WO 2016027077, Cipla Ltd, New patent, Dabigatran

(WO2016027077) PROCESSES FOR THE PREPARATION OF DABIGATRAN ETEXILATE AND INTERMEDIATES THEREOF

WO 2016027077, Cipla Ltd, New patent, Dabigatran

CIPLA LIMITED [IN/IN]; Cipla House Peninsula Business Park Ganpatrao Kadam Marg Lower Parel Mumbai 400 013 (IN).

RAO, Dharmaraj Ramachandra; (IN).
MALHOTRA, Geena; (IN).
PULLELA, Venkata Srinivas; (IN).
ACHARYA, Vinod Parameshwaran; (IN).
SINARE, Sudam Nanabhau; (IN)

Dabigatran etexilate (a compound of Formula I) is the international commonly accepted nonproprietary name for ethyl 3-{[(2-{[(4-{(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]methyl}-1 -methyl-1 H- benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate,

 

(I)

Dabigatran etexilate is the pro-drug of the active substance, dabigatran. The mesylate salt (1 : 1 ) of dabigatran etexilate is known to be therapeutically useful as an oral anticoagulant from the class of the direct thrombin inhibitors and is commercially marketed as oral hard capsules as Pradaxa™ in Australia, Europe and in the United States; as Pradax™ in Canada and as Prazaxa™ in Japan. Additionally, it is also marketed in Europe under the same trade mark for the primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery.

Dabigatran etexilate was first described in U.S. Patent No. 6,087,380, according to which the synthesis of dabigatran etexilate was carried out in three synthetic steps as depicted in Scheme 1.

Scheme 1

 

1. HCL , EtOH

2. (NH4)2C03, EtOH

 

Dabigatran etexilate

II. HCI

The process involves the condensation between ethyl 3-{[3-amino-4-(methylamino)benzoyl] (pyridin-2-yl)amino}propanoate (compound VI) and N-(4-cyanophenyl)glycine (compound VIII) in the presence of Ν,Ν'-carbonyldiimidazole (CDI) in tetrahydrofuran (THF) to give the hydrochloride salt of ethyl 3-{[(2-{[(4-cyanophenyl)amino]methyl}-1-methyl-1 H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino} propanoate (compound IV), which is subsequently reacted with ethanolic hydrochloric acid, ethanol and ammonium carbonate to give the hydrochloride salt of ethyl 3-{[(2-[{(4-carbamimidoylphenyl)amino]methyl}-1-methyl-1 H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino} propanoate (compound II). Finally, the reaction between compound II and n-hexyl chloroformate (compound IX), in the presence of potassium carbonate, in a mixture of THF and water, affords dabigatran etexilate of Formula (I) after work- up and chromatographic purification. However, no information is given about the purity of the isolated dabigatran etexilate (I) product. Further, the process is not viable industrially as it requires chromatographic purification in several of its steps, thus making it very difficult and costly to implement on an industrial scale.

In order to simplify the process for obtaining dabigatran etexilate described in U.S. Patent No. 6,087,380, several alternative processes have been developed and reported in the art.

EP2118090B discloses a process for the preparation of the intermediate compound of Formula (II) by crystallization from a salt with p-toluenesulfonic acid. The amidine salt (ll-pTsOH) is obtained from a compound of formula (IV), which is also isolated in the form of a hydrobromide salt, (IV-HBr).

EP2262771A discloses a process for the preparation of the intermediate compound of Formula (IV), which is obtained in the form of a salt with oxalic acid. This document indicates that the oxalate intermediate of the compound (IV) crystallizes easily and is a good synthesis intermediate to obtain the amidine hydrochloride salt (ll-HCI) with high purity on an industrial scale. The compound (IV) in oxalate salt form is transformed in dabigatran following the process disclosed in WO 98/37075.

WO 2006/000353 describes an alternative process for the synthesis of dabigatran etexilate as depicted in Scheme 2.

 

Dabigatran etexilate

The process involves condensation between ethyl 3-{[3-amino-4-(methylamino)benzoyl](pyridin-2-yl)amino}propanoate (compound VI) and 2-[4-(1 ,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid (compound Villa) in the presence of a coupling agent such as CDI, propanephosphonic anhydride (PPA), or pivaloyl chloride, to give ethyl 3-{[(2-{[(4-{1 ,2,4-oxadiazol-5-on-3-yl}phenyl)amino]methyl}-1 -methyl-1 H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound IVa), which is subsequently hydrogenated in the presence of a palladium catalyst to give ethyl 3-{[(2-{[(4-carbamimidoylphenyl)amino]methyl}-1-methyl-1 H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino} propanoate (compound II). The compound II is acylated with n-hexyl chloroformate (compound I) to give dabigatran etexilate. Finally, dabigatran etexilate is converted into its mesylate salt. Although the patent describes the HPLC purities of intermediate compounds II, IVa, Villa and VI, no information is given concerning the purity of the isolated dabigatran etexilate or the mesylate salt thereof.

WO 2010/045900 discloses a process to prepare the intermediate amidine hydrochloride compound (ll-HCI) from the oxalate salt of the compound (IV) by reacting with hydrogen chloride in ethanol, followed by reaction with ammonium carbonate to avoid chromatography which is not feasible on an industrial scale.

WO 2014/012880 discloses a process to prepare an intermediate of dabigatran etexilate (compound IV) by reacting carboxylic acid (compound VIII) with diamaine (compound VI) in the presence of the coupling agent CDI, followed by reaction with 6 equivalents of acetic acid at 130°C to obtain compound IV in acetate salt form, having a purity of 94%. The isolated solid is further recrystallized from ethanol to obtain a purity of 99%. The purified (compound IV. acetate) is reacted with hydrogen chloride in the presence of an alcohol, and then with ammonia in an aqueous medium to form the amidine hydrochloride salt (compound ll-HCI) in the presence of water.

The synthesis of intermediate compound II has been reported in the patent literature and known methods require either chromatographic purification or a lengthy purification procedure, such as converting the compound into the HCI salt followed by recrystallization, to obtain 97% pure intermediate compound II. In previously reported methods, the product yield is undesirably less than 50 %.

Similarly, the intermediate compound IV prepared by CDI mediated coupling with glycine derivatives followed by acetic acid mediated cyclization according to known methods results in the formation of highly impure products, which require purification by either column chromatography or by converting the crude reaction mixture to suitable salts. Previously reported methods afford low product yields and purity, which mean that such processes are not suitable for the commercial scale production of dabigatran.

In view of the foregoing, it is of great interest to continue investigating and develop other alternative simplified processes for the large scale industrial production of the active pharmaceutical ingredient dabigatran etexilate or salts thereof, which avoid complicated and costly purification steps in the synthesis of intermediates, while maintaining a high quality of synthesis intermediates and improving the yields of each step of reaction.

SCHEME 3

SCHEME4

Examples:

Example 1. Preparation of DAB Glycin-CDI complex of Formula (VII)

71.02 g (0.438 mol) of CDI was dissolved in 700 ml dichloromethane under nitrogen atmosphere. Added 66.89 g (0.379 mol) of 2-(4-cyanophenylamino)acetic acid of Formula (VIII), under stirring at 20-25°C and stirred for 90-100 minutes. Solid was isolated by filtration under nitrogen atmosphere and washed with 100 ml dichloromethane to yield DAB Glycin-CDI complex.

Example 2. Preparation of ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV)

DAB Glycin-CDI Complex obtained in Example 1 was stirred in 650 ml toluene. Added 100 g (0.292 mol) of ethyl 3-(3-amino-4-(methyl amino)-N-(pyridin-2-yl)benzamido)propanoate of Formula (VI) to the reaction mass and stirred for 3 hours at -45-50°C. The reaction mass was further refluxed for 3 hours. The reaction mass was cooled to 75-80°C, added 50 ml ethanol, further cooled to 20-25°C and stirred for 6 hours. The solid was isolated by filtration and washed with 100 ml toluene.

The wet cake was stirred in 500 ml water at 20-25°C for about 1 hour. The solid was isolated by filtration, washed with 100 ml water and dried in vacuum below 60 °C.

Yield: 120 g

Efficiency: 85%

Example 3. Preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]imidazole-5-carboxamido) propanoate of Formula (II)

100 g (0.207 mol) of ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV) was added to 1000 ml EtOH.HCI (32-35%w/w) at 5-10°C under nitrogen atmosphere and stirred for 24 hours at 15-20°C. The solvent was distilled off in vacuum below 40°C. Added 500 ml ethanol and cooled to 0-5°C. The pH of the reaction mass was adjusted to 9.5-10.0 by addition of 400 ml EtOH.NH₃ (10-13%w/w). The temperature of the reaction mass was raised to 20-25°C and stirred for 12 hours. The reaction mass was filtered and the clear filtrate was partially distilled to the half volume below 40°C. The temperature of the reaction mass was raised to 55-60°C. Added 600 ml ethyl acetate at reflux. The reaction mass was cooled to 20-25°C and stirred further for 5 hours. The solid was isolated by filtration and washed with 100 ml-ethyl acetate. The solid was dried in vacuum below 45 °C.

Yield: 72.5 g

Efficiency: 70%

Example 4. Preparation of DAB etexilate of Formula (I)

120 ml acetone, 60 ml water, 16.6 g (0.120 mol) potassium carbonate and 20g (0.040 mol) of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]imidazole-5-carboxamido) propanoate of Formula (II) were stirred at 20-25°C. A solution of 9.88 g (0.060 mol) of hexyl chloroformate of Formula (IX) in 50 ml acetone was added to the reaction mass at 15-20°C in 1 .5 hours. The reaction mass was further stirred for 2 hours at 15-20°C. The precipitated solid was filtered and washed with 40 ml water.

The wet cake was dissolved in 160 ml acetone at 20-25°C. The insoluble were removed by filtration. Added 160 ml water to the clear filtrate at 20-25°C in 2 hours and the reaction mass was further stirred for 2 hours. The solid was isolated by filtration, washed with mixture of acetone : water (1 : 1), and dried under vacuum below 45°C to obtain dabigatran etexilate.

Yield: 18.85 g

Efficiency: 75%

Purification:

18 g of Dabigatran etaxilate was stirred in mixture of acetone: ethanol: ethyl acetate (1.5:0.5:6 volumes) at 50-55°C and stirred for 20 minutes. The reaction mass was cooled to 20-25°C and further chilled to 15-20 °C for 3 hours. The solid was isolated by filtration, washed with ethyl acetate and dried under vacuum below 45°C to obtain dabigatran etexilate.

Yield: 13.5 g

Efficiency: 75%

Example 5. Preparation of DAB etexilate mesylate

10 g (0.02 mol) of dabigatran etexilate was dissolved in 200 ml acetone under nitrogen atmosphere. The temperature of the reaction mass was raised to 50-55°C and treated with a solution of 1.86 g (0.0193 mol) of methane sulfonic acid in 50 ml acetone. The reaction mixture was stirred for 45 minutes, then cooled to 20-25 °C and further stirred for 45 minutes. The solid was isolated by filtration, washed with acetone and dried under vacuum below 45°C to obtain dabigatran etexilate mesylate.

Yield: 10 g

Efficiency: 86%

Example 6. Preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]imidazole-5-carboxamido) propanoate of Formula (ll)using N-acetyl cysteine

10 g (0.020 mol) of ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV) was dissolved in 600 ml EtOH.NH₃ (15-18%w/w) and stirred at 25°C. Added 3.38 g (0.020 mol) of N-acetyl cysteine to the reaction mass and stirred for 24 hours at 70-75°C under 2.0-2.3 kg of pressure. The ethanol was distilled under vacuum and residue was purified by column.

Yield: 5.5 g

Efficiency: 53%

Example 7. Preparation of DAB Amidine of Formula (II) using N-acetyl cysteine

10 g (0.020 mol) of ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV) with 3.5 g (0.021 mol) of N-acetyl-(S)cysteine were initially charged in 10 ml of ethanol. The reaction mixture was heated to 60-65°C, and saturated with ammonia. After 4 hours, ethanol was distilled under vacuum to obtain titled compound as a solid.

Yield: 7.0 g

Efficiency: 67%

Example 8. Preparation of 2-pyridyl impurity B

Part I: 12.0g (0.016 mol) of dabigatran etexilate was added to the solution of 2.8 g (0.07 mol) sodium hydroxide (in 300 ml water and 150 ml ethanol. The reaction mass was stirred for 5 hours. The solution was concentrated under vacuum and neutralized with aq. solution of citric acid (10%v/v). The solid was separated by filtration and washed with cold water and dried under vacuum to afford the acid as a white crystal.

Yield: 8.50 g

Part 11:10 g ( 0.0166 mol) of DAB-Acid obtained in part I was stirred with 25 ml thionyl chloride under nitrogen The temperature of the reaction mass was raised to 40-45°C and maintained for 1 hour. Thionyl chloride was distilled under vacuum completely The residue was stirred in solution of 100 ml toluene and 10 ml triethyl amine at 5-10°C. Added 3.1 g (0.0329 mol) 2-amino pyridine to the reaction mass at 5-10°C under nitrogen atmosphere. Temperature of the reaction mass was raised to 50-55°C and stirred. Toluene was distilled under vacuum and the residue was dissolved in 150 ml DCM. The organic layer was washed with water, dried on sodium sulfate. The organic layer was distilled under vacuum to obtain t crude 2-Pyridyl impurity which was purified by column chromatography.

Yield: 4.0 g

Example 9. Preparation of ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV)

To a solution of N, N-Carbonyldiimidazole (1.17kg, 7.21 mol) and dichloromethane (1 1.25 L), added 2-(4-cyanophenylamino)acetic acid of Formula (VIII), (1.15Kg,6.52 mol) at 30°C under nitrogen atmosphere. The reaction mixture was stirred for 90-100 min and the resulting solid was filtered under nitrogen atmosphere to obtain form Dab glycine CDI complex of Formula (VII).

Dab glycine CDI complex of Formula (VII) was stirred in toluene (9.0L). Added ethyl 3-(3-amino-4-(methyl amino)-N-(pyridin-2-yl)benzamido)propanoate of Formula (VI) (1.5Kg, 4.38 mol) and maintained the reaction at 45-55°C for 3.0 hrs to form DAB coupling intermediate of Formula (V), which further heated to 90-100°C for 3.0 hrs. The reaction mixture was cooled to 25-30°C and the solid precipitated out was isolated by filtration. The wet cake was stirred in water (9.0L), filtered and dried in vacuum below 60 °C to obtain titled compound.

Yield: 1.80kg

Efficiency: 85 %

Example 10. Preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]imidazole-5-carboxamido) propanoate of Formula (II)

A mixture of ethyl 3-(2-((4-cyanophenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]-imidazole-5-carboxamido) propanoate of Formula (IV) (1.73 kg,3.58mol) was stirred in ethanol denatured with toluene HCI (32-35 % w/w) (20.76 L) at 15- 20°C for 24 hrs. Reaction mass was distilled out completely and the residue was treated with ethanol denatured with toluene. NH₃ (at 10-15% w/w) was added to get the pH 9.0-9.5. The reaction mixture was stirred further for 12.0 hrs. The inorganic was separated by filtration and the filtrate was distilled out and the residue was stirred in ethyl acetate (10 L) . The solid was isolated by filtration and washed with ethyl acetate. The solid was dried in vacuum below 45°C to obtain titled compound.

Yield: 1.70kg

Efficiency: 95 %

Example 11. Preparation of DAB etexilate of Formula (I)

To a solution of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]imidazole-5-carboxamido) propanoate of Formula (II) (1.61 kg, 3.22mol ), acetone (19.32 L), water( 9.66 L) and potassium carbonate (1.34Kg, 9.69moles ) was added hexyl chloroformate (0.795 kg, 83 moles) slowly at 20-25°C in 2-3 hrs. The reaction mixture was stirred further for 90 min. The solid was filtered and stirred in 7.5 volumes of acetone at 35-40°C. To the clear solution was added dropwise, 7.5 volumes of purified water. The reaction mixture was stirred further for 2 hours at 20-25°C, solid was isolated by filtration and dried at 45°C. The solid was stirred in a mixture of ethanol: ethyl acetate (1 : 10 volume) at 35-40°C to get clear solution, then gradually cooled to 10-15°C and further stirred for 6.0 hours. The solid was isolated by filtration, washed with ethyl acetate and dried under vacuum below 45°C to obtain dabigatran etexilate.

Yield: 1.10 kg

Efficiency: 65%

Example 12. Preparation of DAB etexilate mesylate

Dabigatran etexilate (1.0Kg, 1.59mol) was dissolved in acetone (20.0L) at 50-55°C under nitrogen atmosphere and treated with a solution of methane sulfonic acid (0.15Kg, 1 .56mol) in acetone (1 .5L). The reaction mixture was stirred for 45 minutes, then cooled to 20-25 °C and further stirred for 45 minutes. The solid was isolated by filtration, washed with acetone and dried under vacuum below 45°C to obtain dabigatran etexilate mesylate.

Yield: 1.10kg Efficiency: 95 %

//////////WO-2016027077, WO 2016027077, Cipla Ltd, New patent, Dabigatran

MEGAFINE PHARMA (P) LTD, NEW PATENT, WO2015128875 A PROCESS FOR PREPARATION OF DABIGATRAN ETEXILATE MESYLATE AND INTERMEDIATES THEREOF

WO2015128875
A PROCESS FOR PREPARATION OF DABIGATRAN ETEXILATE MESYLATE AND INTERMEDIATES THEREOF
MEGAFINE PHARMA (P) LTD. [IN/IN]; Sethna, 4th Floor 55, Maharishi Karve Road, Marine Lines Mumbai 400002 (IN)

MEGAFINE
The present invention relates to an improved process for the preparation of Dabigatran etexilate and its acid addition salts thereof, wherein the said process substantially eliminates the potential impurities. The present invention also relates to an intermediate of Dabigatran etexilate and process for preparation thereof.

Dabigatran etexilate mesylate is an oral anticoagulant from the class of the direct thrombin inhibitors. Direct thrombin inhibitors (DTIs) are a class of medication that act as anticoagulants (delaying blood clotting) by directly inhibiting the enzyme thrombin. It is used to help prevent strokes or serious blood clots in people who have atrial fibrillation (a condition in which the heart beats irregularly, increasing the chance of clots forming in the body and possibly causing strokes) without heart valve disease. Dabigatran etexilate mesylate is approved in both US and Europe and commercially available under the brand name of Pradaxa.
Dabigatran etexilate mesylate is a double prodrug of the active substance, Dabigatran of formula (II). It is the pharmacologically active molecule formed through hydrolysis c

Dabigatran and process for its preparation was first disclosed in WO9837075 (henceforth Ό75) disclosed process involves the reaction of l-methyl-2-[N-[4amidinophenyl] aminomethyl]benzimidazol-5 -yl-carboxylicacid-N-(2-pyridyl)- N-(2-ethoxycarbonylethyl)amide hydrochloride of formula (VI) with hexylchloroformate in presence of potassium carbonate in tetrahydrofuran/water to provide l-methyl-2-[N -[4-(N -n-hexyloxycarbonylamidino) phenyl Jaminomethyl Jbenzimidazol- 5-yl-carboxylicacid- N-(2-pyridyl)- N-(2-ethoxy carbonylethyl)amide (herein after referred as dabigatran etexilate) of compound of formula (I). But WO'075 does not discuss or exemplify process for preparation of Dabigatran etexilate mesylate salt.
The key step of the disclosed process is the conversion of the nitrile of the Formula (V) into the amidine hydrochloride of formula (VI) by pinner reaction. The low yields of the pinner reaction can be derived from the water sensibility of the reaction on the one hand while the realization of the reaction is rendered more difficult on the other by the fact that the ester as well as amide, function of the molecule is susceptible to hydrolysis. According to Example 58b of said patent in an analogous manner to Example 25d 1.2 g of l-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-5-benzimidazole-carboxylic acid-N-(2-pyridyl)-N-[2-(ethoxycarbonylethyl]-amide (V) is reacted with ethanol saturated with hydrochloric acid in large dilution. The evaporated crude product is then converted to hydrochloric acid salt of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-5- benzimidazole-carboxylic acid-N-(2-pyridyl)-N-[2-(ethoxycarbonyl)-ethyl]- amide compound of formula(VI) using ethanol and ammonium carbonate. The disclosed process was not suitable for large scale production because of tedious workup procedures, less yield, low purity, separation by column chromatography, which in turn results in excessive production time and costlier process and less eco-friendly. The purification step performed by using large dilutions and column chromatography makes scale up and
commercialization of the process strongly limited. Hence, this process commercially viable.

Formula (VI)
SCHEME - I
Example 1 13 of WO'075 reveals the total yield of the final compound (I) is 22%.
J.Med.Chem. 2002, 45, 1757-1766 describes a process for preparation of compound of formula (III) as depicted in scheme -II.

SCHEME - II
The process for preparation of mesylate salt of dabigatran etexilate and its polymorphic forms was disclosed in US2005/234104. The disclosed process involves the reaction of Dabigatran etexilate with methane sulfonic acid in acetone to provide Dabigatran etexilate mesylate.
According to WO 2012/153158 (henceforth W0' 158) dabigatran etexilate base compound of formula (I) is characterized by mass spectrum, 1H NMR and melting point (128-129°C).WO 2008/059029 reports the melting point of 128 ±3°C for the anhydrous form-Ill. Further W0' 158 discloses that according to WO2006/000353 dabigatran etexilate of formula (I) is prepared as described in Examples 5A and 5B by reacting the tosylate salt of (6) and hexylchloroformate in an acetone-aqueous medium, obtained product is dried at 45°C and is not characterized by analytical data. On the basis of the calculations the product is presumed to be anhydrous. Thus according to WO 2006/000353 dabigatran etexilate is prepared by crystallization from an acetone/water system (Example 5A) and in said process no drying agent or other dehydrating agent is used.
Further W0' 158 reveals that on following the example 5A of WO 2006/000353 authors failed to obtain anhydrous dabigatran etexilate but rather modification thereof containing four moles of water was observed in dabigatran etexilate.
Further W0' 158 discloses that two anhydrous and tetrahydro form of dabigatran etexilate are described in WO 2006/131491. In this international patent application no process is disclosed for preparation of dabigatran etexilate but reference is made rather to basic patent and hence the said new forms are obtained by recrystallization from ethyl acetate (anhydrous form-I and anhydrous II Examples 1 and 2) and a mixture of acetone and water (tetrahydrate form, example 3).
According to disclosure of W0' 158, WO 2007/007142 three further variants are disclosed for the preparation of dabigatran etexilate (1) starting from the tosylate salt of the amidine (6); said procedures differ from each other in the reaction conditions and the work-up method. Thus Example 6A is identical with Example 5A of WO 2006/000353, however in the working up method of new variants 6B and 6C an azeotropic distillation is employed using butyl acetate for dehydration. Accordingly in these cases actually the anhydrate of dabigatran etexilate (1) is formed and consequently the yield is lower (yield of 1 using ditosylate of 6).
As per W0' 158, an article published in 2009 (UP .^'Com. Journal 2009, 9, 20) reports a detailed process for the realization of the Pinner-reaction mentioned in the basic patent, wherein the hydrolysis of the nitrile derivative of formula (V) is carried out at room temperature with the aid of an approximately 100 molar amount of hydrochloric acid. The process involves five re-crystallization steps to obtain pure di-hydrochloride (characterized by XRD). The disadvantages of the disclosed process are high dilution ratio, low yield, process is restricted to smaller batch size at commercial scale, process results in formation of impurities and is not cost effective at commercial scale, and involve 5 purification steps thereby making the said process unsuitable at industrial scale.
WO 2010/045900 discloses the preparation of free base of dabigatran etexilate of formula (I), from oxalate salt of nitrile compound of formula (V) via monohydrochloride and dihydrochloride of the amidine of formula (VI). These salts are found to degrade and lead to the formation of impurities and thereby yield dabigatran etexilate with low purity. Thus making the process less favorable at industrial scale.
Like any synthetic compound, Dabigatran etexilate mesylate contain extraneous compounds or impurities that can come from many sources. They may be un-reacted starting materials, by-products of reaction, products ,of side reaction, and/or degradation products. To meet the regulatory quality norms, identification, isolation, synthesis and characterization of the impurities followed by their control to the ICH levels in the final drug compound is a must. Potential impurities of Dabigatran etexilate mesylate are disclosed in EP2522662 and it also addresses the stability issues associated with dabigatran etexilate mesylate. Additionally W0' 158 discloses the additional set of impurities which are formed due to the use of poor quality of hexyl chloroformate. Hence, there is a need of simple, efficient and production friendly process for the preparation of dabigatran etexilate mesylate with high purity, yield and higher throughput.

The present invention relates to an improved process for preparation of l-methyl-2- [N-[4-(N-nhexyloxycarbonylamidino)phenyl]aminomethyl]benz imidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula (I) also known as dabigatran etexilate and its methane sulfonate salt compound of formula (la), represented by the following structural formulae:

Dabigatran Etexilate Dabigatran Etexilate Mesylate
The process of the present invention is an improved, commercially viable and industrially advantageous process for the preparation of Dabigatran etexilate mesylate wherein, the said process substantially eliminates the impurities formed during the preparation of Dabigatran etexilate mesylate.
Further, the present invention also provides novel acid additions salts of ethyl N-[(2- { [(4-cyanophenyl)amino]methyl} - 1 -methyl- 1 -H-benzimidazol-5-yl0carbonyl]-N- pyridin-2-yl-beta-alaninate (DEM-III), preferably p-toluene sulfonic acid salt, represented by structural formula (V), an useful intermediate in the synthesis of highly pure compound (la).

.p-toluene sulfonic acid addition sail
Formula (V)
............................

Formula (la)

Formula (la)



n)Dabigatran etexilate mesylate:
52.6 gm ' of ethyl 3-[(2{[4(hexyloxycarbonylaminoiminomethyl)phenylamino] methyl} - 1 -methyl- 1 H-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate dihydrate was added to 293 gm of acetone. The obtained mixture was heated to 40-46° C. with stirring. After a clear solution has formed, the contents of the apparatus was filtered and the filtrate was cooled to 30° C. to 36° C. 42 gm of acetone was precooled to 0° C. to 5° C and to it was added 7.5gm of 99.5% methanesulfonic acid. The obtained methanesulfonic acid solution was added in to the solution of ethyl 3-[(2- { [4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl } - 1 -methyl- 1 H-benzimi-dazole-5-carbonyl)pyridin-2-ylamino]propionate base at 26° C. to 36° C. within 15 to 40 minutes. Then the mixture was stirred for 40 to 60 minutes at 26° C. to 33° C. It was then cooled to 17° C. to 23° C. and stirred for a further 40 to 80 minutes. The crystal suspension was filtered and washed 270 ml of acetone. The product was dried under vacuum at 45-50° C. for at least 4 hours.
Yield: 53g (91.93%); Purity by HPLC: 99.81%.
CLAIM
Claim:
1. A process for the preparation of dabigatran etexilate of formula (I) or its acid addition salts thereof, comprising;
a. reacting hexyl-4-riitrophenyl carbonate compound of formula (XII) with 1- methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide (VI) or its acid addition salt in presence of a base and in a suitable organic solvent to provide dabigatran etexilate (I);

CLIPPED 2-43
44. The process as claimed in claim 18, wherein the form-I of dabigatran etexilate mesylate has purity greater than 99%; preferably 99.5%; more preferably 99.81% when determined by HPLC.
45. The process of any of the preceding claims, dabigatran etexilate of formula (I) or its acid addition salt of formula (la) has less than about 0.2% of DBIMP-1 impurity, has less than about 0.2% of DBIMP-2 impurity, has less than about 0.2% of DBIMP-3 impurity, has less than about 0.2% of DBIMP-4 impurity, has less than about 0.2% of DBIMP-5 impurity, has less than about 0.2% of DBIMP-6 impurity, has less than about 0.2% of DBIMP-7 impurity, has less than about 0.2% of DBIMP-8 impurity, has less than about 0.2% of DBIMP-9 impurity, has less than about 0.2% of DBIMP-10 impurity, has less than about 0.2% of DBIMP-11 impurity, has less than about 0.2% of DBIMP-12 impurity.

DBIMP-8

DBIMP- 1 DBIMP-12

ABOUT MEGAFINE

PROFILE

The company's R&D strengths are in creating intellectual property assets by developing non-infringing, novel, cost effective and environmentally friendly processes for APIs and finding easier solutions to complex chemistry challenges. We are specialized in constructing chiral molecules with strong expertise and experience in the resolution processes. Our R&D team consists of more than 60 qualified scientists with extensive expertise and experience in Process Research and Development activities for APIs and their critical intermediates. Our main philosophy is backward integration of APIs synthesis starting from basic raw material, thereby being self-dependent for critical intermediates to control cost and quality. Solid state studies, particularly polymorphism and particle size are proving to be bottle neck in marketing newer APIs. At Megafine, scientists are skilled in providing solutions to the problems associated with them. We have two research centres, one at Nashik, Maharashtra, India and another at Vapi, Gujarat, India. R&D centre at Vapi is mainly focused to provide critical intermediates with high purity and low cost through intensive research to our main R&D centre at Nashik and as well as to API manufacturers around the globe. A well - equipped R&D centre is supported by kilo lab having reactors from 5 lit to 250 lit, SSR/GLR vessels to solve scale-up issues at production. We are very specific in creating online documentations for various phases of process development including the scale-up, safety, and engineering reports which help production to have a safe and robust process and also to support regulatory filings.

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Megafine, established in 1995, is a privately owned and professionally managed enterprise with it's corporate office in Mumbai and two multipurpose manufacturing sites at Vapi & Nashik in India, both successfully inspected by US-FDA & the Nashik facility is also approved by EMEA, PMDA & KFDA. Both the plants are also certified by WHO GMP, ISO 9001:2008, 14001:2004 & OHSAS 18001:2007 and have been audited by several Innovators and leading Generic companies from time to time.
Megafine provides innovative & integrated API solutions with it's decades of experience and skill in the development of novel chemical processes catering to the global drug discovery and generic companies. Our continuous investment in research and development generates a steady flow of APIs enabling timely introduction of new products in the market. Megafine is committed to respecting third party intellectual property rights, manufacture products which are commercially competitive and meet the most stringent quality standards. Besides manufacturing its own Active Pharmaceutical Ingredients (APIs) & Advanced Intermediates, we also contract manufacture for global drug discovery and generic companies.
Our focus is on niche products; with a presence in more than 40 countries. Our partners are essentially drug discovery and generic drug companies across the globe for whom we develop a range of new niche products in select therapeutic categories like Anthelmintic, Cardiology, Urinary Incontinence, CNS (Central Nervous System), & a few others. We supply a wide range of high quality generic and custom manufactured APIs in volumes that range from a few grams to tons.
Megafine has special expertise in Polymorphs and Chiral products.
A perfect blend of Human talent, R&D Labs, Pilot Plant & cGMP manufacturing facilities backed by our Quality Assurance, Regulatory Affairs and Intellectual Property cell gives Megafine an edge.
Our regulatory team is well trained & experienced to comply with US-FDA, EDQM, Japanese PMDA & other regulatory authority requirements. The company has over 150 regulatory filings across the globe for its APIs to its credit with an impressive pipeline.

/////////MEGAFINE PHARMA (P) LTD, NEW PATENT, WO 2015128875  A PROCESS FOR PREPARATION OF DABIGATRAN ETEXILATE MESYLATE AND INTERMEDIATES THEREOF