by controlling the order of addition of reaction components and adding a tertiary amine in divided portions. However, this approach to impurity control can be operationally challenging to implement on an industrial scale.
Therefore, there was a need to develop an environment friendly and cost-effective process by replacing class II solvent acetonitrile which can yield good quality product.

SUMMARY OF THE INVENTION:
The present invention relates to improved cost effective and environment friendly processes for preparation of tert-Butyl ((1S,2R,5S)-2-(2-((5-chloro pyridin-2-yl)amino)-2-oxoacetamido)-5-dimethyl carbamoyl)cyclohexyl)carbamate (III) intermediate and its further use for preparation of Edoxaban Tosylate. This intermediate was further converted to N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino] cyclohexyl]oxamide-4-Methylbenzenesulphonic acid Monohydrate (B) or Edoxaban Tosylate Monohydrate. During the process special emphasis was laid on the usage of industrially friendly green and low-cost solvents aliphatic alcohols like methanol i.e. replacement of costly and non-eco friendly solvents with green solvents.
Chemical Structures and Codes of various stages of Edoxaban Tosylate used are given below:
Stage Code Structure
I .(COOH)2

II

III

IV

A

B

DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, a novel environment friendly, easy to commercialize and cost effective process for the preparation of tert-Butyl ((1S,2R,5S)-2-(2-((5-chloro pyridin-2-yl)amino)-2-oxoacetamido)-5-dimethyl carbamoyl)cyclohexyl)carbamate (III) is disclosed which comprises:
1. A solution of tert-Butyl ((1S,2R,5S)-2-amino-5-(dimethylcarbamoyl) cyclohexyl) carbamate oxalate (I) in aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol or a mixture thereof at 20-30°C is taken.
2. Triethylamine is added to the above solution followed by addition of Ethyl [(5-chloropyridin-2-yl)amino]oxoacetate Hydrochloride (II).
3. The reaction mass is stirred at 50-70°C for 6-10 hours to ensure reaction completion.
4. The reaction mass is cooled to 5-15°C.
5. The reaction mass is stirred for 3-4 hours to ensure complete crystallization.
6. The product is isolated as wet cake by routine filtration and drying at 40-50°C for 10-20 hours under vacuum to get desired tert-Butyl ((1S,2R,5S)-2-(2-((5-chloro pyridin-2-yl)amino)-2-oxoacetamido)-5-dimethyl carbamoyl) cyclohexyl)carbamate (III).
According to another aspect of the current embodiment, the material obtained above may be purified by recrystallization by using the same aliphatic alcohol solvent.
According to the second embodiment of the present invention, a novel environment friendly, easy to commercialize and cost effective process for preparation of N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide (A) is disclosed which comprises:
1. Deprotection of tert-Butyloxycarbonyl group of tert-Butyl ((1S,2R,5S)-2-(2-((5-chloro pyridin-2-yl)amino)-2-oxoacetamido)-5-dimethylcarbamoyl)cyclohexyl)carbamate (III) in chlorinated aliphatic hydrocarbons like methylene dichloride, chloroform, carbon tetrachloride, etc. or a mixture thereof in the presence of methane sulphonic acid at 20-40°C.
2. Adding Triethylamine to the reaction mass of step 1 followed by adding 5-Methyl-4,5,6,7-tetra hydro thiazolo[5,4-c]pyridine-2-carboxylic Acid Hydrochloride (IV) at 20-40°C.
3. Adding 1-hydroxy benzotriazole and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride at 20-40°C.
4. Stirring for 3-10 hours at 20-40 °C for reaction completion.
5. Isolation of product as residue by complete removal of solvent.
6. Isolation of product as solid in aliphatic alcohols like methanol, ethanol, etc. by filtration and drying at 40-50°C for 10-20 hours under vacuum to get the desired product N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino] cyclohexyl] oxamide or Edoxaban Base (A).
According to the third embodiment of the present invention, a novel process for preparation of N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino] cyclohexyl]oxamide-4-Methyl benzenesulphonic acid Monohydrate (B) or Edoxaban Tosylate Monohydrate is disclosed which comprises:
1. To the aqueous solution of aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol or a mixture thereof, adding N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl) amino] cyclohexyl] oxamide (A) at 20-30°C.
2. Heating the reaction mass to 55-65°C.
3. Adding solution of p-Toluene sulphonic acid in solvent as used in step 1 to the reaction mass.
4. Stirring for 60-90 minutes at 55-65°C temperature to ensure complete salt and monohydrate formation.
5. Cooling the reaction mass to 20-30°C.
6. Stirring for 2-3 hours to ensure complete crystallization.
7. Isolation of product as wet cake by routine filtration and drying at 40-50°C for 10-20 hours under vacuum to get desired pure N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide-4-Methyl benzene sulphonic acid Monohydrate (B) or Edoxaban Tosylate Monohydrate Form I having XRD as shown in figure 1 and TGA as per figure 3.
The above-mentioned invention is supported by the following non limiting examples:
Example 1: Preparation of tert-Butyl ((1S,2R,5S)-2-(2-((5-chloro pyridin-2-yl)amino)-2-oxoacetamido)-5-dimethyl carbamoyl)cyclohexyl)carbamate (III): To 100g of tert-Butyl ((1S,2R,5S)-2-amino-5-(dimethylcarbamoyl) cyclohexyl) carbamate oxalate (I) in methanol (300ml), triethylamine (120g) is added followed by addition of Ethyl [(5-chloropyridin-2-yl)amino]oxoacetate hydrochloride (II) at 20-30°C and the reaction mixture was heated to 50-70°C and stirred for 3-6 hours. After reaction completion, the reaction mass was cooled to 5-15°C and stirred for 1-3 hours for complete crystallization. The product was isolated by filtration and drying at 40-50°C for 10-20 hours to give 117g of tert-Butyl((1S,2R,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-dimethyl carbamoyl) cyclohexyl) carbamate (III) having HPLC purity 98.13%.
Example 2: Purification of tert-Butyl ((1S,2R,5S)-2-(2-((5-chloro pyridin-2-yl)amino)-2-oxoacetamido)-5-dimethyl carbamoyl)cyclohexyl)carbamate (III): 100gm of tert-Butyl ((1S,2R,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-dimethyl carbamoyl) cyclo hexyl)carbamate (III) in methanol (300ml) was heated to 50-70°C and stirred for 1-2 hours. Then the reaction mass was cooled and stirred at 5-15°C for 1-3 hours for complete crystallization. The product was isolated by filtration and dried at 40-50°C for 10-20 hours to give 90g of tert-Butyl((1S,2R,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-dimethylcarbamoyl) cyclohexyl) carbamate (III) having HPLC purity 98.54%.
Example 3: Preparation of tert-Butyl ((1S,2R,5S)-2-(2-((5-chloro pyridin-2-yl)amino)-2-oxoacetamido)-5-dimethyl carbamoyl)cyclohexyl)carbamate (III): To 100gm of tert-Butyl ((1S,2R,5S)-2-amino-5-(dimethylcarbamoyl) cyclohexyl) carbamate oxalate (I) in ethanol (300ml), triethylamine (120g) was added followed by addition of Ethyl [(5-chloropyridin-2-yl)amino]oxoacetate Hydrochloride (II) at 20-30°C. The reaction mixture was heated and stirred at 50-70°C for 2-5 hours. After reaction completion, the reaction mass was cooled and stirred at 5-15°C for 1-3 hours for complete crystallization. The product was isolated by filtration and drying at 40-50°C for 10-20 hours to give 100g of tert-Butyl ((1S,2R,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-dimethylcarbamoyl)cyclohexyl) carbamate (III) having HPLC purity 99.41%.
Example 4: Purification of tert-Butyl ((1S,2R,5S)-2-(2-((5-chloro pyridin-2-yl)amino)-2-oxoacetamido)-5-dimethyl carbamoyl)cyclohexyl)carbamate (III): 100gm of tert-Butyl ((1S,2R,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-dimethylcarbamoyl)cyclo hexyl)carbamate (III) in ethanol (300ml) was heated and stirred at 50-70°C for 1-2 hours. Then the reaction mass was cooled and stirred at 5-15°C for 1-3 hours to ensure complete recrystallization. The product was isolated by filtration and drying at 40-50°C for 10-20 hours to give 91g of tert-Butyl((1S,2R,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-dimethyl carbamoyl) cyclohexyl)carbamate (II) having HPLC purity>98%.
Example 5: To 100gm of tert-Butyl((1S,2R,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-dimethylcarbamoyl)cyclohexyl)carbamate (III) in methylene dichloride (1000ml) at 20-30°C, Methane Sulphonic Acid (103g) was added and the reaction mixture was stirred for 3-7 hours for reaction completion. Then the reaction mass was cooled to 0-5°C and triethyl amine (119g) was added followed by addition of 5-Methyl-4,5,6,7-tetra hydro thiazolo[5,4-c]pyridine-2-carboxylic Acid Hydrochloride (60g), 1-Hydroxy Benztriazole (23g) and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride (82g) and the resulting reaction mixture was stirred for 3-7 hours for completion of reaction. Thereafter, water (100 ml) was added to it and the pH was adjusted to 7.5-8.2 using aqueous sodium bicarbonate solution. The methylene chloride layer was separated followed by complete recovery to get residue and the product was isolated using methanol to get 104g N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl) amino] cyclohexyl] oxamide (A) or Edoxaban base as white solid having HPLC Purity= 99.52%.
Example 6: To 100g of tert-Butyl((1S,2R,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-dimethylcarbamoyl)cyclohexyl)carbamate (III)) in chloroform (1000ml) at 20-30°C, Methane Sulphonic Acid (103g) was added and the reaction mixture was stirred for 3-7 hours for reaction completion. The reaction mass was cooled to 0-5°C and triethyl amine (119g) was added followed by addition of 60g 5-Methyl-4,5,6,7-tetra hydro thiazolo[5,4-c]pyridine-2-carboxylic Acid Hydrochloride (IV), 1-Hydroxy Benztriazole (23g) and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride (82g) and the resulting reaction mixture was stirred for 3-7 hours for completion of reaction. Then, water (100ml) was added to it and the pH was adjusted to 7.5-8.2 using aqueous sodium bicarbonate solution. The chloroform layer was separated followed by complete recovery to get residue and the product was isolated using methanol to get 102g of N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl) amino] cyclohexyl] oxamide (A) or Edoxaban base as white solid having HPLC Purity= 99.61%.
Example 7: Preparation of Edoxaban Tosylate: 100g of N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl) amino] cyclohexyl] oxamide (A), ethanol (680ml) and water (120ml) mixture was heated to 55-65°C and slowly added PTSA solution in ethanol (35g in 100ml) and the reaction mixture was stirred for 60-90 minutes. Then the reaction mass was cooled and stirred at 20-30°C for 1-3 hours till complete crystallization. The product was isolated by filtration and drying at 40-50°C for 8-20 hours to get 120g of pure product Edoxaban Tosylate Monohydrate (B) having HPLC Purity = 99.94% & XRD as per Figure 1 and TGA as per figure 3.
Example 8: Preparation of Edoxaban Tosylate: 100g of N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl) amino] cyclohexyl] oxamide (A), methanol (680ml) and water (120ml) mixture was heated to 55-65°C and slowly added PTSA solution in ethanol (35g in 100ml) and the reaction mixture was stirred for 60-90 minutes. Then the reaction mass was cooled and stirred at 20-30°C for 1-3 hours till complete crystallization. The product was isolated by filtration and drying at 40-50°C for 8-20 hours to get 120g of pure product Edoxaban Tosylate Monohydrate (B) having HPLC Purity = 99.88% & XRD as per Figure 2 & TGA as per figure 4.

WE CLAIM:

1.A novel eco-friendly and cost effective process for preparation of tert-Butyl ((1S,2R,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-dimethylcarbamoyl)cyclohexyl) carbamate (III) which comprises:
I. stirring tert-Butyl ((1S,2R,5S)-2-amino-5-(dimethylcarbamoyl) cyclohexyl) carbamate oxalate (I) in aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol or a mixture thereof at 20-30°C;
II. adding Triethylamine followed by addition of Ethyl [(5-chloropyridin-2-yl)amino]oxoacetate Hydrochloride (II);
III. stirring the reaction mass at 50-70°C for 6-10 hours;
IV. cooling the reaction mass to 5-15°C;
V. stirring for 3-4 hours at 5-15°C; and
VI. isolating crude product as wet cake by filtration and semi drying the material at 40-50°C for 10-20 hours to get desired tert-Butyl((1S,2R,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacet amido)-5-dimethyl carbamoyl) cyclohexyl)carbamate (III).

2. An eco-friendly and cost effective process for preparation of N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide (A) which comprises:
I. stirring tert-Butyl ((1S,2R,5S)-2-(2-((5-chloro pyridin-2-yl)amino)-2-oxoacetamido)-5-dimethyl carbamoyl)cyclohexyl)carbamate (III) in chlorinated aliphatic hydrocarbons like methylene dichloride, chloroform, carbon tetrachloride or a mixture thereof in the presence of methane sulphonic acid at 20-40°C;
II. adding triethylamine to the reaction mass followed by adding 5-methyl-4,5,6,7-tetra hydro thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (IV) at 20-40°C;
III. adding 1-hydroxy benzotriazole and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride at 20-40°C;
IV. stirring for 3-10 hours at 20-40°C;
V. isolation of product as residue by vacuum distillation;
VI. stirring the residue in aliphatic alcohols like methanol, ethanol followed by filtration; and
VII. drying of the wet cake at 40-50°C for 10-20 hours to get desired product N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(di methylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino] cyclohexyl] oxamide or Edoxaban Base (A).
3. A novel process for preparation of N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(di methylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino] cyclohexyl]oxamide-4-Methyl benzenesulphonic acid monohydrate (B) or edoxaban tosylate monohydrate is disclosed which comprises:
I. N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl) amino] cyclohexyl] oxamide (A) or edoxaban base is dissolved in aqueous solution of aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol or a mixture thereof at 20-30°C;
II. heating the reaction mass to 55-65°C and adding solution of p-Toluene sulphonic acid in solvent of step i);
III. stirring for 60-90 minutes at 55-65°C;
IV. cooling the reaction mass to 20-30°C and stirring for 2-3 hours; and
V. isolating the crude product as wet cake by filtration and drying the material at 40-50°C for 10-20 hours to get desired pure N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(di methylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide-4-Methyl benzene sulphonic acid Monohydrate (B) or Edoxaban Tosylate Monohydrate Form I having XRD as per figure 1.