Synthesis of potential impurities of dabigatran etexilate

Article abstract of DOI:10.1080/00397911.2017.1321126

The present work describes the origin, control, and synthesis of two potent impurities of dabigatran etexilate 1, dabigatran dimer 2, and dabigatran n-propyl ester 3 from the commercially available raw materials 2-[(4-cyanophenyl)amino]acetic acid (4) and

Full text of DOI:10.1080/00397911.2017.1321126

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Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis of Potential Impurities of Dabigatran
Etexilate
U. Rajasekhar Reddy, B. Sreenivasulu, D. Satheesh, Dhanraj T. S. S.
Sundaram, G. Srikanth & S. Paul Douglas
To cite this article: U. Rajasekhar Reddy, B. Sreenivasulu, D. Satheesh, Dhanraj T. S. S.
Sundaram, G. Srikanth & S. Paul Douglas (2017): Synthesis of Potential Impurities of Dabigatran
Etexilate, Synthetic Communications, DOI: 10.1080/00397911.2017.1321126
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1321126
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Date: 28 April 2017, At: 22:11

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Synthesis of Potential Impurities of Dabigatran Etexilate
U. Rajasekhar Reddy1,2, B. Sreenivasulu1, D. Satheesh1, Dhanraj T. S. S. Sundaram1, G.
Srikanth1, S. Paul Douglas2
1Chemical Research and Development, APL Research Center II, Aurobindo Pharma Ltd.,
Indrakaran (V), Telangana, India 2Department of Engineering Chemistry, Andhra
University College of Engineering (A), Andhra University, Visakhapatnam, Andhra
Pradesh, India
Address corresponds to U. Rajasekhar Reddy, Chemical Research and Development,
APL Research Center-II, Aurobindo Pharma Ltd., Survey No. 71 & 72, Indrakaran (V),
Medak district-502329, Telangana, India. E-mail: rajasekhar.ummadi@gmail.com
Abstract
The present work describes the origin, control and synthesis of two potent impurities of
dabigatran etexilate 1, dabigatran dimer 2 and dabigatran n-propyl ester 3 from the
commercially available raw materials 2-[(4-Cyanophenyl)amino]acetic acid (4) and N-[3-
Amino-4-(methylamino)benzoyl]-N-2-pyridinyl-β-alanine ethyl ester (5). These
impurities are the process related impurities and may affect the quality of drug substance,
during its manufacturing in large scale. These impurities are not only the crucial
components in determining the quality and safety of the drug substance 1 but also provide
a better understanding of impurity profiling.
Graphical Abstract
1

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KEYWORDS: Dabigatran etexilate, dabigatran dimer, dabigatran n-propyl ester, related
substance, impurities
INTRODUCTION
Dabigatran etexilate 1 (Fig. 1) is an oral pro-drug of thrombin inhibitor dabigatran.[1]
Chemically it is known as N-{[2-({[4-
({[(hexyloxy)carbonyl]amino}iminomethyl)phenyl] amino}methyl)-1-methyl-1H-
benzimidazol-5-yl]carbonyl}-N-2-pyridinyl -β-alanine ethyl ester (1). This drug is widely
used to reduce the risk of stroke in patients with non-valvular atrial fibrillation (AF). [2]
Many synthetic routes are available in the chemical literature to synthesis 1, which
involves the condensation of two commercially available key raw materials, 2-[(4-
Cyanophenyl)amino]acetic acid (4) and N-[3-Amino-4-(methylamino)benzoyl]-N-2-
pyridinyl-β-alanine ethyl ester (5) as shown in Figure 1. This condensed product after
internal cyclization in acidic medium, followed by Pinner reaction and reaction with n-
hexyl chloroformate yields 1.[3]
During the process development of 1 in our laboratory, we came across two potent
impurities of 1 namely Ethyl 3-(2-{[(4-{N-[3-(2-{[(4-{N-
[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino] methyl}-1-methyl-N-(pyridin-2-yl)-
1H-benzimidazol-5-carboxyamido)propanoyl]carbamimi doyl}phenyl)amino]methyl}-1-
methyl-N-(pyridine-2-yl)-1H-benzimidazol-5-carboxamido) propanoate (2) and N-{[2-
({[4-({[(hexyloxy)carbonyl]amino}iminomethyl)phenyl]amino} methyl)-1-methyl-1H-
benzimidazol-5-yl]carbonyl}-N-2-pyridinyl -β-alanine - n-propyl ester (3), which are
2

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present in a level of 0.1-0.5 %. It is recommended by ICH (International Council on
Harmonization) that Impurities or related substances which are present in a level of <
0.1% w/w should be identified, based on the fact that unidentified impurities may cause
health hazards by making the API (Active Pharmaceutical Ingredient) inferior in
quality.[4] It is generally observed that during the multi-step chemical synthesis of API,
trace level of unwanted chemical entity were also formed in the previous steps, which
reacts in a similar way as do API and contaminates the drug substance.[5]
To have a better understanding of impurity profiling these impurities has to be identified,
synthesized and controlled in the manufacturing process. Furthermore these impurities in
a pure form are of great importance in determining the analytical parameters such as
specificity, linearity, accuracy, limit of detection (LOD), limit of quantification (LOQ)
and relative retention factor.[6]
Based on the above facts and their importance among the drug regulatory authorities of
United States, Europe and Japan, we have described here the origin, synthesis,
characterization and control of this two impurities (2 and 3) which are not reported so
far.[7–10]
RESULT AND DISCUSSION
Dabigatran dimer 2 is a process related impurity, which originates during the preparation
of amidine 7. Reaction of 4 with 5 leads to the formation of a condensed product 6 which
on Pinner reaction yields amidine 7. It is assumed that, during Pinner reaction while
3