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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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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

DABIGATRAN PART 2/3


 

 

 

  • Dabigatran etexilate (a compound of formula (I)) is the international commonly accepted non-proprietary name for ethyl 3-{[(2-{[(4-{[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate, which has an empirical formula of C34H41N7O5 and a molecular weight of 627.73.

    Figure imgb0001
  • Dabigatran etexilate is the pro-drug of the active substance, dabigatran, which has a molecular formula C25H25N7O3 and molecular mass 471.51. The mesylate salt (1:1) of dabigatran etexilate is known to be therapeutically useful and is commercially marketed as oral hard capsules in the United States and in Europe under the trade mark Pradaxa for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. 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 (see Scheme 1). Example 58 describes the condensation between ethyl 3-{[3-amino-4-(methylamino)benzoyl](pyridin-2-yl)amino}propanoate (compound II) and N-(4-cyanophenyl)glycine (compound III) in the presence of N,N‘-carbonyldiimidazole (CDI) in tetrahydrofuran to give the hydrochloride salt of ethyl 3-{[(2-{[(4-cyanophenyl)amino]methyl}-1-methyl-1H-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-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound V). Finally, example 113 describes the reaction between compound V and n-hexyl chloroformate (compound VI), in the presence of potassium carbonate, in a mixture of tetrahydrofuran and water, to give dabigatran etexilate after work-up and chromatographic purification. However, no information is given about the purity of the isolated dabigatran etexilate.
    Figure imgb0002
    Figure imgb0003
  •  U.S. Patent No. 7,202,368 describes an alternative process for the synthesis of dabigatran etexilate (see Scheme 2). Example 3 describes the condensation between ethyl 3-{[3-amino-4-(methylamino)benzoyl](pyridin-2-yl)amino}propanoate (compound II) and 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid (compound VII) in the presence of a coupling agent such as N,N‘-carbonyldiimidazole (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-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound VIII), which is subsequently hydrogenated (Example 4) in the presence of a palladium catalyst to give ethyl 3-{[(2-{[(4-carbamimidoylphenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound V). Then, Example 5 describes the acylation of compound V with n-hexyl chloroformate (compound VI) to give dabigatran etexilate. Finally, Example 6 describes the conversion of dabigatran etexilate into its mesylate salt. Although the patent describes the HPLC purities of intermediate compounds II, VII, VIII and V, no information is given neither about the purity of the isolated dabigatran etexilate nor about its mesylate salt.
    Figure imgb0004
    Figure imgb0005
  •  European Patent Applications EP 1966171A and EP 1968949Adescribe similar processes for the synthesis of dabigatran etexilate to that depicted in Scheme 2, but without isolating some of the intermediate compounds. HPLC purities higher than 99% are described for both dabigatran etexilate (see Examples 6B and 6C ofEP 1966171A ) and its mesylate salt (see Example 9 ofEP 1966171A and Example 7 ofEP 1968949A). However, no information is given about the structure of the impurities present in dabigatran etexilate and / or its mesylate salt.
  •  PCT Patent Application WO 2010/045900 describes the synthesis of dabigatran etexilate mesylate with 99.5% purity by HPLC (Examples 3 and 4) by following a similar synthetic process to that described in Scheme 1. However, no information is given about the structure of the impurities present in the mesylate salt of dabigatran etexilate.
  •  The Committee for Medicinal Products for Human use (CHMP) assessment report for Pradaxa (i.e. dabigatran etexilate mesylate salt 1:1) reference EMEA/174363/2008, as published in the European Medicines Agency website on 23/04/2008, describes (page 8) that the proposed specifications for impurities in the active substance are for some specified impurities above the qualification threshold of the ICH guideline “Impurities in new drug substances”, i.e. above 0.15%. However, no information is given about the structure of the impurities present in the mesylate salt of dabigatran etexilate.

 

…………..

Patent

http://www.google.com/patents/EP2522662A1?cl=en

There is still further provided by the present invention a process of preparing dabigatran etexilate mesylate, which process comprises the following synthetic steps:

Figure imgb0024

wherein X is a leaving group, such as chloro.

 

Typically, intermediate (I) is prepared, preferably as a hydrochloride salt, by the following intermediate steps.

Figure imgb0025

Example 1: Synthesis of dabigatran etexilate mesylate

    • The overall synthetic scheme, and associated reagents, is as follows.

      Figure imgb0026

a) 4-(Methylamino)-3-nitrobenzoic acid

    • Figure imgb0027
    • 300 g (1.49 mol) of 4-chloro-3-nitrobenzoic acid were suspended in 769 g of a 25-30% aqueous solution of methylamine. After heating to reflux temperature, a clear solution was obtained. The solution was kept at reflux temperature for 2 hours and total consumption of 4-chloro-3-nitrobenzoic acid was checked by TLC. The solution was cooled to room temperature, and pH was adjusted to about 1 by addition of 2M aqueous sulphuric acid. Precipitation of a yellow solid was observed, which was isolated by filtration. The filtered cake was washed with water and subsequently with methanol to obtain 331 g of wet 4-(methylamino)-3-nitrobenzoic acid as a yellow powder. Purity (HPLC, method 2): 99.1 %.

b) Ethyl 3-(2-pyridylamino)propanoate

    • Figure imgb0028
    • 75.2 g (0.80 mol) of 2-aminopyridine and 88.0 g (0.88 mol) of ethyl acrylate were dissolved in 20 mL of acetic acid. The mixture was heated to 80°C and stirred for 24 hours at the same temperature. Solvent was removed under vacuum, and the title compound was isolated by vacuum distillation (b.p. 160-172°C, 10-15 mmHg) to obtain 77.0 g of ethyl 3-(2-pyridylamino)propionate as a white solid. Yield: 49.6 %.

c) Ethyl 3-{[{1-(methylamino)-2-nitrophen-4-yl}carbonyl](pyridyn-2-yl)aminolpropanoate hydrochloride

    • Figure imgb0029
    • 50 g (0.25 mol) of 4-(methylamino)-3-nitrobenzoic acid as obtained in step (a) were suspended in a mixture of 459.2 g of thionyl chloride and 3 mL of N,N-dimethylformamide. The mixture was stirred at reflux temperature for 45 minutes. Excess thionyl chloride was removed by vacuum distillation. The residue was dissolved in 300 mL of toluene, which was subsequently removed by vacuum distillation to remove completely any residual thionyl chloride. The brownish crystalline residue obtained was dissolved in 280 mL of tetrahydrofuran at 60°C. At this point, 35.1 g of triethylamine were added to the solution. Then, a solution of 45 g (0.23 mol) of ethyl 3-(2-pyridylamino)propanoate as obtained in step (b) in 95 mL of tetrahydrofuran was added dropwise over the reaction mixture, keeping the temperature at about 30°C. The resulting mixture was stirred overnight at room temperature. Solvent was removed by vacuum distillation, and the residue was dissolved in 1 L of dichloromethane. The resulting solution was washed with 500 mL of water, 500 mL of 2M hydrochloric acid, 500 mL of saturated sodium bicarbonate and 500 mL of water. The organic phase was dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved with 600 mL of ethyl acetate, and dry hydrogen chloride was bubbled into the solution until precipitation was completed. The solid was isolated by filtration and dried to obtain 63 g of the title compound, which was recrystallized in a mixture of 450 mL of ethanol and 50 mL of acetonitrile at reflux temperature. After cooling to 10°C, solid was isolated by filtration and dried to yield 44.7 g of ethyl 3-{[{1-(methylamino)-2-nitrophen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate hydrochloride as a yellow solid. Yield: 47.2 %. Purity (HPLC, method 1): 97.6 %.

d) Ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate (compound II)

    • Figure imgb0030
    • 82.2 g (0.20 mol) of ethyl 3-{[{1-(methylamino)-2-nitrophen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate hydrochloride as obtained in step (c) were suspended in 1.1 L of isopropanol, in the presence of 126.7 g of ammonium formate and 17.5 g of a 5 % Pd/C catalyst (55% water content). The reaction mixture was stirred at reflux temperature for 2.5 hours. After cooling to room temperature, the catalyst was removed by filtration, the filtrate was concentrated under vacuum, and the residue was dissolved in 1.5 L of ethyl acetate. The resulting solution was washed with 800 mL of saturated sodium bicarbonate and with 800 mL of water. The organic phase was dried with anhydrous sodium sulfate and was concentrated under vacuum to yield 44 g of ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate as a dark oil. Yield: 63.9 %. Purity (HPLC, method 2): 90.8 %.

e) 2-(4-Cyanophenylamino)acetic acid (compound III)

    • Figure imgb0031
    • 54.0 g (0.46 mol) of 4-aminobenzonitrile and 106.5 g (0.92 mol) of sodium chloroacetate were suspended in 750 mL of water, and the resulting mixture was stirred at reflux temperature for 4 hours. After cooling to room temperature, pH was adjusted to 8-9 with sodium bicarbonate. The resulting solution was washed with 2 x 200 mL of ethyl acetate, and 5M hydrochloric acid was added to the aqueous phase until pH=3. The precipitated solid was isolated by filtration, washed with 100 mL of water and dried to yield 57.1 g of 2-(4-cyanophenylamino)acetic acid as an off-white solid. Yield: 70.9 %. Purity (HPLC, method 3): 88.4 %.

f) Ethyl 3-{[(2-{[(4-cyanophenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate oxalate (salt of compound IV)

    • [0081]
      Figure imgb0032
    • 25.7 g (0.15 mol) of 2-(4-cyanophenylamino)acetic acid as obtained in step (e) and 22.8 g (0.14 mol) of 1,1′-carbonyldiimidazole were suspended in 720 mL of tetrahydrofuran. The mixture was stirred at reflux temperature for 1 hour. Then, a solution of 44.0 g (0.13 mol) of ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate as obtained in step (d) in 180 mL of tetrahydrofuran was added dropwise over the reaction mixture. The resulting mixture was stirred overnight at reflux temperature, and the solvent was removed by distillation under vacuum. The resulting residue was dissolved in 486 mL of acetic acid and heated to reflux temperature for 1 hour. After cooling to room temperature, solvent was removed by distillation under vacuum. The resulting residue was dissolved in 450 mL of ethyl acetate, and the solution was washed with 450 mL of water. The organic phase was dried with anhydrous sodium sulfate and heated to 50-60°C. At this temperature, 15.1 g (0.17 mol) of oxalic acid were added, and the resulting mixture was stirred for 1 hour at 50-60°C. After cooling to room temperature, the precipitated solid was filtered and dried under vacuum, to yield 47.7 g of ethyl 3-{[(2-{[(4-cyanophenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate oxalate as a brownish solid. Yield: 64.8 %. Purity (HPLC, method 1): 87.9 %

g) Ethyl 3-{[(2-{[(4-{carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound V)

    • Figure imgb0033
    • [0084]
      47.7 g (83 mmol) of ethyl 3-{[(2-{[(4-cyanophenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate oxalate as obtained in step (f) and 21.8 g of p-toluenesulfonic acid were suspended in 142 g of a 10M hydrogen chloride solution in ethanol. The mixture was stirred at room temperature for 24 hours. At this point, 400 mL of ethanol were added and the resulting mixture was cooled to 0°C. Ammonia gas was bubbled at this temperature until formation of precipitate was completed. The mixture was stirred at 10°C for 2 hours, and then was stirred at room temperature overnight. Solvent was removed by distillation under vacuum. The residue was dissolved in a mixture of 400 mL of ethanol, 400 mL of water and 2.3 g of sodium hydroxide at 55°C, and was stirred at this temperature for 45 minutes. After cooling to 10°C, the mixture was stirred at this temperature for 1 hour. The solid was removed by filtration and discarded. The mother liquors were concentrated under vacuum to remove ethanol. The precipitated solid was isolated by filtration, washed with 200 mL of water and with 2 x 100 mL of acetone, to yield 34.7 g of ethyl 3-{[(2-{[(4-{carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate as an off-white solid. Yield: 83.4 %. Purity (HPLC, method 3): 83 %.

h) Dabigatran etexilate

    • Figure imgb0034
    • 33.7 g (67 mmol) of ethyl 3-{[(2-{[(4-{carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate as obtained in step (g) and 24.7 g of potassium carbonate were suspended in a mixture of 280 mL of water and 1.4 L of tetrahydrofuran. After stirring at room temperature for 15 minutes, 9.2 g (56 mmol) of hexyl chloroformate were added dropwise. The resulting mixture was stirred at room temperature for 1 hour. The organic phase was extracted, washed with 400 mL of brine and dried with anhydrous sodium sulfate. The solvent was removed under vacuum, and the resulting solid was purified by column chromatography eluting with ethyl acetate, to yield 24.9 g of dabigatran etexilate as an off-white solid. Yield: 71.0 %. Purity (HPLC, method 1): 96.3 %.

i) Dabigatran etexilate mesylate

    • 18.7 g (30 mmol) of dabigatran etexilate as obtained in step (h) were suspended in 103 g of acetone. The mixture was heated to 45°C. After cooling to 36°C, a solution of 2.83 g of methanesulfonic acid in 11.6 g of acetone at 0°C was added dropwise over the reaction mixture. The reaction was stirred at 23-33°C for 90 minutes and at 17-23°C for 60 minutes. The resulting solid was isolated by filtration, washed with 97 mL of acetone and dried at 50°C under vacuum, to yield 18.7 g of dabigatran etexilate mesylate as a pale yellow solid. Yield: 86.7 %. Purity (HPLC, method 1): 98.8 %.

 

…………….

PATENT

http://www.google.com/patents/WO2010045900A1?cl=en

One of the advanced intermediates during the production of dabigatran is the substance of formula VI.

Figure imgf000004_0001

VI

The compound of formula VI is prepared by a reaction of substance IV with reagent V as shown in Scheme 1.

Figure imgf000004_0002

Scheme 1

The procedure described in WO 9837075 produces compound VI in the form of its base or acetate. Both these products require chromatographic purification, which is very difficult to apply in the industrial scale. This purification method burdens the process economy very much and has a negative impact on the yield.

In the next stage acidic hydrolysis of the nitrile function of compound VI and a reaction with ammonium carbonate is performed to produce the substance of formula VII. The reaction is shown in Scheme 2.

Figure imgf000004_0003

Vl VII

Scheme 2 The procedure in accordance with WO 9837075 produces substance VII in the monohydro chloride form.

When reproducing the procedure of WO 9837075 we found out, in line with WO 9837075, that compound VII prepared by this method required subsequent chromatographic purification as it was an oily substance with a relatively high content of impurities. We did not manage to find a solvent that would enable purification of this substance by crystallization.

The last stage is a reaction of intermediate VII with hexyl chloroformate producing dabigatran and its transformation to a pharmaceutically acceptable salt; in the case of the above mentioned patent application it is the methanesulfonate.

Scheme 3.

EtOH

Figure imgf000009_0001
Figure imgf000009_0002
Figure imgf000009_0003

DABIGATRAN

Example 3: Preparation of dabigatran mesylate

To 9.1 g of compound VII-2HC1 (0.016 mol) 270 ml of chloroform and 9 ml (0.064 mol) of triethylamine are added. Then, a solution of 3.1 ml (0.018 mol) of hexyl chloroformate in chloroform is added dropwise at the laboratory temperature. After one hour the reaction mixture is shaken with brine and the organic layer is separated, which is dried with sodium sulfate and concentrated. The obtained evaporation residue is crystallized from ethyl acetate. Yield: 8.6 g (86%)

This product is dissolved in acetone and an equimolar amount of methanesulfonic acid is added dropwise. The separated precipitate is aspirated and dried at the laboratory temperature. Yield: 75%; content according to HPLC: 99.5%. 27

Example 4:

Preparation of dabigatran mesylate

9 g of compound VII-HCl (0.017 mol) were dissolved in 300 ml of chloroform. 6, ml of triethylamine were added to this solution and then a solution of 3.4 ml (0.02 mol) of hexyl chloroformate in chloroform was added dropwise. After one hour the reaction mixture is shaken with brine, the organic layer is separated, which is dried with sodium sulfate and concentrated. The obtained evaporation residue is crystallized from ethyl acetate. Yield: 9.6 g (90%)

This product is dissolved in acetone and an equimolar amount of methanesulfonic acid is added dropwise. The separated evaporation residue is aspirated and dried at the laboratory temperature. Yield: 73%; content according to HPLC: 99.5%.

………………..

PATENT

http://www.google.com/patents/WO2014009966A2?cl=en

DabigatranEtexilateMesylate chemically know as N-[[2-[[[4-[[[(hexyloxy) carbonyl] amino]-iminomethyl] phenyl] amino] . methyl]-l -methyl-lH- benzimidazol-5-yl] carbonyI]-N-2- pyridinyl-beta-Alanine ethyl ester methanesulfonate having the formula I as provided below,

Figure imgf000003_0001

Formula I

is a direct thrombin inhibitor having anti – coagulant activity when administered orally.

DabigatranEtexilate is first time reported in the US patent 6087380 (hereinafter referred as US’380) in which the process fo the preparation of DabigatranEtexilate is disclosed in the Example 49, 58a and Example 59, said process for the preparation of DabigatranEtexilate is depicted below:

Figure imgf000004_0001

Dabigatran etexilate

In accordance to the process in the Patent US’380 the substance requires complex purifying operations, such as chromatography for the production of high- quality API. Further the chromatographic purification is expensive and difficult to implement in large scale. The impurity in the Dabigatran single prodrug and Dabigatran Etexilate affects the purity of the final product DabigatranEtexilateMesylate.. Hence there is a necessity to maintain the purity level of every intermediate involved in the preparation of DabigatranEtexilateMesylate.

The patent application US201 1082299 discloses a process for the preparation Dabigatran from 3- ([2-[(4-cyanophenyl amino)-methyl]- l-methyl- l H-benzimidazole-5-carbonyl]-pyridin-2-yl-amino) ethyl propionate oxalate as one of the intermediate in order to overcome the problem of the process depicted in the product pate

Figure imgf000004_0002

The patent US81 19810 discloses the process for the preparation Dabigatran from 3- ([2-[(4-cyanophenylamino)-methyl]-l-methyl-lH- benzimidazole-5-carbonyl]-pyridin-2-yl-amino) ethyl propionate hydro bromide as one of the intermediate in order to overcome the problem of the process depicted in the product patent.

Figure imgf000005_0001

The single prodrug of Dabigatran having the formula-II,

and double

Figure imgf000005_0002

which is DabigatranEtexilate are exemplified in the examples of the patent US’380. The patent US’380 has no information about the solid state properties of the single prodrug of Dabigatran and DabigatranEtexilate. However, a similar process described in a publication of Hauel et al in Journal of Medicinal Chemistry, 2002, 45, .1757 – 1766, wherein DabigatranEtexilate is characterized by 128 – 129°C.

The PCT publication WO2006131491 discloses the anhydrous form [ of DabigatranEtexilate having the melting point 135°C, anhydrous form II of DabigatranEtexilate having the melting point 150°C, and hydrate form of DabigatranEtexilate having the melting point 90°C.

The PCT publication WO2008059029 discloses anhydrous form III of DabigatranEtexilate having melting point 128°C, anhydrous form IV of DabigatranEtexilate having the melting point 133°C, and mono hydrate form I of DabigatranEtexilate having melting point 128°C and mono hydrate form II of DabigatranEtexilate having melting point 123°C.

The different forms of the single prodrug of Dabigatran and/or the DabigatranEtexilate are disclosed in the patent applications of WO2012027543, WO2012004396 and WO 2012044595.

The patent application US2007185333 discloses the process ; for the preparation of DabigatranEtexilateMesylate from the DabigatranEtexilate by adding acetone solution of , methanesulfonic acid in an acetone solution of DabigatranEtexilate.

The patent application US 200601 83779 discloses the process for the preparation of DabigatranEtexilateMesylate from the DabigatranEtexilate by adding ethylacetate solution of methanesulfonic acid in an ethylacetate solution of DabigatranEtexilate.

Example-9: Process for the preparation of DabigatranEtexilateMesylate from DabigatranEtexilate

[0086] The DabigatranEtexilate (0.04 mol) was dissolved in acetone (250.0 ml) and added Methanesulfonic acid (0.04 mol) in Ethyl acetate (25 ml) at 25-30°C. Stirred the reaction mass for 3 hrs at the same temperature, the isolated solid was filtered and washed with acetone, dried under vacuum to get the DabigatranEtexilateMesylate. Yield: 85 %, Purity: Not less than 99.0%

Example 10: Process for the preparation of DabigatranEtexilateMesylate

[0087] To a solution of DabigatranEtexilate (0.04 mol) in Acetone (8 volumes) and Ethanol (2 volumes), Methanesulfonic acid solution [Methanesulfonic acid (0.04 mol) was dissolved in Ethyl acetate (25 ml) was added at 25-30°C and stirred for 3 hrs at the same temperature. After completion of the reaction, the resultant solid was filtered, washed with acetone and dried under vacuum. Yield: 93%

 

……………

http://www.google.com/patents/WO2013150545A2?cl=en

l-methyl-2-|Tvi-[4-(TSi-n-hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazole- 5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide is commonly known as Dabigatran etexilate. Dabigatran is an anticoagulant from the class of the direct thrombin inhibitors developed by Boehringer Ingelheim and is used for the treatment of thrombosis, cardiovascular diseases, and the like. Dabigatran etexilalte mesylate was approved in both US and Europe and commercially available under the brand name Pradaxa.

Dabigatran etexilate and process for its preparation was first disclosed in WO 98/37075.

The disclosed process involves the reaction of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2- yl)benzamido)propanoate with 2-(4-cyanophenylamino) acetic acid in the presence of N,N- carbonyldiimidazole in tetrahydrofuran to provide ethyl 3-(2-((4-cyanophenylamino)methyl)-l- methyl-N-(pyridin-2-yl)-lH-benzo[d] imidazole-5-carboxamido)propanoate, which is further converted into l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-ylcarboxylicacid- N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride by reacting with ammonium carbonate in ethanol, followed by treating with ethanolic hydrochloric acid. The obtained compound was reacted with n-hexyl chloroformate in presence of potassium carbonate in tetrahydrofuran/water provides Dabigatran etexilate and further conversion into its mesylate salt was not disclosed. The purity of Dabigatran etexilate prepared as per the disclosed process is not satisfactory, and also the said process involves chromatographic purification which is expensive and difficult to implement in the large scale. Hence the said process is not suitable for commercial scale up.

Moreover, the said process proceeds through the l-methyl-2-[N-[4-amidinophenyl] aminomethyl]benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride (herein after referred as “Dabigatran hydrochloride”), which degrades to form impurities and resulting in the formation of Dabigatran etexilate with low purity. In view of intrinsic fragility of Dabigatran hydrochloride, there is a need in the art to develop a novel salt form of 1 -methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-ylcarboxylicacid-N-(2- pyridyl)-N-(2-ethoxycarbonyl ethyl)amide, which enhances the purity of the final compound.

The prior reported processes disclosed in WO2012004396 and WO2008095928 Al involves the usage of inorganic salts like hydrochloride and hydrobromide salts of ethyl 3-(2-((4- cyanophenylamino)methyl)- 1 -methyl -N-(pyridin-2-yl)- 1 H-benzo[d]imidazole-5-carboxamido) propanoate (herein after referred as “cyano intermediate”) and ethyl 3-(2-((4-carbamimidoyl phenylamino)methyl)- 1 -methyl -N-(pyridin-2-yl)- 1 H-benzo[d]imidazole-5-carboxamido) propanoate (herein after referred as “amidino intermediate”). The inorganic acid addition salts are less stable when compared to the organic acid addition salts and also the process for the preparation of organic acid addition salts is very much easy when compared to inorganic acid addition salt. Inorganic acid addition salts of amidine intermediate seem to be hygroscopic in nature. Therefore, organic acid addition salts are always preferable to synthesize stable salts which in-turn enhances the purity of the final compound.

The oxalate salt of cyano intermediate was disclosed in WO2009111997. However as on date, there is no other organic acid addition salts of cyano intermediate were reported in the prior art for preparing pure Dabigatran etexilate. Henceforth, there is a need to develop a novel organic acid addition salt of cyano intermediate compound which is very much efficient when compared to its corresponding oxalate salt and that result in the formation of final compound with high purity and yield.

The process disclosed in WO 98/37075 also involves the reduction of, ethyl 3-(4- (methylamino)-3-nitro-N-(pyridin-2-yl)benzamido)propanoate (herein after referred as “nitro compound”) using Pd-C in a mixture of dichloromethane and methanol under hydrogen pressure to provide ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate (herein after referred as “diamine compound”).

The reduction of nitro compound through catalytic hydrogenation in the presence of tertiary amine under hydrogen pressure was also disclosed in WO2009153214; and in presence of inorganic base under hydrogen pressure was also disclosed in WO2012004397.

However, most of the prior art processes proceed through catalytic hydrogenation which involves the pressure reactions. Handlings of these pressure reactions are not suitable for the large scale process. Therefore, there is a significant need in the art to provide a simple reduction process which avoids the difficulties associated with catalytic hydrogenation.

JMC, 2002, 45(9), 1757-1766 disclosed a process for the preparation of ethyl 3-(3-amino- 4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate starting from 4-(methylamino)-3- nitrobenzoic acid. The disclosed process involves the conversion of 4-(methylamino)-3- nitrobenzoic acid into its acid chloride using thionyl chloride and the obtained compound was reacted with ethyl 3-(pyridin-2-ylamino)propanoate to provide nitro compound, followed by catalytic reduction using Pd-C to provide diamine compound.

However, particularly in large scale synthesis the reduction reaction occasionally stops due to catalyst poisoning which leads to incomplete reaction and requires additional catalyst to complete the reaction. Moreover the sulfur impurities which are present in nitro compound formed due to the reaction with thionyl chloride in the previous stages of the synthesis of diamine compound are strongly influence the reaction time, quality and catalyst consumption in the manufacturing process.

Surprisingly, the problem associated with the catalytic hydrogenation and catalyst poisoning is solved by the present invention by adopting a suitable reducing agent such as Fe- acetic acid and Fe-hydrochloric acid.

The crystalline forms-I, II, V and VI of Dabigatran etexilate oxalate were disclosed in WO2008043759 and WO2011110876.

The crystalline forms-Ill, IV and V of Dabigatran etexilate fumarate were disclosed in WO2008043759 and WO2011110876.

Various different salts for Dabigatran etexilate and their polymorphs were reported in WO98/37075, WO03074056, WO2005028468, WO2006114415, WO2008043759, WO2011110876, WO2012027543 and WO2012044595.

The process for the preparation of crystalline form-I of Dabigatran etexilate mesylate was described in WO2005028468 and WO2012027543.

HPLC analysis of Innovator Tablet

The present inventors has also analyzed the Pradaxa 110 mg tablet having Lot no: 808809 and compared with dabigatran etexilate mesylate obtained from the present invention and found that, the impurity profile of both the products are similar to each other i.e., amide impurity, despyridyl ethyl ester etc. are well present even in Pradaxa tablet. Henceforth, we can presume that these impurities are known from the art.

Amide Impurity: 0.31%; Despyridyl ethyl ester: 0.10%; Deshexyl Impurity: 0.08%. HPLC Method of Analysis:

a) Dabigatran etexilate (Formula-1) and Dabigatran etexilate mesylate (Formula-la):

Apparatus: A liquid chromatographic system is to be equipped with variable wavelength

UV-detector; Column: Zorbax Eclipse XDB CI 8, 100 X 4.6mm, 3.5 μιη θΓ Equivalent; Flow Rate: 1.0 mL/min; Wavelength : 300 nm; Column temperature: 25°C; Injection volume: 5 μΐ,; Run time: 50 minutes; Auto sampler temperature: 5°C; Buffer: Dissolve 0.63gm of Ammonium formate in lOOOmL of Milli-Q- Water and mix well. Adjust its pH to 8.2 with Ammonia and filtered through 0.22 μιη nylon membrane and degas it. Mobile phase-A: Buffer; Mobile phase- B: Acetonitrile: Water (80:20) v/v; Diluent: N,N-Dimethylformamide; Needle wash: Diluent; Elution: Gradient. b) Ethyl 3-(2-((4-cyanophenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d] imidazole-5-carboxamido)propanoate methanesulfonate (Formula-10)

Apparatus : A liquid chromatograph is equipped with variable wavelength UV- Detector; Column: Zorbax SB CN 150 x 4.6mm, 5μπι (or) Equivalent (Make: Agilent and PNo: 883975- 905); Flow Rate: 1.0 mL / min; Column temperature: 25°C; Wave length: 290 nm; Injection volume: 5 μΐ-.; Run time: 60 minutes; Elution: Gradient; Diluent: Water: Acetonitrile (70:30) v/v; Needle wash: Diluent; Buffer: Weigh accurately about 2 g of 1 -Octane sulphonic acid sodium salt anhydrous and add 5 mL of Ortho phosphoric acid in 1000 mL of Milli-Q- Water and mix well, filter this solution through 0.22 μηι^ΐοη membrane and sonicate to degas; Mobile Phase- A: Buffer(100%);Mobile Phase- B: Acetonitrile: Methanol (90: 10) v/v. c) Ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH- benzo[d] imidazole-5-carboxamido)propanoate methanesulfonate (Formula-11)

Apparatus : A liquid chromatographic system is to be equipped with variable wavelength UV- Detector and Integrator; Column : Zodiac CI 8 250 X 4.6 mm, 5 μηι (or) equivalent (Make: Zodiac and PNo. ZLS.C18.46.250.0510 ); Flow Rate: 1.0 mL/min; Wavelength: 290 nm; Column temperature: 25°C; Injection Volume: 5μί; Run time: 55 min; Elution: Gradient;

Buffer: Take 5 mL of Ortho phosphoric acid(85%) and 2 g of 1 -Octane sulfonic acid sodium salt anhydrous in 1000 mL of Milli-Q-water and adjust its pH to 2.5 with Triethyl amine filter, through 0.22 μπι Nylon membrane filter paper and sonicate to degas it; Mobile Phase-A: Buffer(l 00%) Mobile Phase-B: Acetonitrile: Water (90: 10) v/v; Diluent : Water: Acetonitrile (80:20) v/v.

Morphology: Method of analysis: Samples were mounted on aluminium stubs using double adhesive tape, coated with gold using HUS-5GB vacuum evaporation and observed in Hitachi S-3000 N SEM at an acceleration voltage of 10KV.

Following are the impurities observed during the preparation of Dabigatran etexilate mesylate.

Figure imgf000027_0001

Deshexyl Impurity Despyridyl Ethyl Ester

Figure imgf000027_0002

Methyl Carbamate Ethyl Carbamate

Figure imgf000027_0003

The present invention is schematically represented as follows:

Figure imgf000028_0001

Formula-2 ene

Figure imgf000028_0002

Formula-6

Fe-AcOH

Figure imgf000028_0003

Formula-7

Figure imgf000028_0004

Dabigatran etexilate Dabigatran etexilate Mesylate The process described in the present invention was demonstrated in examples illustrated below.

Example-13: Preparation of Dabigatran etexilate (Formula-1)

n-hexanol (30.8 g) was added to a solution of N, N-carbonyldiimidazole (61.15 g) and dichloromethane (360 ml) at 15-25°C and stirred for 3 hours. The organic layer was washed with water followed by sodium chloride solution. Distilled off the solvent from the organic layer completely under reduced pressure to get amide compound. Acetonitrile (157.5 ml) was added to the obtained amide compound. This was added to a mixture of ethyl 3-(2-((4- carbamimidoylphenylamino)methyl)-l-methyl-N-( yridin-2-yl)-lH-benzo[d]imidazole-5- carboxamido)propanoate mesylate compound of formula- 11 (90 g), potassium carbonate (62.5 g), acetonitrile (378 ml) and water (252 ml) at 25-35°C. The reaction mixture was heated to 40- 50°C and stirred for 8 hours. After completion of the reaction, both the organic and aqueous layers were separated; the organic layer was cooled to -5 to +5°C and stirred for 2 hours. Filtered the precipitated solid washed with acetonitrile and water. The obtained compound was dissolved in a mixture of acetone (270 ml) and acetonitrile (270 ml) at 45-50°C. Cooled the reaction mixture to 25-30°C and water (360 ml) was added to it. Filtered the obtained solid and dissolved in the mixture of dichloromethane and sodium chloride solution at 35-40°C. Both the organic and aqueous layers were separated; the organic layer was distilled under reduced pressure and then co-distilled with ethyl acetate. The obtained crude compound was dissolved in ethyl acetate (540 ml) by heating it to 70-80°C and stirred for 30 minutes. Filtered the reaction mixture, the filtrate was cooled to 35-45°C and ethanol (8 ml) was added to the reaction mixture. The reaction mixture was again cooled to 25-35°C and stirred for 3 hours. Filtered the precipitated solid and then dried to get pure title compound.

Yield: 44 g; MR: 128-131 °C. Purity by HPLC: 99.63%.

……………….

http://www.google.com/patents/WO2014020555A2?cl=en

Figure imgf000014_0001

Figure imgf000016_0001

Figure imgf000021_0001

Figure imgf000023_0001

EXAMPLE 6

Preparation of dabigatran etexilate mesylate: l-methyl-2-[N-[4-( -n-hexyloxycarbonylamidino)phenyl] amino methyl]benzimidazol-5- yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonyl ethyl) amide (100 gm) was dissolved acetone (1000 ml) under heating at 25-35 °C. A solution of methane sulfonic acid (13.77 gm) in acetone (100 ml) was added to the reaction mixture. The solution is filtered and after the addition of acetone cooled to approximately 20° C. The precipitated product was filtered and washed with acetone then dried at 50° C under reduced pressure.

Wet weight : 0.120-0.140 kg

Dry weight : 0.90-1.0 kg

Yield (W/W) : 0.90-1.0

Theoretical Yield (w/w) : 1.15

Percentage Yield : 78.2-86.9%

………………….

US20050095293 * Sep 3, 2004 May 5, 2005 Boehringer Ingelheim Pharma Gmbh Co. Kg Administration form for the oral application of poorly soluble drugs
US20070185173 * Dec 21, 2006 Aug 9, 2007 Georg Zerban Process for the Preparation of the Salts of 4-(Benzimidazolylmethylamino)-Benzamides
Citing Patent Filing date Publication date Applicant Title
WO2014020555A2 * Jul 31, 2013 Feb 6, 2014 Alembic Pharmaceuticals Limited An improved process for the preparation of dabigatran etexilate mesylate
WO2014009966A2 * Jul 5, 2013 Jan 16, 2014 Rao Davuluri Ramamohan An improved process for the preparation of dabigatran etexilate mesylate and its intermediates thereof
WO2014009966A3 * Jul 5, 2013 Mar 6, 2014 Rao Davuluri Ramamohan An improved process for the preparation of dabigatran etexilate mesylate and its intermediates thereof
EP1966171A1 Dec 20, 2006 Sep 10, 2008 Boehringer Ingelheim International GmbH Improved process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof
EP1968949A1 Dec 20, 2006 Sep 17, 2008 Boehringer Ingelheim International GmbH Improved process for the preparation of the salts of 4-(benzimidazolylmethylamino)-benzamides
US6087380 Feb 18, 1998 Jul 11, 2000 Boehringer Ingelheim Pharma Kg Disubstituted bicyclic heterocycles, the preparations and the use thereof as pharmaceutical compositions
US7202368 Jun 9, 2005 Apr 10, 2007 Boehringer Ingelheim International Gmbh Process for the preparation of 4-(benzimidazolymethylamino) benzamidines
WO2000005207A1 * Jul 20, 1999 Feb 3, 2000 Boehringer Ingelheim Pharma Substituted phenylamidines with antithrombotic action
WO2007071742A1 * Dec 20, 2006 Jun 28, 2007 Boehringer Ingelheim Int Improved process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof
WO2010045900A1 Oct 26, 2009 Apr 29, 2010 Zentiva, K.S. A method for the preparation of dabigatran and its intermediates
Reference
1 * European Medicines Agency (EMEA): “CHMP ASSESSMENT REPORT FOR Pradaxa“, , 1 January 2008 (2008-01-01), pages 1-36, XP55003938, London Retrieved from the Internet: URL:http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000829/WC500041062.pdf [retrieved on 2011-08-01]
2 * HAUEL N H ET AL: “STRUCTURE-BASED DESIGN OF NOVEL POTENT NONPEPTIDE THROMBIN INHIBITORS“, JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 45, no. 9, 1 January 2002 (2002-01-01), pages 1757-1766, XP001098844, ISSN: 0022-2623, DOI: DOI:10.1021/JM0109513
CN103058920A * Jan 21, 2013 Apr 24, 2013 上海应用技术学院 Preparation method of 3-(2-pyridineamino)ethyl propionate
CN1861596A * May 18, 2006 Nov 15, 2006 复旦大学 Process for synthesizing antithrombin inhibitor of non-asymmetric non-peptide kind
CN101875626A * Nov 6, 2009 Nov 3, 2010 广东光华化学厂有限公司;北京理工大学 Method for synthesizing N-benzyl maleimide from immobilized supported acid catalyst
EP2522662A1 * May 11, 2011 Nov 14, 2012 Medichem, S.A. Dabigatran etexilate and related substances, processes and compositions, and use of the substances as reference standards and markers
JP2004315371A * Title not available

See full gatran series at………………http://apisynthesisint.blogspot.in/p/argatroban.html

DABIGATRAN PART 3/3


front page image

WO2015124764

ERREGIERRE S.P.A. [IT/IT]; Via Francesco Baracca, 19 I-24060 San Paolo D’argon (IT)

Erregierre SpA

DABIGATRAN ETEXILATE MESYLATE, INTERMEDIATES OF THE PROCESS AND NOVEL POLYMORPH OF DABIGATRAN ETEXILATE”

Abstract

A novel process is described for the production of Dabigatran etexilate mesylate, a 5 compound having the following structural formula: and two novel intermediates of said process.

(WO2015124764) SYNTHESIS PROCESS OF DABIGATRAN ETEXILATE MESYLATE, INTERMEDIATES OF THE PROCESS AND NOVEL POLYMORPH OF DABIGATRAN ETEXILATE click herefor patent

Dabigatran etexilate mesylate is an active substance developed by Boehringer

Ingelheim and marketed under the name Pradaxa® in the form of tablets for oral administration; Dabigatran etexilate mesylate acts as direct inhibitor of thrombin (Factor I la) and is used as an anticoagulant, for example, for preventing strokes in patients with atrial fibrillation or blood clots in the veins (deep vein thrombosis) that could form following surgery.

Dabigatran etexilate mesylate is the INN name of the compound 3-({2-[(4-{Amino-[(E)-hexyloxycarbonylimino]-methyl}-phenylamino)-methyl]-1 -methyl-1 H-benzimidazol-5-carbonyl}-pyridin-2-yl-amino)-ethyl propanoate methanesulphonate, having the following structural formula:

The family of compounds to which Dabigatran etexilate belongs was described for the first time in patent US 6,087,380, which also reports possible synthesis pathways.

The preparation of polymorphs of Dabigatran etexilate or Dabigatran etexilate mesylate is described in patent applications US 2006/0276513 A1 , WO 2012/027543 A1 , WO 2008/059029 A2, WO 2013/124385 A2, WO 2013/124749 A1 , WO 2013/1 1 1 163 A2 and WO 2013/144903 A1 , while patent applications WO 2012/044595 A1 , US 2006/0247278 A1 , US 2009/0042948 A2, US 2010/0087488 A1 and WO 2012/077136 A2 describe salts of these compounds.

One of the objects of the invention is to provide an alternative process for the preparation of Dabigatran etexilate mesylate and two novel intermediates of the process.

These objects are achieved with the present invention, which, in a first aspect thereof, relates to a process for the production of Dabigatran etexilate mesylate, comprising the following steps:

a) reacting 4-methylamino-3-nitrobenzoic acid (I) with thionyl chloride to give 4- methylamino-3-nitrobenzoyl chloride hydrochloride (II):

(I) (ID

b) reacting compound (II) with 3-(2-pyridylamino) ethyl propanoate (III) to give the compound 3-[(4-methylamino-3-nitro-benzoyl)-pyridyn-2-yl-amino]-ethyl propanoate (IV):

(II) (IV)

reducing compound (IV) with hydrogen to 3-[(3-amino-4-methyl benzoyl)-pyridin-2-yl-amino]ethyl propanoate (V):

(IV) (V)

d) reacting N-(4-cyanophenyl)glycine (VI) with 1 ,1 -carbonyldiimidazole (CDI) to give 4-(2-imidazol-1 -yl-2-oxo-ethylamino)-benzonitrile (VII):

(VI) (VII)

e) reacting compound (VII) with compound (V) obtained in step c) to give one of compounds 3-({3-[2-(4-cyano-phenylamino)-acetylamino]-4-methylamino- benzoyl}-pyridin-2-yl-amino)-ethyl propanoate (VIII) and 3-[(3-amino-4-{[(2- (4-cyano-phenylamino)-acetyl]-methylamino}-benzoyl)-pyridin-2-yl- amino]ethyl propanoate (IX), or a mixture of the two compounds (VIII) and (IX):

f) transforming, through treatment with acetic acid, compounds (VIII) or (IX) or the mixture thereof into the compound 3-({2-[(4-cyano-phenylamino)-methyl]- 1 -methyl-1 H-benzimidazol-5-carbonyl}-pyridin-2-yl-amino)-ethyl propanoate (X), and then treating compound (X) with hydrochloric or nitric acid to form the corresponding salt (XI):

CHsCOOH

[(VIII) ; (IX)]

wherein A is a chlorine or nitrate anion;

liberating in solution compound (X) from salt (XI), and reacting compound (X) in solution with ethyl alcohol in the presence of hydrochloric acid and 2,2,2-trifluoroethanol to give the compound 3-({2-[(4-ethoxycarbonimidoyl-phenylamino)-methyl]-1 -methyl-1 H-benzimidazol-5-carbonyl}-pyridin-2-yl-amino)-ethyl propanoate hydrochloride (XII):

reacting compound (XII) with ammonium carbonate to form compound Dabigatran ethyl ester (XIII):

reacting compound (XIII) with maleic acid to produce the maleate salt thereof (XI 11 ‘) and isolating the latter:

j) reacting maleate salt (XI 11 ‘) with hexyl chloroformate to give compound Dabigatran etexilate (XIV :

hexyl chloroformate

k) reacting compound (XIV) with methanesulfonic acid to give the salt Dabigatran etexilate mesylate:

a gatran etex ate mesy ate

EXAMPLE 12

Preparation of Dabigatran etexilate mesylate (step k).

All the Dabigatran etexilate obtained in Example 1 1 (4.7 kg; 7.49 moles) is loaded into a reactor along with 28.2 kg of acetone and the mass is heated at 50-60 °C until a complete solution is obtained; it is then filtered to remove suspended impurities. The filtered solution is brought to 28-32 °C. Separately, a second solution is prepared by dissolving 0.705 kg (7.34 moles) of methanesulfonic acid in 4.7 kg of acetone; the second solution is cooled down to 0-10 °C. The second solution is poured into the Dabigatran etexilate solution during 30 minutes, while maintaining the temperature of the resulting solution at 28-32 °C with cooling. The salt of the title is formed. The mass is maintained at 28-32 °C for 2 hours, then cooled to 18-23 °C to complete precipitation and the system is maintained at this temperature for 2 hours; lastly, centrifugation takes place, washing the precipitate with 5 kg of acetone. The precipitate is dried at 60 °C.

4.88 kg of Dabigatran etexilate mesylate, equal to 6.74 moles of compound, are obtained, with a yield in this step of 90%.

EXAMPLE 13

0.5 g of the crystalline compound (XIV) obtained in Example 1 1 are ground thoroughly and loaded into the sample holder of a Rigaku Miniflex diffractometer with copper anode.

The diffractogram shown in Figure 1 is obtained; a comparison with the XRPD data of the known Dabigatran etexilate polymorphs allows to verify that the polymorph of Example 1 1 is novel.

EXAMPLE 14

0.7 g of the crystalline compound (XIV) obtained in Example 1 1 are loaded into

the sample holder of a Perkin-Elmer DSC 6 calorimeter, performing a scan from ambient T to 350 °C at a rate of 10 °C/min in nitrogen atmosphere. The graph of the test is shown in Figure 2, and shows three endothermic phenomena with peaks at 83.0-85.0 °C, 104.0-104.2 °C and 129.9 °C; events linked to the thermal decomposition of the compound are evident at about 200 °C.

Figure 1 is an XRPD spectrum of the novel polymorph of Dabigatran etexilate of the invention;

Figure 2 is the graph of a DSC test on the novel polymorph of Dabigatran etexilate of the invention.

1H NMR OF

Dabigatran etexilate mesylate 872728-81-9

1h nmr.

PATENT

http://www.google.com/patents/WO2012044595A1?cl=en

Examples

Reference examples:

Preparation of starting material: Dabigatran etexilate mesylate form I according to US 2005/0234104 example 1:

Ethyl 3 – [(2- { [4-(hexyloxycarbonylarninoimmomemyl)phenylammo]methyl } –

1 – methyl- lH-benzimidazole-5-carbonyl)pyridm-2-ylamino]propionate base (52.6 kg) (which has preferably been purified beforehand by recrystallization from ethyl acetate) is placed in an agitator apparatus which has been rendered inert and then 293 kg of acetone is added. The contents of the apparatus are heated to 40° C to 46° C with stirring. After a clear solution has formed, the contents of the apparatus is filtered into a second agitator apparatus through a lens filter and then cooled to 30° C to 36° C. 33 kg of acetone precooled to 0° C to 5° C, 7.9 kg of 99.5% methanesulfonic acid, and for rinsing another 9 kg of acetone are placed in the suspended container of the second apparatus. The contents of the suspended container are added in metered amounts to the solution of ethyl 3-[(2-{[4-(hexyloxycarbonylamino- iminomethyl)phenylamino]methyl} – 1 -methyl- 1 H-benzimidazole-5-carbonyl)pyridin-

2- ylamino]propionate base at 26° C to 36° C within 15 to 40 minutes. Then the mixture is stirred for 40 to 60 minutes at 26° C to 33° C. It is then cooled to 17° C to 23° C and stirred for a further 40 to 80 minutes. The crystal suspension is filtered through a filter dryer and washed with a total of 270 L of acetone. The product is dried in vacuum at a maximum of 50° C for at least 4 hours. Yield: 54.5-59.4 kg;

90%-98% of theory based on ethyl 3-[(2-{[4-(hexyloxycarbonyl- ammoiminomethyl)phenylamino]methyl} – 1 -methyl- 1 H-benzimidazole-5-carbonyl)- pyridm-2-ylamino]propionate base.

Preparation of starting material: Dabigatran Etexilate free base

Dabigatran Etexilate free base can be prepared according to the procedures disclosed in US 6087380 – example 113 or US 7202368 – example 5 Example 1

2.08 g of dabigatran etexilate free base was dissolved in 14.7 ml of acetone at 30 – 36 °C. 0.210 ml of methanesulfonic acid diluted in 2.20 ml of acetone was added within 15 – 40 min. at 26 – 36 °C. The resulting mixture was first steered for 40 – 60 min. at 26 – 36 °C and then for 40 – 80 min at 17 – 23 °C.

The resulting crystalline product was filtered off, washed with 17.87 ml of acetone and dried at 50 °C for 18 hours at 540 mbar.

………………..

PAPER

Chinese Journal of Applied Chemistry
Synthesis of Dabigatran Etexilate
LIU Xiaojun, CHEN Guohua*
(Department of Medicinal Chemistry,China Pharmaceutical University,Nanjing 210009,China)

4-Methylamino-3-nitrobenzoic acid(3) was prepared from 3-nitro-4-chlorobenzoic acid by methylamination. 3-[(Pyridin-2-yl)amino]propinoic acid ethyl ester(5) was prepared from 2-aminopyridine and ethyl acrylate by Michael addition. Dabigatran etexilate was synthesized from compounds 3 and 5 via condensation, catalytic hydrogenation, acylation with N-(4-cyanophenyl)glycine(9), cyclization, Pinner reaction, followed by reaction with n-hexyl chlorofomate. The overall yield is about 40% and the structure of the product was determined by IR, 1H NMR and MS.

ESIMS(m/z):628[M+H]+;1 HNMR(500MHz,DMSOd6), δ:091(t,3H,J=90Hz,CH3),116(t,3H,J=85Hz,CH3),125~169(m,8H,4×CH2),274(t, 2H,J=145Hz,CH2CO),379(s,3H,CH3N),395~403(m,4H,2CH2O),428(t,2H,J=140Hz, CH2),451(d,2H,J=55Hz,CH2N),676(d,J=85Hz,2H,Ar—H),688(d,J=75Hz,1H,Ar— H), 702(s,1H,N—H),713~721(m,2H,Py—H),740(d,J=85Hz,1H,Ar—H),747(d,J=15Hz, 1H,Ar—H),755~759(m,1H,Py—H),786(d,J=85Hz,2H,Ar—H),836~843(m,1H,Py—H), 902(brs,2H,NH2);IR(KBr),σ/cm-1 :3374,2953,2929,1730,1640,1610,1470,1389,1326,1256,1192, 1145,1127,1021,945,835,811,768,747。

Synthesis of Dabigatran Etexilate.pdf

DATA OF BASE

DATA OF DABI

…………

PAPER

Identification, Synthesis, and Strategy for the Reduction of Potential Impurities Observed in Dabigatran Etexilate Mesylate Processes

Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, 1111 North Zhongshan No. 1 Road, Shanghai 200437, P. R. China
Department of Pharmacy, Shandong Provincial Hospital affiliated to Shandong University, Jinan 250021,P. R. China
Org. Process Res. Dev., 2014, 18 (6), pp 744–750
DOI: 10.1021/op500084q
Abstract Image

Synthetic impurities that are present in dabigatran etexilate mesylate were studied, and possible pathways by which these impurities are formed during the manufacturing process were examined. The impurities were monitored by high-performance liquid chromatography, and their structures were determined by mass spectrometry and 1H and 13C NMR. Potential causes for the formation of these impurities are discussed, and strategies to minimize their formation are also described.

Figure

…………….

1H NMR PREDICT

Dabigatran etexilate 211915-06-9 H-NMR

Dabigatran etexilate 211915-06-9C-NMR S

13 C NMR PREDICT ABOVE

WO2015044375A1 * Sep 26, 2014 Apr 2, 2015 Ratiopharm Gmbh Pharmaceutical preparation comprising dabigatran etexilate bismesylate

See full gatran series at………………http://apisynthesisint.blogspot.in/p/argatroban.html

 

 

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DABIGATRAN PART 1/3


Dabigatran etexilate structure.svg

 

Dabigatran (Pradaxa in Australia, Canada, Europe and USA, Prazaxa in Japan) is an oral anticoagulant from the class of the direct thrombin inhibitors. It is being studied for various clinical indications and in some cases it offers an alternative towarfarin as the preferred orally administered anticoagulant (“blood thinner”) since it cannot be monitored by blood tests forinternational normalized ratio (INR) monitoring while offering similar results in terms of efficacy. There is no specific way to reverse the anticoagulant effect of dabigatran in the event of a major bleeding event,[2][3] unlike warfarin,[4] although a potential dabigatran antidote (pINN: idarucizumab) is undergoing clinical studies.[5] It was developed by the pharmaceutical company Boehringer Ingelheim.

Medical uses

Dabigatran is used to prevent strokes in those with atrial fibrillation (afib) due to non heart valve causes, as well as deep venous thrombosis (DVT) and pulmonary embolism (PE) in persons who have been treated for 5–10 days with parenteral anticoagulant (usually low molecular weight heparin), and to prevent DVT and PE in some circumstances.[6]

It appears to be as effective as warfarin in preventing nonhemorrhagic strokes and embolic events in those with afib not due to valve problems.[7]

 

Contraindications

Dabigatran is contraindicated in patients who have active pathological bleeding since dabigatran can increase bleeding risk and can also cause serious and potentially life-threatening bleeds.[8] Dabigatran is also contraindicated in patients who have a history of serious hypersensitivity reaction to dabigatran (e.g. anaphylaxis or anaphylactic shock).[8] The use of dabigatran should also be avoided in patients with mechanical prosthetic heart valve due to the increased risk of thromboembolic events (e.g. valve thrombosis, stroke, and myocardial infarction) and major bleeding associated with dabigatran in this population.[8][9][10]

Adverse effects

The most commonly reported side effect of dabigatran is GI upset. When compared to people anticoagulated with warfarin, patients taking dabigatran had fewer life-threatening bleeds, fewer minor and major bleeds, including intracranial bleeds, but the rate of GI bleeding was significantly higher. Dabigatran capsules contain tartaric acid, which lowers the gastric pH and is required for adequate absorption. The lower pH has previously been associated with dyspepsia; some hypothesize that this plays a role in the increased risk of gastrointestinal bleeding.[11]

A small but significantly increased risk of myocardial infarctions (heart attacks) has been noted when combining the safety outcome data from multiple trials.[12]

Reduced doses should be used in those with poor kidney function.[13]

Pharmacokinetics

Dabigatran has a half-life of approximately 12-14 h and exert a maximum anticoagulation effect within 2-3 h after ingestion.[14] Fatty foods delay the absorption of dabigatran, although the bio-availability of the drug is unaffected.[1] One study showed that absorption may be moderately decreased if taken with a proton pump inhibitor.[15] Drug excretion through P-glycoprotein pumps is slowed in patients taking strong p-glycoprotein pump inhibitors such as quinidine, verapamil, and amiodarone, thus raising plasma levels of dabigatran.[16]

History

Dabigatran (then compound BIBR 953) was discovered from a panel of chemicals with similar structure to benzamidine-based thrombin inhibitor α-NAPAP (N-alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide), which had been known since the 1980s as a powerful inhibitor of various serine proteases, specifically thrombin, but also trypsin. Addition of ethyl ester and hexyloxycarbonyl carbamide hydrophobic side chains led to the orally absorbed prodrug, BIBR 1048 (dabigatran etexilate).[17]

On March 18, 2008, the European Medicines Agency granted marketing authorisation for Pradaxa for the prevention of thromboembolic disease following hip or knee replacement surgery and for non-valvular atrial fibrillation.[18]

The National Health Service in Britain authorised the use of dabigatran for use in preventing blood clots in hip and knee surgery patients. According to a BBC article in 2008, Dabigatran was expected to cost the NHS £4.20 per day, which was similar to several other anticoagulants.[19]

Pradax received a Notice of Compliance (NOC) from Health Canada on June 10, 2008,[20] for the prevention of blood clots in patients who have undergone total hip or total knee replacement surgery. Approval for atrial fibrillation patients at risk of stroke came in October 2010.[21][22]

The U.S. Food and Drug Administration (FDA) approved Pradaxa on October 19, 2010, for prevention of stroke in patients with non-valvular atrial fibrillation.[23][24][25][26] The approval came after an advisory committee recommended the drug for approval on September 20, 2010[27] although caution is still urged by some outside experts.[28]

On February 14, 2011, the American College of Cardiology Foundation and American Heart Association added dabigatran to their guidelines for management of non-valvular atrial fibrillation with a class I recommendation.[29]

In May 2014 the FDA reported the results of a large study comparing dabigatran to warfarin in 134,000 Medicare patients. The Agency concluded that dabigatran is associated with a lower risk of overall mortality, ischemic stroke, and bleeding in the brain than warfarin. Gastrointestinal bleeding was more common in those treated with dabigatran than in those treated with warfarin. The risk of heart attack was similar between the two drugs. The Agency reiterated its opinion that dabigatran’s overall risk/benefit ratio is favorable.[30]

On July 26, 2014, the British Medical Journal (BMJ) published a series of investigations that accused Boehringer of withholding critical information about the need for monitoring to protect patients from severe bleeding, particularly in the elderly. Review of internal communications between Boehringer researchers and employees, the FDA and the EMA revealed that Boehringer researchers found evidence that serum levels of dabigatran vary widely. The BMJ investigation suggested that Boehringer had a financial motive to withhold this concern from regulatory health agencies because the data conflicted with their extensive marketing of dabigatran as an anticoagulant that does not require monitoring.[31][32]

Research

In August 2015, an article found that idarucizumab was able to reverse the anticoagulation effects of dabigatran within minutes.[33]

References

  1.  Pradaxa Full Prescribing Information. Boehringer Ingelheim. October 2010.
  2.  Eerenberg, ES; Kamphuisen, PW; Sijpkens, MK; Meijers, JC; Buller, HR; Levi, M (2011-10-04). “Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects”. Circulation 124(14): 1573–9. doi:10.1161/CIRCULATIONAHA.111.029017. PMID 21900088. Retrieved 2012-03-15.
  3.  van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, Clemens A (Department of Drug Discovery Support, Boehringer Ingelheim Pharma) (Jun 2010).“Dabigatran etexilate–a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity”. Thrombosis and Haemostasis103 (6): 1116–27. doi:10.1160/TH09-11-0758. PMID 20352166. Retrieved2012-03-15. Although there is no specific antidote to antagonise the anticoagulant effect of dabigatran, due to its short duration of effect drug discontinuation is usually sufficient to reverse any excessive anticoagulant activity.
  4.  Hanley JP, J P (Nov 2004). “Warfarin reversal”. Journal of Clinical Pathology 57 (11): 1132–9. doi:10.1136/jcp.2003.008904. PMC 1770479. PMID 15509671.
  5.  “Boehringer Ingelheim’s Investigational Antidote for Pradaxa® (dabigatran etexilate mesylate) Receives FDA Breakthrough Therapy Designation” (Press release). Ridgefield, CT: Boehringer Ingelheim’. 2014-06-26. Retrieved 2014-07-26.
  6.  http://www.drugs.com/pro/pradaxa.html Pradaxa
  7. Gómez-Outes, A; Terleira-Fernández, AI; Calvo-Rojas, G; Suárez-Gea, ML; Vargas-Castrillón, E (2013). “Dabigatran, Rivaroxaban, or Apixaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-Analysis of Subgroups.”. Thrombosis 2013: 640723. doi:10.1155/2013/640723. PMC 3885278.PMID 24455237.
  8. Pradaxa (dabigatran etexilate mesylate) Prescribing Information:http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ba74e3cd-b06f-4145-b284-5fd6b84ff3c9#Section_5.4, accessed October 29, 2014.
  9. “FDA Drug Safety Communication: Pradaxa (dabigatran etexilate mesylate) should not be used in patients with mechanical prosthetic heart valves”. U.S. Food and Drug Administration (FDA). Retrieved October 29, 2014.
  10.  Eikelboom, JW; Connolly, SJ; Brueckmann, M et al. (September 2013). “Dabigatran versus Warfarin in Patients with Mechanical Heart Valves”. N Engl J Med 369: 1206–1214.doi:10.1056/NEJMoa1300615. PMID 23991661.
  11.  ML Blommel et al. (2011). “Dabigatran etexilate: A novel oral direct thrombin inhibitor”.Am J Health Syst Pharm 68 (16): 1506–19. doi:10.2146/ajhp100348. PMID 21817082.
  12.  Uchino K, Hernandez AV; Hernandez (2012). “Dabigatran associated with higher risk of acute coronary events – meta-analysis of noninferiority randomized controlled trials”.Arch. Intern. Med. Online first (5): 397–402. doi:10.1001/archinternmed.2011.1666.PMID 22231617.
  13.  18/12/2014 Pradaxa -EMEA/H/C/000829 -II/0073
  14.  Chongnarungsin D; Ratanapo S; Srivali N; Ungprasert P; Suksaranjit P; Ahmed S; Cheungpasitporn W (2012). “In-Depth Review of Stroke Prevention in Patients with Non-Valvular Atrial Fibrillation”. Am. Med. J. 3 (2): 100. doi:10.3844/amjsp.2012.100.103.
  15.  Stangier J, Eriksson BI, Dahl OE et al. (May 2005). “Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement”. J Clin Pharmacol 45 (5): 555–63.doi:10.1177/0091270005274550. PMID 15831779.
  16.  “Pradaxa Summary of Product Characteristics”. European Medicines Agency.
  17.  Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W; Nar; Priepke; Ries; Stassen; Wienen (April 2002). “Structure-based design of novel potent nonpeptide thrombin inhibitors”. J Med Chem 45 (9): 1757–66. doi:10.1021/jm0109513.PMID 11960487. Lay summary.
  18.  “Pradaxa EPAR”. European Medicines Agency. Retrieved 2011-01-30.
  19.  “Clot drug ‘could save thousands'”. BBC News Online. 2008-04-20. Retrieved2008-04-21.
  20.  “Summary Basis of Decision (SBD): Pradax” Health Canada. 2008-11-06.
  21.  Kirkey, Sharon (29 October 2010). “Approval of new drug heralds ‘momentous’ advance in stroke prevention”. Montreal Gazette. Retrieved 29 October 2010.
  22.  “Pradax (Dabigatran Etexilate) Gains Approval In Canada For Stroke Prevention In Atrial Fibrillation” Medical News Today. 28 October 2010.
  23.  Connolly, SJ; Ezekowitz, MD; Yusuf, S et al. (September 2009). “Dabigatran versus warfarin in patients with atrial fibrillation” (PDF). N Engl J Med 361 (12): 1139–51.doi:10.1056/NEJMoa0905561. PMID 19717844.
  24.  Turpie AG (January 2008). “New oral anticoagulants in atrial fibrillation”. Eur Heart J 29(2): 155–65. doi:10.1093/eurheartj/ehm575. PMID 18096568.
  25.  “Boehringer wins first US OK in blood-thinner race”. Thomson Reuters. 2010-10-19. Retrieved 2010-10-20.
  26.  “FDA approves Pradaxa to prevent stroke in people with atrial fibrillation”. U.S. Food and Drug Administration (FDA). 2010-10-19.
  27.  Shirley S. Wang (2010-09-20). “New Blood-Thinner Recommended by FDA Panel”. The Wall Street Journal. Retrieved 2010-10-20.
  28. Merli G, Spyropoulos AC, Caprini JA; Spyropoulos; Caprini (August 2009). “Use of emerging oral anticoagulants in clinical practice: translating results from clinical trials to orthopedic and general surgical patient populations”. Ann Surg 250 (2): 219–28.doi:10.1097/SLA.0b013e3181ae6dbe. PMID 19638915.
  29.  Wann LS, Curtis AB, Ellenbogen KA, Estes NA, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM, Jacobs AK; Curtis; Ellenbogen; Estes Na; Ezekowitz; Jackman; January; Lowe; Page; Slotwiner; Stevenson; Tracy; Fuster; Rydén; Cannom; Crijns; Curtis; Ellenbogen; Halperin; Kay; Le Heuzey; Lowe; Olsson; Prystowsky; Tamargo; Wann; Jacobs; Anderson; Albert et al. (March 2011). “2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation (Update on Dabigatran): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines”. Circulation123 (10): 1144–50. doi:10.1161/CIR.0b013e31820f14c0. PMID 21321155.
  30. “FDA Drug Safety Communication: FDA study of Medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with Pradaxa (dabigatran) compared to warfarin”.
  31. Cohen, D (July 2014). “Dabigatran: how the drug company withheld important analyses”.BMJ 349: g4670. doi:10.1136/bmj.g4670. PMID 25055829.
  32. Moore TJ, Cohen MR, Mattison DR; Cohen; Mattison (July 2014). “Dabigatran, bleeding, and the regulators”. BMJ 349: g4517. doi:10.1136/bmj.g4517. PMID 25056265.
  33. Pollack, Charles V.; Reilly, Paul A.; Eikelboom, John; Glund, Stephan; Verhamme, Peter; Bernstein, Richard A.; Dubiel, Robert; Huisman, Menno V.; Hylek, Elaine M. (2015-01-01).“Idarucizumab for Dabigatran Reversal”. New England Journal of Medicine 373 (6).doi:10.1056/nejmoa1502000.
Dabigatran etexilate
Dabigatran etexilate structure.svg
Systematic (IUPAC) name
Ethyl N-[(2-{[(4-{N‍ ’​-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl]-N-2-pyridinyl-β-alaninate
Clinical data
Trade names Pradaxa, Pradax, Prazaxa
Licence data EMA:Link, US FDA:link
Pregnancy
category
  • US: C (Risk not ruled out)
Legal status
Routes of
administration
oral
Pharmacokinetic data
Bioavailability 3–7%[1]
Protein binding 35%[1]
Biological half-life 12–17 hours[1]
Identifiers
CAS Registry Number 211915-06-9 
ATC code B01AE07
PubChem CID: 6445226
DrugBank DB06695 Yes
ChemSpider 4948999 Yes
ChEMBL CHEMBL539697 Yes
Chemical data
Formula C34H41N7O5
Molecular mass 627.734 g/mol

External links

 

The chemical name for dabigatran etexilate mesylate, a direct thrombininhibitor, is β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate. The empirical formula is C34H41N7O5 • CH4O3S and the molecular weight is 723.86 (mesylate salt), 627.75 (free base). The structural formula is:

PRADAXA®(dabigatran etexilate mesylate) Structural Formula Illustration

Dabigatran etexilate mesylate is a yellow-white to yellow powder. A saturated solution in pure water has a solubility of 1.8 mg/mL. It is freely soluble in methanol, slightly soluble in ethanol, and sparingly soluble in isopropanol.

The 150 mg capsule for oral administration contains 172.95 mg dabigatran etexilate mesylate, which is equivalent to 150 mg of dabigatran etexilate, and the following inactive ingredients: acacia, dimethicone, hypromellose, hydroxypropyl cellulose, talc, and tartaric acid. The capsule shell is composed of carrageenan, FD&C Blue No. 2 (150 mg only), FD&C Yellow No. 6, hypromellose, potassium chloride, titanium dioxide, and black edible ink. The 75 mg capsule contains 86.48 mg dabigatran etexilate mesylate, equivalent to 75 mg dabigatran etexilate, and is otherwise similar to the 150 mg capsule.

See full gatran series at………………http://apisynthesisint.blogspot.in/p/argatroban.html

/////////DabigatranPradaxa

USV Limited , WO 2014167577 Synthesis of dabigatran….NEW PATENT FEATURE ON NEWDRUGAPPROVALS


USV Limited

http://www.usvindia.com/

16-Oct-2014        pub date

WO-2014167577-A2

PATENT FEATURE ON THIS BLOG
Title of the invention: “”SYNTHESIS OF DABIGATRAN”.”

Applicants: USV LIMITED (IN).

Inventors: Laxmikant Narhari Patkar (IN), Harish Kashinath Mondkar (IN), Sachin Shivaji Patil (IN), Tanaji Shamrao Jadhav (IN), Nitin Nivrutti Hagavane (IN), Rajesh Ganpat Bopalkar (IN) and Nitin Dnyaneshwar Arote (MY).

 

 

The present invention relates to a process for preparation of Dabigatran etexilate or pharmaceutically acceptable salt thereof. The present invention relates to novel compounds, in particular Ethyl-3-{[(2-formyl-l-methyl-lH-benzimidazole-5-yl) carbonyl] -(2-pyridinyl) amino} propanoate and Ethyl-3-{[(2-dichloromethyl-l-methyl -lH-benzimidazole-5-yl)carbonyl]- (2-pyridinyl) amino}propanoate and process for preparation thereof. The present invention further relates to the use of these novel compounds in the preparation of Dabigatran etexilate or pharmaceutically acceptable salt thereof.

Dabigatran is used to prevent strokes in those with atrial fibrillation due to non heart valve causes

Process for preparing dabigatran etexilate mesylate, useful for treating thrombosis, stroke and embolism. Also claims novel intermediates of dabigatran and their synthesis. Represents the first patenting from USV on this API, which was originally developed and launched, by Boehringer Ingelheim for treating conditions such as stroke, thrombosis and atrial fibrillation.

Dabigatran (Pradaxa in Australia, Europe and USA, Pradax in Canada, Prazaxa in Japan) is an oral anticoagulant from the class of the direct thrombin inhibitors. It is being studied for various clinical indications and in some cases it offers an alternative to warfarin as the preferred orally administered anticoagulant (“blood thinner”) since it does not require frequent blood tests for international normalized ratio (INR) monitoring while offering similar results in terms of efficacy. There is no specific way to reverse the anticoagulant effect of dabigatran in the event of a major bleeding event, unlike warfarin, although a potential dabigatran antidote (pINN: idarucizumab) is undergoing clinical studies. It was developed by the pharmaceutical company Boehringer Ingelheim.

Dabigatran etexilate structure.svg

Family members of its product case, WO9837075, have SPC protection in most EU states until February 2023, and expiry dates in the US until July 2020. The FDA Orange Book lists US7932273 (product derivative) and US7866474 (describing film blister-card containers for pradaxa®), which expire in September 2025 and August 2027 respectively, for dabigatran.

The drug also has New Chemical Entity exclusivity expiring on October 19, 2015. As of October 2014, Newport Premium™ reports that USV has dabigatran under development.

SEE

http://worldwide.espacenet.com/publicationDetails/biblio?DB=worldwide.espacenet.com&II=0&ND=3&adjacent=true&locale=en_EP&FT=D&date=20141016&CC=WO&NR=2014167577A2&KC=A2

РЕФЕРАТ WO2014167577


Настоящее изобретение относится к способу приготовления дабигатран этексилата или его фармацевтически приемлемой соли.
Настоящее изобретение относится к новым соединениям, в частности этил-3 – {[(2-формил-L-метил-LH-бензимидазол-5-ил) карбонил] – (2-пиридинил) амино} пропаноата и этил-3-{ [(2-дихлорметил-L-метил-бензимидазола-5-ил) карбонил] – (2-пиридинил) амино} пропаноат и процесс его подготовки.
Настоящее изобретение дополнительно относится к применению этих новых соединений в подготовке дабигатран этексилата или его фармацевтически приемлемой соли.

 

 

요약서 WO2014167577


본 발명은 다비가 트란 이텍 실 레이트, 또는 이들의 약학 적으로 허용 가능한 염의 제조 방법에 관한 것이다.
{[(2 – 포르 밀-L-LH-메틸 벤즈 이미 다졸 -5 – 일) 카르 보닐] – – (2 – 피리 디닐) 아미노} 프로판 산 에틸 3 – {} 본 발명은 특히 에틸 3에서, 신규 화합물에 관한 것이다 [(2 – 디클로로 메틸-L–LH 벤즈 이미 다졸 -5 – 일) 카르 보닐] – 이들의 제조 (2 – 피리 디닐) 아미노} 프로판 산 및 방법.
또한, 본 발명은 다비가 트란 이텍 실 레이트, 또는 이들의 약학 적으로 허용 가능한 염의 제조에서 이러한 신규 한 화합물의 용도에 관한 것이다.

要約書 WO2014167577


本発明は、ダビガトランまたは薬学的に許容される塩の製造方法に関する。
{[(2 – ホルミル-L-メチル – イソキノリン-ベンゾイミダゾール-5 – イル)カルボニル] – – (2 – ピリジニル)アミノ}プロパノエート及びエチル3 – {本発明は、特定のエチル3に、新規化合物に関する[(2-ジクロロ-1-メチル-1H-ベンゾイミダゾール-5 – イル)カルボニル] – その製造(2 – ピリジニル)アミノ}プロパノエートおよびプロセス。
さらに、本発明は、ダビガトランまたは薬学的に許容される塩の調製におけるこれらの新規化合物の使用に関する。

摘要 WO2014167577


本发明涉及一种用于制备达比加群酯或其药学上可接受的盐的方法。
本 发明涉及新的化合物,特别是乙基-3 – {[(2 – 甲酰基-L-甲基-LH-苯并咪唑-5 – 基)羰基] – (2 – 吡啶基)氨基}丙酸乙酯和乙基3 – { [(2 – 二氯甲基-L-甲基-1H-苯并咪唑-5 – 基)羰基] – (2 – 吡啶基)氨基}丙酸乙酯和方法,及其制备方法。
本发明还涉及在达比加群酯或其药学上可接受的盐的制备中使用这些新化合物的。
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