DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. 2327/CHE/2015 filed on May 07, 2015.
BACKGROUND OF THE INVENTION
FIELD OF THE DISCLOSURE
The present invention relates generally to processes for manufacturing active pharmaceutical ingredients and more specifically to a novel process for the preparation of daclatasvir and its pharmaceutically acceptable salts. The present invention also relates to novel intermediates formed during the process of the preparation of daclatasvir.
BACKGROUND OF THE INVENTION
Daclatasvir is an inhibitor of HCV nonstructural protein 5A (NS5A). Daclatasvir often comes in the form of its hydrochloride salt, daclatasvir hydrochloride. The chemical name for daclatasvir hydrochloride is carbamic acid, N,N'-[[1,1'-biphenyl]-4,4'-diylbis[1H-imidazole-5,2-diyl-(2S)-2,1-pyrrolidinediyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl]]]bis-,C,C'-dimethyl ester, hydrochloride (1:2) and is represented by the following chemical structure:

Daclatasvir hydrochloride is marketed in tablet form the United States under the trade name DAKLINZA by Bristol-Meyers Squibb.
Daclatasvir is disclosed in U.S. Patent No. 8,329,159, which is hereby incorporated in its entirety by reference.
The present invention provides a process for the preparation of daclatasvir and pharmaceutically acceptable salts thereof. The present invention further provides novel intermediates that may be used in processes for the preparation of daclatasvir and pharmaceutically acceptable salts thereof.
SUMMARY OF THE DISCLOSURE
The present invention provides a process for the preparation of daclatasvir or its pharmaceutically acceptable salts, which may include the following steps:
a. acetylating biphenyl by reacting with acetylating agent to get a compound of formula X;

b. reacting the compound of formula X with a compound of formula IX to get formula VIII;

c. reacting the compound of formula VIII with N-protected-L-proline to obtain a compound of formula VII;

d. converting the compound of formula VII to a compound of formula V;

e. reacting the compound of formula V with N-protected-L-proline to obtain a compound of formula IV;

f. converting the compound of formula IV to obtain a compound of formula III;

g. deprotecting the compound of formula III to get a compound of formula II or its pharmaceutically acceptable salts; and

h. coupling the compound of formula II or its pharmaceutically acceptable salt with N-Moc-L-valine to get daclatasvir of formula I.

wherein LG, LG', and LG'' are leaving groups and P is an amine protecting group.
Within the context of this embodiment, LG, LG' and LG'' are each a leaving group which independently may be, for example, a sulfonate or a halo group. P is a protecting group, for example, an acyl group, a sulfonyl group, or a carbamate-forming group.
Examples of suitable sulfonate leaving groups include tosylate, mesylate, and benzyl sulfonate. Examples of suitable halo groups include chloro, bromo, and iodo.
Examples of suitable acyl protecting groups include acetyl, benzoyl, 2-bromoacetyl, 4-bromobenzoyl, tert-butylacetyl, carboxaldehyde, 2-chloroacetyl, 4-chlorobenzoyl, a-chlorobutyryl, 4-nitrobenzoyl, o-nitrophenoxyacetyl, phthalyl, pivaloyl, propionyl, trichloroacetyl, and trifluoroacety groups. Examples of suitable sulfonyl protecting groups include benzenesulfonyl and p-toluenesulfonyl groups. Examples of suitable carbamate-forming protecting groups include benzyloxycarbonyl, benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), p-chlorobenzyloxycarbonyl, and p-methoxybenzyloxycarbonyl groups.
In particularly useful embodiments, LG, LG', and LG'' are bromide and P is a tert-butyloxycarbonyl (Boc) group.
According to this embodiment, step a) and step b) may be performed in the presence of a Lewis acid.
Examples of suitable Lewis acids include BF3, MgBr2, SnCl4, TiCl4, FeCl3, AlCl3, CH3AlCl2, (CH3)2AlCl, LiClO4, and mixtures thereof.
According to this embodiment, step c) and step e) may be performed in the presence of a base and a solvent.
Examples of suitable bases include pyridine, imidazole, methyl amine, diisopropyl ethyl amine, triethylamine, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, alkali metal hydroxides, alkali metal carbonates, and mixtures thereof. The solvent may be a polar aprotic solvent, for example, acetonitrile, dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetone, N-methylpyrrolidone, or mixtures thereof.
According to this embodiment, converting the compound of formula VII to a compound of formula V may be performed in the presence of a brominating agent and a solvent. The brominating agent may be, for example, boron tribromide, phosphorus tribromide, carbon tetrabromide, bromine, N-bromoacetamide, N-bromophthalimide, N-bromosuccinimide, bromotrichloromethane, pyridinium tribromide, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, benzyltrimethyl ammoniumtribromide, bromodimethylsulfonium bromide, 1-butyl-3-methylimidazolium tribromide, 1,2-dibromo-1,1,2,2-tetrachloroethane, 4-dimethylaminopyridinium bromide perbromide, 2,4,4,6-tetrabromo-2,5-cyclohexadienone, or mixtures thereof.
The solvent may be, for example, an alcohol solvent, an ester solvent, an ether solvent, a chlorinated hydrocarbon solvent, or mixtures thereof.
According to this embodiment, converting the compound of formula VII to the compound of formula V may be carried out indirectly by first converting the compound of formula VII to compound of formula VI and then converting the compound of formula VI to compound of formula V.

According to this embodiment, compound of formula VII may be treated with a brominating agent in the presence of a solvent to result in compound of formula VI.
Examples of suitable brominating agents include boron tribromide, phosphorus tribromide, carbon tetrabromide, bromine, N-bromoacetamide, N-bromophthalimide, N-bromosuccinimide, bromotrichloromethane, pyridinium tribromide, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, benzyltrimethyl ammoniumtribromide, bromodimethylsulfonium bromide, 1-butyl-3-methylimidazolium tribromide, 1,2-dibromo-1,1,2,2-tetrachloroethane, 4-dimethylaminopyridinium bromide perbromide, 2,4,4,6-tetrabromo-2,5-cyclohexadienone, and mixtures thereof.
The solvent may be, for example, an alcohol solvent, an ester solvent, an ether solvent, a chlorinated hydrocarbon solvent, or mixtures thereof.
According to this embodiment, compound of formula VI may then be treated with an amine protecting agent in the presence of a solvent and a base to result in compound of formula V.
Suitable bases include, for example, pyridine, imidazole, methyl amine, diisopropyl ethyl amine, triethylamine, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, alkali metal hydroxides, alkali metal carbonates, and mixtures thereof. The solvent may be, for example, an alcohol solvent, an ester solvent, an ether solvent, a chlorinated hydrocarbon solvent, or mixtures thereof.
Within the context of this embodiment, converting the compound of formula IV to compound of formula III may be carried out in the presence of ammonium acetate, ammonium formate, ammonium sulfamate, ammonium phosphate, ammonium citrate, ammonium carbamate, ammonia, or mixtures thereof in the presence of a solvent. Suitable solvents include, as examples, aromatic hydrocarbons, cyclic hydrocarbons, and mixtures thereof.
According to this embodiment, deprotection of the compound of formula III may be carried out using a deprotecting agent in the presence of solvent. Examples of suitable deprotecting agents include HCl, H2SO4, HNO3, trimethylsilyl iodide, morpholine, and mixtures thereof. The solvent may be, for example, an alcohol solvent, an ester solvent, or mixtures thereof.
According to this embodiment, the coupling of compound of formula II with N-Moc-L-valine to result in daclatasvir of formula I may be performed in the presence of a coupling agent, a base, and a solvent.
Suitable coupling agents include, as examples, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), isobutyl chloroformate, carbonyldiimidazole (CDI), pivaloyl chloride, o-benzotriazole-l-yl-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium (HBTU), benzotriazole-1-y 1-oxy-tris(dimethylamino)phosphonium (BOP), benzotriazole-l-yl-oxy-tris(pyrrolidino) phosphonum (PyBOP), bromo-tris-pyrrolidino-phosphoniumhexaflurophosphate (PyBrOP), tris(pyroolidino)phosphonium hexaflurophosphate (pyCOP), ethyl cyanoglyoxyIate-2-oxime, o-(6-chloro-l-hydroxybenzotriazol-l-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TCTU), 2-(lH-7-azabenzotriazol-l-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU), l-cyano-2-ethoxy-2-oxoethydenminooxy)dimethylamino-morpholion-carbenium hexafluorophosphate (COMU), or mixtures thereof; base is selected from base may be, for example, N-methylmorpholine (NMM), N,N-diisopropylethylamine, triethylamine, N,N’-dimethylpiperazine, N-methylpiperidine, pyridine, and mixtures thereof.
The solvent may be a polar aprotic solvent, for example, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, acetone, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, or mixtures thereof.
Optionally, daclatasvir may be converted into a pharmaceutically acceptable salt of daclatasvir.
Optionally, compound of formula III may be converted into a pharmaceutically acceptable salt of formula II and the coupling of step h) may be carried out by coupling a pharmaceutically acceptable salt of formula II with N-Moc-L-valine.
Another aspect of the present invention provides novel intermediates that may be used in the preparation of daclatasvir.
One such intermediate is Formula VII, shown below,

The “P” moiety of formula VII is an amine protecting group.
Another such intermediate is Formula VI, shown below,

The LG'' moiety of formula VI is a leaving group.
DETAILED DESCRIPTION OF THE INVENTION
It is to be understood that the descriptions of the present invention have been simplified to illustrate elements that are relevant for a clear understanding of the invention.
The present invention provides novel synthetic schemes for the synthesis of daclatasvir. Within the context of the present invention, novel intermediates are generated as part of the novel synthetic schemes. Together, these schemes and intermediates provide an improved, efficient method for the synthesis of daclatasvir or pharmaceutically acceptable salts thereof.
One aspect of the present invention provides a process for the preparation of daclatasvir or pharmaceutically acceptable salts thereof.
In one embodiment, daclatasvir or pharmaceutically acceptable salts thereof may be prepared by the following steps:
a) acetylating biphenyl to get a compound of formula X;

b) reacting the compound of formula X with compound of formula IX to get a compound of formula VIII;

c) reacting the compound of formula VIII with N-protected-L-proline to obtain a compound of formula VII;

d) converting the compound of formula VII to a compound of formula V;

e) reacting the compound of formula V with N-protected-L-proline to obtain a compound of formula IV;

f) converting the compound of formula IV to compound of formula III;

g) deprotecting the compound of formula III to get compound of formula II or its pharmaceutically acceptable salts; and

h) coupling the compound of formula II or its pharmaceutically acceptable salts with N-Moc-L-valine to get daclatasvir of formula I.

Within the context of this embodiment, the LG, LG' and LG'' moieties are leaving groups and the P moiety is an amine protecting group.
The term “leaving group” is well-known and understood in the art. The term “leaving group” as used herein, refers to a group that is capable of being displaced by a nucleophile. Examples of leaving groups includes halo (e.g., fluoro, chloro, bromo, iodo), alkyl sulfonyloxy (e.g., methanesulfonyloxy, trifluoromethanesulfonyloxy), aryl sulfonyloxy (e.g., benzylsulfonyloxy, p-toluenesulfonyloxy, (4-bromo-benzene)sulfonyloxy, (4-nitro-benzene)sulfonyloxy, (2-nitro-benzene)-sulfonyloxy, (4-isopropyl-benzene)sulfonyloxy, benzenesulfonyloxy, (4-methoxy-benzene)sulfonyloxy)). Within the context of this embodiment LG, LG' and LG'' may be the same or may be different leaving groups.
The term "alkyl" as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, unless otherwise specified. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
The term "aryl," as used herein, means a monocyclic (i.e., phenyl), bicyclic, or tricyclic ring fused or bridged system containing at least one phenyl ring. Non-phenyl rings that are part of a bicyclic or tricyclic ring system may be fully or partially saturated, may contain one or more heteroatoms, each selected from N, S, and O, and may be optionally substituted with one or two oxo and/or thia groups. Examples of aryl groups include phenyl, napthyl, anthracenyl, and fluorenyl.
The term “amine protecting group” is well known and understood in the art. Examples of suitable amine protecting groups, as well as suitable conditions for protecting and deprotecting, can be found in prior art, such as J. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973; T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999; “The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981; in “Methoden der organischen Chemie”, Houben-Weyl, 4th edition, Vol. 15/1, Georg Thieme Verlag, Stuttgart 1974; H.-D. Jakubke and H. Jescheit, “Aminosauren, Peptide, Proteine”, Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982; and Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharide und Derivate”, Georg Thieme Verlag, Stuttgart 1974.
Particular examples of amine protecting groups include, carbonyls (e.g., methyl carbamate, 9-fluorenylmethyoxycarbonyl (Fmoc), trichloroethoxycarbonyl (Troc), p-chlorobenzyloxycarbonyl, tert-butyloxycarbonyl (BOC), 2-trimethylsilylethyloxycarbonyl (Teoc), allyloxycarbonyl (Alloc), p-methoxybenzyl carbonyl (Moz), and carboxybenzyl (Cbz)), sulfonyls (e.g., p-toluenesufonyl (Ts), trimethylsilylethanesulfoyl (Ses), tert-butylsulfonyl (Bus), benzenesulfonyl, 4-methoxyphenylsulfonyl, 4-nitrobenzenesulfonyl (nosyl)), trityl (trt), benzyl (Bn), 3,4-dimethyoxybenzyl (Dmpm), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), acetyl (Ac), formyl, trifluoroacetyl (Tfa), trichloroacetyl, benzoyl (Bz), 4-chlorobenzoyl, tert-butylacetyl, 4-nitrobenzoyl, 2-bromoacetyl, 2-chloroacetyl, 4-bromobenzoyl, o-nitrophenoxyacetyl, phthalyl, pivaloyl, propionyl, a-chlorobutyryl , carboxaldehyde, or 2-nitrophenylsulfenyl (Nps).
According to this embodiment, biphenyl may be acetylated to get compound of formula X. This reaction may be carried out in the presence of an acylating agent and a Lewis acid in a solvent.
Within the context of this embodiment, the acetylating agent may be, for example, acetyl chloride, acetyl bromide, acetic anhydride, or mixtures thereof. The Lewis acid may be, for example, BF3, MgBr2, SnCl4, TiCl4, FeCl3, AlCl3, CH3AlCl2, (CH3)2AlCl, LiClO4 or mixtures thereof. The solvent may be an ether, for example, tetrahydrofuran or isopropyl ether, an aromatic hydrocarbon, for example, toluene, a chlorinated hydrocarbon, for example, dichloromethane, or mixtures thereof. In particularly useful embodiments, biphenyl is reacted with acetyl chloride in the presence of AlCl3 and dichloromethane. One of the skill in the art will recognize numerous acetylating agents and Lewis acids that may be useful for acetylating biphenyl.
According to this embodiment, the compound of formula X may then be reacted with compound of formula IX. This reaction may occur in the presence of a Lewis acid and a solvent.
Within the context of this embodiment, the Lewis acid may be, for example, BF3, MgBr2, SnCl4, TiCl4, FeCl3, AlCl3, CH3AlCl2, (CH3)2AlCl, LiClO4, or mixtures thereof. One of the skill in the art will recognize numerous Lewis acids that may be useful for this reaction. The solvent may be an ether, for example, tetrahydrofuran or isopropyl ether, an aromatic hydrocarbon, for example, toluene, a chlorinated hydrocarbon, for example, dichloromethane, or mixtures thereof.
Next, the compound of formula VIII may be treated with N-protected-L-proline to get compound of formula VII. This reaction may be carried out in the presence of a base and a solvent.
Within the context of this embodiment, the base may be organic or inorganic. Examples of suitable organic bases include pyridine, imidazole, methyl amine, N,N-diisopropylethylamine, triethylamine, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, and mixtures thereof. Examples of suitable inorganic bases include alkali metal hydroxides, alkali metal carbonates, and mixtures thereof. In some embodiments, N,N-diisopropylethylamine was found to be a particularly useful base. One of the skill in the art will recognize numerous well-known organic and in organic bases that may be useful within the context of this embodiment.
Within the context of this embodiment, the solvent may be a polar aprotic solvent. Examples of suitable polar aprotic solvents include acetonitrile, dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetone, N-methylpyrrolidone, and mixtures thereof. In some embodiments, acetonitrile is used as the solvent. One of the skill in the art will recognize numerous polar aprotic solvents that may be useful within the context of this embodiment.
Within the context of this embodiment, the compound of formula VII may then be converted to compound of formula V directly (“direct conversion”) or by first converting compound of formula VII to compound of formula VI, which is then converted to compound of formula V (“indirect conversion”), as shown in the two synthetic schemes and described below.
Direct conversion

In one embodiment, the compound of formula VII may be directly converted to compound of formula V. This reaction may be carried out in the presence of a brominating agent and a solvent.
Within the context of this embodiment, suitable brominating agents include, for example, boron tribromide, phosphorus tribromide, carbon tetrabromide, bromine, N-bromoacetamide, N-bromophthalimide, N-bromosuccinimide, bromotrichloromethane, pyridinium tribromide, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, benzyltrimethyl ammoniumtribromide, bromodimethylsulfonium bromide, 1-butyl-3-methylimidazolium tribromide, 1,2-dibromo-1,1,2,2-tetrachloroethane, 4-dimethylaminopyridinium bromide perbromide, and 2,4,4,6-tetrabromo-2,5-cyclohexadienone. In some embodiments, pyridinium tribromide was found to be a particularly useful brominating agent. One of the skill in the art will recognize numerous brominating agent that may be useful within the context of this embodiment.
Suitable solvents include, for example, alcohol solvents, ester solvents, ether solvents, chlorinated hydrocarbon solvents, and mixtures thereof. Examples of suitable alcohol solvents include methanol, ethanol, isopropyl alcohol, and mixtures thereof. Examples of suitable ester solvents include ethyl acetate, isopropyl acetate, and mixtures thereof. Examples of suitable ether solvents include tetrahydrofuran, isopropyl ether, and mixtures thereof. One example of a suitable chlorinated hydrocarbon solvent is dichloromethane. In particular embodiments, a mixture of methanol and dichloromethane is used as a solvent.
Indirect conversion

In an another embodiment, the conversion of the compound of formula VII to compound of formula V can be carried out by converting the compound of formula VII to compound of formula VI or its acid addition salt then converting formula VI or its acid addition salt to formula V. The conversion of compound of formula VII to compound of formula VI may be carried out in the presence of a brominating agent and a solvent.
Within the context of this embodiment, examples of suitable brominating agents include boron tribromide, phosphorus tribromide, carbon tetrabromide, bromine, N-bromoacetamide, N-bromophthalimide, N-bromosuccinimide, bromotrichloromethane, pyridinium tribromide, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, benzyltrimethyl ammoniumtribromide, bromodimethylsulfonium bromide, 1-butyl-3-methylimidazolium tribromide, 1,2-dibromo-1,1,2,2-tetrachloroethane, 4-dimethylaminopyridinium bromide perbromide, and 2,4,4,6-tetrabromo-2,5-cyclohexadienone. In some embodiments, pyridinium tribromide was found to be a particularly useful brominating agent. One of the skill in the art will recognize numerous brominating agent that may be useful within the context of this embodiment.
Suitable solvents include, for example, alcohol solvents, ester solvents, ether solvents, chlorinated hydrocarbon solvents, and mixtures thereof. Examples of suitable alcohol solvents include methanol, ethanol, isopropyl alcohol, and mixtures thereof. Examples of suitable ester solvents include ethyl acetate, isopropyl acetate, and mixtures thereof. Examples of suitable ether solvents include tetrahydrofuran, isopropyl ether, and mixtures thereof. One example of a suitable chlorinated hydrocarbon solvent is dichloromethane. In particular embodiments, a mixture of methanol and dichloromethane is used as a solvent.
Next, compound of formula VI may be treated with an amine protecting agent to get compound of formula V. This reaction may be carried out in the presence of base and solvent.
Within the context of this embodiment, the base may be organic or inorganic. Examples of suitable organic bases include pyridine, imidazole, methyl amine, diisopropyl ethyl amine, triethylamine, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, and mixtures thereof. Examples of suitable inorganic bases include alkali metal hydroxides, alkali metal carbonates, and mixtures thereof. In some embodiments, triethylamine was found to be a particularly useful base. One of the skill in the art will recognize numerous well-known organic and inorganic bases that may be useful within the context of this embodiment.
Suitable solvents include, for example, alcohol solvents, ester solvents, ether solvents, chlorinated hydrocarbon solvents, and mixtures thereof. Examples of suitable alcohol solvents include methanol, ethanol, isopropyl alcohol, and mixtures thereof. Examples of suitable ester solvents include ethyl acetate, isopropyl acetate, and mixtures thereof. Examples of suitable ether solvents include tetrahydrofuran, isopropyl ether, and mixtures thereof. One example of a suitable chlorinated hydrocarbon solvent is dichloromethane. In particular embodiments, a mixture of methanol and dichloromethane is used as a solvent.
After compound of formula V is obtained, compound of formula V may be treated with N-protected-L-proline to get a compound of formula IV. This reaction may be carried out in the presence of a base and a solvent.
Within the context of this embodiment, the base may be organic or inorganic. Examples of organic bases include pyridine, imidazole, methyl amine, diisopropyl ethyl amine, triethylamine, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, and mixtures thereof. Examples of inorganic bases include alkali metal hydroxides, alkali metal carbonates, and mixtures thereof. In some embodiments, diisopropylethylamine was used as a base. One of the skill in the art will recognize numerous well-known organic and inorganic bases that may be useful within the context of this embodiment.
Within the context of this embodiment, the solvent may be a polar aprotic solvent, for example, acetonitrile, dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetone, N-methylpyrrolidone, or mixtures thereof. In some embodiments, acetonitrile was found to be a particularly useful solvent. One of the skill in the art will recognize numerous polar aprotic solvents that may be useful within the context of this embodiment.
According to this embodiment, compound of formula IV may next be converted to compound of formula III. Within the context of this embodiment, this reaction may be carried out in the presence of an ammonium compound, for example, ammonium acetate, ammonium formate, ammonium sulfamate, ammonium phosphate, ammonium citrate, ammonium carbamate, ammonia, or mixtures thereof.
This reaction may also be carried out in the presence of a solvent, which may be, for example, an aromatic hydrocarbon, such as toluene, xylene, mesitylene, or mixtures thereof, or a cyclic hydrocarbon such as cyclohexane, or mixtures thereof. In particular embodiments, formula IV is treated with ammonium acetate in toluene.
Within the context of this embodiment, compound of formula III may then be isolated. This may be carried out using an ester solvent, such as ethyl acetate, isopropyl acetate, or mixtures thereof, an organic carboxylic acid solvent such as acetic acid, or mixtures thereof.
Next, compound of formula III may be deprotected to get compound of formula II. This reaction may be carried out in the presence of a deprotecting agent and a solvent.
Suitable deprotection agents depend on the protecting group used. One of skill in the art will be familiar with suitable deprotecting agents and conditions for deprotection. For example, many protecting groups may be removed by hydrogenolysis or through the use of an acid or a base. Specific examples of suitable acids include mineral acids such as HCl, H2SO4, and HNO3. Other agents that may be used as a deprotecting agent may be, for example, trimethylsilyl iodide or morpholine.
In some embodiments, suitable solvents may include alcohol solvents, ester solvents, and mixtures thereof. Examples of suitable alcohol solvents include methanol, ethanol, isopropyl alcohol, and mixtures thereof. Suitable ester solvents include, for example, ethyl acetate, isopropyl acetate, and mixtures thereof. Again, one of skill in the art will be familiar with suitable reaction conditions and times for a particular choice of deprotecting agent.
Optionally, compound of formula II may be converted to a pharmaceutically acceptable salt of compound of formula II.
In some embodiments, the formation of a pharmaceutically acceptable salt of compound of formula II may be performed in situ during the conversion of compound of formula III to compound of formula II.
According to this embodiment, compound of formula II or a pharmaceutically acceptable salt thereof may then be converted to daclatasvir or a pharmaceutically acceptable salt thereof. This may be carried out by coupling compound of formula II or a pharmaceutically acceptable salt thereof with N-methoxylcarbony-L-valine (N-Moc-L-valine). This reaction may be carried out with a base and a coupling agent in the presence of a suitable solvent.
Within the context of this embodiment, the base may be, for example, N-methylmorpholine (NMM), N,N-diisopropylethylamine, triethylamine, N,N’-dimethylpiperazine, N-methylpiperidine, pyridine, or mixtures thereof. In particularly useful embodiments, N-methylmorpholine is used as a base. One of skill in the art will recognize numerous bases that may be useful for this reaction.
Within the context of this embodiment, the coupling agent may be, for example, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), isobutyl chloroformate, carbonyldiimidazole (CDI), pivaloyl chloride, o-benzotriazole-l-yl-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium (HBTU), benzotriazole-1-y 1-oxy-tris(dimethylamino)phosphonium (BOP), benzotriazole-l-yl-oxy-tris(pyrrolidino) phosphonum (PyBOP), bromo-tris-pyrrolidino-phosphoniumhexaflurophosphate (PyBrOP), tris(pyroolidino)phosphonium hexaflurophosphate (pyCOP), ethyl cyanoglyoxyIate-2-oxime, o-(6-chloro-l-hydroxybenzotriazol-l-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TCTU), 2-(lH-7-azabenzotriazol-l-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU), l-cyano-2-ethoxy-2-oxoethydenminooxy)dimethylamino-morpholion-carbenium hexafluorophosphate (COMU), or mixtures thereof. In particularly useful embodiments, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) is used as a coupling agent. One of skill in the art will recognize numerous additional coupling agents that may be useful for this reaction.
Within the context of this embodiment, examples of suitable solvents include polar aprotic solvents such as ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, acetone, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide and mixtures thereof. In particularly useful embodiments, N,N-dimethylformamide is used as a solvent.
Optionally, an additive may be also be used in this reaction. Within the context of this embodiment, the additive may enhance the reaction, for example, to increase the rate of the reaction or to control the product distribution.
Within the context of this embodiment, the additive may be, for example, hydroxyl benzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 6-chloro-1-hydroxy-1H-benzotriazole (Cl-HOBt), hydroxypyridines (HOPy), imidazole or its salts, 1,8-diazabicyclo[5.4.0]undec-7-en (DBU), dimethylaminopyridine (DMAP), or mixtures thereof.
In some embodiments, if compound of formula II was converted to a pharmaceutically acceptable salt of compound of formula II, a pharmaceutically acceptable salt of daclatasvir may be prepared by coupling of N-Moc-L-valine to the pharmaceutically acceptable salt of compound of formula II. In other embodiments, the free base form of daclatasvir may be formed from a pharmaceutically acceptable salt of compound of formula II. The reaction conditions and the particular choice of pharmaceutically acceptable salt will dictate the final daclatasvir product formed.
In some embodiments, the free-base form of daclatasvir may be optionally converted into a pharmaceutically acceptable salt of daclatasvir.
The term “pharmaceutically acceptable salt” is well known and understood in the art and refers to salts of pharmaceutically active agents which are suitable for use in contact with the tissues of humans and lower animals without undue adverse effects (e.g., toxicity, irritation, allergic response). Examples of pharmaceutically acceptable salts may be found in S. M. Berge, et al., J. Pharmaceutical Sciences, 66: 1-19 (1977), in which all information pertaining to the pharmaceutically acceptable salts and processes for preparation thereof are hereby incorporated by reference.

Preparation of a pharmaceutically acceptable salt of an active pharmaceutical agent is well known in the art. For example, the salts can be prepared in situ during the final isolation and purification of the compounds taught herein or separately by reacting a free base or free acid moiety on the active pharmaceutical agent with a suitable reagent. For example, a free base moiety on daclatasvir can be reacted with a suitable acid to obtain a pharmaceutically acceptable salt of daclatasvir.

Pharmaceutically acceptable salts of daclatasvir include, acid salts include, for example, mineral acid salts such as hydrochloride, sulfates salts, nitrate salts, phosphates salts, carbonates salts, hydrogencarbonates or perchlorate; organic acid salts such as acetates, propionates, lactates, maleates, fumarates, tararic acid salts, malates, citrates salts, ascorbates, formic acid; sulfonates such as methanesulfonates, isethionates, benzenesulfonates, or p-toluenesulfonates; and acidic amino acid salts such as aspartates or glutamates. In some embodiments, the dihydrochloride salt of daclatasvir is formed.
In particularly useful embodiments, the leaving group “LG' moiety of compound of formula IX is Br, the leaving group LG and LG'' moieties of formulas IX, VIII, VI, and V are Br, and the protecting group “P” of formulas VII, V, IV, and II are each tert-butoxy carbonyl (Boc) groups. Scheme I below represents this particular embodiment.

Scheme I
Suitable reaction conditions for Scheme I include all the conditions outlined above for the conversion of biphenyl through general formulas X, VIII, VII, optionally VI, V, IV, III, II, resulting in compound of formula I (daclatasvir). The nomenclature used in Scheme I is simply the formula as disclosed above followed by “a”, denoting a particular choice of leaving group or protecting group. For example, formula IXa is formula IX wherein LG=LG'=Br.
In some embodiments, the following described conditions are found particularly useful.
In particularly useful embodiments, compound of formula X is reacted with bromoacetyl bromide (compound of formula IXa) in the presence of AlCl3 and dichloromethane.
In particularly useful embodiments, wherein the conversion of compound of formula VIIa to compound of formula Va is direct, compound of formula VIIa is reacted with pyridinium tribromide in a mixture of methanol and dichloromethane at a temperature of 25 °C-35 °C for a period of 50 minutes to 70 minutes to get compound of formula Va.
In particularly useful embodiments, wherein the conversion of compound of formula VIIa to compound of formula Va is indirect, compound of formula VIIa is reacted with pyridinium tribromide in a mixture of methanol and dichloromethane at a temperature of 25 °C-35 °C for a period of 22 hours to 26 hours to get compound of formula VIa. The compound of formula VIa is then reacted with di-t-butyl dicarbonate (Boc anhydride) in the presence of triethylamine and dichloromethane at a temperature of 25 °C-35 °C for a period of 4 hours to 6 hours to get compound of formula Va.
In some embodiments, the conversion of compound of formula IVa to compound of formula IIIa is carried out at a temperature of 85 °C-110 °C for a period of 10 hours to 20 hours.
In some embodiments, deprotection of compound of formula IIIa to get compound of formula II is carried out using methanolic HCl.
Another aspect of the present invention provides compound of formula VII and compound of formula VI, which can be used as intermediates in the preparation of daclatasvir or pharmaceutically acceptable salts thereof.

In formula VII and formula VI, “LG” ” and “P” are as defined above.
In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules, compositions, and formulations according to the present invention. All references made to these examples for the purpose of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present invention.
EXAMPLES
Example 1: Preparation of 1-(biphenyl-4-yl)ethanone (formula X):
A reaction vessel was charged with AlCl3 (9.5 g) followed by dichloromethane (60 mL). The suspension was cooled to about -10 °C and acetyl chloride (7.12 g) was added to the reaction mixture over 30 minutes while maintaining the internal temperature at below about -5 °C. The reaction mixture was stirred at the same temperature for an additional 30 minutes and then a solution of biphenyl (10.0 g) in dichloromethane (30 mL) was added over a period of 60 minutes while maintaining the internal temperature at below about -5 °C. The resulting reaction mixture was stirred for an additional 60 minutes at the same temperature and upon reaction completion (monitored by TLC), the reaction was quenched into ice cold water (100 mL). The resulting aqueous reaction mass was extracted with dichloromethane (100 mL), the organic layer was concentrated, and the desired compound 1-(biphenyl-4-yl)ethanone was isolated as a solid with the aid of hexanes.
Yield: 10.0 g
Example 2: Preparation of 1-(4'-acetylbiphenyl-4-yl)-2-bromoethanone (formula VIIIa):
A reaction vessel was charged with AlCl3 (84.7 g) followed by dichloromethane (65 mL). The suspension was cooled to about -10 °C and bromoacetyl bromide (Formula IXa, 154.3 g) was added to the reaction over 30 minutes while maintaining the internal temperature at below about -5 °C. The reaction mixture was stirred at the same temperature for an additional 30 minutes and then a solution of 1-(biphenyl-4-yl)ethanone (50.0 g) in dichloromethane (65 mL) was added over a period of 60 minutes by maintaining the internal temperature at below about -5 °C. The resulting reaction mixture was stirred for an additional 180 minutes at the same temperature. Upon reaction completion (monitored by TLC), the reaction was quenched into ice cold water (2000 mL). The resulting aqueous reaction mass was extracted with dichloromethane (2000 mL). The organic layer was washed with 10% aqueous sodium bicarbonate solution (100 mL), followed by water (100 mL), and was then concentrated. The desired compound 1-(4'-acetylbiphenyl-4-yl)-2-bromoethanone was isolated as a solid with the aid of isopropyl ether.
Yield: 60.0 g

Example 3: Preparation of 2-[2-(4'-acetylbiphenyl-4-yl)-2-oxoethyl] 1-tert-butyl pyrrolidine-1,2-dicarboxylate (formula VIIa):
A reaction vessel was charged with 1-(4'-acetylbiphenyl-4-yl)-2-bromoethanone (formula VIIIa, 50.0 g), N-Boc-L-proline (34.3 g), and acetonitrile (500 mL). Disopropylethylamine (20.8 g) was added to the reaction mixture over a period of 30 minutes at ambient temperature and the mixture was stirred for about 18 hours at the same temperature. Upon completion of the reaction, as monitored by TLC, ethyl acetate (400 mL) and 15% aqueous sodium chloride solution (400 mL) was added to the reaction mass. The organic layer was separated and concentrated under vacuum. The desired product was isolated as a solid with the aid of isopropyl ether (400 mL).
Yield: 60.0 g
1HNMR: (300 MHz, CDCl3) d 1.45-1.47, (s, 9H), 1.91-2.12 (m, 2H), 2.27-2.38 (m, 2H), 3.39-3.64 (m, 2H), 4.41-4.53 (m, 1H), 5.22-5.65 (m, 2H), 7.67-7.80 (m, 4H), 7.99-8.08 (m, 4H).

Example 4: Preparation of 2-[2-(4'-(bromoacetyl)biphenyl-4-yl]-2-oxoethyl prolinate hydrobromide (HBr salt of formula VIa)
A reaction vessel was charged with 2-[2-(4'-acetylbiphenyl-4-yl)-2-oxoethyl] 1-tert-butyl pyrrolidine-1,2-dicarboxylate (formula VIIa, 20.0 g), methanol (80 mL), and dichloromethane (120 mL) at 25 – 35 °C. Pyridinium tribromide (14.2 g) was added to the reaction mass and stirred at the same temperature for about 24 hours. Upon completion of the reaction (as monitored by TLC), the reaction mass was filtered to obtain a product which was washed with dichloromethane (50 mL).
Yield: 13.0 g
1HNMR: (300 MHz, DMSO) d 1.96-2.06, (m, 2H), 2.19-2.29 (m, 1H), 2.36-2.41 (m, 1H), 3.27-3.29 (m, 2H), 4.66 (br, 1H), 5.003 (s, 2H), 5.70-5.88 (q 2H), 7.92-8.01 (m, 4H), 8.11-8.15 (m, 4H), 9.02 (br, 1H), 9.55 (br, 1H).
Example 5: Preparation of 2-{2-[4'-(bromoacetyl)biphenyl-4-yl]-2-oxoethyl} 1-tert-butyl pyrrolidine-1,2-dicarboxylate (formula Va)
A reaction vessel was charged with 2-[2-(4'-(bromoacetyl)biphenyl-4-yl]-2-oxoethyl prolinate hydrobromide (Formula VIa, 1.0 g), dichloromethane (10 mL), and triethylamine (0.48 g) at 25 – 35 °C. Boc anhydride (0.56 g) was added to the reaction mixture at 25 – 35 °C and the contents were stirred at the same temperature for about 6 hours. Upon completion of the reaction (as monitored by TLC), the reaction mass was washed with water and concentrated to yield crude 2-{2-[4'-(bromoacetyl)biphenyl-4-yl]-2-oxoethyl} 1-tert-butyl pyrrolidine-1,2-dicarboxylate.

Example 6: Preparation of 2-{2-[4'-(bromoacetyl)biphenyl-4-yl]-2-oxoethyl} 1-tert-butyl pyrrolidine-1,2-dicarboxylate (formula Va)
A reaction vessel was charged with 2-[2-(4'-acetylbiphenyl-4-yl)-2-oxoethyl] 1-tert-butyl pyrrolidine-1,2-dicarboxylate (formula VIIa, 20.0 g), methanol (80 mL), and dichloromethane (120 mL) at 25 – 35 °C. Pyridinium tribromide (14.2 g) was added to the reaction mass and stirred at the same temperature for about 60 minutes. Upon completion of the reaction (as monitored by TLC), the reaction mixture was diluted with dichloromethane (100 mL), washed with water, and concentrated under vacuum to afford crude 2-{2-[4'-(bromoacetyl)biphenyl-4-yl]-2-oxoethyl} 1-tert-butyl pyrrolidine-1,2-dicarboxylate.

Example 7: Preparation of 2,2'-[biphenyl-4,4'-diylbis(2-oxoethane-2,1-diyl)] 1,1'-di-tert-butyl dipyrrolidine-1,2-dicarboxylate (formula IVa)
A reaction vessel was charged with 2-{2-[4'-(bromoacetyl)biphenyl-4-yl]-2-oxoethyl} 1-tert-butyl pyrrolidine-1,2-dicarboxylate (formula Va, 50.0 g), N-boc-L-proline (22.3 g), and acetonitrile (500 mL). Diisopropylethylamine (13.4 g) was added to the reaction mixture over a period of 30 minutes at ambient temperature and the mixture was stirred for about 4 hours at the same temperature. Upon completion of the reaction, as monitored by TLC, ethyl acetate (400 mL) and 15% aq. sodium chloride solution (400 mL) were added to the reaction mass. The organic layer was separated and concentrated under vacuum. The desired product was isolated as a solid with the aid of isopropyl ether (400 mL).
Yield: 30.0 g
Example 8: Preparation of di-tert-butyl (2S,2'S)-2,2'-[biphenyl-4,4'-diylbis(1H-imidazole-5,2-diyl)]dipyrrolidine-1-carboxylate (formula IIIa)
A reaction vessel was charged with 2,2'-[biphenyl-4,4'-diylbis(2-oxoethane-2,1-diyl)] 1,1'-di-tert-butyl dipyrrolidine-1,2-dicarboxylate (formula IVa, 50.0 g), ammonium acetate (115.9 g), and toluene (750 mL). The reaction mass was stirred and the temperature was raised to reflux and stirring continued for about 18 hours. Upon completion of the reaction (as monitored by TLC), the reaction mass was cooled to below about 60 °C and toluene (~400 mL) was distilled off under vacuum. After distillation, ethyl acetate (600 mL) and 5% aqueous acetic acid (600 mL) were added. Stirring was continued for an additional 3 hours. The solution was filtered and the resulting solid washed with ethyl acetate (200 mL) to afford di-tert-butyl (2S,2'S)-2,2'-[biphenyl-4,4'-diylbis(1H-imidazole-5,2-diyl)]dipyrrolidine-1-carboxylate.
Yield: 100 g
Example 9: Preparation of 5,5'-biphenyl-4,4'-diylbis{2-[(2S)-pyrrolidin-2-yl]-1H-imidazole} tetrahydrochloride (tetrahydrochloride salt of formula II)
A reaction vessel was charged with di-tert-butyl (2S,2'S)-2,2'-[biphenyl-4,4'-diylbis(1H-imidazole-5,2-diyl)]dipyrrolidine-1-carboxylate (formula IIIa, 220.0 g), methanol (660 mL), and methanolic HCl (on 100% assay of HCl) (82.25 g) at 25 – 35 °C. The internal temperature of the reaction mixture was raised to about 60 °C and stirring continued for 6 hours. Upon completion of the reaction, as monitored by TLC, ~300 mL of methanol was distilled off from the reaction mass which was subsequently cooled to 25 – 35 °C. The solution was stirred for an additional 5 hours at 25 – 35 °C and filtered to yield 5,5'-biphenyl-4,4'-diylbis{2-[(2S)-pyrrolidin-2-yl]-1H-imidazole} tetrahydrochloride (tetrahydrochloride salt of formula II) as a solid.
Yield: 120.0 g

Example 10: Preparation of daclatasvir dihydrochloride

A reaction vessel was charged with N-Moc-L-valine (183.9 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (tetrahydrochloride salt of formula II, 132.85 g), hydroxybenzotriazole (93.3 g), and dimethylformamide (960 mL) at 25 – 35 °C. The reaction mixture was cooled to about -10 °C and added N-methylmorpholine (140.19 g) over a period of about 60 minutes. The reaction mixture was stirred for additional 60 minutes at the same temperature and 5,5'-biphenyl-4,4'-diylbis{2-[(2S)-pyrrolidin-2-yl]-1H-imidazole} tetrahydrochloride (tetrahydrochloride salt of formula II, 120.0 g) was added in portions so as to maintain the internal temperature at below -5 °C. After the addition, the resulting reaction mixture was warmed to 25 – 35 °C and stirred for 6 hours. Upon completion of the reaction (as monitored by TLC), the reaction mixture was quenched into water (3 L, held at below 20 °C) and the pH was adjusted to 6.0-7.0 with aqueous sodium bicarbonate solution. The reaction mass was then extracted with ethyl acetate (2 x 600 mL). The organic layer was washed with water (2 x 600 mL) and then concentrated under vacuum to afford daclatasvir free base.
The daclatasvir free base was taken in ethanol (480 mL) and added with HCl in isopropyl alcohol (129.86 g) at about 40°C and stirred for about 6 hours. The resulting suspension was cooled to 25 – 35 °C and stirring continued for an additional 12 hours. The reaction mass was filtered and the solid was washed with ethanol (120 mL) to yield daclatasvir dihydrochloride as a solid.
Yield: 120.0 g

,CLAIMS:What is claimed is:
1. A process for the preparation of daclatasvir or its pharmaceutically acceptable salts, comprising the steps of:
a. acetylating biphenyl by reacting with acetylating agent to get compound of formula X;

b. reacting the compound of formula X with a compound of formula IX to get a compound of formula VIII;

c. reacting the compound of formula VIII with N-protected-L-proline to obtain a compound of formula VII;

d. converting the compound of formula VII to compound of formula V;

e. reacting the compound of formula V with N-protected-L-proline to obtain a compound of formula IV;

f. converting the compound of formula IV to obtain a compound of formula III;

g. deprotecting the compound of formula III to get a compound of formula II or its pharmaceutically acceptable salt; and

h. coupling the compound of formula II or its pharmaceutically acceptable salt with N-Moc-L-valine to get daclatasvir of formula I

wherein LG, LG', and LG'' are leaving groups and P is an amine protecting group.
2. The process according to claim 1, wherein LG, LG' and LG'' are independently selected from the group consisting of sulfonate and halo group, and P is selected from the group consisting of acyl group, sulfonyl group, and carbamate-forming group.
3. The process according to claim 1, wherein the acylating step and the reacting compound of formula X with compound of formula IX step are performed in the presence of a Lewis acid.
4. The process according to claim 1, wherein the converting of compound of formula VII to compound of formula V is carried out by converting the compound of formula VII to compound of formula VI and then converting compound of formula VI to compound of formula V.

5. The process according to claim 1, wherein the converting compound of formula IV to compound of formula III is carried out in the presence of a reagent selected from the group consisting of ammonium acetate, ammonium formate, ammonium sulfamate, ammonium phosphate, ammonium citrate, ammonium carbamate, ammonia, and mixtures thereof.
6. The process according to claim 1, wherein deprotection of compound of formula III is carried out using a deprotecting agent, which is selected from the group consisting of HCl, H2SO4, HNO3, trimethylsilyl iodide, morpholine, and mixtures thereof.
7. The process according to claim 1, wherein coupling of compound of formula II with N-Moc-L-valine is performed in the presence of a coupling agent, which is selected from 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), isobutyl chloroformate, carbonyldiimidazole (CDI).
8. A process for the preparation of formula VII, comprising:
a. acetylating biphenyl with an acetylating agent to get formula X;

b. reacting formula X with formula IX to get formula VIII; and

c. treating formula VIII with N-protected-L-proline to obtain formula VII.

wherein LG and LG’ are leaving groups and P is an amine protecting group.

9. Compounds of formula VII and formula VI

wherein P is an amine protecting group and LG'' is a leaving group .

10. Process for preparing daclatasvir or its pharmaceutically acceptable salts substantially as herein described with reference to foregoing examples.