WO2018134842A1

WO2018134842A1 - Process for the preparation of carbamic acid, n,n'-[[1,1'-biphenyl] -4,4'-diylbis]- 1 h-imidazole-5,2 diyi-(2s)-2,1-pyrrolidinediyl[(1 s)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl]]] bis-,c,c'-dimethyl ester and its salts and polymorphs

Info

Publication number: WO2018134842A1
Application number: PCT/IN2018/000005
Authority: WO
Inventors: Srinivasan Thirumalai Rajan; Sajja Eswaraiah; Ghojala Venkat Reddy; Sagyam RAJESHWAR REDDY; Boge RAJESHAM; Porala SUBBANARASIMHULU
Original assignee: MSN Laboratories Pvt Ltd
Current assignee: MSN Laboratories Pvt Ltd
Priority date: 2017-01-23
Filing date: 2018-01-22
Publication date: 2018-07-26
Anticipated expiration: 2019-07-23

Abstract

The present invention relates to the process for the preparation of carbamic acid, N,N'-[[1,1'biphenyl]- 4,4'-diylbis[ I H-imidazole-5,2-diyl-(2S)-2, 1-pyrrolidinediyl[ (1S)-1-( 1-methylethyl)-2- oxo-2,1-ethanediyl]]]bis-,C,C'-dimethyl ester of formula (I), salts and its polymorphs. The chemical structure of compound of formula (I) is shown below

Description

PROCESS FOR THE PREPARATION OF CARBAMIC ACID. Ν.Ν'-Γίΐ.ΐ'- BIPHENYLl-4,4'-DIYLBISflH-IMIDAZOLE-5,2-DIYL-f2S)-2J-PYRROLIDINEDIYL [(lSl-l-ri-METHYLETHYL)-2-OXO-2,l-ETHANEDIYLlllBIS-_<C.C'-DIMETHYL

ESTER AND ITS SALTS AND POLYMORPHS

Related applications

This patent application claims the benefit of priority of our Indian patent application numbers 201741002446 filed on 23^rd January 2017 and 201741022326 filed on 26^th June 2017 which are incorporated herein by reference.

Field of the invention

The present invention relates to a process for the preparation of carbamic acid, Ν,Ν'- [[1,1 '-biphenyl]-4,4'-diylbis[ 1 H-imidazole-5 ,2-diyl-(2S)-2, 1 -pyrrolidinediyl [( 15)- 1 -( 1 -methyl ethyl)-2-oxo-2₎I-ethanediyl]]]bis-,C,C'-dimethyl ester of formula (I). The chemical structure of said compound is shown below:

The present invention also relates to crystalline forms of carbamic acid, Ν,Ν'-[[1 ,Γ- biphenyl]-4,4'-diylbis[ lH-imidazole-5,2-diyl-(2S 2, 1 -pyrrolidinediyl[(l S 1 -( 1 -methyl ethyl)-2-oxo-2,l-ethanediyl]]]bis-,C,C'-dimethyl ester, hydrochloride (1 :2) of formula (la) and process for their preparation thereof.

The present invention also relates to carbamic acid, N,N^,-[[l_sr-biphenyl]-4₎4'- diylbis[ 1 H-imidazole-5 ,2-diyl-(25 -2, 1 -pyrroIidinediyl[( 1S)-1-(1 -methylethyl) -2-oxo-2, 1 - ethanediyl]]]bis-,C,C'-dimethyl ester, oxalic acid (1 :2) of formula (lb) and process for its preparation thereof.

Formula (lb)

Background of the invention

Carbamic acid, N_JN'-[[l,l'-biphenyl]-4₎4^diylbis[lH-imidazole-5_J2-diyl-(2-?)-2,l- pyirolidinediyltil.yi-l-f l -methylethyli^-oxo^^-ethanediy^JJbis-jCjC'-dimethyl ester hydrochloride (1 :2) of formula (la) is also generically known as Daclatasvir hydrochloride (1 :2) or Daclatasvir dihydrochloride. Daclatasvir dihydrochloride is a hepatitis C virus (HCV) NS5A inhibitor and indicated for the treatment of chronic HCV genotype 3 infections in combination with Sofosbuvir. Daclatasvir dihydrochloride is approved by United States Federal Drug Administration (US FDA) under the brand name of Daklinza® on July 24, 2015 to Bristol Myers Squibb (BMS).

US 7728027 (published on June 01 , 2010) and US 8329159 (published on December 11, 2012) both of patents assigned to BMS and describes the Daclatasvir dihydrochloride product and its preparation which comprises:

a) bromination of l, -(biphenyl-4,4'-diyl)diethanone with bromine in presence of methylene chloride to give the compound of formula (3);

b) the compound of formula (3) was coupled with l-(/er/-butoxycarbonyl)-L-proline in presence of diisopropylethylamine in acetonitrile and later the product contained acetonitrile solution was exchanged into toluene by vacuum distillation to give the compound of formula (5) with less than 0.5 vol % acetonitrile;

c) the solution of compound of formula (5) in toluene was reacted with ammonium acetate at 95-100°C for 15 hours and after completion of reaction, cumbersome and repeated work up/washing with multiple of solvents like acetic acid, n-butanol, aqueous acetic acid, toluene, methanol and mixture of toluene and methanol to give the compound of formula (6);

d) the compound of formula (6) was deprotected with aqueous hydrochloride in methanol followed by filtration and then washed successively with methanol and water to give the compound of formula (7);

e) the compound of formula (7) was coupled with N-(methoxycarbonyl)-L-valine in presence of acetonitrile, hydroxybenzotriazole hydrate, l-(3-dimethylaminopropyl)-3- ethylcarbodiimide HC1, diisopropylethylamine. After completion of the reaction, tedious and repeated work up/washing with multiple of solvents like aqueous sodium chloride, isopropyl acetate, aqueous sodium hydroxide and the mixture was then solvent exchanged into isopropyl acetate by vacuum distillation. Again the product contained isopropyl acetate solution was solvent exchanged into ethanol by vacuum distillation and then treating with HC1 in ethanol and seed crystal to produce the Daclatasvir dihydrochloride of formula (la).

Disadvantages of the above process:

• Using of multiple of solvents like acetonitrile and toluene in step-b) (coupling stage) & step-c) (cyclization stage),

• Cyclization of the compound of formula (5) in step-c) at higher temperatures which is not suggestable at industrial scale up.

• Carrying the reaction in step-c) at higher temperatures also causes for racemization of required isomer product.

• Consumption of multiple solvents like acetic acid, n-butanol, aqueous acetic acid, - toluene, methanol and mixture of toluene & methanol repeatedly for work up, washing, and isolation which is not eco-friendly process;

• Using of aqueous acids like aqueous hydrochloride for deprotection reaction in step-d) which causes the loss of yield due to miscibility of obtained compound of formula (7) in aqueous solutions; and

• Tedious and repeated work up with multiple of solvents & repeatedly solvent exchanged with isopropyl acetate followed by ethanol.

US 8629171 (published on January 14, 2014) discloses crystalline Form-N2 of Daclatasvir dihydrochloride and its single crystal unit cell parameters, PXRD pattern, solid state C-l 3 NMR spectrum and melting point.

WO 2016/192691 Al (published on December 08, 2016) discloses various solid salt forms of Daclatasvir with hydrochloric acid, hydrobromic acid, sulphuric acid, 2- naphthalenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid and fumaric acid and their process for preparation.

In general, polymorphism refers to the ability of a substance to exist as two or more crystalline phases that have different spatial arrangements and/or conformations of molecules in their crystal lattices. Thus, "polymorphs" refer to different crystalline forms of the same pure substance in which the molecules have different spatial arrangements of the molecules, atoms, and/or ions forming the crystal. Different polymorphs may have different physical properties such as melting points, solubilities, X-ray diffraction patterns, etc. The variation in solid forms may appreciably influence the pharmaceutical properties, such as bioavailability, handling properties, dissolution rate, and stability, and in turn such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorphic form. For these reasons, regulatory authorities require drug manufacturing companies to put efforts into identifying all polymorphic forms, e.g., crystalline, amorphous, solvates, stable dispersions with a pharmaceutically acceptable carriers, etc., of new drug substances.

The existence and possible numbers of polymorphic forms for a given compound cannot be predicted, and there are no "standard" procedures that can be used to prepare polymorphic forms of a substance. This is well-known in the art, as reported, for example, by A. Goho, "Tricky Business," Science News, Vol. 166(8), August 2004.

The present invention provides crystalline forms and process for the preparation of compound of formula (I) which is efficient, industrially viable, cost effective, eco-friendly and avoids the disadvantages above noticed in the prior art process. W

Advantages of the present invention:

• Novel process for the preparation of compound of formula (I) and its salts.

• Using single solvent for coupling and cyclization reactions in support of developing eco-friendly processes.

• Carrying cyclization at less temperatures and avoids the formation of racemization;

• Using non-aqueous condition for deprotection reactions which control the loss of yield.

• Self-coupling of the compounds of formula (VIII) to provide the compound of formula (I) which avoids the usage of expensive or non-commercially available borylating agent and chiral metal catalyst or ligand catalyst.

• Recovery of metal catalyst used in the self-coupling reaction.

Brief description of the invention

The first aspect of the present invention is to provide a process for the preparation of carbamic acid, N,N'-[[l, -biphenyl]-4,4'-diylbis[lH-imidazole-5,2-diyl-(25)-2,l -pyrrolidine diyl^l^-l-Cl-methylethy ^-oxo^.l-ethanediylJlJbis-.C^'-dimethyl ester of formula (I) or its salts.

The second aspect of the present invention is to provide carbamic acid, Ν,Ν'-[[1,Γ- biphenyl]-4,4'-diylbis[ 1H-imidazole-5,2-diyl-(2S)-2, 1 -pyrrolidine diyl [( 1 S)-l -( 1 - methylethyl)-2-oxo-2,l-ethanediyl]]]bis-,C,C'-dimethyl ester oxalic acid (1 :2) of formula (lb) and process for its preparation thereof.

The third aspect of the present invention is to provide a process for the purification of carbamic acid, N,N'-[[l,r-biphenyl]-4₅4'-diylbisilH-i^

ester oxalic acid (1 :2).

The fourth aspect of the present invention is to provide crystalline form of carbamic acid, N-N'-KU'-bipheny^ ^ diyl[(15)- l-(l-methylethyl)-2-oxo-2,l-ethanediyl]]]bis-,C,C'-dimethyl ester hydrochloride (1 :2) of formula (la), hereinafter designated as "Form-S" and process for its preparation thereof. The fifth aspect of the present invention is to provide crystalline form of carbamic acid, N'-ftl.l'-biphenylJ^^'-diylbistlH-imidazole-S^-diyl^^ -pyrrolidine diyl[(15)- l-(l-methylethyl)-2-oxo-2,l-ethanediyl]]]bis-,C,C'-dimethyl ester hydrochloride (1 :2) of formula (la), hereinafter designated as "Form-N" and process for its preparation thereof.

The sixth aspect of the present invention is to provide a process for the preparation of crystalline Form-M of carbamic acid, N,N'-[[l, -biphenyl]-4,4'-diylbis[lH-imidazole-5,2- diyl-(2S 2, 1 -pyrrol idinediyl [( 15)- 1 -( 1 -methylethyl)-2-oxo-2, 1 -ethanediylJJJbis- C- dimethyl ester hydrochloride (1 :2) of formula (la).

Brief description of the drawings

Figure-1: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous form of Daclatasvir oxalic acid (1 :2)

Figure-2: Illustrates the Infra-Red Spectra of amorphous form of Daclatasvir oxalic acid (1 :2) Figure-3: Illustrates the PXRD pattern of crystalline Form-M of Daclatasvir hydrochloride (1 :2).

Figure-4: Illustrates the PXRD pattern of crystalline Form-M of Daclatasvir hydrochloride (1 :2)

Figure-5: Illustrates the Thermo Gravimetric Analysis (TGA) of crystalline Form-M of Daclatasvir hydrochloride (1 :2)

Figure-6: Illustrates the of pattern of solid state C-13 NMR crystalline Form-M of Daclatasvir hydrochloride (1 :2)

Figure-7: Illustrates the PXRD pattern of crystalline Form-S of Daclatasvir hydrochloride (1 :2)

Figure-8: Illustrates the solid state C-13 NMR spectrum of crystalline Form-S of Daclatasvir hydrochloride (1 :2)

Figure-9: Illustrates the PXRD pattern of crystalline Form-N of Daclatasvir hydrochloride (1 :2)

Detailed description of the invention

The present invention provides a process for the preparation of carbamic acid, Ν,Ν'- [[1,1 '-biphenyl]-4,4'-diylbis[ 1 H-imidazole-5 ,2-diyl-(2S)-2, 1 -pyrrolidinediyl [( 15)-l -( 1 -methyl ethyl)-2-oxo-2,l-ethanediyl]]]bis-,C,C'-dimethyl ester of formula (I) and acid addition salts.

Unless otherwise specified, as used herein the term "suitable solvent" refers to the solvent selected from "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and glycol solvents such as ethylene glycol, propylene glycol and the like; "chloro solvents" such as to methylene chloride, chloroform, ethylene dichloride and carbon tetra chloride; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone; "hydrocarbon solvents" such as to toluene, hexane, heptane and cyclohexane; "nitrile solvents" such as acetonitrile, propionitrile; "ester solvents" such as ethyl acetate, methyl acetate and isopropyl acetate, isobutyl acetate; "ether solvents" such as tetrahydrofuran, 1 ,3- dioxane, diethyl ether and methyl tert-butyl ether; "polar protic solvents" such as water, alcohol solvents, "polar aprotic solvents" such as dimethylformamide, dimethylacetamide and dimethylsulfoxide or mixture of solvents.

As used herein the term "suitable base" refers to the bases selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; alkali metal phosphates such as potassium hydrogen phosphate, trisodium phosphate; organic bases such as sodium tertiary butoxide, potassium tertiary butoxide methylamine, ethylamine, isopropylamine, diisopropyl ethylamine, triethylamine, ammonia or their aqueous solution.

As used herein the term "suitable acid" refers to the acid selected from inorganic acids like HCl, HBr, HI, H2SO ; organic acids like oxalic acid, succinic acid, formic acid, acetic acid, methane sulfonic acid (MsOH), p-toluene sulfonic acid (p-TsOH), trifluoro acetic acid (TFA). These acids can be used to prepare the acid addition salts of compound of formula (I) by the methods in the art or by the present invention.

In the present invention, the amine protecting group (PG) is selected from but not limited to tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenyImethyloxy carbonyl (Fmoc), benzyl (Bn), carbamate group, p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), 3,4-dimethoxy benzyl (DMPM), trityl (Tr), alkyl/aryl sulfonyl such as methanesulfonyl, ethanesulfonyl, benzenesulfonyl, toluenesulfonyl and the like; acyl groups such as acetyl (Ac), trifluoroacetyl (TFA), benzoyl (Bz) group and the like.

The suitable amine protecting agent is selected such that it is capable of protecting the nitrogen atom with any of the above mentioned amine protecting groups.

Suitable amine protecting agent is selected from but not limited to di-tert.butyl dicarbonate (DIBOC), benzyl chloroformate, fiuorenylmethyloxy carbonyl chloride (FMOC chloride), trityl chloride, acetyl chloride, acetic anhydride, trifluoroacetic acid, trifluoroacetic anhydride, benzoyl halides, benzyl halides, alkyl/arylsulfonic acids/acid halides/anhydrides such as methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, p- toluenesulfonic anhydride and the like; alkyl trifluoroacetates such as methyl trifluoroacetate, ethyl trifluoroacetate, isopropyl trifluoroacetate, vinyl trifluoroacetate; trifluoroacetic acid, trifluoroacetyl chloride and the like.

The suitable deprotecting agent is selected based on the protecting group employed. The suitable deprotecting agent is selected from but not limited to acids such as hydrochloric acid (aqueous hydrochloride, methanolic hydrochloride, ethanolic hydrochloride, isopropanolic hydrochloride, ethyl acetate.hydochloride, acetonitrile.hydrochloride), hydrobromic acid, sulfuric acid, nitric acid, aq.phosphoric acid, trifluoroacetic acid, methane sulfonic acid, p-toluenesulfonic acid and the like; acetyl chloride in combination with alcohols; bases such as alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, cesium carbonate/imidazole, ammonia, cerium(IV) ammonium nitrate (CAN); organic bases such as methylamine, ethylamine, diethylamine, triethylamine, piperidine and the like; hydrogenating agents such as Pd/C, Pd(OH)₂/C (Pearlman's catalyst), palladium acetate, platinum oxide, platinum black, sodium borohydride, Na-liquid ammonia, Raney-Ni, tri(Ci-C6)alkylsilanes, tri(C|-C₆)alkylsilyl halides and the like.

The term suitable "coupling agent" used in the present invention refers to Ν,Ν'- dicyclohexylcarbodiimide (DCC), Ν,Ν'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl), alkyl or aryl chloroformates such as ethyl chloroformate, benzylchloroformate, diphenyl phosphoroazidate (DPPA), thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4- methyl-2-oxopentanoyl chloride (i-BuCOCOCI), benzotriazol-l-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP), methane sulfonyl chloride and the like optionally, in combination with 1 -hydroxy-7-azatriazole (HOAt), 1-hydroxybenzotriazole (HOBt), l -hydroxy-lH-l ,2,3-triazole-4-carboxylate (HOCt), O-(benzotriazol-l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), N- hydroxysulfosuccinimide (Sulfo-NHS), 4-dimethylaminopyridine and the like.

The first aspect of the present invention provides a process for the preparation of carbamic acid, N,N'-[[l, -biphenyl]-4,4'-diylbis[lH-imidazole-5,2-diyl-(2S)-2,l-pyn-olidine diyl[(l-S)-l-(l -methylethyl)-2-oxo-2,l-ethanediyl]]]bis-,C,C^,-dimethyl ester of formula (1) or its salts, comprising the steps of:

a) (i): reacting the compound of general formula (VIII) with the suitable borylating agent in presence of a catalyst, suitable base in a suitable solvent to produce the compound of general formula (IX) followed by in-situ reacting with the compound of general formula (VIII) in presence of catal st, base in a solvent,

wherein R represents W 201

(or)

a) (ii): self-condensing the two molecules of compound of general formula (VIII) (self-coupling) in presence of suitable catalyst and suitable base to provide the

wherein X is selected from bromine, chlorine or iodine,

b) optionally, converting the compound of formula (I) into its acid addition salts. wherein, in step-a) (i) the suitable borylating agent is selected from bis(pinacolato)diboron or bis(neopentylglycolato)diboron; the catalyst is selected from PdCl₂[P(t-Bu)₂Ph]_2, Pd(dppf)Cl2_, Pd(PPh₃)₄ and the like; in step-a) (ii), the suitable catalyst is selected from Pd, Pd(OH)₂, [jPdCh, Pd(0₂CCH₃)_2s PdS0 , Pd 0₃)2, Fe, Ni, copper sulfate, copper oxide, copper chloride and the like in presence of charcoal. The metal catalyst used in the step-a (ii) can be recovered by filtration after completion of the coupling reaction. The same recovered metal catalyst can be used in the coupling reaction of other batches of the compounds of formula (VIII).

The suitable base in step-a) (i) & (ii) selected from alkali metal hydroxides like sodium hydroxide, potassium hydroxide; alkali metal carbonates like sodium carbonate, potassium carbonate; alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate; alkali metal phosphates like dipotassium hydrogen phosphate, tripotassium phosphate, trisodium phosphate; organic bases like sodium acetate, potassium acetate, potassium propionate, sodium tertiary butoxide, potassium tertiary butoxide, methylamine, ethylamine, isopropylamine, diisopropyl ethylamine, triethylamine, ammonia or their aqueous solution. The suitable solvent in step-a) (i) & (ii) is selected from alcohol solvents, glycol solvents, hydrocarbon solvents, chloro solvents, polar protic solvents, polar aprotic solvents, ester solvents, ether solvents, nitrile solvents or mixtures.

The reaction in step-a) (i) & (ii) optionally carried out in presence of phase transfer catalyst.

The another aspect of the present invention provides a process for the preparation of carbamic acid, N,N'-[[1 , -biphenyl]-4,4'-diylbis[lH-imidazole-5_s2-diyl-(2S -2,l -pyrrolidine diyl[(lS)-l-(l-methylethyl)-2-oxo-2,l-ethanediyl] ]]bis-,C,C'-dimethyl ester, oxalic acid (1 :2) of formula (l

Formula (lb)

comprising the steps of:

a) self-condensation of two molecules of compound of general formula (VIII) in presence of suitable catalyst and suitable base in a suitable solvent to provide the compound of formula (I)

Formu a (VllI) wherein X represents bromine, chlorine or iodine.

b) treating the compound of formula (I) with oxalic acid to provide the compound of formula (lb). wherein in step-a) , the suitable catalyst is selected from Pd, Pd(OH)₂, fPdCl₂, Pd(0₂CCH₃)₂, PdS0_4} Pd (N0₃)₂₎ Fe, Ni, copper sulfate, copper oxide, copper chloride and the like in presence of charcoal. The suitable base in step-a) selected from alkali metal hydroxides like sodium hydroxide, potassium hydroxide; alkali metal carbonates like sodium carbonate, potassium carbonate; alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate; alkali metal phosphates like dipotassium hydrogen phosphate, tripotassium phosphate, trisodium phosphate.

The suitable solvent in step-a) is selected from alcohol solvents, glycol solvents, hydrocarbon solvents, chloro solvents, polar protic solvents, polar aprotic solvents, ester solvents, ether solvents, nitrile solvents or mixtures.

Yet another aspect of the present invention provides a process for the preparation of carbamic acid, N,N'-[[l,r-biphenyl]-4,4'-diylbis(lH-imidazole-5,2-diyl-(25)-2,l -pyrrolidine diyl[(15)-l-(l-methylethyl)-2-oxo-2,l-ethanediyl] ]]bis-,C,C'-dimethyl ester, hydrochloric acid (1 :2) of

Formu a (la) comprising the steps of:

a) self-condensation of two molecules of compound of general formula (VIII) in presence of suitable catalyst and suitable base in a suitable solvent to provide the

wherein X represents bromine, chlorine or iodine,

b) treating the compound of formula (I) with oxalic acid to provide the compound of formula (lb).

Formula (lb) c) treating the product obtained in step-b) with suitable base in presence of a suitable solvent followed by treating the obtained compound with suitable hydrochloric acid source in suitable solvent to provide the compound of formula (la). wherein, in step-a) the suitable metal catalyst, suitable base, suitable solvent are same as defined hereinbefore in previous aspects. In step-c) the suitable base is selected from alkali metal hydroxides or alkali metal carbonates, alkali metal bicarbonates and the like; the suitable solvent is selected from chloro solvents, alcohol solvents, glycol solvents, ketone solvents, ester solvents, ether solvents, polar protic solvents, polar aprotic solvents, nitromethane or mixtures; the suitable hydrochloric acid source is selected from hydrochloride, hydrochloride gas, SOCb/alcohol solvents, aqueous hydrochloride, ethyl acetate hydrochloride, acetonitrile hydrochloride, isopropanolic hydrochloride, methanolic hydrochloride, ethanolic hydrochloride and the like.

The preferred embodiment of the present invention provides a process ^"for the preparation of carbamic acid, N,N'-[[l,r-biphenyl]-4,4'-diylbis[lH-imidazoIe-5,2-diyl-(25)- 2, 1 -pyrrolidine diyl[(l S)-\ -( 1 -methylethyl)-2-oxo-2, 1 -ethanediyl]]]bis-,C,C'-dimethyl ester hydrochloride (1 :2) of formula (la), comprising the steps of: a) self-condensing the two molecules of compound of formula (Villa) with each other (self-coupling) in presence of Pd(OH)₂/C and dipotassium hydrogen phosphate

b) treating the product obtained in step-a) with oxalic acid to provide the compound of formula

Formula (lb)

c) treating the product obtained in step-b) with aqueous sodium hydroxide solution in presence of methylene chloride followed by treating the obtained compound with aqueous hydrochloric acid in methylene chloride to provide the compound of formula (la).

The another aspect of the present invention provides a process for the preparation of carbamic acid, N,N'-[[ 1 , 1 '-biphenyl]-4,4'-diylbis[ 1 H-imidazole-5,2-diyI-(2S)-2, 1 -pyrrolidine diyl[(15 -l-(l-methylethyl)-2-oxo-2,l-ethanediyl]]]bis-,C,C'-dimethyl ester of formula (I) or its salts, comprising the steps of:

a) reacting the compound of general formula (II) with the compound of general formula (III) in presence of a suitable base in a suitable solvent to provide the compound of formula (IV) which is in-situ cyclized to produce the compound of formula (V);

Formula (II) Formula (III)

la (IV)

Formula (V) wherein, X refers to chlorine, bromine, fluorine, iodine, methanesulfonyl group, ethanesulfonyl group,- benzenesulfonyl group, toluenesulfonyl group and the like; "PG" refers to amine protecting group

b) treating the compound of general formula (V) with suitable deprotecting agent in nonaqueous condition to produce the compound of general formula (VI) or acid addition salt;

addition salt

Formula (V) Formula (VI)

c) reacting the compound of general formula (VI) or its acid addition salts with the compound of formula (VII) in presence of a suitable coupling agent, base in a suitable solvent to provide the compound of general formula (VII

Formula (VI) Formula (VI!) d) (i): treating the compound of formula (VIII) with the suitable borylating agent in presence of a catalyst, suitable base in a solvent to produce the compound of general formula (IX) followed by in-situ reacting with the compound of general formula (VIII) in presence of a suitable catalyst, base in a solvent. Boiylation

Catalyst

ormu a wherein X is same as d represents

(or)

d) (ii): self-condensing the two molecules of the compound of general formula (VIII) in

e) optionally, treating the compound of formula (I) obtained in step-d(i) or (ii) with oxalic acid to provide the compound of formula (lb),

f) optionally, treating the product obtained in step-f) with suitable base in presence of a suitable solvent followed by treating the obtained compound with suitable hydrochloric acid source in a suitable solvent to provide the compound of formula (la). wherein, in step-a) the suitable base is selected from alkylamine, dialkylamine or trialkylamine or alkali metal hydroxides, alkali metal carbonates; the solvent is selected from hydrocarbon solvents, ester solvents, ether solvents, nitrile solvents, alcohol solvents, polar aprotic solvents, chloro solvents and the like; the cyclization is carried out using ammonium acetate, ammonium hydroxide, acetamide or di(trimethylsilyl)amines in a suitable solvents such as hydrocarbon solvents, nitrile solvents, chloro solvents, alcohol solvents, ester solvents, ether solvents and the like. in step-b) deprotection is carried out by using suitable deprotecting agent such as non-aqueous acid solutions such as isopropanolic hydrochloride, methanolic hydrochloride, ethanolic hydrochloride, ethyl acetate hydrochloride, acetonitrile hydrochloride and the like. in step-c) the suitable coupling agent is selected from dicyclohexyl carbodiimide, diisopropylcarbodiimide, ethyl-(N,N'-dimethylaminopropyl)carbodiimide hydrochloride (EDC. HC1), Ν,Ν'-carbonyldiimidazole (CDI), hydroxy benzotriazole (HOBt) or mixtures; and the suitable base is selected from organic or inorganic base; and the suitable solvent is selected from chloro solvents, ester solvents, ketone solvents, hydrocarbon solvents, polar aprotic solvents and alcohol solvents or mixtures. in step-d) (i) the suitable borylating agent is selected from bis(pinacolato)diboron or bis(neopentylglycolato)diboron; the catalyst is selected from PdCl2[P(t-Bu)₂Ph]2_, Pd(dppf)Cl_2, Pd(PPh3) and the like; the base is selected from potassium acetate, potassium propionate, sodium alkoxides such as sodium methoxide, sodium ethoxide and the like; the suitable solvent is selected from dimethoxyethane, 1 ,2-dichloroethane, hydrocarbon solvents, chloro solvents, polar protic solvents, polar aprotic solvents, ester solvents, ether solvents, nitrile solvents and the like. in step-d) (ii) the self-coupling is carried out in presence of suitable catalyst, suitable base in a suitable solvent and optionally in presence of phase transfer catalyst.

in step-f) the suitable base is selected from alkali metal hydroxides or alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates or aqueous mixtures; the suitable hydrochloric acid source is selected from hydrochloride, aqueous hydrochloride, ethyl acetate hydrochloride, acetonitrile hydrochloride, isopropanolic hydrochloride, methanolic hydrochloride, ethanolic hydrochloride, SOCl₂ / alcohol solvents and the like. The preferred embodiment of the present invention provides a process for the preparation of carbamic acid, N_JN'-[[l, -biphenyl]-4,4'-diylbis[lH-imidazole-5,2-diyI-(2S - 2,1 -pyrrolidine diyl[(15)-l-(l-methylethyl)-2-oxo-2,l-ethanediyl]]]bis-,C, -dimethyl ester of formula (I), comprising the steps of:

a) reacting the compound of formula (Ila) with the compound of formula (Ilia) in presence of diisopropylethylamine (DIPEA) in toluene to provide the compound of formula (IVa) which on in-situ cyclization in presence of ammonium acetate to produce the compound of formula (Va);

Formula (Ila) Formula (Ilia)

Formula (Va) b) treating the compound of formula (Va) with isopropanolic HCl to prod

dihydrochloride com ound of formula (Via);

Formula (Via)

Formula^" (Va) c) reacting the dihydrochloride compound of formula (Via) with the compound of formula (VII) in presence of EDC. HCl, HOBt / triethylamine in methylene chloride (DC ) to provide the compound of formula (Villa);

Formula (Via) Formula (VI I) d) self-condensing the two molecules of the compound of formula (Villa) with each other (self-coupling) in presence of Pd(OH)₂/C in presence of dipotassium hydrogen phosphate (K₂HP0₄) in ethylene glycol to provide the compound of formula (I).

Formula (Villa) °^CH' Formula (I) e) treating the compound of formula (I) obtained in step-d) with oxalic acid to provide the oxalic acid salt compound of formula (lb),

f) treating the product obtained in step-e) with aqueous NaOH solution in presence of methylene chloride followed by treating the obtained compound with aqueous hydrochloric acid in methylene chloride to provide the hydrochloride salt compound of formula (la).

The process of the present invention schematically represented as below:

wherein X refers to leaving group such as chlorine, bromine, fluorine, iodine, methanesulfonyl group, ethanesulfonyl group, benzenesulfonyl group, toluenesulfonyl group and the like; "PG" refers to amine protecting group and 'R' refers to

The second aspect of the present invention provides carbamic acid, Ν,Ν'-[[1 , - biphenyl]-4,4'-diylbis[lH-imidazole-^^^

2-0X0-2, l-eth

Formula (ib)

Another aspect of the present invention provides a process for the preparation of Daclatasvir oxalic acid (1 :2) of formula (Ib), comprising:

a) self-condensation of two molecules of methyl ((S')-l-((S)-2-(5-(4-bromophenyl)-lH- imida2ol-2-yl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl)carbamate with each other in presence of Pd(OH)₂/C, dipotassium hydrogen phosphate in ethylene glycol in to provide the compound of formula (I);

b) adding the obtained compound in step-a) to oxalic acid or its solution to provide the Daclatasvir oxalic acid (1 :2).

Another aspect of the present invention provides amorphous form of Daclatasvir oxalic acid (1 :2) of formula (Ib) substantially characterized by the PXRD pattern as shown in Figure- 1 and also characterized by the IR Spectra as shown in Figure-2 and having IR characteristic peaks at 3840.11, 3410.86, 3142-83, 3033.73, 2966.38, 2878.26, 2722.51, 1925.23, 1718.91 , 1639.36, 1555.98, 1532.15, 1492.35, 1444.22, 1422.80, 1370.44, 1359.93, 1304.40, 1239.04, 1195.92, 1100.48, 1035.02, 1004.95, 970.29, 945.55, 920.45, 825.56, 779.40, 719.50, 628.76, 608.36, 561.21 , 523.92, 484.47 and 473.76 cm^*1.

The oxalic acid content in the compound of formula (Ib) is ranging between 17-24%. Preferably between 20-24%. The another aspect of the present invention provides a process for the preparation of carbamic acid, N,N'-[[1 , 1 ^,-biphenyl]-4,4'-diylbis[ lH-imidazole-5,2-diyl-(25 -2, 1 - pyrrolidinediyl[(15)-l-(l-methylethyl)-2-oxo-2,l-ethanediyl]]]bis-C₎C'-dimethyl ester, oxalic acid of formula (lb), comprising:

a) providing carbamic acid, N,N'-[[l, -biphenyl]-4,4'-diylbis[lH-imidazole-5,2-diyl- (2S)-2, 1 -pyrrolidinediyl[(15)-l -(1 -methylethyl)-2-oxo-2, 1 -ethanediyl]]]bis-C,C- dimethyl ester of formula (I) in a suitable solvent;

b) adding oxalic acid or its solution to the reaction mixture obtained in step-a);

c) stirring the resulting reaction mixture;

d) isolating the compound of formula (lb). wherein, in step a) the suitable solvent is selected from ketone solvents; ether solvents, ester solvents, nitrile solvents, chloro solvents, hydrocarbon solvents, polar protic solvents, polar aprotic solvents.

In step-b), the oxalic acid solution is can be prepared by dissolving oxalic acid in suitable solvents like alcohol solvents such as methanol, ethanol, isopropanol; ketone solvents such as acetone and the like. in step-d) the term "isolating" refers to the removal of solvent by filtration, distillation, distillation and co-distillation or decantation from the reaction mixture or suitable techniques which may be used for the removal of solvent include filtration, using a rotational distillation device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), and the like or any other suitable technique.

The preferred aspect of the present invention provides a process for the preparation of amorphous form of carbamic acid, N,N'-[[l, -biphenyI]-4,4'-diylbis[lH-imidazole-5,2-diyl- (2S)-2, 1 -pyrrol idinediyl[( IS)- 1 -(1 ^

ester, oxalic acid (1 :2) of formula (lb), comprising:

a) providing carbamic acid, NjN'-ftl.r-biphenylJ^^'-diylbisflH-imidazole-S^-diyl-

(2S)-2, 1 -pyrrolidinediyl[(lS 1 -(1 -methylethyl)-2-oxo-2, 1 -ethanediyl]]]bis-C,C- dimethyl ester of formula (I) in ethanol;

b) combining the reaction mixture obtained in step-a) with oxalic acid in isopropanol; c) stirring the resulting reaction mixture;

d) filtering the precipitated solid to provide amorphous compound of formula (lb).

In yet another preferred embodiment of the present invention provides a process for the preparation of carbamic acid, N,N'-[[l,r-biphenyl]-4,4'-diylbis[lH-imida2ole-5,2-diyl- (25)-2,l -pyrrolidine diyl^l.SJ-l-Cl -methylethy ^-oxo^^-ethanediylJllbis-^.C'-dimethyl ester oxalic acid (1 :2) of formula (lb), comprising the steps of:

a) providing carbamic acid, N,N'-[[l, -biphenyl]-4,4'-diylbis[lH-imidazole-5,2- diyl-(25)-2, 1 -pyrrolidinediyl [( 1 S 1 -( 1 -methylethy l)-2-oxo-2, 1 -ethanediyl]]]bis- C,C'-dimethyl ester in methylene chloride;

b) adding oxalic acid to the reaction mixture obtained in step-a);

c) stirring the resulting reaction mixture;

d) distillating off the solvent from the reaction mixture;

e) co-distilling and stirring the obtained compound from step-d) using methyl tert- butyl ether;

f) isolating carbamic acid, N,N'-[[l, -biphenyl]-4,4'-diylbis[lH-imidazole-5,2-diyl- (25 2,1 -pyrrolidinediyI[( 1 S)-l -( 1 -methylethyl)-2-oxo-2, 1 -ethanediyl]]]bis-C,C'- dimethyl ester oxalic acid (1 :2). in step-f) the term "isolating" refers to filtration, distillation, precipitation by cooling he reaction mixture, solvent and anti-solvent technique by using the suitable solvents such as alcohol solvents, chloro solvents, ester solvents, ketone solvents, nitrile solvents. Prefarebly alcohol solvents like methanol, ethanol, isopropanol. The suitable anti-solvent is selected from ether solvents such as 1 ,4-dioxane, tetrahydrofuran, diethyl ether; nitrile solvents, ester solvents, hydrocarbon solvents. The preferably methanol- 1 ,4-dioxane and ethanol-acetonitrile solvent systems used for isolation purification by solvent and anti-solvent technique either in regular addition or reverse mode of addition.

Another embodiment of the present invention provides an alternate process for the preparation of Daclatasvir oxalic acid (1 :2) of formula (lb), comprising:

a) reacting methyl ((5 -l -((S -2-(5-(4-bromophenyl)-lH-imidazol-2-yl)pyrrolidin-l-yl)- 3-methyl-l-oxobutan-2-yl)carbamate of formula (Villa) with methyl ((5}-3 -methyl- 1- oxo-1 -((S)-2-(5-(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)- 1 H- imidazol-2-yl)pyrrolidin-l-yl)butan-2-yl)carbamate of formula (IXa) in presence of a suitable catalyst and suitable base in a suitable solvent;

b) adding oxalic acid solution to the reaction mixture;

c) filtering the precipitated solid to provide the compound of formula (lb). wherein, in step-a), the suitable catalyst is selected from palladium- tetrakis(triphenylphosphine) (Pd(PPh3) ), dichlorobis(triphenylphosphine)palladium(II) (Pd(PPh₃)₂Cl₂), dichlorobis(tricycIohexylphosphine)palladium(II) (Pd(PCy₃)₂Cl₂), [1,2- bis(diphenylphosphino)ethaneJdichloropalladium(II) (Pd(dppe)Cl₂), [1 ,1 '-bis

(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)C ), dichlorobis(tri-o- tolylphosphine)palladium(II) (Pd(P(o-tol)3)Cl₂); the suitable base is selected from alkali metal hydroxides or alkali metal carbonates, alkali metal bicarbonates or aqueous mixtures; chloro solvents, polar protic solvents, polar aprotic solvents, ester solvents, ether solvents, nitrile solvents and the like.

Another aspect of the present invention provides a process for the preparation of amorphous form of Daclatasvir oxalic acid (1 :2) of formula (lb), comprising:

c) self-condensation of two molecules of methyl ((5)-l-((5)-2-(5-(4-bromophenyl)-lH- imidazol-2-yl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yI)carbamate with each other in presence of Pd/C, trisodium phosphate in methanol in presence of tetra butyl ammonium bromide (TBAB) to provide the compound of formula (I);

d) adding the obtained compound in step-a) to oxalic acid in isopropanol;

e) stirring the reaction mixture obtained in step-c);

f) filtering the precipitated solid to provide the amorphous form of formula (lb).

The preferred embodiment of the present invention provides a process for the preparation of amorphous form of Daclatasvir oxalic acid (1 :2) of formula (lb), comprising: a) self-condensing of methyl ((iS)-l-((5)-2-(5-(4-bromophenyl)-lH-imidazol-2- yl)pyrTolidin-l-yl)-3-methyl-l-oxobutan-2-yl)carbamate with each other in presence of Pd(OH)₂ / C, dipotassium hydrogen phosphate in ethylene glycol to provide the compound of formula (I);

b) adding oxalic acid to the product obtained in step-a);

c) isolating the amorphous form of dioxalic acid of formula (lb).

The third aspect of the present invention provides a process for the purification of Daclatasvir oxalic acid (1 :2) of formula (lb), comprising:

a) dissolving carbamic acid, N,N'-[[l,l'-biphenyl]-4,4'-diylbis[lH-imidazole-5,2-diyl- (2S 2,1 -pyrrolidinediyl[(15 - 1 -(1 -methylethyl)-2-oxo-2, 1 -ethanediyl]]]bis-,C,C- dimethyl ester, oxalic acid (1 :2) in a suitable solvent;

b) optionally, adding charcoal to the reaction mixture;

c) stirring the reaction mixture obtained in step-a) or step-b);

d) filtering the reaction mixture obtained in step-c);

e) distilling off the solvent from the filtrate obtained in step-d);

f) adding suitable solvent to the compound obtained in step-e);

g) stirring the reaction mixture obtained in step-f);

h) filtering and washing the product obtained in step-g) to provide pure amorphous form of Daclatasvir oxalic acid (1 :2)

Another embodiment of the present invention provides the use of Daclatasvir oxalic acid (1 :2) of formula (lb) in the preparation of highly pure Daclatasvir hydrochloride (1 :2) of formula (la).

The fourth aspect of the present invention provides crystalline Form-S of carbamic acid, N,N'-[[1 , 1 *-biphenyl]-4,4'-diylbis[ 1H-imidazole-5 ,2-diyl-(2S)-2, 1 -pyrrolidinediyl [(15)- l-il-methylethyl^-oxo^.l-ethanediylJJJbis-.CC'-dimethyl ester, hydrochloride (1 :2).

Crystalline Form-S of the present invention is characterized by its Powder X-Ray Diffraction (PXRD) pattern having peaks at about 8.2, 9.5, 15.2 ± 0.2 degrees of two-theta. Crystalline Form-S of the present invention further characterized by its X-Ray powder diffraction pattern having additional peaks at about 8.5, 10.5, 11.0, 13.1, 13.5, 14.8, 16.5, 17.1 , 17.8, 18.3, 21.0, 21.2, 21.5, 22.2, 22.5, 23.1, 23.6, 24.1 , 24.6, 25.3, 25.8, 26.5, 26.6, 27.8, 28.2, 28.6, 28.9, 29.4, 29.9, 30.5, 31.2, 32.1 , 33.5, 35.4, 36.0, 40.3, 42.1 ± 0.2 degrees of two-theta. The crystalline Form-S of carbamic acid, N,N'-[[l,r-biphenyl]-4,4'-diylbis[lH- imidazole-5,2-diyl-(2S>2,l -pyrrolidinediyl[( 1 S)-\ -( 1 -methy!ethyl)-2-oxo-2, 1 -ethanediyl]]] bisT,C,C'-dimethyl ester, hydrochloride (1 :2) is further characterized by the PXRD pattern as illustrated in figure-7.

The crystalline Form-S of carbamic acid, N,N'-[[l, -biphenyl]-4,4'-diylbis[lH- imidazoIe-5,2-diyl-(25)-2, 1 -pyrrolidinediyl[(lS)- 1-( 1 -methylethyl)-2-oxo-2, 1 -ethanediyl]]] bis-,C,C'-dimethyl ester, hydrochloride (1 :2) is further characterized by the solid state C-13 NMR spectrum as illustrated in figure-8.

Another embodiment of the present invention provides crystalline Form-S of compound of formula-la having particle size distribution of D90 less than 100 μπι. Prefarebly less than 50 μτη.

In another aspect of the present invention provides a, process for the preparation of crystalline Form-S of carbamic acid, N,N'-[[l,l'-biphenyl]-4,4'-diylbis[l H-imidazole-5_>2- diyl -(25)-2, 1 -pyrroIidinediyl[(15)- 1 -(1 -methylethyl)-2-oxo-2,l -ethanediyl]]]bis-,C,C- dirriethyl ester, hydrochloride (1 :2) compound of formula (la), comprising the following steps of:

a) providing carbamic acid, N,N'-[[l, -biphenyl]-4,4'-diylbis[lH-imidazole-5,2- diyl-(2S)-2, 1 -pyrrotidinediyl[(lS 1 -(1 -methy lethyl)-2-oxo-2, 1 -ethanediyl]]]bis- C,C-dimethyl ester, hydrochloride (1 :2) in a suitable solvent at a suitable temperature;

b) stirring the reaction mixture obtained in step-a) at a suitable temperature;

c) isolating the crystalline Form-S of formula (la). wherein, in step-a) the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, chloro solvents, polar aprotic solvents, alcoholic solvents, polar solvents, water and/or mixtures and the suitable temperature is 25°C to reflux temperature of the solvent used. in step-b) the suitable temperature is ranging from 40°C to 100°C.

in step-c) the term "isolating" refers to removing of the solvent by known techniques such as filtration, using a rotational distillation device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), and the like or any other suitable technique.

The preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of carbamic acid, N_?N'-[[l,r-biphenyl]-4,4 -diylbis[lH- imidazoIe-5,2-diyl-(25 2, 1 -pyrrol idinediyl[( 15)- 1 -(1 -methyl ethyl) -2 -oxo-2, 1 -ethanediyl]]] bis-,C,C- dimethyl ester, hydrochloride (1 :2) of formula (la), comprising the following steps of:

a) adding carbamic acid, NjN'-tfl ^'-biphenylJ^^'-diylbisflH-imidazole-S^-diyl- (250-2, 1 -pyrrolidinediyl[(1 l -(1 -methylethyl)-2-oxo-2, 1 -ethanediyl]]]bis-C,C'- dimethyl ester, hydrochloride (1 :2) to a mixture of isobutyl acetate and methyl isobutyl ketone at 25-30°C;

b) heating the reaction mixture to 40-45°C and stirring the reaction mixture;

c) adding water to the reaction mixture and stirring at 50°C;

d) filtering the precipitated solid to provide crystalline Form-S of formula (la).

The another preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of carbamic acid, N,N'-[[l, -biphenyl]-4,4'-diylbis[l-/ - imidazole-5,2-diyl-(2S)-2, 1 -pyrrolidinediyl[( 15)- 1 -(1 -methylethyl)-2-oxo-2, 1 -ethanediyl]]] bis-,C,C- dimethyl ester, hydrochloride (1 :2) of formula (la), comprising the following steps of:

a) adding aqueous carbamic acid, N,N'-[[l,l'-biphenyl]-4,4'-diylbis[lH-imida2ole- 5,2-diyl-(25)-2,l-pyrrolidinediyl[(l 5)- l-(l-methylethyl)-2-oxo-2,l -ethanediyl]]] bis-C_}C'-dimethyl ester, oxalic acid (1 :2) solution to methylene chloride; b) basifying the reaction mixture with aqueous sodium bicarbonate solution;

c) separating the organic and aqueous layers;

d) removing the solvent from the organic layer,

e) dissolving the product obtained in step-d) in isobutyl acetate at 25-30°C; f) cooling the reaction mixture to-15°C to -20°C;

g) adding isopropanolic HC1 to the reaction mixture obtained in step-f);

h) raising the temperature of the reaction mixture to 0-5°C and stirring the reaction mixture^

i) adding water to the reaction mixture and stirring at 0-5°C;

j) filtering the precipitated solid to provide crystalline Form-S of formula (la).

The fifth aspect of the present invention provides crystalline Form-N of carbamic acid, N,N'-[[1 , 1 '-biphenyl].4,4'-diylbis[lH-imida2ole-5,2-diyl-(2S)-2, 1 -pyrrol id inediyl [( 15)- l-(l-methylethyl)-2-oxo-2,l-ethanediyl]]]bis-,C,C'-dimethyl ester, hydrochloride (1 :2).

Crystalline Form-N of the present invention is characterized by its Powder X-Ray Diffraction (PXRD) pattern having peaks at about 19.6, 24.1 ± 0.2 degrees of two-theta. Crystalline Form-N of the present invention further characterized by its X-Ray powder diffraction pattern having additional peaks at about 8.3, 9.8, 12.8, 13.6, 16.1, 18.8, 19.6, 22.2, 23.4, 24.1, 25.1, 26.2 and 29.6 ± 0.2 degrees of two-theta. The crystalline Form-N of the present invention is further characterized by the PXRD pattern as illustrated in figure-9.

In another aspect of the present invention provides a process for the preparation of crystalline Form-N of Daclatasvir hydrochloride (1 :2) of formula (la), comprising the following steps of:

a) adding carbamic acid, N_jN'-if l^'-biphenylJ^^'-diylbistlH-imidazole-S^-diyl- . (2S)-2, 1 -pyrrolidinediyl[(l S)- 1 -(1 -methylethyl)-2-oxo-2, 1 -ethanediyl]]]bis-C,C- dimethyl ester, hydrochloride (1 :2) to isobutyl acetate at 25-30°C;

b) heating the reaction mixture to 70-75°C;

c) stirring the reaction mixture;

d) isolating the crystalline Form-N of formula (la).

Crystalline Form-N of the present invention is partially isobutyl acetate solvate form.

The sixth aspect of the present invention provides a process for the preparation of crystalline Form-M of Daclatasvir, hydrochloride (1 :2) of formula (la), comprising: a) adding carbamic acid, N,N'-[[l, -biphenyl]-4,4'-diylbis[lH-imidazole-5,2-diyl-(25 - 2, 1 -pyrrolidinediyI[( 1 S)- 1 -(1 -methylethyl)-2-oxo-2, 1 -ethanediylJjjbis-.C^'-dimethyl ester, oxalic acid (1 :2) of formula (lb) to a suitable solvent;

b) adding a suitable base to the reaction mixture obtained in step-a);

c) stirring the reaction mixture obtained in step-b);

d) separating the organic and aqueous layers;

e) distilling off the solvent from the organic layer;

f) adding a suitable solvent to the compound obtained in step-e);

g) acidifying the reaction mixture obtained in step-f) using hydrochloric acid;

h) stirring the reaction mixture obtained in step-g);

i) isolating the crystalline Form-M of Daclatasvir, hydrochloride (1:2) wherein, in step-a) and step-f), the suitable solvent is selected from alcohol solvents, glycol solvents, chloro solvents, hydrocarbon solvents, ether solvents, ester solvents or mixtures, in step-b), the suitable base is selected from NaOH, KOH, Na2C0₃, NaHC0₃, sodium alkoxides, potassium alkoxides or their aqueous solutions or mixtures thereof,

in step-e), distillating off the solvent from the organic layer is carried out partially or completely under reduced pressure.

in step-g), the acidification is carried out using hydrochloric acid source either in aqueous condition such as aqueous hydrochloride or non-aqueous condition such as isopropanolic hydrochloride, methanolic hydrochloride, ethanolic hydrochloride, acetonitrile hydrochloride, acetone hydrochloride, or hydrochloric acid gas, or SOC^/suitable alcohol solvent.

The another aspect of the present invention provides crystalline Form-M of carbamic acid, N,N [l,l'-biphenyI]-4,4'-diylbis^ [(15)- l-(l -methylethyl)-2-oxo-2,l-ethanediyl]]]bis-,C,C^,-dimethyl ester, hydrochloride (1 :2) of formula (la) is hemihydrate.

Another embodiment of the present invention provides crystalline Form-M of carbamic acid, HN'-ttl '-biphenylJ- '-diylbisflH-imidazole-S^-diyl^S)^,!- pyrrolidinediyl [(15)-l -( 1 -methylethyl)-2-oxo-2, 1 -ethanediyl]]]bis-,C,C'-dimethyl ester, hydrochloride (1 :2) of formula (la) having water content about 1.1 to 1.5% in its crystal lattice.

Another embodiment of the present invention provides crystalline Form-M of carbamic acid, N,N^*-[[ 1 , 1 '-biphenyrj- '-diylbis.1 H-imidazole-5 ,2-diyl-(25 -2, 1 - pyrrolidinediyl [(1S)-1 -(l-methylethy^^-oxo^^-ethanediyllJJbis-jC^'-dimethyl ester hydrochloride (1 :2) of formula (la) showing weight loss of about 1.17% and same illustrated by its thermo gravimetric analysis (TGA) in figure-5.

Another embodiment of the present invention provides solid state C-13 NMR spectrum of crystalline Form-M of formula (la) is illustrated in figure-6.

Another embodiment of the present invention provides crystalline Form-M of compound of formula (la) having particle size distribution of D90 less than 300 μτη. preferably less than 100 μηι. More prefarebly less than 15 μιη.

The crystalline Form-M, Form-S, Form-N of Daclatasvir hydrochloride (1 :2) of formula (la) and amorphous form of Daclatasvir oxalic acid (1 :2) of formula (lb) of the present invention can be further micromzed or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction includes but not limited to single or multi-stage micronization using wet milling, cutting mills, pin cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling or micronization may be performed before drying or after drying of the product.

The other aspect of the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of crystalline Form-M, S, N of Daclatasvir hydrochloride (1 :2) of formula (la) or amorphous form of Daclatasvir oxalic acid (1 :2) of formula (lb) and one or more pharmaceutically acceptable carriers.

Pharmaceutical compositions containing crystalline Form-M, S, N of Daclatasvir hydrochloride (1 :2) or Daclatasvir oxalic acid (1 :2) of the present invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants. Various modes of administration of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

The oral pharmaceutical composition may contain one or more additional excipients such as diluents, binders, disintegrants and lubricants. Exemplary diluents include lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, microcrystalline cellulose, magnesium stearate and mixtures thereof. Exemplary binders are selected from L-hydroxy propyl cellulose, povidone, hydroxypropyl methyl cellulose, hydroxylethyl cellulose and pre- gelatinized starch.

Exemplary disintegrants are selected from croscarmellose sodium, cros-povidone, sodium starch glycolate and low substituted hydroxylpropyl cellulose.

Exemplary lubricants are selected from sodium stearyl fumarate, magnesium stearate, zinc stearate, calcium stearate, stearic acid, talc, glyceryl behenate and colloidal silicon dioxide. A specific lubricant is selected from magnesium stearate, zinc stearate, calcium stearate and colloidal silicon dioxide.

The PXRD analysis of crystalline Form-M, crystalline Form-S, crystalline Form-N of Daclatasvir hydrochloride (1 :2) and the amorphous form of Daclatasvir oxalic acid (1 :2) of the present invention was carried out using BRUKER-AXS D8 Advance X-Ray diffractometer using Cu Keel radiation of wavelength 1.5406 A° and at continuous scan speed of 0.03°/min.

The HPLC analysis of compound of formula (I), (la) and (lb) of the present invention was analyzed by HPLC under the following conditions:

Apparatus: A liquid chromatographic system equipped with variable wavelength UV detector; Column; Kromasil 100-5-C18, 250*4.6 mm, 5μηι (or) equivalent; Column temperature: 40°C; Wave length: 210 run; Injection volume: 5μί; Elution: Gradient; Diluent: acetonitrile: milli- Q-water (1 : 1 v/v); Buffer: weigh accurately about 1.74 gm of dipotassium dihydrogen phosphate and added into 1000 mL of Milli-Q-water and 2.0 ml of triethylamine was added to above 1000 mL of milli-Q-water solution and adjust pH to 3.5 with orthbphosphoric acid (85%), mix well. Filter this solution through 0.22μηι Nylon membrane filter paper; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile: Buffer (60:40 v/v).

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention:

Examples:

Example-1: Preparation of (S)-tert-butyl 2-(5-(4-bromophenyl)-l//-imidazol-2-yl) pyrrolidine-l-carboxylate of formula (Va)

2-Bromo-l-(4-bromophenyl)ethanone (100 gms) was added to toluene (1000 ml) at 25-30°C and stirred for 10 min at same temperature. To the above reaction mixture, (Sj-1 - (ier/-butoxycarbonyl)pyrrolidine-2-carboxylic acid (100.67 gms) and diisopropylethylamine (106.53 gms) were added at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 4 hrs at same temperature. Cooled the reaction mixture to 25-30°C and added aqueous sodium bicarbonate solution and then stirred for 15 min. Separated the both organic and aqueous layer and added aqueous sodium chloride solution to the organic layer at 25-30°. Stirred the above reaction mixture 15 min at 25-30°C and separated the both organic and aqueous layers.

Ammonium acetate (277.3 gms) was added to the above obtained organic layer at 25- 30°C Heated the reaction mixture to 90-95°C and stirred for 16 hrs at same temperature. Ethyl acetate (300 ml) and water (700 ml) were added to the reaction mixture and stirred for 15 min. Separated the both organic and aqueous layers. Washed the organic layer with aqueous sodium bicarbonate solution. Distilled off the solvent completely from the organic layer under reduced pressure and then co-distilled with cyclohexane. Cyclohexane (400 ml) and water (25 ml) were added to the above obtained material and stirred for 90 min at 25- 30°C Filtered the precipitated solid, washed with cyclohexane and then dried the obtained material to get the title compound.

(Yield: 141.14 gms, % of yield: 88.4%, M.R: 162-166°C, HPLC purity: 99.4 %, bromo acetophenone: 0.01%)

ExampIe-2: Preparation of (S)-5-(4-bromophenyI)-2-(pyrrolidin-2-yl)-lH-iinidazoIe dihydrochloride

Isopropanolic hydrochloride (500 ml) was added to the (S)-tert-but \ 2-(5-(4- bromophenyl)-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (100 gms) at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 4 hrs at same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Added acetone (100 ml) to the distillate and again distilled off the solvent completely from the reaction mixture under reduced pressure. Acetone (500 ml) was added to the reaction mixture and stirred for 60 min at 25-30°C. Filtered the precipitated solid, washed with acetone and then dried to produce the title compound.

(Yield: 89.5 gms, M.R: 230-238°C, Purity by HPLC: 99.9%, (S)-/er/-butyl 2-(5-(4- bromophenyl)-lH-imidazo 1-2 -yl)pyrrolidine-l-carboxy ate impurity: not morethan 0.02%)

Example-3: Preparation of methyl((S)-l-((S)-2-(5-(4-bromophenyl)-lH-imidazoI-2-yl) pyrrolidin-l-yl)-3-methyI-l-oxobutan-2-yl)carbamate

(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HC1) (31.5 gms) was added to a pre-cooled mixture of methylene chloride (500 ml), hydroxybenzotriazole (25.9 gms), (S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acid (28.7 gms) (S)-5-(4- bromophenyl)-2-(pyrrolidin-2-yl)-lH-imidazole dihydrochloride (50 gms) at 15-20° and stirred the reaction mixture for 90 min at same temperature. Cooled the reaction mixture to 0- 5°C and added (5 -5-(4-bromophenyl)-2-(pyrrolidin-2-yl)-lH-imidazole dihydrochloride (50 gms) and stirred for 15 min at same temperature. Triethylamine (37.9 ml) was added to the reaction mixture at 0-5 °C and raised the temperature of reaction mixture to 15-20°C and stirred for 14 hrs at same temperature. Cooled the reaction mixture to 0-5°C and washed with aqueous sodium hydroxide solution and separating the aqueous layer and organic layers. Washed the organic layer with sodium chloride solution. Distilled off the solvent completely from the organic layer and co-distilled with n-heptane (100 ml). n-Heptane (200 ml) was added to the obtained compound at 25-30°C and stirred for 30 min at same temperature. Filtered the solid, washed with n-heptane and then dried to afford the title compound.

(Yield: 56.5 gms, % of yield: 91.8 %, M.R: 52.5-59.4°C, Purity by HPLC: 99.4%, R,R isomer impurity: absent (not detected), R,S isomer impurity: 0.02% or S,R isomer impurity: 0.01%)

Example-4: Preparation of methyl ((S)-3-methyl-l-oxo-l-((S)-2-(5-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-lH-imidazol-2-yl)pyrr01idin-l-yl)butan-2- yl)carbamate

((S)-l -((5)-2-(5-(4-Bromophenyl)- 1 H-imidazol-2-yl)pyrrolidin- 1 -yl)-3-methyl- 1 - oxobutan-2-yl)carbamate (10 gms), 4,4,4,4,5,5,5,5-octamethyI-2,2-bi(l,3₎2-dioxaborolane) (16.9 ml) and 1,4-dioxane (150 ml) were charged into a clean and dry round bottom flask at 25-30°C. To the above resulting reaction mixture, Pd(dppf)Cl₂ (0.88 ml) and potassium acetate (6.5 ml) were added and heated the reaction mixture to 80-85°C and stirred for 15 hours at same temperature. Cooled the reaction mixture to 25-30°C and added water. Separated the both organic and aqueous layers and distilled off the solvent completely from the organic layer. Cyclohexane was added to the obtained compound and concentrated under reduced pressure. Cyclohexane (30 ml) was added to the above resulting compound and stirred for 30 min at 25-30°C. Filtered the precipitated solid, washed with cyclohexane and then dried to get the title compound. (Yield: 6.7 gms, 55%)

Example-5: Preparation of dimethyl ((25,2'5)-((25, 2'S)-2,2'-(5,5'-([l,l^,-biphenyl]-4,4'- diyl)bis(lH-imidazole-5,2-diyI))bis(pyrroIidine-2^

diyl))dicarbamate oxalic acid (1:2)

Methyl ((5)-3-methyl-l -oxo-l-((S)-2-(5-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)-lH-imidazol-2-yl)pyrrolidin-l-yl)butan-2-yl)carbamate (10 gms), methyl ((5)-l- ((5)-2-(5-(4-bromophenyl)- 1 H-imidazol-2-yl)pyrrolidin- 1 -yl)-3-methyl- 1 -oxobutan-2-yl) carbamate (9.0 gms), Pd(TPP)₄ (5.9 gms), K₂C0₃ (8.3 gms), water (30 ml) and 1,4-dioxane (150 ml) were charged into a clean and dry round bottom flask at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 15 hours at same temperature. Water and ethyl acetate were added to the reaction mixture and separated the both organic and aqueous layers. Combined the total organic layers and dried over sodium sulfate. Oxalic acid solution (5.4 gms of oxalic acid in 50 ml of acetone) was slowly added to the above dried organic layer in another round bottom flask at 25-30°C and stirred for 4 hours at same temperature. Filtered the precipitated solid and washed with acetone and dried the obtained material to get the title compound. (Yield: 9.25 gms, 50%)

Example-6: Preparation of carbamic acid, N^'-Hl. -biphenylJ^^'-diylbisflH- imidazole-5,2-dίyl-(2S)-2 -p rΓOlίdinedi l[(lS)- (l--nethyleth l)-2-oxo-2,l-ethanedi yl]]]bis-,C,C-dimethyl ester, oxalic acid (1:2)

Methanol (300 ml) was added to methyl((S)-l-((5)-2-(5-(4-bromophenyl)-lH- imidazol-2-yl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl)carbamate (10 gms) at 25-30°C under nitrogen atmosphere. To the above reaction mixture, trisodium phosphate dodeca hydrate (16.92 gms), tetrabutylammonium bromide (3.58 gms) and 10% Pd/C (5 gms) were added at 25-30°C under nitrogen atmosphere. Heated the reaction mixture to 65-70°C and stirred for 5 hrs at same temperature. Cooled the reaction mixture to 25-30°C and filtered the reaction mixture on hy-flow bed under nitrogen atmosphere. Distilled off the solvent completely from the filtrate. Methylene chloride (100 ml) was added to the above distillate followed by aqueous sodium chloride solution (10 gms dissolved in 100 ml of water) and stirred for 20 min at 25-30°C Separated the both organic and aqueous layers and distilled off the solvent completely from the organic layer. Dissolved the above obtained material in ethanol (30 ml) at 25-30°C and slowly added to pre-cooled oxalic acid (6.01 gms) in isopropanol (60 ml) at 5-10°C and stirred for 6 hrs at same temperature. Filtered the precipitated solid, washed with isopropanol and then dried to afford the title compound. (Yield: 29.3 gms, M.R: 175- 87°C).

ExampIe-7: Preparation of pure dimethyl ((2S,2'5)-((2S, Z'SJ^^'-i^S'-ffl '-biphen l]- 4,4^,-diyl)bis(lH-imidazole-5,2-diyI))bis(pyrroHdine-2,l-diyl))bis(3-methyl-l-oxobutane- 2,l-diyl))dicarbamate oxalic acid (1 :2)

Methanol (50 ml) was added to crude dimethyl ((2S,2'S)-((2S, 2'S)-2,2'-(5,5^,-([U'- biphenyl]-4,4'-diyl)bis(lH-imidazole-5,2-diyl))bis(pyrrolidine-2,l-diyl))bis(3-methyl-l^ oxobutane-2,l-diyl))dicarbamate oxalic acid (1 :2) (10 gms) at 25-30°C and stirred for 15 min. at same temperature. Charcoal (2.5 gms) was added to the reaction mixture and stirred for 2 hours at 25-30°C. Filtered the reaction mixture through hy-flow bed and washed with methanol. Distilled off the solvent completely from the above filtrate under reduced pressure. Slowly added methanol (50 ml) and acetone (150 ml) to the above obtained distillate at 25- 30°C and stirred for 6 hours at the same temperature. Filtered the precipitated solid and washed with acetone and dried the obtained material to get title compound. (Yield: 6 gms, content of oxalic acid: 21.4%)

The PXRD pattern and Infra-Red Spectra of the title compound was illustrated in figure- 1 and figure-2 respectively.

Example-8: Preparation of carbamic acid, N,N'-[[l,l'-biphenyl]-4,4'-diylbis[lH- imidazole-S^-diyl-^S^U-p r olidinediylt ^^

yI]]]bis-,C,C'-dimethyI ester, oxalic acid (1:2)

Ethylene glycol (1250 ml) was added to methyl((S)-l-((S>2-(5-(4-bromophenyl)-lH- imidazol-2-yl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl)carbamate (50 gms) under nitrogen atmosphere at 25-30°C. Potassium hydrogen phosphate (32.94 gms) and 20% Pd(OH)₂/C (12.5 gms, 50% wet) in 50 ml of water were added at 25-30°C under nitrogen atmosphere. Heated the reaction mixture to 90-95°C and stirred for 12 hrs at same temperature. Cooled the reaction mixture to 25-30°C and filtered on hy-flow bed. Water and methylene chloride were added to the above obtained filtrate and stirred for 15 min at 25-30°C. Separated the both organic and aqueous layers. Extracted the aqueous layer using methylene chloride and combined the total organic layers. Oxalic acid (30.05 gms) was added to the organic layer at 25-30°C and stirred the reaction mixture for 4 hrs. Distilled off the solvent completely from the reaction mixture under reduced pressure and co-distilled with methyl tert-butyl ether. Methyl tert-butyl ether (500 ml) was added to the obtained compound at 25-30°C and stirred for 45 min at same temperature. Filtered the solid, washed with methyl tert-butyl ether to afford the crude compound. Dissolved the obtained crude compound in methanol (250 ml) at 25-30°C and added 1 ,4-dioxane (750 ml) to the reaction mixture at 25-30°C and stirred for 1 hr at the same temperature. Heated the reaction mixture to 50-55°C and stirred for 3 hrs at same temperature. Cooled the reaction mixture to 25-30°C and stirred for 10 hrs at same temperature. Filtered the solid, washed with 1,4-dioxane. Dissolved the obtained solid compound in methanol (250 ml) and added 1 ,4-dioxane (750 ml) to the mixture at 25-30°C and stirred for 1 hr at same temperature. Heated the reaction mixture to 50-55°C and stirred for 3 hrs at same temperature. Cooled the reaction mixture to 25-30°C and stirred for 10 hrs at same temperature. Filtered the solid, washed with 1,4-dioxane and then dried to afford the title compound. (Yield: 22.0 gms, M.R: 175-187°C, content of oxalic acid: 22%)

Example-9: Preparation of crystalline Form-M of dimethyl ((2S,2'5)-((2S, 2'5)-2,2'-(5,5*- ([U'-biphenylM^'-diy bisil/Mm

methyl-l-oxobutane-2,l-diyl))dicarbamate, hydrochloride (1:2)

Aqueous NaOH solution (10 gms of NaOH in 100 ml of water) was added to dimethyl ((25,2^,S)-((25, 2'S)-2,2^,-(5₃5^,-([l,l^,-biphenyl]-4,4^,-diyl)bis(lH-imidazole-5,2-diyl)) bis(pyrrolidine-2,l-diyl))bis(3-methyl-l -oxobutane-2,l-diyl))dicarbamate, oxalic acid (1 :2) (10 gms) in methylene chloride (100 ml) solution at 25-30°C and stirred for 15 min at same temperature. Separated the both aqueous and organic layers and partially distilled off the solvent from the organic layer to get the compound of formula (I).

, Added nitromethane (100 ml) to the obtained free base compound of formula (I) at 25- 30°C. Acidified the above reaction mixture with HC1 (10 ml) at 25-30°C and stirred for 6 hours at same temperature. Filtered the precipitated solid, washed with nitromethane and then dried to get the title compound. (Yield: 5. 6 gms, 63%).

The PXRD pattern of the title compound was illustrated in figure-3.

Example-10: Preparation of crystalline Form-M of dimethyl ((2S,2'S)-((2S, 2'5)-2,2'- (5,5'-([i ^,-biphenyl]-4,4^diyI)bis(l /-imidazole-5 -diyl))bis(pyrrolidine-2,l-diyl))bts(3- methyl-l-oxobutane-2,l-diyl))dicarbamate, hydrochloride (1:2)

Dissolved the Daclatasvir (2 gr) in methylene chloride (20 ml) at 25-30°C. Acidify the above obtained reaction mixture with aqueous HC1 (0.8 ml) at 25-30°C and stirred for 3 hours at same temperature. Filtered the precipitated solid and washed with methylene chloride and dried the obtained material under reduced pressure to get the title compound. (Yield: 1.3 gr).

The PXRD pattern of the title compound was similar to the PXRD pattern illustrated in figure-3.

Example- 11: Preparation of crystalline Form-M of dimethyl ((2S,2'S)-((2S, 2\S)-2,2'-

(S.S'-ilU'-biphenylH^'-diyObisilH-^

methyl-l-oxobutane-2,l-diyl))dicarbamate, hydrochloride (1:2)

Methylene chloride (20 ml) and nitromethane (0.2 ml) were charged to Daclatasvir (2 gr) at 25-30°C and stirred for 10 min. at same temperature. Acidified the above obtained clear solution with aqueous HC1 (0.8 ml) at 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid and washed with methylene chloride and dried the obtained material under reduced pressure to get the title compound. (Yield: 1.4 gr).

Example-12: Preparation of crystalline Form-M of dimethyl ((2S,2^,S)-((2S, 2'S)-2,2*- (5,5'-([ia^biphenyl].4,4^diyl)bis(l^-imidazole-5,2-diyl))bis(pyrrolidine-2,^

methyl-l-oxobutane-2,l-diyl))dicarbamate, hydrochloride (1:2)

Acetone (20 ml) added to Daclatasvir (2 gr) at 25-30°C and stirred for 10 min. at same temperature. Acidify the above obtained clear solution with aqueous HC1 (0.8 ml) at 25-30°C and stirred for 3 hours at same temperature. Filtered the precipitated solid and washed with methylene chloride followed by dried under vacuum to get the title compound. (Yield: 1.6 gr). The PXRD pattern of the title compound was similar to the PXRD pattern illustrated in figure-3.

Example-13: Preparation of pure crystalline Form-M of dimethyl ((2S,2'5)-((2S, 2'5)- 2,2^,-(5,5'-([l,l'-biphenyl]-4,4^,-diyI)bis(lH-imidazole-5,2-diyl))bis(pyrrolidine-2,l- diyl))bis(3-methyl-l-oxobutane-2,l-diyl))dicarbamate, hydrochloride (1:2)

Methylene chloride (2.25 lit), water (2.25 lit) were added to added to Daclatasvir oxalic acid (1 :2) (225 gms) at 25-30°C. Basified the above obtained reaction mixture with 5% aqueous Na₂C03 solution at 25-30°C and stirred for 15 min at same temperature. Separated the both organic and aqueous layers. Extracted the aqueous layer with methylene chloride (2.25 lit). Combined the organic layers and washed with water. Passed the organic layer through 0.4 micron paper for particle free. Distilled off the solvent completely from the organic layer under reduced pressure. Dissolved the above obtained distillate in methylene chloride (1.8 lit) at 25-30°C and add aqueous HC1 (22 gms) at 0-10°C and stirred the reaction mixture for 15 min at same temperature. Slowly raised the reaction mixture temperature to 25- 30°C and stirred for 7 hrs at same temperature. Filtered the precipitated solid an washed with methylene chloride and then dried. Added acetone (1.8 lit) and methanol (2 ml) to the above obtained compound at 25-30°C and stirred for 90 min at same temperature. Filtered the solid, washed with acetone and then dried for 4-6 hours to get the title compound (Yield: 170 gms, 85%, purity by HPLC: 99.90%, water content: 1.17%), MR: 215-225°C).

The PXRD pattern of the title compound obtained was illustrated in figure-4.

Thermo Gravimetric Analysis (TGA) of crystalline Form-M of Daclatasvir hydrochloride (1 :2) was illustrated in figure-5.

The C-13 solid state NMR spectrum of crystalline Form-M of Daclatasvir hydrochloride (1 :2) was illustrated in figure-6.

Example-14: Preparation of crystalline Form-S of carbamic acid, N,N'-[[l, -biphenyl]- 4,4^,-diy-bis[lH-imidazoIe-5,2-d-yH^

2,l-ethanediyl]]]bis-,C,C'-dimethyl ester, hydrochloride (1:2)

Isobutyl acetate (40 ml) and methyl isobutyl ketone (40 ml) were added to carbamic acid, N,N'-[[1 ,l'-biphenyl]-4,4^diylbis[lH-imidazole-5,2-diyl-(2S)-2,l-pyrrolidinediyl^ l-(l-methylethyl)-2-oxo-2,l-ethanediyl]]]bis-,C,C'-dimethyl ester, hydrochloride (1 :2) (10 gms) at 25-30°C. The resulted reaction mixture was stirred for 10 min at 25-30°C. Slowly heated the temperature of the reaction mixture to 60-65°C and then stirred for 60 min at same temperature. Filtered the precipitated solid and dried to get the title compound. (Yield: 8 gms, particle size distribution D(90) is 31.47μηι).

The PXRD pattern of obtained compound was illustrated in figure-7.

Example-15: Preparation of crystalline Form-S of carbamic acid, N,N'-[[l,l'-biphenyl]- 4,4'-diylbis[lH-imidazole-5,2-diyl-(2S)-2,l-pyrrolidinediyl[(lS)-l-(l-methylethyl)-2-oxo- 2,l-ethanediyl]]]bis-,C,C'-dimethyI ester, hydrochloride (1:2)

Methylene chloride (280 ml) was added to Daclatasvir oxalic acid (1 :2) (70 gms) in water (350 ml) at 25-30°C and stirred for 20 min. Basified the reaction mixture with aqueous NaHCCb solution at 25~30°C. Separated both the organic and aqueous layers. Methylene chloride (210 ml) was added to the aqueous layer and separated the organic and aqueous layers. Combined the total organic layers and washed with water. Added charcoal to the organic layer and stirred for 40 min and filtered through highflow bed. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with isobutyl acetate. Dissolved the above obtained material in isobutyl acetate (400 ml) at 25-30°C and filtered for particle free solution and washed with methyl isobutyl ketone. Cooled the reaction mixture to -20°C and added isopropanol.HCl (41 ml) at -20°C to -15°C and stirred for 15 min at the same temperature. Slowly raised the reaction mixture temperature to 0-5°C and stirred for 15 min at the same temperature. Raised the reaction mixture temperature to 25-30, water was added to it and stirred for 10 hrs at the same temperature. Filtered the precipitated solid and washed with isobutyl acetate and then dried to get the title compound (Yield: 51 gms, water content by KFR: 4.0%, purity by HPLC: 99.77%, des moc impurity (chemically known as methyl ((S)-l-((S)-2-(5-(4^,-(2-((S)-l-((S)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl)-lH- imidazol-5-yl)-[l , 1 '-biphenyl]-4-yl)- 1 H-imidazol-2-yl)pyrrolidin- 1 -yl)-3-methyl- 1 -oxobutan- 2-yl)carbamate, absence of one methoxy carbonyl in Daclatasvir): 0.02%, SRSS impurity: 0.02%, bromo boc impurity ((S)-t-butyl 2-(5-(4-bromophenyl)-l H-imidazol-2-yl)pyrrolidine- 1-carboxylate): 0.03%.

Particle size distribution: D(10) is 0.79 μπι, D(50) is 7.05 μπι, D(90) is 87.05 μι^η.

The PXRD pattern of above obtained crystalline Form-S was similar to the PXRD pattern illustrated in figure-7. The C-13 solid state NMR spectrum of crystalline Form-S was illustrated in figure-8.

Example-16: Preparation of crystalline Form-S of carbamic acid, N,N'-[[l,l'-biphenyl]-

4,4^diyIbis[lH-imidazole-5,2-diyl-(2S)-2,l^

2,l-ethanediyl]]]bis-,C,C'-dimethyl ester, hydrochloride (1:2)

Methylene chloride (400 ml) was added to Daclatasvir oxalic acid (1 :2) (50 gms) in water (150 ml) at 25-30°C and stirred for 20 min. Basified the obtained reaction mixture with aqueous NaHC0₃ solution at 25-30°C. Separated the both organic and aqueous layers. Extracted the aqueous layer with methylene chloride. Combined the total organic layers and washed with water. Separated the organic layer filtered through 0.2 Micron paper and washed with methylene chloride. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with isobutyl acetate. Isobutyl acetate (500 ml) was added to the above obtained compound at 25-30°C and cooled to 0-5°C. Isopropanolic hydrochloride (27.02 ml, 0.108 moles) was slowly added to the above cooled reaction mixture at 0-5°C and stirred for 15 min at same temperature. Water (40 ml) was added to the reaction mixture and slowly raised the reaction mixture temperature to 20-25°C and stirred for 16 hrs at same temperature. Filtered the precipitated solid and washed with isobutyl acetate and then dried to get the title compound (Yield: 35.1 gms, purity by HPLC: 99.57%, M.R: 210-220°).

The PXRD pattern of above obtained crystalline Form-S was similar to the PXRD pattern illustrated in figure-7.

Example-17: Preparation of crystalline Form-N of Daclatasvir hydrochloride (1:2).

Isobutyl acetate (200 ml) was added to Daclatasvir hydrochloride (1 :2) (5 gms) at 25- 30°C. Heated the reaction mixture to 70-75°C and stirred for 5 hrs at same temperature. Filtered the solid and dried to get the title compound. (Yield: 4 gms).

The PXRD pattern of above obtained crystalline Form-N was illustrated in figure-9.

Claims

We claim:

1. A process for the preparation of carbamic acid, NjN'-ftl '-biphenylJ^^'-diylbisflH- imidazole-5,2-diyl-(25 -2, 1 -pyrrolidine diyl[( 15)- 1 -( 1 -methyIethyl)-2-oxo-2, 1 -ethanediyl] ]]bis-,C,C

comprising the steps of:

a) self-condensation of two molecules of compound of general formula (VIII) in presence of a suitable catalyst and suitable base in a suitable solvent to provide the

wherein X represents bromine, chlorine or iodine.

b) optionally converting the compound of formula (I) into its acid addition salts.

2. The process according to claim 1, in step-a) the suitable metal catalyst is selected from Pd, Pd(OH)₂₎

Pd(0₂CCH₃)₂, PdS0₄, Pd (N0₃)₂, Fe, Ni, copper sulfate, copper oxide, copper chloride optionally in presence of charcoal.

3. The process according to claim 1, in step-a) the suitable base is selected from sodium acetate, potassium acetate, potassium propionate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, dipotassium hydrogen phosphate, tripotassium phosphate, trisodium phosphate.

4. The process according to claim 1, in step-a) the suitable solvent is selected from glycol solvents such as ethylene glycol, propylene glycol; alcohol solvents such as methanol, isopropanol, ethanol; nitrile solvents such as acetonitrile, propionitrile; ester solvents such as ethyl acetate, methyl acetate, butyl acetate, isobutyl acetate; ether solvents such as tetrahydrofuran, methyl tert-butyl ether, 1 ,3 dioxane and the like.

5. The process according to claim 1, the suitable metal catalyst used in step-a) can be recovered by filtration after completion of the coupling reaction.

6. The process according to claim 1, step-a) is optionally carried out in presence of phase transfer catalyst.

7. The process according to claim 1, the compound of formula (I) can be converted to the acid addition salt on treating with suitable acid selected from inorganic acids like suitable hydrochloric acid source, hydroiodide, nitric acid, sulfuric acid; organic acids selected from oxalic acid, succinic acid, formic acid, acetic acid, methane sulfonic acid (MsOH), p-toluene sulfonic acid (p-TsOH), trifluoro acetic acid (TFA).

8. A process for the preparation of carbamic acid, N,N'-[[l, -biphenyl]-4,4'-diylbis[lH- imidazole-5,2-diyl-(25)-2, 1 -pyrrolidine diyl[( IS)- 1 -( 1 -methylethyl)-2-oxo-2, 1 -ethanediyl] ]]bis-,C,C'-dimethyl ester of formula (I), comprising, self-condensation of two molecules of compound of general formula (Villa) in presence of Pd(OH)₂/C and dipotassium hydrogen phosphate in ethylene glycol to provide the compound of formula (I)

Formula (Villa) ^0CH' ^ ftmnnta O)

9. Carbamic acid, KN'-tC^r-biphenylJ^^'-diylbistlH-imidazole-S^-diyl^-?)^,!- pyrrolidine diyl[(lS)-l-(l-methylethyl)-2-oxo-2,l-ethanediyl] ]]bis-,C,C'-dimethyl ester, oxalic acid (1 :2) of formula (lb)

Formula (lb)

10. A process for the preparation of carbamic acid, N,N'-[[l,r-biphenyl]-4,4'-diylbis[lH- imidazole-5,2-diyl-(25)-2, 1 -pyrrolidine diyl [( 15)-l -( 1 -methylethyl)-2-oxo-2 , 1 -ethanediyl] ]]bis-,C,C'-dimethyl ester, oxalic acid (1 :2) of formula (lb)

comprising the steps of:

a) self-condensation of two molecules of compound of general formula (VIII) in presence of suitable metal catalyst and suitable base in a suitable solvent to

Formu a (VIII) wherein X represents bromine, chlorine or iodine,

1 1. The process according to claim 10, in step-a) the suitable metal catalyst is selected from Pd, Pd(OH)₂, PdCl₂, Pd(0₂CCH₃)₂, PdS0_4> Pd(N0₃)2, Fe, Ni, copper sulfate, copper oxide, copper chloride optionally in presence of charcoal; the suitable base is selected from sodium acetate, potassium acetate, potassium propionate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, dipotassium hydrogen phosphate, tripotassium phosphate, trisodium phosphate; the suitable solvent is selected from glycol solvents such as ethylene glycol, propylene glycol; alcohol solvents such as methanol, isopropanol, ethanol; nitrile solvents such as acetonitrile, propionitrile; ester solvents such as ethyl acetate, methyl acetate, butyl acetate, isobutyl acetate; ether solvents such as tetrahydrofuran, methyl tert-butyl ether, 1,3 dioxane and the like.

12. A process for the preparation of carbamic acid, N,N'-[[l,r-biphenyl]-4,4'-diylbis[lH- imidazole-5,2-diyl-(2S)-2,l-pyrrolidine diyl[(lS)-l-(l-methylethyl)-2-oxo-2,l-ethanediyl] ]]bis-,C,C'-dimethyl ester, oxalic acid (1 :2) of formula (lb) comprising the steps of:

a) self-condensation of two molecules of compound of formula (Villa) in presence of Pd(OH)₂/C and dipotassium hydrogen phosphate in ethylene glycol to provide the compound of formula (I);

13. Use of carbamic acid, N.N'-ttl^'-biphenyll- '-diylbisClH-imidazole-S^-diyl^^,! - pyrrolidinediyl[(15 -l-(l -memylethyl)-2-oxo-2,l-ethanediyl]]]bis-C,C'-dimethyl ester, oxalic acid (1 :2) of formula (lb) in the preparation of highly pure carbamic acid, Ν,Ν'- [[1,1 '-biphenyl]-4,4'-diylbis[ 1 H-imidazole-5,2-diyl-(2S)-2, 1 -pyrrolidinediy 1[( 1 S)- 1 -( 1 - methylethyl)-2-oxo-2,l-ethanediyl]]]bis-C,C'-dimethyl ester, hydrochloride (1 :2) of formula (la)

14. Amorphous form of carbamic acid, N^'-tf ljl '-biphenylJ^^'-di lbistlH-imidazole-S^- diyl-(2S)-2, 1 -pyrrolidinediyl[( 15)- 1 -(1 -methylethyl)-2-oxo-2, 1 -ethanediyl]]]bis-C,C- dimethyl ester, oxalic acid (1 :2) of formula (lb) characterized by: a) the PXRD pattern as shown in figure- 1 ; and

b) the I Spectra as shown in figure-2.

15. A process for the preparation of amorphous form of carbamic acid, N,N'-[[1 ,Γ-biphenyl]- 4,4*-diylbis[lH-imidazole-5,2-diyH

2,l-ethanediyl]]]bis-C_}C'-dimethyl ester, oxalic acid (1 :2) of formula (lb), comprising the steps of,

a) providing carbamic acid, N,N'-[[l, -biphenyl]-4,4'-diylbis[lH-imidazole-5,2- diyl-(25)-2, 1 -pyrrolidinediyl[(15)- 1 -(1 -methylethyl)-2-oxo-2,l -ethanediyl]]]bis- C,C'-dimethyl ester in a suitable solvent; b) adding oxalic acid to the reaction mixture obtained in step-a);

c) stirring the resulting reaction mixture;

d) isolating amorphous form of carbamic acid, N,N'-[[l,r-biphenyl]-4,4'- diylbis[ 1 H-imidazole-5,2-diyl-(2S)-2, 1 -pyrrolidinediyl [( 15)- 1 -( 1 -methylethyl 2- oxo-2,l-ethanediyl]]]bis-C,C-dimethyl ester oxalic acid (1 :2).

16. The process according to claim 15, wherein "isolating" refers to filtration, distillation, precipitation by cooling the reaction mixture, solvent and anti-solvent technique by using the suitable solvents such as alcohol solvents, chloro solvents, ester solvents, ketone solvents, nitrile solvents; the suitable anti-solvent is selected from ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether; nitrile solvents, ester solvents, hydrocarbon solvents.

17. The process according to claim 15, methanol- 1,4-dioxane and ethanol-acetonitrile solvent systems used for isolation/purification of formula (lb) by solvent and anti-solvent technique either in regular addition or reverse mode of addition.

18. A process for the preparation of amorphous form of carbamic acid, N,N'-[[l, -biphenyl]- 4,4'-diylbis[ 1 H-imidazole-5,2-diyl-(2^

2,l-ethanediyl]]]bis-C,C'-dimethyl ester, oxalic acid (1 :2) of formula (lb), comprising the steps of,

a) dissolving carbamic acid, NjN'-tf l'-biphenylJ^^'-diylbistlH-imidazole-S^- diyl-(25)-2, 1 -pyrrolidinediyllXlS)- 1-(1 -methylethyl)-2-oxo-2, 1 -ethanediyl]]]bis- C,C'-dimethyl ester in methylene chloride;

b) adding oxalic acid to the reaction mixture obtained in step-a);

c) stirring the resulting reaction mixture;

d) distillating off the solvent from the reaction mixture;

e) co-distilling and stirring the obtained material with methyl tert-butyl ether;

f) isolating amorphous form of carbamic acid, N,N'-[[l,r-biphenyl]-4,4'- diylbis[ 1 H-imidazole-5,2-diyl-(25)-2,l -pyiTolidinediyl[( 15)- 1 -( 1 -methylethyl)-2- oxo-2,l-ethanediyl]]]bis-C,C'-dimethyl ester oxalic acid (1 :2).

19. A process for the preparation of carbamic acid, N,N'-[[l, -biphenyl]-4,4'-diylbis[lH- imidazole-5,2-diyl-(2S)-2, 1 -pyrrolidine diyl[( 15)-l -( 1 -methylethyl)-2-oxo-2, 1 -ethanediyl] ]]bis-,C,C'-dirnethyl ester of formula (lb), comprising the steps of:

a) reacting methyl ((S)-l-((S)-2-(5-(4-bromophenyl)-l H-imidazol-2-yl)pyrrolidin-l - yl)-3-methyl-l -oxobutan-2-yi)carbamate with methyl ((5)-3 -methyl- 1-oxo-l -((5)- 2-(5-(4-(4₎4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-lH-imidazol-2- yl)pyrrolidin-l -yl)butan-2-yl)carbamate in presence of a suitable catalyst and suitable base in a suitable solvent;

b) adding oxalic acid solution to the reaction mixture;

c) isolating the compound of formula (lb).

20. The process according to claim 19, in step-a), the suitable catalyst is selected from

palladium-tetrakis(triphenylphosphine), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(tricyclohexylphosphine)palladium(II), [l ,2-bis(diphenylphosphino)ethane] dichloropalladium(II), [Ι ,Γ-bis (diphenylphosphino)ferrocene]palladium(II) dichloride, dichlorobis(tri-o-tolylphosphine)palladium(II).

21. A process for the preparation of amorphous form of carbamic acid, N,N'-[[l ,l'-biphenyl]- 4 ,4'-diylbis[ 1 H-imidazole-5 ,2-diyl-(2S)-2, 1 -pyrrolidinediyl[( 1 S)- 1 -( 1 -methylethy l)-2-oxo- 2,l-ethanediyl]]]bis-,C_sC'-dimethyl ester, oxalic acid (1 :2) of formula (lb), comprising: a) self-condensing the methyl ((S -l-((S)-2-(5-(4-bromophenyl)-lH-imidazol-2- yl)pyrrolidin-l -yl)-3 -methyl- -oxobutan-2-yl)carbamate with each other in presence of Pd/C, trisodium phosphate in methanol in presence of tetra butyl ammonium bromide (TBAB) to provide the compound of formula (I); b) adding oxalic acid in isopropanol to the compound obtained in step-a);

c) isolating the compound of formula (lb).

22. A process for the preparation of amorphous form of Daclatasvir oxalic acid (1 :2) of formula (lb), comprising:

a) Condensation of two molecules of the methyl ((S)-l-((S)-2-(5-(4-bromophenyl)- 1 H-imidazol-2-yl)pyrrolidin- 1 -yl)-3-methyl- 1 -oxobutan-2-yl)carbamate with each other in presence of Pd/C, trisodium phosphate in methanol in presence of TBAB to provide the compound of formula (I);

b) combining the reaction mixture obtained in step-a) with oxalic acid in isopropanol;

c) filtering the obtained amorphous form of formula (lb).

23. A process for the purification of Daclatasvir oxalic acid (1 :2) of formula (lb), comprising: a) dissolving carbamic acid, ^^-[[l.r-biphenylJ^^'-diylbistlH-imidazole-S^- diyl-(2S)-2, 1 -pyrrolidinediyl[( 15)- 1 -(1 -methyl ethyl) -2 -oxo-2, 1 -ethanediyl]]]bis- ,C,C'-dimethyl ester, oxalic acid (1 :2) in methanol;

b) adding charcoal to the reaction mixture;

c) optionally, filtering the reaction mixture obtained in step-b);

d) distilling off the solvent from the filtrate obtained in step-c);

e) adding methanol and acetone to the material obtained in step-d);

f) stirring the reaction mixture obtained in step-e);

g) filtering the solid to produce pure compound of formula (lb).

24. A process for the preparation of carbamic acid, N.N'-ffl '-biphenylJ^^'-diylbisflH- imidazole-5,2-diyl-(25)-2_s 1 -pyrrolidine diyl[(15 1 -(1 -methyIethyl)-2-oxo-2, 1 -ethanediyl] ]]bis-,C,C'-dimethyl ester hydrochloride (1 :2) of formula (la),

comprising the steps of:

a) self-condensation of the two molecules of compound of general formula (VIII) in presence of suitable catalyst and suitable base in a suitable solvent to provide the compound of formula (I),

b) treating the compound of formula (I) with oxalic acid to provide the compound of formula (lb), c) treating the product obtained in step-b) with suitable base in a suitable solvent followed by treating with suitable hydrochloride source to provide the compound of formula (la).

25. The process according to claim 24, in step-a) the suitable metal catalyst is selected from Pd, Pd(OH)₂, PdCl₂, Pd(0₂CCH₃)₂, PdS0₄, Pd(N0₃)_2> Fe, Ni, copper sulfate, copper oxide, copper chloride optionally in presence of charcoal; the suitable base is selected from sodium acetate, potassium acetate, potassium propionate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, dipotassium hydrogen phosphate, tripotassium phosphate, trisodium phosphate; the suitable solvent is selected from glycol solvents such as ethylene glycol, propylene glycol; alcohol solvents such as methanol, isopropanol, ethanol; nitrile solvents such as acetonitrile, propionitrile; ester solvents such as ethyl acetate, methyl acetate, butyl acetate, isobutyl acetate; ether solvents such as tetrahydrofuran, methyl tert-butyl ether, 1,3 dioxane and the like; in step-c) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates; hydrochloride acid source is selected from hydrochloride, hydrochloride gas, SOCl₂/alcohol solvents, aqueous hydrochloride, ethyl acetate, hydrochloride, acetonitrile hydrochloride, isopropanol hydrochloride, methanol hydrochloride, ethanol hydrochloride.

26. A process for the preparation of carbamic acid, N,N^,-[[l₅l'-biphenyl]-4,4'-diylbis[lH- imidazoIe-5,2-diyl-(2S)-2, 1 -pyrrolidine diyl[( 15)- 1 -( 1 -methylethyl)-2-oxo-2, 1 -ethanediyl] Jjbis-.CC

comprising the steps of: a) self-condensation of the two molecules of compound of formula (Villa) in presence of Pd(OH)2/C and dipotassium hydrogen phosphate in ethylene glycol to provide the compound of formula (I),

b) treating the compound of formula (I) with oxalic acid in methylene chloride to provide the compound of formula (lb),

c) treating the product obtained in step-b) with aqueous sodium hydroxide solution in a methylene chloride followed by treating with isopropanolic hydrochloric acid to provide the compound of formula (la).

27. A process for the preparation of carbamic acid, N,N'-[[l, -biphenyl]-4,4'-diylbis[lH- imidazole-5,2-diyl-(2S 2, 1 -pyrrolidine diyl[( 15)- 1 -( 1 -methylethyl)-2-oxo-2, 1 -ethanediyl] ]]bis-,C,C'-dimethyl ester of formula (I), comprising the steps of: a) reacting the compound of general formula (II) with the compound of general formula (III) in presence of a suitable base in a suitable solvent to provide the compound of formula (IV) which on ϊη-situ cyclized to produce the compound of

Formula (V) wherein, X refers to chlorine, bromine, fluorine, iodine, methanesulfonyl group, ethanesulfonyl group, benzenesulfonyl group, toluenesulfonyl group; "PG" refers to amine protecting group b) treating the compound of general formula (V) with suitable deprotecting agent to produce the compound of general formula (VI) or its acid addition salt;

addition salt

Formula (V) Formula (VI) c) reacting the compound of general formula (VI) or its acid addition salts with the compound of formula (VII) in presence of a suitable coupling agent, base in a suitable solvent to provide the compound of general formula (VIII);

Formula (VI) Formula (VII) d) (i): treating the compound of formula (VIII) with the suitable borylating agent in presence of a catalyst, suitable base in a solvent to produce the compound of general formula (IX) followed by in-situ reacting with the compound of general formula (VIII) in presence of a suitable catalyst, base in a solvent to provide the

wherein X is same as represented above, R represents

(or)

d) (ii): self-condensing the two molecules of compound of general formula (VIII) to

ormu a e) optionally, converting the compound of formula (I) into acid addition salts.

28. The process according to claim 27, in step-a) the suitable base is selected from alkylamine, dialkylamine or trialkylamine; the solvent is selected from hydrocarbon solvents, ester solvents, ether solvents, nitrile solvents, alcohol solvents, polar aprotic solvents, chloro solvents; the cyclization is carried out in presence of ammonium acetate; in step-b) the suitable deprotecting agent selected from hydrochloride, isopropanolic hydrochloride, methanolic hydrochloride, ethanolic hydrochloride, ethyl acetate hydrochloride, acetonitrile.hydrochloride, acetone.hydrochloride;

in step-c) the suitable coupling agent is selected from dicyclohexyl carbodiimide, diisopropylcarbodiimide, EDC. HC1, CDI, HOBt, DABAL-Me₃ or mixtures thereof; and the suitable base is selected from organic or inorganic base; and the suitable solvent is selected from chloro solvents, ester solvents, ketone solvents, hydrocarbon solvents, polar aprotic solvents and alcohol solvents or mixtures thereof;

in step-d) (i) the suitable borylating agent is selected from bis(pinacolato)diboron or bis(neopentylglycolato)diboron; the catalyst is selected from PdCl2[P(t-Bu)₂Ph]₂, Pd(dppf)Cl₂₍ Pd(PPh₃)4 and the like; the base is selected from potassium acetate, potassium propionate; the suitable solvent is selected from dimethoxyethane, hydrocarbon solvents, chloro solvents, polar protic solvents, polar aprotic solvents, ester solvents, ether solvents, nitrile solvents and the like.

29. A process for the preparation of carbamic acid, N,N'-[[l, -biphenyl]-4,4'-diylbis[lH- imidazole-5,2-diyl-(2S)-2_J 1 -pyrrolidine diyl[( IS)- 1 -( 1 -methylethyl)-2-oxo-2, 1 -ethanediyi] ]]bis-_}C,C'-dimethyl ester of formula (I) or its hydrochloride salt of formula (la), comprising the steps of: a) reacting the compound of formula (Ila) with the compound of formula (Ilia) in presence of diisopropylethylamine in toluene to provide the compound of formula (IVa) which on in-situ cyclization in presence of ammonium acetate to produce the com ound of formula (Va);

Formula (Ha) Formula (Ilia)

Formula (IVa)

Formula (Va) b) treating the compound of formula (Va) with isopropanolic hydrochloride to produce the dihydrochloride salt compound of formula

Formula (Va) Formula (Via) c) reacting the salt compound of formula (Via) with the compound of formula (VII) in presence of EDC. HC1, HOBt / triethylamine in methylene chloride to provide the compound of formula (Villa);

Formula (VII) ormu a a

d) coupling the compound of formula (Villa) with each other (self-coupling) in presence of Pd(OH)₂/C to provide the compound of formula (I),

e) optionally, treating the compound of formula (I) obtained in step-d) with oxalic acid to provide the oxalic acid salt compound of formula (lb), f) optionally, treating the compound obtained in step-e) with aqueous NaOH in presence of methylene chloride followed by treating the obtained compound with aqueous hydrochloride in methylene chloride to provide the hydrochloride salt compound of formula (la).