FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION (SECTION 10)
"AN IMPROVED PROCESS FOR THE PREPARATION OF DABIGATRAN ETEXILATE MESYLATE"
UNICHEM LABORATORIES LIMITED, A COMPANY REGISTERED
UNDER THE INDIAN COMPANY ACT. 1956, HAVING ITS REGISTERED
OFFICE LOCATED AT UNICHEM BHAVAN, PRABHAT ESTATE, S. V.
ROAD, JOGESHWARI (WEST), MUMBAI -400 102,
MAHARASTRA, INDIA

"AN IMPROVED PROCESS FOR THE PREPARATION OF DABIGATRAN ETEXILATE MESYLATE"
TECHNICAL FIELD
The present invention provides an efficient and improved process for the
preparation of Dabigatran Etexilate Mesylate; a direct thrombin inhibitor, is (3-
Alanine. N-j[2-[[[4-[[[(he\ylo\Y)carbonyl]amino]irninomethy]]
phenyl]amino]methyl]-l -methyl-1 H-benzimidazol-5-yl]carbony l]-N-2-pyridinyl-.ethyl ester, methanesulfonate (FORMULA-!) with high pharmaceutical purity. The present invention is also provides novel crystalline form of hydrochloride dihydrate salt of elhyl-3{[(2-{f(4-carbamimidoylphenyl)-amino] methyl}-1-methyl-lH-benzimidazoleo-yl) carbonyl] (pyridine-2-yl) amino} propanoate compound of Formula (V).
BACKGROUND OF THE INVENTION
The chemical name for Dabigatran etexilate mesylate, is (3-Alanine, N-[[2-[[[4-[[['(hexyloxy}carbonyi]amino]iminomethyl] phenyI]amino]methyI]-l-melhy[-lH-benzimidazol-5-yl]carbonyl]-N-2-pyndinyl-.ethyl ester, methanesulfonate. The empirical Formula is C34H41N7O5 • CH4O3S and the molecular weight is 723.85(mesylate salt), 627.75 (free base), Dabigatran etexilate mesylate, a direct thrombin inhibitor used for the treatment of reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation and the product is marketed by Boehringer Ingeiheim as Pradaxa. The methane sulfonate salt of Dabigatran etexilate mesylate is structurally represented a FORMULA-].


US6087380 is the basic product patent for the synthesis of Dabigalran etexilate which comprises the following reaction
i) condensing elhyl-3{[3-amino-4-(meihylamino)benzoyl](pyridine-2-
yl)amino}propanoate Formula-II with N-(4-cyanophenyl glycine) Formula 111 in presence of N.N-Carbonyl diimidazolc (CDI) in tetrahydrofuran as a solvent followed by cyclization using acetic acid to get ethy 1-3{[(2-{[(4-cyanophenyl)-amino]methyl}-l-methyl-1H-benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate Formula-IV as a hydrochloride salt;
ii) reaction of hydrochloride salt of ethyl-3{[(2-{[(4-cyanophenyl)-amino]methyl}-1-methyl-IH-benzim idazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoale Formula-!V with ethanolic hydrochloric acid, followed by reaction with ethanol and ammonium carbonate to produce ethyl-3 {[(2-{[(4-carbamimidoylphenyl)-amino] methyl}-!-methyl-1H-benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate Formula-V as a hydrochloride salt;
iii) finally reaction between hydrochloride salt of ethyl-3 {[(2-{[(4-carbamimidoylphcnyl)-amino]methyI}-l -methyl- IH-benzim idazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate Formula-V with n-hexyl chloro formate Formula-VI in presence of potassium carbonate in a mixture of tetrahydrofuran and water to produce Dabigalran etexilate Formula-VI I .
The above mentioned process has several disadvantages such as use of column chromatographic separation for the purification process and extensive workup procedure which is very difficult to apply in the industrial scale production. The patent is also silent about the purity of the final Dabigalran etexilate Formula-VII which negates its commercial production.


Various other methods are also known in the literature for the synthesis of Dabigatran etexilate or its mesylate salt; few of them are described below
WO2009/111997 discloses a process for the synthesis of Dabigatran etexilate of Formula-VIIby the condensation of compound of Formula-!! with compound of Formula-Ill in presence of N, N-Carbonyl diimidazole (CDI) as coupling agent and tetrahydrofuran as a solvent followed by salt formation using oxalic acid to get Formula-IV as oxalate salt, which on reaction with ethanolic hydrochloric acid followed by ammonium carbonate produces Formula-V as a hydrochloride salt. Formula-V on reaction with N-hexyl chloro formate in presence of triethyl amine as a base and chloroform as a solvent produces Dabigatran etexilate of compound of Formula-VII. Finally the compound of Formula-Vll is reacted with methane sulphonic acid in acetone to produce Dabigatran etexilate mesylate of Formula-1
WO2009/111997 process has several draw backs such as use of oxalic acid for the formation of oxalate salt of compound of Formula-IV. Use of chloroform

in the final slep for the preparation of compound of Formula-VII limits its commercial production. Dabigatran etexilate mesylate prepared in this process is having purity 99.5% (HPLC) with 75% yield in the final step.
WO2013/024384 describes a process for the synthesis of Dabigatran etexilate (Formula-VII) by the condensation of compound of Formula-ll with compound of Formula-Ill in presence of N.N-Carbonyl diimidazole (CDI) and THF followed by cyclization with acetic acid lo get Formula-IV, which on reaction with ethanolic hydrochloric acid followed by ethanolic ammonia gives hydrochloride salt of compound of Formula-V. Compound of Formula-V on reaction with N-hexyl chloro formate in presence of triethyl amine as a base and dichloromethane as a solvent produces Dabigatran etexilate of compound of Formula-VII.
WO2013/024384 process has several draw backs such as use of excess volume of ethanolic ammonia in the conversion of Formula-IV to Formula-V producing excess of inorganic salt which is very difficult lo remove in commercial scale production. Moreover the process is silent about the yield and purity of the final Dabigatran etexilate of compound of Formula-VII which limits its large scale production.
WO2013/111163 discloses a process for the synthesis of Dabigatran etexilate mesylate of Formula-] by the condensation of compound of Formula-]] with compound of Formula-Ill in presence of N. M-Carbony) diimidazole (CDI) as coupling agent and toluene as a solvent at 55-60 C to get Formula-IV. which on reaction with ethanolic hydrochloric acid followed by ammonia or ammonium carbonate produces compound of Formula-V as a hydrochloride salt, Compound of Formula-V on reaction with N-hexyl chloro formate in presence of potassium carbonate as a base and mixture of acetone and water as a solvent produces Dabigatran etexilate of compound of Formula-VII. Dabigatran etexilate of

compound of Formula-II on reaction with methane sulphonic acid in acetone produces Dabigatran etexilate mesylate of Formula-!.
WO2013/111163 process has several draw backs with respect to use of ammonia or ammonia solution in the conversation of compound of Formula-lV to compound of Formula-V producing excess amount of inorganic salt, which is very difficult to dispose at commercial scale. Moreover the process is silent about the overall yield and detailed stage wise purity of the intermediate of Dabigatran etexilate mesylate of compound of Formula-I.
WO2013111163 discloses crystalline form of compound of Formula-V having X-ray diffraction peak at 7.1, 7.7, 9.7, 12.0, 13.5. 14.3, 15.4, 17.2, 19.2, 20.4, 21.5, 22.3, 23.9, 24.3, 25.4, 26.5, 27.4 and 28.8 ±2 degrees two theta.
WO2014012880 discloses crystalline form of compound of Formula-V having X-ray diffraction peak at 7.7, 9.7, 12.6 and 15.4 ±2 degrees two theta. Same PCT application discloses novel polymorphic form of compound Formula-lV having X-ray diffraction peaks at .6, 10.3, 10.9, 11.0, 14.7, 15.3, 17.2, 20.6, 25.5 and 25.6 ± 0.2 degrees two theta.
WO2013/144903 depicts a process for the synthesis of Dabigatran etexilate mesylate of (Formula-I) by reaction of compound of Formula-lV with triethyl orthoformate and hydrochloric acid gas followed by purging ammonia gas in N,N-dimethyl formamide (DMF) as a solvent to obtain compound of Formula-V as a hydrochloride salt. Formula-V on reaction with N-hexyi chloro formate in presence of potassium carbonate as a base and acetone / tetrahydrofuran and water mixture or dichloromethane as ,a solvent produces Dabigatran etexilate of compound of Formula-VIl. Reacting Dabigatran etexilate compound of Formula-Vll on reaction with methane sulphonic acid in acetone to produces Dabigatran etexilate mesylate of Formula-1.

WO2013/144903 process has several draw backs such as;
i) Use of triethyl orthoformate for the generation of ethanol.
ii) Use of N.N-dimelhyl formamide (DMl:) as a solvent which is very
difficult to recover in commercial scale production, iii) Use of dry hydrochloric acid which is very corrosive in nature also limits
its commercial production, iv) The process is silent about the final impurity level or 1CH quality of
Dabigatran etexilate mesylate of Formula-1 (HPLC purity 99.65%)
The processes taught by prior art have several drawbacks namely expensive, not suitable for commercial scale production, difficult, giving lower yields, forcing use of corrosive acids, longer duration of corrosive reactions and less user friendly. Considering the drawbacks of prior art and very complex methodologies applied, for the preparation of the Dabigatran etexilate mesylate, there is a urgent and pressing need for simple, energy economical financially cheaper plant friendly and. environment friendly process for the preparation of Pormula-L particularly an improved process which will give us the 1CH quality o\' Dabigatran etexilate mesylate with higher yield.
OBJECT OF THE INVENTION
The object of the present invention is to provide an improved process for the synthesis of Dabigatran etexilate mesylate(Fonnula-l) which has better overall yields having ICH quality.
Another object of the present invention is to provide an improved process for the synthesis of Dabigatran etexilate mesylate (Formula-I) as a pharmaceutical!}' acceptable salt.

Yet another object of the present invention is to avoid column chromatography for preparation of different stages of Dabigatran etexilate mesylate.
Yet another object of the present invention is providing a novel crystalline polymorphic form of hydrochloride dihydrate salt of ethyl-3{[(2-{[(4-carbamimidoy!phenyl)-amino]methyl}-l -methyl- lH-benzimidazole-5-yl)carbony!](pyridine-2-yi)amino}propanoate compound of Formula-V and its preparation process. A novel crystalline polymorphic form of hydrochloride dihydrate salt of cthyl-3{[(2-{|(4-carbamimidoylphenyl)-amino]methyl}-l-methyl-IH-benzimidazole-5-yl)carbony]](pyridine-2-yl)amino}propanoale compound of Formula-V which is characterized by X-ray diffraction pattern (Fig 1) with peaks at 5.8, 8.6, 13.3, 15.8, 16.0, 17.3, 21.6, 23.4, 24.0 and 29.4 ± 0.2 degrees two theta.
Yet another object if the present invention is to provide a process for the preparation of crystalline form of compound of Formula-IV which is characterized by X-ray diffraction pattern (Fig 4) with peaks al 7.6, 10,3, 10.9, 11.0, 14.7, 15.3, 17.2,20.6. 25.5 and 25.6 ±0.2 degrees two theta.
Yet another object of the present invention is to provide a simple process which will avoid stringent requirements like maintaining anhydrous conditions during reaction and can be scaled up easily.
SUMMARY OF THE INVENTION:
The first aspect of the present invention is to providcan improved process for the preparation of Dabigatran etexilate mesylale(l) which comprises:
i) condensing ethyl-3{[3-amino-4-(methylamino)benzoyl](pyridine-2-
yl)amino}propanoate compound of Formula-!I with N-(4-cyanophenyl

glycine) compound oi' Formula-ill in presence of N,'N-Carbonyl diimidazolc (CDI) in presence of a solvent at up to reflux temperature followed by cyclization using acetic acid at up to 70-120 C to get crude ethy1-3{[(2-{[(4-cyanophenyl)-amino]methyl}-]-methyl-1H-benzimidazole-5-yl)carbony!](pyridine-2-yl)amino}propanoate compound of Fonnula-l V as a gummy mass;
ii) optional isolation followed by purification of crude gummy mass of ethyl-3{[(2-{[(4-eyanophenyl)-amino]methyl}-l-methyl-l l-l-benzimidazole-5-y])carbonyl|{pyridine-2-yl)amino}propanoate compound of Formula-IV using an appropriate solvent to get crystalline ethyl-3{[(2-{|(4-cyanophenyl)-amino]methyl}-l-methyl-lH-benzimidazole-5-yl)carbonyl |(pyridine-2-y])amino}propanoate compound of Formula-IV as free base;
iii) reaction of gummy mass of ethyl-3{[(2-{[(4-cyanopheny!)-amino]methyl}-l-methyl-lH-benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-lV or its optionally isolated crystalline free base with ethanolic hydrochloric acid, followed by ethanol and ammonium carbonate to producecrude and gummy mass of ethyl-3{[(2-{[(4-carbamimidoylphenyl)-amino]mcthy!}-l-methyl-lH-bcnzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoatc compound of Formula-V as a free base or hydrochloride salt as crude and gummy mass;
iv) isolation and purification of crude gummy mass of ethyl-3{|(2-{[(4-carbamimidoylphenyl)-aminojmelhyl}-l -methyl-1 H-benzimidazolc-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-V as a free base or hydrochloride salt using an appropriate solvent to get ethyl-3{|(2-{[(4-carbamimidoylphenyl)-amino]methyi}-l-methyl-1 l-l-benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-V as a free base or crystalline hydrochloride dihydrale salt;
v) reaction between ethyl-3{[(2-{|'(4-carbamimidoylphenyl)-amino]methyl}-
1-mcthyl-1H-benzimidazole-5-yl)carbonyf|(pyridine-2-

yl)amino}propanoale compound of Formula-V as a free base or crystalline hydrochloride dihydrate sail with n-hcxyl chloro formate compound of Formula-VI in presence of potassium carbonate in presence of a solvent at 0-25 C produces crude dabigatran etexilatc compound of Formula-VII :
vi) optionally purifying crude Dabigatran ctcxilate compound of Formula-VH in presence of a solvent to obtain pure ICH quality of Dabigatran etexilate compound of Formula-VII;
vii) converting Dabigatran etexilate compound of Formula-VII into Dabigatran etexilate mesylate of Formula-I using methane sulphonic acid in presence of a solvent.
The process disclosed above.synthesis of Dabigatran etexilate mesylate (Formula-I) as a pharmaceutical!}' acceptable salt is rendered possible. The process also avoids use of column chromatography for preparation of different stages of Dabigatran etexilate mesylate.
Another aspect of (he present invention is to provide novel crystalline form of hydrochloride dihydrate salt of ethyi-3{[(2-{[(4-carbamimidoytphenyl)-amino'|methyl}-l-methyl-lH-benzimidazolc-5-yl)carbonyl](pyridine-2-y])amino}propanoate compound of Formula-V and its preparation process.
Yet another aspect of the present invention is to provide a process for the preparation of crystalline form of compound of Formula-lV.
BKIEK DESCRIPTION OF 'ITIE FIGURES
FIG. 1: X-Ray powder diffraction pattern of novel crystalline form of hydrochloride dihydrate salt of ethyl-3 [[(2-{[(4-carbamimidoylphenyl)-amino] methyl}-1-methyl-lH-benzimidazole-5-yI) carbonyl] (pyridine-2-yl) amino}propanoale compound of Formula-V.

FIG. 2: DSC thermo gram of novel crystalline form of hydrochloride dihydrate salt of ethyl-3{[(2-{[(4-carbamimidoylphenyl)-amino] methyl}-l-methy]-lH-benzimidazole-5-yl) carbonyl] (pyridine-2-yl) amino) propanoate compound of Formula-V.
FIG. 3: 1R spectrum of novel crystalline form of hydrochloride dihydrate salt of ethyl-3{[(2-{[(4-carbamimidoylphenyl)-amino] methyl} -1 -methyl-1H-benzimidazole-5-yl) carbonyl] (pyridine-2-yl) amino}propanoate compound of Formula-V.
FIG. 4: X-Ray powder diffraction pattern of elhyi-3{[(2-{[(4-cyanophenyl)-amino]methyl}-l -methyl- lH-benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-lV.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly is provided an improved, efficient, process for producing
pharmaceutical!)' acceptable Oabigatran elexilate mesylate of Formula-I
comprising;
i) condensing ethyl-3{[3-amino-4-(methylamino)benzoyl](pyridine-2-
yl)amino}propanoate compound of Formula-[I with N-(4-cyanophenyl glycine) compound of Formula!!! in presence of N,N-Carbonyl diimidazole (CD1) in presence of a solvent at up to reflux temperature followed by cyclization using acetic acid at 70-120°C to get crude ethyl-3{[(2-{[(4-cyanophenyl)-amino]methyl}-l-methyl-l H-benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-lV as a gummy mass;
ii) optional isolation followed by purification of crude gummy mass of ethyl-3 {[(2-{["(4-cyanophenyl)-amino(methyl}-1-methyl-1 H-benzimidazoleo-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of FormulalV using an appropriate solvent to gel crystalline ethyl-3{|(2-{[(4-

cyanophcny l)-am ino]methy I} -1 -methyl-1 H-benzimidazole-5-yl)carbonyI](pyridine-2-yl)amino}propanoate compound of Formula-!V as free base;
iii) reaction of gummy mass of cthyl-3{[(2-{[(4-cyanophenyl)-amino]methyl}-]-methyl-1H-benzimidazo]e-5-yl)carbonyl](pyridine-2-. yl)amino}propanoate compound of Formula-lV or ils optionally isolated crystalline free base with ethanolic hydrochloric acid, followed by ethanol and ammonium carbonate produces crude gummy mass of elhyl-3{[(2-{|(4-carl→amimidoylphcnyl)-amino]melhyl}-l-methy|-lH-ben/jmidazolc-5-yl)carbonyI](pyridine-2-yl)amino}propanoate compound of Formula-V as a free base or hydrochloride salf as crude gummy mass;
iv) isolation and purification of crude gummy mass of ethyl-3{[(2-{['(4-carbamimidoylphcnyl)-amino]mclhyl} -1 -methyl- IH-benzim idazole-5-yl)carbonyl](pyridinc-2-yl)amino}propanoate compound of Formula-V as a free base or hydrochloride salt using an appropriate solvent to get ethyl-3{[(2-{|'(4-carbamimidoylphenyl)-amino]methyl}-l-methyl-lH-benzimidazole-5-yl)carbony!](pyridinc-2-yl)amino}propanoate compound of Formula-V as a free base or crystalline hydrochloride dihydrate salt;
v) reaction between ethyl-3{[(2-{[(4-carbamimidoylphenyl)-amino]melhyl}-
1 -methyl-1 H-benzimidazolc-5-yl)carbonyl](pyridine-2-yl)aminojpropanoatc compound of Formula-V as a free base or crystalline hydrochloride dihydrate salt with n-hexyl chloro formate compound of Formula-Vl in presence of potassium carbonate and a solvent at 0-25 C produces crude dabigatran ctcxilate compound of Formula-VI I;
vi) optionally purifying crude Dabigatran ctcxilate compound of Formula-VIl in presence of a solvent to obtain pure ICH quality of Dabigatran etexilaie compound of Formula-VIl ;
vii) converting Dabigatran etexilaie compound of Formula-VIl into Dabigatran etexiiate mesylate compound of Formula-I using methane sulphonic acid in presence of a solvent.

In the present invention the starting material ethyl-3{[3-amino-4-
(methylamino)benzoyl](pyridinc-2-yl)amino}propanoate compound of
FormulaFonnula-ll , N-(4-cyanophenyl glycine) compound of Formula-Ill and n-hexyl chloro formate compound of Forrmula-V[ was obtained from commercially available source and used directly.
Ethyl-3{[3-amino-4-(methylamino)benzoyl] (pyridine-2-
yl)amino}propanoateeompound of Formula-II is condensed with N-(4-cyanophenyl glycine) compound of Formula-Ill in presence of N.N-Carbonyl diimidazole (CD!) in presence of a solvent such as dichloromeihane , tetrahydrofuran , toluene ethyl acetate or mixture thereof at 35 to 40 °C (for dichloromeihane) or up to reflux temperature to produce amide intermediate.
After the complete formation of amide intermediate, acetic acid is added to the reaction mixture and the solvent is distilled off while raising the temperature and maintaining it between 85°C to 110°C to get cyclized crude product ethyl-3{[(2-{| (4-cyanophcnyl)-amino]mcthyl}-l -methyl- lH-bcnzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-lV as a gummy mass.
Optionally, isolating crude gummy mass of ethyl-3{[(2-{[(4-cyanophenyl)-amino][methyl}-1 -methyl- lH-benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-IV. by basification using a base such as 25% sodium hydroxide solution followed by extraction in dichloromeihane. Distillation of dichloromeihane furnished viscous impure material of compound of Formula IV. The viscous mass of compound of Formula-IV is then purified by Ethyl acetate, methanol, elhanol, isopropyl alcohol, acetone, tetrahydrofuran, toluene, water and mixture thereof to get crystalline solid ethy[-3{[(2-{|(4-cyanophenyl)-amino]methyl}-1 -methyl-1 H-benzimidazole-5-

y])carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-IV as free base.
Reaction of gummy mass of ethyl-3{[(2-{[(4-cyanophenyl)-amino]melhyl}-l-
melhyl-lH-benzimidazole-5-y])carbonyl](pyridine-2-yl)amino}propanoate
compound of Formula-IV or optionally isolated crystalline free base with
ethanolic hydrochloric acid, at room temperature (25°C - 30°C) followed by
reaction with ammonium carbonate in ethanol produces compound of Formula-V.
After the reaction the inorganic salt is filtered off and the filtrate is distilled under
vacuum to get crude gummy mass of ethyl-3{|(2-{|(4-carbamimidoylphenyl)-
amino] methyl}-1-methy 1-1 H-benzimidazole-5-yl) carbonyl](pyridine-2-
yl)amino}propanoatecompound of Formula-V as a free base or its hydrochloride salt;
The crude mass of ethyl-3{[(2-{[t4-carbamimidoylphenyl)-amino]methyl}-l-methyl-1H-benzimidazolc-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-V as a free base or its hydrochloride salt is isolated and purified by using methanol, ethanol ethyl acetate, isopropyl alcohol, acetone, water or a mixture thereof to get ethyl-3{|(2-{[(4-carbamimidoylphenyl)-amino]methyl}-]-methy 1-1 H-benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-V as a free base or crystalline hydrochloride dihydrate salt:.
Reaction between ethylo{[(2-{[(4-carbamimidoylphenyl)-amino]methyl}-J-me(hyl-lH-benzimidazole-5-yl)carbonyl](pyn'dine-2-yl)amino}propanoate compound of Formula-V as a free base or crystalline hydrochloride dihydrate salt: with n-hexyl chloro formate compound of Formula-VI in presence of potassium carbonate and a solvent such as methyl ethyl ketone. acetone; telrahydrofuran, dichloro methane, water of mixture thereof at 0-25°C produces crude dabigatran etexilate compound of Formula-VI! .

Optionally purifying Dabigatran elcxilalc compound of Formula-VIl in presence of a solvent such as ethyl acetate. Isopropyl alcohol, methanol, ethanol. acetone, dichloromethane. water or mixture thereof to obtain pure ICH quality of Dabigatran etexilale compound of Formula-VIl having HPLC purity NLT 99.7% with no individual impurity greater than 0.1 %.
Sail formation of Dabigatran etexilate compound of Formula-VIl with methane sulphonic acid in presence of a solvent such as ethyl acetate, methyl ethyl ketone, acetone, dichioromethane, telrahydrofuran or mixture thereof produces Dabigatran etexilate mesylate of Formula-I.
The reaction scheme for the synthesis of Dabigatran etexilate mesylate is shown in Schcmc-I.

According to one aspect of the present invention is to provide a novel crystalline form of hydrochloride dihydratc salt of ethyl-3{[(2-{[(4-carbamimidoylphenyl)-amino]methyl}-l -methyl-1 H-benzimidazoleo-yI)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-V having an X-ray diffraction pattern with peaks at 5.7, 8.6, 13.3. 15.8, 16.0, 17.3, 21.6, 23.4, 24.0 and 29.4 ± 0.2 degrees two theta. X-rav diffraction intensity with the diffraction anale 20 as

shown in Table 1 and an X-ray diffraction pattern as shown in FIG. 1 DSC thermograph which shows a melting point of about 111-112° C as shown in FIG.2. IR spectrum as shown in FIG. 3.
Novel crystalline form of hydrochloride dihydrate salt of ethy 1-3{[(2-{[(4-carbam imidoylphenyl)-amino]meihy I }-l-methyl-IH-benzim idazole-5-yl)carbonyl](pyridinc-2-yl)arnino}propanoatc compound of Formula-V is further characterized by X-ray diffraction pattern with peaks at 11.7, 17.5, 19.0, 19.2, 19.7, 22.2, 23.6, 25.4, 26.2 and 26.6 ± 0.2 degrees two theta.
Novel crystalline form of hydrochloride dihydrate salt of elhyl-3{|(2-{|'(4-carbamimidoylphenyl)-amino|mcthyl}-l-methyl-||-|-benzim idazole-5-yl)carbonyl](pyridine-2-yI)amino}propanoate compound of Formula-V may present in the form of dihydrate. Water is present in the dihydrate form upto 6.5%.
The present invention provides a process for the preparation of novel crystalline form of hydrochloride dihydrate salt of ethyl-3{|(2-{[(4-carbamimidoylphenyl)-amino]meihyl}-1-meihy 1-1 H-benzim idazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoale compound of Formula-V. comprising steps of;
i) reacting crystalline free base of cthyl-3{[(2-{[(4-cyanophenyl)-
amino]mcthyl}-1-methyl-1 ll-bcnzimidazolco-y])carbonyl](pyridine-2~ yl)amino}propanoaie compound of Formula-! V with ethanolic hydrochloric acid, followed by ethanoi and ammonium carbonate produces crude gummy mass of ethy 1-3 {[(2-{|(4-carbamim idoylpheny 1)-amino]methyl}-i -methyl- 1H-benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoale compound of Formula-V as hydrochloride salt
ii) isolation and purification of crude gummy mass of ethyl-3{[(2-{|(4-carbamimidoylphcnyl)-amino]methyl}-l -methyl- 1H -benzimidazoie-5-yl)carbonyl](pyridinc-2-yl)amino}propanoate compound of Formula-V as hydrochloride salt using an appropriate solvent to get novel crystalline

form of hydrochloride dihydratc salt of ethyl-3{|(2-{f(4-ca rbamimidoylphenyl)-amino]methyl}-1-methyl-IH-benzim idazole-5-yl)carbony]](pyridine-2-yl)amino}propanoale compound of Formula-V which has an X-ray diffraction pattern with peaks at 5.7, 8.6, 13.3, 15.8. ] 6.0, 17.3, 21.6, 23.4, 24.0 and 29.4 d- 0.2 degrees two theta.
The present invention also' provides a process for the preparation of novel crystalline form of hydrochloride di hydrate salt of ethyl-3{[(2-{[(4-carbam imidoylphenyl)-amino]rnethyl}-l -methyl- i H-benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-V, comprising steps of;
i) reacting crude elhyl-3{[(2-{[(4-cyanophenyl)-amino]methyl}-l-methyl-
lH-bcnzimidazolc-5-yl)carbonyll(pyridinc-2-yl)amino}propanoale compound of Formula-IV as a gummy mass; with ethanolic hydrochloric acid, followed by ethanol and ammonium carbonate produces crude gummy mass of ethyl-3{|'(2-{[(4-carbamimidoylphenyl)-amino]methyl}-l-methy|-l!-f-bcnzimidazole-5-yl)carbony|](pyridine-2-yl)amino}propanoate compound of Formula-V as hydrochloride salt; ii) 'isolation and purification of crude gummy mass of ethyl-3{[(2-{|(4-carbamim idoylphenyl)-amino]methyl}-l-methyl-1 H-benzimidazolc-5-yl)carbonyl|(pyridine-2-yl)amino}propanoate compound of Formula-V as hydrochloride salt using an appropriate solvent to get of hydrochloride salt of ethyl-3{[(2-{[(4-carbamimidoylphenyl)-amino]methyl}-l-methyl-IH-benzimida/Jole-5-yl)carbonyl](pyridine-2-yl)amino}propanoale compound of Formula-V as solid wet cake.
The obtained wet solid hydrochloride salt of ethyl-3{[(2-{[(4-carbamimidoylphenyl)-amino]melhyl}-l -methyl- ll-l-benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoatc compound of Formula-V is purified by using waterto obtain a novel crystalline polymorphic form of compound of

Formula- Vexhibiting X-ray diffraction pattern with peaks at 5.7, 8.6, 13.3, 15.8. 16.0, 17.3, 21.6. 23.4, 24.0 and 29.4 ± 0.2 degrees two theta.
The example of solvent i.e. appropriate solvent used in step ii) is selected from Ethyl acetate, methanol, ethanol, isopropyl alcohol, acetone, telrahydrofuran, toluene, water and mixture thereof.
Table 1:

Fornuils V
2 Theta d value Intensity
% 2 Theta d value Intensity % 2 Thcta d value Intensity
%
5,750 15.357 12,3 20,360 4,358 32,9 28,084 3,174 20.4
8.611 10.259 64.9 21.659 4.099 53,7 28,464 3.133 4.9
11,724 7,542 28.7 22.222 3.997 32.7 29,472 3.028 48.3
12,118 7,297 4.2 22.859 3.887 16.9 29,722 3.003 11,2
13.3.8O 6.612 88.8 23.462 3.788 65,7 30,909 2.890 7.2
15,485 57.177 10.6 23:65 3 3.75S 32,0 31.285 2.856 15.8
15.891 5,572 76,0 24.011 3.703 3.662 100,0 32,219 2.776 17.9
16.067 5,511 58.3 24.282
8,4 32,565 2.747 8.6
16300 5,433 15.4 24.698 3,601 8,4 33,585 2.666 8.3
17,011 5.208 4,5 25.444 3.497 33,1 34,155 2,623 9,8
17,385 5.096 42,5 26,238 3,393 26,0 34,457 2,600 7,5
17,514 5,059 32,6 26,631 3,344 26;2 34,745 2,579 13.0
19,099 4,643 27,9 26.673 3.339 26,3 35.303 2,540 10.7
19,290 4,597 38.5 27,310 3.262 7,0 35,569 2.521 6,7
19.745 4.492 34.9 27,809 3.205 11,8 36.849 2.437 4.4
37,112 2.420 6.7
According to one aspect the present invention provides a process for the preparation of crystalline form of compound of formula-IV, comprising steps of;
i) condensing cthyl-3{[3-amino-4-(methylamino)benzoyl](pyridine-2-
yl)amino}propanoate compound of Formula-ll with N-(4-cyanophenyl

glycine) compound of Formula-Ill in presence of N.N-Carbony!
diimidazole (CDI) in presence of a solvent up lo reflux temperature
followed by cyclization using acetic acid at 70-120 C to get crude ethyl-
3{[(2-{[(4-cyanophcnyl)-amino]methyl}-l -methyl- lH-benzimidazole-5-
yl)carbonyl](pyridine-2-yl)amino]propanoate compound of Formula-IV as
a gummy mass;
ii) isolation followed by purification of crude gummy mass of ethyl-3 {[(2-
{[(4-cyanophenyl)-amino|methyl]-l -methyl- lM-benzim idazole-5-yl)carbonyl](pyridinc-2-yl)amino}propanoate compound of Formula-]V using an appropriate solvent lo get crystalline ethyl-3{|(2-{[(4-cyanophcnyl)-amino]methyl}-l-melhyl-1H-benzimidazole-5-y!)carbonyl|(pyridine-2-yl)amino]propanoate compound of Formula-IV as free base, has an X-ray diffraction pattern with peaks at 7.6. 10.3. 10.9. 11.0, 14.7, 15.3, 17.2, 20.6, 25.5 and 25.6 ± 0.2 degrees two theta as shown in FIG. 4. X-ray diffraciion intensity with the diffraction angle 2G as shown in Table 2.
The example of solvent used in step i) may be selected from dichloro methane or telrahydrofuran or toluene or a mixture thereof.
The example of solvent i.e. appropriate solvent used in step ii) may include such as methanol, ethanol. ethyl acetate, acetone, water or a mixture thereof, preferably mixture of 15% water and ethy] acetate.
"Appropriate solvent" means a single or a combination of two or more solvents.
Table 2:

Formula 1V
2Theta d value
11.540 Inden sity % 2 Thita d value Intensity
%
7.654
20.2 22.127 41,406 24.2
10,311 85.720 47.7 2.312 38,431 5.7

10,973 80.562 46,6 2:408 36,921 31.4
i
11,058 79,948 51.2 2.439 36.455 15,7
11,201 78.930 16.5 2.460 36,158 16.4
14,720 60.129 65.3 2.491 35,704 30,5
15,310 57.828 60,5 2.551 34,880 55,8
16,000 55.350 13,6 2.564 34,711 100,0
17,279 51.277 52,8 2,813 31,687 6,4
17.470 50.723 20,9 2,835 31,449 6,0
17,731 499,808 24,4 2,972 30,034 9.1
18,564 47,756 27,3 3,343 26,780 3,2
19,000 46,67 1 6,0 2,451 25,964 3,8
19,512 45,459 10,8 3,597 24,946 2,1
20,654 42.969 39,9 3,846 23.385 3.2
21,193 41.889 9,6 3,933 2.889 5,9
The main inventive step of the present invention is
i) Use of a suitable solvent for the synthesis of ethyl-3{[(2-{[(4-
cyanophenyl)-amino]melhyl}-l -methyl-1 H-benzimidazole-5-
yl)carbonyl](pyridine-2-yl)amino}propanoatc compound of Formula-IV
from the condensation between ethyl-3{[3-amino-4-
(methylamino)bcnzoyl](pyridine-2-yl)amino}propanoate compound of Formula-II and N-(4-cyanophcnyl glycine) compound of Formula-Ill
ii) Optionally isolation, followed by purification of crude ethyl-3{[(2-{|(4-cyanophenyl)-amino]mel"hyl}-l-methyl-1H-benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-IV and crude ethy!-3{|(2-{[(4-carbamimidoylphcnyl)-amino|methyl}-l-methyl-l H-henzimidazole-5-yl)carbonyl|(pyridine-2-yl)amino}propanoatc compound of Formula-V
iii) Purification of Oabigatran etexilate compound of Formula-VII to obtain pure Oabigatran etexilate compound of Formula-Vll with HPLC purity of 99.5% more preferably 99.7% with no individual impurity greater than 0.1 %.

iv) A compound of eithyl-3{[(2-{[(4-cyanophenyl)-amino]methy]}-l-methyl-lH-bcnzimidazole-5-yI)carbonyl](pyridine-2-yl)amino}propanoate. compound of" Pormula-lV and ethyl-3{[(2-{[(4-carbamimidoylpheny])-amino]methyl}-] -methyl-1 l-l-benzimidazolc-5-yl)carbonyl] (pyridine-2-yl)amino}propanoale compound of Formula-V having new polymorphic crystalline form
The following examples arc presented for illustration only, and are not intended to limit the scope of the invention or appended claims
EXAMPLES
EXAMPLE-1: Preparation of cthyl-3{[(2-{l(4-cyanoplienyl)-amino]methyl}-
I-methyl-1H-benzimidazole-5-yl)earbonyli(pyri(line-2-yl)amino}propanoate
compound of Formula-IV :
Dichloro methane (500 mL). 4-cyanophenyl glycine (61.73 gm) and 63.94 gm of
CD1 at is taken in an assembly heated to 38-40oC and stirred for 1 h. A solution of
100 gm ethyl-3{[3-amino-4-(methylamino) benzoy l](pyr id ine-2-
yl)amino}propionate compound of Formula-ll in 250 mL MDC is then added to the reaction mass slowly at 25-30"C and stirred reaction mass at 25-30T- until starting material consumed as monitored by HPLC. 100 mL of acetic acid was added to the reaction followed by distillation of MDC at atmospheric pressure to attain temperature of 90-100 C. The reaction mass was then stirred for 1 hr as monitored by HPLC. After that the reaction mixture was gradually cooled to 25-30°C, 400 mL MDC followed bv 400 mL water was added to the reaction mass. The pH of the reaction mass was then adjusted to 10-11 by adding 25% NaOH solution. After that separated MDC layer was washed with water and then the organic layer was distilled out at atmospheric pressure to get oily mass. The oily mass was then crystallized by using a mixture of 15% water and ethyl acetate lo get crystalline solid intermediate ofcompound of formula-] V.
Dry Wt = 120-125 g (off white solid compound)
%Yield= 80-85%

Purity= 95-98 %(HPLX)
EXAMPLE-2: Preparation of hydrochloride salt of ethyl-3{[(2-{[(4-
carbamimidoylphenyl) aminol methyl}-1-methyl-lH-
benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate (Formula V):
Dichloro methane (500 mL). 4-cyanophenyl glycine (61.73 gm) and 63.94 gm of CD1 at are taken in an assembly heated to 38-40°C and stirred for 1 h. A solution of 100 gm clhyl-3{|3-amino-4-(mclhylamino) benzoyl](pyridine-2-yl)amino}propanoatecompound of Formula-11 in 250 mL MDC is then added to the reaction mass slowly at 25-30°C and stirred reaction mass at 25-30°C until starting material consumed as monitored by HPLC. 100 mL of acetic acid was added to the reaction followed by distillation of MDC at atmospheric pressure to attain temperature of 90-100°C. The reaction mass was then stirred for 1 hr at ambient and progress of reaction was temp monitored by HPLC. After that the reaction mixture was gradually cooled to 25-30°C. 400 mL MDC followed by 400 mL water was added to the reaction mass. The pH of the reaction mass was then adjusted to 10-11 by adding 25% NaOH solution. After that separated MDC layer was washed with water and then the organic layer was distilled out at atmospheric pressure to get oily mass. 800 ml BtOH: MCI. (30%) solution was added to the oily mass and stirred for 14-16 hrs at ambient tempand progress of reaction was monitored by HPLC. After the complete consumption of starting material, eihanol was distilled out under vacuum at 40-45 C till reaction mass becomes viscous liquid. This viscous mass is dissolved in 400 mL ethanol and then added slowly into a suspension of 120 gm (NH4)2CO3 in 400 mL Ethanol at 25-30°C and stirred for 14-16 hrs at ambient tempand progress of reaction was monitored by HPLC. After the complete consumption of intermediate the solution was filtered out to remove solid material. After that the ethanol layer was distilled out under vacuum at 40-45 C till reaction mass becomes viscous liquid. The viscous liquid was then

treated with a mixture of Ethanol (1-2V) and Ethyl acetate (2-6 V) at 55-60°C followed by filtration to get compound of Formula-V as wet cake. Purily= 90-95% (HPLC)
EXAMPLE-2a: Preparation of hydrochloride salt of cthyl-3{[(2-{[(4-
carbamimidoylphenyl) amino] methyl}-1 -mcthyl-1 H-
benzimida/ole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-V): lOOgm of solid intermediate compound of Formula (IV) was taken in 800 ml BtOH: HCl. (30%) solution and stirred for 14-16 firs at ambient temp. The reaction process was monitored by HPLC. After the complete consumption of starting material, ethanol was distilled out under vacuum at 40-45 C till reaction mass becomes viscous liquid. This viscous mass is dissolved in 400 mL ethanol and then added slowly into a suspension of 100 gm (NH4)2COs in 400 mL Ethanol at 25-30°C and stirred for 14-16 hrs at ambient tempand progress of reaction was monitored by HPLC. After the complete consumption of intermediate the solution was filtered out to remove solid material. After that the ethanol layer was distilled out under vacuum at 40-45°C till reaction mass becomes viscous liquid. The viscous liquid was treated with mixture of Ethanol (1-2V) and Ethyl acetate (2-6 V) at 55-60°C to get title compound of Formula -V as wet cake.
%yield= 75-80%
Purity= 90-95% (HPLC)
EXAMPLE-3: Purification of hydrochloride salt of cthyl-3{|(2-{[(4-
carbamimidoylphcnyl)-amino] mcthyl}-1 -mcthyl-1 H-
bciiziniidazolc-5-yl) carbonyl|(pyricline-2-
yI)amino}propanoatc compound of Formula-V):
Wei cake of Hydrochloride salt of Ethyl-3{[(2-{[(4-carbamimidoylphenyl)-
amino] methyl }-l-methyl-lM-bcnzimidazoIe-5-y I) carbonyf|(pyridine-2-
yl)amino}propanoatecompound of Formula-V (100 gm) was taken in an assembly and 500 mL of water was added to it. The reaction mixture was then stirred for 2 h

at 25-30° C .The reaction mixture was then filtered to get solid material. The solid material was then dried to get pure title compound ofFormula-V as off white solid.
Dry Wt= 70-75 g (off while solid)
%yield= 70-75%
Purity→ 96% (HPLC)
EXAMPLES:
The product obtain in example no. 3 which is crystalline form of hydrochloride dihydratc salt of elhyl-3{|(2-{[(4-carbamimidoylphenyl)-amino]methyl}-l-methyl-1 H-benzimidazole-5-yI)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-V exhibit following characteristics;
X-ray diffraction pattern with peaks at 5.7,8.6, 13.3, 15.8, 16.0, 17.3, 21.6, 23.4, 24.0 and 29.4 + 0.2 degrees two thela. X-ray diffraction intensity with the diffraction angle 20 as shown in Table 1 and an X-ray diffraction pattern as shown in FIG. 1 DSC thermograph which shows a melting point of about 111-112° C as shown in FIG.2. 1R spectrum shows in FIG. 3.
KXAMPLK-5: Preparation of Dabigatran erexilate compound of Formula-VII:
Water 400 mL . 82.50 gm of K2CO3, 600 mL of acetone was taken in an
assembly and stirred for 1 h. The reaction mass was then cooled to 5-10 C and
then 100 gm of hydrochloride salt of ethyl-3{[(2-{[(4-carbamimidoylphenyl)-
amino] mcthyl}-l -methyl- lH-benzimidaz.ole-5-yl) carbonyl](pyridine-2-
yl)amino}propanoalecompound of Formula -V was added to the reaction mixture. After that 45.93 gm of n-Hexyl chloroformate in 100 mL acetone is added to the reaction mass between 5-10°C and stirred for i hr as monitored by HPLC. The temperature of the reaction mass was then gradually increased up to 45-50 C to get clear solution. The organic layer was separated from the aqueous layer. 400 mL of water was then added to the organic layer and cooled to room temperature to precipitate Dabigatran etexilate effectively. The reaction mixture was then

filtered to get wet Dabigatran ctexilate as a solid material. The wet Dabigalran
elexilate was then dried in air oven at 50-55oC for 15-18 h to get dried material.
The solid was then purified by crystallization using Ethyl acetate (900 mL) to get
Dabigatran elexilate as a pure solid.
Dry wl=58-64 gm
% yield= 50-55 %
Purily=>99.5%(HPLC)
EXAMPLE-6: Preparation of Dabigatran ctexilate mesylate compound of Formuln-1 :
Acetone (700 ml), Dabigatran ctexilate (100 urn) was taken in an assembly and heated the reaction mass to 35-38 C till clear solution observed. The reaction mixture was then gradually cooled to 25-30 C. Meanwhile 15 gm of methane sulphonic acid in 100 mL acetone was taken separately and cooled the solution to 10-15°C and then added to the reaction mixture slowly within 50-60 min. the reaction mass was then stirred for 2 h at 25-30°C and then filtered the solid lo get wet Dabigalran ctexilate mesylate. The wet material was then dried under vacuum at 50(C for 6-8 h to get pure Dabigatran ctexilate mesylate.
Dry Wt= 105-110 g (Off white to paie yellow solid)
% Yicld= 90-95%
Purily=>99.7%
KXAMPLE-7: Preparation of Dabigatran ctexilate mesylate (Formula-I):
Ethyl acetate (2500 ml). Dabigatran elexilate (100 gm) was taken in an assembly and healed the reaction mass to 45-50 C to get a suspension. Meanwhile 15 gm of methane sulphonic acid in 100 mL Ethyl acetate was added to the reaction mixture slowly within 50-60 min. The reaction mass was then stirred for 2 h at 25-30 C. The solid obtained was filtered to met wet Dabigatran ctexilate mesylate. The wet material was then dried under vacuum at 50 C for 6-8 h to gel pure Dabigatran ctexilate mesylate.
Dry Wt- 105-110 g (Off white to pale yellow solid)

%Yield= 90-95%
]>urity= >99.7 %
Although the invention has been described with reference to specific embodiments, it is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments and alternate embodiments of the said invention will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the true spirit or scope of the present invention as exemplified and claimed herein below.

We claim:
1. A process for the preparation of Dabigatran etexilate mesylate of Formula-I comprising:
i) condensing ethyl-3{[3-amino-4-(methylamino)ben7.oyl|(pyridine-
2-yl)amino}propanoate compound of Formula-11 with N-(4-cyanophenyl glycine) compound of Formula -III in presence of N,N-Carbonyl diimidazole (CDI) in presence of a suitable solvent at up to reflux temperature followed by cyclizalion using acetic acid at 85-110°C to gel crude ethy!-3{[(2-{[(4-cyanophenyl)-amino]methyl}-]-methyl-IH-benzimidazolc-5-yI)carbonyl](pyridine-2-yl)amino}propanoate compound of Formuia-lV as a gummy mass:
ii) optional isolation followed by purification of crude gummy mass of elhyl-3{|(2-{[(4-cyanophenyl)-amino]methyl}-l-methyl-lH-benzimidazole-5-yl)carbony!](pyridine-2-yl)amino}propanoatc compound of Formula-lV obtained in step i). using an appropriate solvent to get crystalline ethyl-3{[(2-{[(4-cyanophenyl)-amino]m ethyl} -1-methy 1-1 H-bcnzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-IV as free base:
iii) reacting of gummy massof ethyl-3{[(2-{[(4-cyanophenyl)-amino]methyl}-l-rnethyl-lH-benzimidazole-5-yl)carbonyl](pyridinc-2-yl)amino}propanoate compound of Formula-lV obtained in step i) or its optionally isolated crystalline free base obtained in step ii) with cthanolic hydrochloric acid, followed by ethanol and ammonium carbonate to produce crude gummy mass of ethyl-3{[(2-{[(4-carbmimidolphenyl)-amino]methyl}-l -methyl- 1H-benzimidazolc-5-

yi)carbonyl](pyridine-2-yl)amino}propanoale compound of Formula-V as a free base or hydrochloride salt;
iv) isolating and purifying crude gummy mass of ethyl-3{[(2-{|(4-carbam imidoylphenyl)-amino]methyl}-1 -methyl-1H-benzimidazole-5-yl)carbonyl](pyridine-2-y!)amino}propanoate compound of Formula-V as a free base or hydrochloride salt obtained in step iii) using an appropriate solvent to get pure ethyl-3 {[(2-{[(4-carbam imidoylphenyl)-amino]methyl}-l-methyl-1H-benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoale compound of Formula-V as a free base or crystalline hydrochloride dihydrate salt having X-ray diffraction pattern with peaks at 5.7, 8.6, 13.3, 15.8, 16.0, 17.3, 21.6. 23.4, 24.0 and 29.4 ± 0.2 degrees two theta that shown in FIG. 1 and or DSC thermograph which shows a melting point of about 111-112° C as shown in FIG. 2 and or characterized by IR spectrum as depicted in FIG. 3:
v) reacting ethyl-3{[(2-{[(4-carbamimidoy!phenyl)-amino]methyl}-1-methyl-lH-benzimidazole-5-y[)carbonyl'i(pyridine-2-yl)amino}propanoate compound of Formula-V as a free base or 1 crystalline hydrochloride salt obtained in step iv) with n-hexyl chloro formate (Formula-VI) in presence of potassium carbonate in presence of a solvent at 0-25°C to produce crude Dabigatran eiexilate compound of Formula-VII;
vi) optionally purifying crude Dabigatran etexilate compound of Formula-VII in presence of a solvent to obtain pure 1CH quality of Dabigatran etexilate compound of Formula-VII;

vii) converting Dabigatran ctexilate compound of Formula-VIl into Dabigatran ctexilate mesylate of Formula-1 using methane sulphonic acid in presence of a solvent.
2. The process according to claim l(i) wherein the solvent is selected from the group consisting of dichloro methane, tctrahydrofuran. toluene, ethyl acetate or mixture thereof.
3. The process according to claim l(ii) wherein the solvent is selected from the group consisting of Ethyl acetate, methanol, ethanol, isopropyl alcohol. acetone, tctrahydrofuran, toluene, water and mixture thereof.
4. The process according to claim l(iv) wherein the solvent is selected from the group consisting of Ethyl acetate, methanol, ethanol. isopropyl alcohol, acetone, tctrahydrofuran. water and mixture thereof.
5. The process according to claim l(v) wherein the solvent is selected from the group consisting of dichloro methane, ethyl acetate, ethanol, isopropyl alcohol, acetone, tetrahydrofuran. methyl ethyl ketone, water and mixture thereof.
6. The process according to claim 1 (vi) wherein the solvent is selected from the group consisting of Ethyl acetate, methanol, ethanol, isopropyl alcohol, acetone, dichloromcthane, tetrahydrofuran. water and mixture thereof.
7. The process according to claim l(vii) wherein the solvent is selected from the group consisting of dichloro methane, ethyl acetate, ethanol, isopropyl alcohol, acetone, methyl ethyl ketone, tetrahydrofuran, and mixture thereof.
8. Novel crystalline form of hydrochloride dihydrate salt of ethyl-3{|'(2-{[(4-carbamimidoylphenyl)-amino]methyl}-1 -methyl- lH-benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-V has an

X-ray diffraction pattern with peaks at 5.7. 8.6, 13.3, 15.8, 16.0, 17.3, 21.6, 23.4, 24.0 and 29.4 + 0.2 degrees two iheta that shown in FIG. 1.
9. The novel crystalline form of hydrochloride dihydrate salt of ethy 1-3 {[(2-{[(4-
carbamimidoylphenyl)-amino]methyl}-1-methyl-1 H-bcnzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-V of claim 8. novel crystalline form of hydrochloride dihydrate salt of compound of Formula-V containing 6.5 % w/w water by KF.
10. The novel crystalline Form of hydrochloride dihydrate salt of ethyl-3 {[(2-{[(4-carbamimidoylphenyl)-amino]methyl}-l -methyl- lH-benzimidazole-5-yl)carbony1](pyridine-2-yl)amino}propanoate compound of Formula-V of claim 8, wherein crystalline form compound of Formula-V has DSC thermograph which shows a melting point of about 111-112° C as shown in FIG. 2.
11. The novel crystalline Form of hydrochloride dihydrate salt of ethyi-3 {I (2-{ [(4-carbam imidoylpheny i)-amino]methy I}-1 -methyl- lH-benzim idazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-V of claim 8, wherein crystalline form compound of Formula-V is further characterized by 1R spectrum as depicted in FIG. 3.
12. The process for the preparation of Novel crystalline Form of hydrochloride dihydrate salt of ethyl-3{[(2-{[(4-carbamimidoylphenyl)-amino]methyl}-l-methyl-lll-benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-V, comprising steps of;
i) reacting crystalline free base of ethyl-3{[(2-{|'(4-cyanophenyl)-
amino |melhyl}-l-methyl-IH-benziin idazole-5-yl)earbonyi](pyridine-2-yl)amino}propanoate compound of Formula—IVwith eihanolic hydrochloric acid, followed by ethanol

and ammonium carbonate to produce crude gummy mass of ethyl-3 {[(2-{[(4-carbamimidoylphenyl)-amino]methyl}-l-methyl-1H-benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-V as hydrochloride salt;
ii) isolation and purification of crude gummy mass of ethyl-3{[(2-{[(4-carbamimidoy lphenyl)-amino]methy]}-l -methyl-1H-benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-Vas hydrochloride salt using an appropriate solvent to get novel crystalline form of hydrochloride dihydrate salt of ethyl-3{[(2-{[(4-carbamimidoylphenyl)-amino]methyl}-l-methyl-lH-benzimidazoleo-yl)carbony!](pyridine-2-yl)amino}propanoale compound of Formula-V.
13. The process for the preparation of Novel crystalline Form of hydrochloride dihydrate salt of cthyl-3{[(2-{[(4-carbamimidoylphenyl)-amino]methyl}-I-mcthyl-lH-ben/imidazole-5-yl)carbonyl|(pyridine-2-yl)amino}propanoate compound of Formula-V, comprising steps of;
i) reacting crude ethyl-3{[(2-{[(4-cyanophenyl)-amino]methyl}-l-
methyl-1 H-benzimidazole-5-yl)carbonyl](pyridine-2-
yl)amino}propanoatc compound of Formula-lV as a gummy mass;
with ethanolic hydrochloric acid, followed by ethanol and ammonium
carbonate to produce crude gummy mass of ethyl-3{[(2-{[(4-
carbamimidoylphenyl)-amino]methyl}-l-methyl-lH-benzimidazole-5-
yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-V
as hydrochloride salt;
ii) isolation and purification of crude gummy mass of ethyl-3{[(2-
{|(4-carbamimidoylphenyl)-amino]methyl}-l -methyl- 1H-benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-V as a free base or hydrochloride salt using an appropriate solvent to get novel crystalline form of hydrochloride

dihydratc salt of ethyl-3{[(2-{[(4-carbamimidoylpheny|)-amino]methyl}-1-methyl-lH-benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino]propanoate compound of Formula-V.
14. The process according to claim 12 (ii) and 13(H) wherein the solvent is selected from the group consisting of Ethyl acetate, ethanol. isopropyl alcohol, acetone, tetrahydrofuran. water or mixture thereof.
15. The process for the preparation ofcrystalline Form of compound of Formula (IV), comprising steps of;
i) condensing ethyl-3{[3-amino-4-(methylamino)benzoyl](pyridine-2-
yl)nmino}propanoate compound of Formula-11 with N-(4-cyanophenyl glycine compound of Formula-ill in presence of N.N-Carbony! diimidazole (CDI) in presence of a solvent at up to reflux temperature followed by cyclizalion using acetic acid at up to 70-120 C to get crude ethyl-3 {[(2- {[(4-cyanophenyl)-amino]methyl}-l -methyl-1H-benzimidazole-5-yl)carbonyl](pyridinc-2-yl)amino}propanoate compound of Formula -IV as a gummy mass;
ii) isolation followed by purification of crude gummy mass of ethyl-3{[(2-{[(4-cyanophenyl)-amino]methyl}-l-methyl-lH-benzimidazole-5-yl)carbonyl|(pyridine-2-yl)amino}propanoate compound of Formula-IV using an appropriate solvent to get crystalline ethyl-3{[(2-{[(4-cyanophenyl)-amino] melhyl}-1-methyl-1 H-benzimidazole-5-yl)carbonyl](pyridine-2-yl)amino}propanoate compound of Formula-!V as free base, having an X-ray diffraction pattern with peaks at 7.6, 10.3, 10.9, 11.0, 14.7, 15.3. 17.2, 20.6, 25.5 and 25.6 ±0.2 degrees two theta.
16. The process according to claim 15 (i) wherein the solvent is selected from the
group consisting of ethyl acetate, dichloro methane, tetrahydrofuran. toluene
or mixture thereof.

17. The process according to claim 15 (ii) wherein the solvent is selected from the group consisting of Ethyl acetate, elhanol. isopropyl alcohol, acetone, letrahydrofuran, toluene, water and mixture thereof.
18. Use of novel crystalline Form of hydrochloride dihydrate salt ofethyl-3{[(2-{(4-carbamimidoylphenyl)-amino] methyl}-1-methyl-lH-benzimidazole-5-yl)carbonyi](pyridine-2-yl)amino}propanoate compound of Formula-V for the preparation of Dabigatran etexilate mesylate of Formula-1.