WO2016178250A1 - Procédé de préparation de daclatasvir - Google Patents

Procédé de préparation de daclatasvir Download PDF

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WO2016178250A1
WO2016178250A1 PCT/IN2016/050128 IN2016050128W WO2016178250A1 WO 2016178250 A1 WO2016178250 A1 WO 2016178250A1 IN 2016050128 W IN2016050128 W IN 2016050128W WO 2016178250 A1 WO2016178250 A1 WO 2016178250A1
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formula
compound
group
solvent
process according
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PCT/IN2016/050128
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Lakshmanarao VADALI
Srinivasarao DASARI
Swamy Saidugari
Seshadrirao MANUKONDA
Nagaraju Mittapelly
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Mylan Laboratories Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

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  • 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.
  • 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'-[[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'-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.
  • the present invention provides a process for the preparation of daclatasvir or its pharmaceutically acceptable salts, which may include the following steps: a. acet lating biphenyl by reacting with acetylating agent to get a compound of formula X;
  • LG, LG', and LG" are leaving groups and P is an amine protecting group.
  • 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.
  • suitable sulfonate leaving groups include tosylate, mesylate, and benzyl sulfonate.
  • suitable halo groups include chloro, bromo, and iodo.
  • 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.
  • suitable sulfonyl protecting groups include benzenesulfonyl and p-toluenesulfonyl groups.
  • suitable carbamate-forming protecting groups include benzyloxycarbonyl, benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), p-chlorobenzyloxycarbonyl, and p-methoxybenzyloxycarbonyl groups.
  • LG, LG' and LG" are bromide and P is a tert- butyloxycarbonyl (Boc) group.
  • step a) and step b) may be performed in the presence of a Lewis acid.
  • Lewis acids examples include BF 3 , MgBr 2 , SnCl 4 , TiCl 4 , FeCl 3 , A1C1 3 , CH 3 A1C1 2 , (CH 3 ) 2 A1C1, LiC10 4 , and mixtures thereof.
  • step c) and step e) may be performed in the presence of a base and a solvent.
  • 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.
  • 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, bromotrichlorome thane, pyridinium tribromide, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, benzyltrimethyl ammoniumtribromide, bromodimethylsulfonium bromide, l-butyl-3-methylimidazolium tribromide, 1,2-dibromo- 1 , 1 ,2,2-tetrachloroethane, 4-dimethylaminopyridinium bromide perbromide, 2,4,4,6-tetrabromo- 2,5-
  • the solvent may be, for example, an alcohol solvent, an ester solvent, an ether solvent, a chlorinated hydrocarbon solvent, or mixtures thereof.
  • 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.
  • compound of formula VII may be treated with a brominating agent in the presence of a solvent to result in compound of formula VI.
  • brominating agents include boron tribromide, phosphorus tribromide, carbon tetrabromide, bromine, N-bromoacetamide, N-bromophthalimide, N-bromosuccinimide, bromotrichlorome thane, pyridinium tribromide, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, benzyltrimethyl ammoniumtribromide, bromodimethylsulfonium bromide, l-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.
  • 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.
  • 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.
  • deprotection of the compound of formula III may be carried out using a deprotecting agent in the presence of solvent.
  • suitable deprotecting agents include HCl, H 2 SO 4 , HNO 3 , trimethylsilyl iodide, morpholine, and mixtures thereof.
  • the solvent may be, for example, an alcohol solvent, an ester solvent, or mixtures thereof.
  • 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, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), isobutyl chloroformate, carbonyldiimidazole (CDI), pivaloyl chloride, o-benzotriazole-1- yl-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium (HBTU), benzotriazole-l-y l-oxy-tris(dimethylamino)phosphonium (BOP), benzotriazole-l-yl-oxy-tris(pyrrolidino) phosphonum (PyBOP), bromo-tris-pyrrolidino- phosphoniumhexaflurophosphate (PyBrOP), tris(pyroolidino)phosphonium
  • the solvent may be a polar aprotic solvent, for example, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, acetone, ⁇ , ⁇ -dimethylformamide, acetonitrile, dimethyl sulfoxide, or mixtures thereof.
  • daclatasvir may be converted into a pharmaceutically acceptable salt of daclatasvir.
  • 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.
  • the present invention provides novel synthetic schemes for the synthesis of daclatasvir.
  • 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.
  • daclatasvir or pharmaceutically acceptable salts thereof may be prepared by the following steps: a) acetylating biphenyl to get a compound of formula X;
  • the LG, LG' and LG" moieties are leaving groups and the P moiety is an amine protecting group.
  • leaving group is well-known and understood in the art.
  • 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
  • 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.
  • aryl 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.
  • aryl groups include phenyl, napthyl, anthracenyl, and fluorenyl.
  • amine protecting group is well known and understood in the art.
  • 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)
  • 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.
  • the acetylating agent may be, for example, acetyl chloride, acetyl bromide, acetic anhydride, or mixtures thereof.
  • the Lewis acid may be, for example, BF 3 , MgBr 2 , SnCl 4 , TiCl 4 , FeCl 3 , A1C1 3 , CH 3 A1C1 2 , (CH 3 ) 2 A1C1, LiC10 4 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.
  • biphenyl is reacted with acetyl chloride in the presence of AICI 3 and dichloromethane.
  • AICI 3 and dichloromethane One of the skill in the art will recognize numerous acetylating agents and Lewis acids that may be useful for acetylating biphenyl.
  • 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.
  • the Lewis acid may be, for example, BF 3 , MgBr 2 , SnCl 4 , TiCl 4 , FeCl 3 , A1C1 3 , CH 3 A1C1 2 , (CH 3 ) 2 A1C1, LiC10 4 , 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.
  • 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.
  • the base may be organic or inorganic.
  • suitable organic bases include pyridine, imidazole, methyl amine, N,N-diisopropylethylamine, triethylamine, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, and mixtures thereof.
  • suitable inorganic bases include alkali metal hydroxides, alkali metal carbonates, and mixtures thereof.
  • ⁇ , ⁇ -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.
  • the solvent may be a polar aprotic solvent.
  • suitable polar aprotic solvents include acetonitrile, dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetone, N-methylpyrrolidone, and mixtures thereof.
  • 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.
  • 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.
  • 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.
  • 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, l-butyl-3-methylimidazolium tribromide, l,2-dibromo-l,l,2,2-tetrachloroethane, 4-dimethylaminopyridinium bromide perbromide, and 2,4,4, 6-tetrabromo-2,5-cyclohexadienone.
  • pyridinium tribromide was found to be a particularly useful
  • Suitable solvents include, for example, alcohol solvents, ester solvents, ether solvents, chlorinated hydrocarbon solvents, and mixtures thereof.
  • suitable alcohol solvents include methanol, ethanol, isopropyl alcohol, and mixtures thereof.
  • suitable ester solvents include ethyl acetate, isopropyl acetate, and mixtures thereof.
  • suitable ether solvents include tetrahydrofuran, isopropyl ether, and mixtures thereof.
  • a suitable chlorinated hydrocarbon solvent is dichloromethane. In particular embodiments, a mixture of methanol and dichloromethane is used as a solvent. Indirect conversion
  • 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.
  • 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, l-butyl-3-methylimidazolium tribromide, l,2-dibromo-l,l,2,2-tetrachloroethane, 4-dimethylaminopyridinium bromide perbromide, and 2,4,4, 6-tetrabromo-2,5-cyclohexadienone.
  • pyridinium tribromide was found to be a particularly useful bromin
  • Suitable solvents include, for example, alcohol solvents, ester solvents, ether solvents, chlorinated hydrocarbon solvents, and mixtures thereof.
  • suitable alcohol solvents include methanol, ethanol, isopropyl alcohol, and mixtures thereof.
  • suitable ester solvents include ethyl acetate, isopropyl acetate, and mixtures thereof.
  • suitable ether solvents include tetrahydrofuran, isopropyl ether, and mixtures thereof.
  • a suitable chlorinated hydrocarbon solvent is dichloromethane. In particular embodiments, a mixture of methanol and dichloromethane is used as a solvent.
  • 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.
  • the base may be organic or inorganic.
  • suitable organic bases include pyridine, imidazole, methyl amine, diisopropyl ethyl amine, triethylamine, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, and mixtures thereof.
  • suitable inorganic bases include alkali metal hydroxides, alkali metal carbonates, and mixtures thereof.
  • 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.
  • suitable alcohol solvents include methanol, ethanol, isopropyl alcohol, and mixtures thereof.
  • suitable ester solvents include ethyl acetate, isopropyl acetate, and mixtures thereof.
  • suitable ether solvents include tetrahydrofuran, isopropyl ether, and mixtures thereof.
  • a suitable chlorinated hydrocarbon solvent is dichloromethane. In particular embodiments, a mixture of methanol and dichloromethane is used as a solvent.
  • the base may be organic or inorganic.
  • organic bases include pyridine, imidazole, methyl amine, diisopropyl ethyl amine, triethylamine, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, and mixtures thereof.
  • inorganic bases include alkali metal hydroxides, alkali metal carbonates, and mixtures thereof.
  • diisopropylethylamine was used as a base.
  • the solvent may be a polar aprotic solvent, for example, acetonitrile, dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetone, N-methylpyrrolidone, or mixtures thereof.
  • 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.
  • compound of formula IV may next be converted to compound of formula III.
  • 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.
  • 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.
  • 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.
  • formula IV is treated with ammonium acetate in toluene.
  • 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.
  • an ester solvent such as ethyl acetate, isopropyl acetate, or mixtures thereof
  • an organic carboxylic acid solvent such as acetic acid, or mixtures thereof.
  • 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.
  • many protecting groups may be removed by hydrogenolysis or through the use of an acid or a base.
  • suitable acids include mineral acids such as HC1, H 2 SO 4 , and HNO 3 .
  • Other agents that may be used as a deprotecting agent may be, for example, trimethylsilyl iodide or morpholine.
  • suitable solvents may include alcohol solvents, ester solvents, and mixtures thereof.
  • suitable alcohol solvents include methanol, ethanol, isopropyl alcohol, and mixtures thereof.
  • suitable ester solvents include, for example, ethyl acetate, isopropyl acetate, and mixtures thereof.
  • compound of formula II may be converted to a pharmaceutically acceptable salt of compound of formula II.
  • 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.
  • 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).
  • N-Moc-L-valine N-methoxylcarbony-L-valine
  • This reaction may be carried out with a base and a coupling agent in the presence of a suitable solvent.
  • the base may be, for example, N-methylmorpholine (NMM), ⁇ , ⁇ -diisopropylethylamine, triethylamine, ⁇ , ⁇ '-dimethylpiperazine, N- methylpiperidine, pyridine, or mixtures thereof.
  • NMM N-methylmorpholine
  • ⁇ , ⁇ -diisopropylethylamine triethylamine
  • ⁇ , ⁇ '-dimethylpiperazine N- methylpiperidine
  • pyridine or mixtures thereof.
  • N- methylmorpholine is used as a base.
  • the coupling agent may be, for example, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), isobutyl chloroformate, carbonyldiimidazole (CDI), pivaloyl chloride, o-benzotriazole-l-yl-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2- (lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium (HBTU), benzotriazole-l-y 1-oxy- tris(dimethylamino)phosphonium (BOP), benzotriazole-l-yl-oxy-tris(pyrrolidino) phosphonum (PyBOP), bromo-tris-pyrrolidino-phosphoniumhexaflurophosphate (PyBrOP), tris(pyroolidino)phosphon
  • EDC l
  • l-ethyl-3-(3- dimethylaminopropyl)carbodiimide is used as a coupling agent.
  • EDC l-ethyl-3-(3- dimethylaminopropyl)carbodiimide
  • suitable solvents include polar aprotic solvents such as ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, acetone, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide and mixtures thereof.
  • polar aprotic solvents such as ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, acetone, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide and mixtures thereof.
  • ⁇ , ⁇ -dimethylformamide is used as a solvent.
  • an additive may be also be used in this reaction.
  • the additive may enhance the reaction, for example, to increase the rate of the reaction or to control the product distribution.
  • the additive may be, for example, hydroxyl benzotriazole (HOBt), l-hydroxy-7-azabenzotriazole (HO At), 6-chloro-l -hydroxy- lH-benzotriazole (Cl- HOBt), hydroxypyridines (HOPy), imidazole or its salts, l,8-diazabicyclo[5.4.0]undec-7-en (DBU), dimethylaminopyridine (DMAP), or mixtures thereof.
  • HOBt hydroxyl benzotriazole
  • HO At l-hydroxy-7-azabenzotriazole
  • Cl- HOBt 6-chloro-l -hydroxy- lH-benzotriazole
  • HPy hydroxypyridines
  • imidazole or its salts imidazole or its salts
  • DBU dimethylaminopyridine
  • DMAP dimethylaminopyridine
  • 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.
  • 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.
  • the free-base form of daclatasvir may be optionally converted into a pharmaceutically acceptable salt of daclatasvir.
  • 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.
  • a pharmaceutically acceptable salt of an active pharmaceutical agent is well known in the art.
  • 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.
  • a free base moiety on daclatasvir can be reacted with a suitable acid to obtain a pharmaceutically acceptable salt of daclatasvir.
  • compositions 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.
  • the dihydrochloride salt of daclatasvir is formed.
  • 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
  • the protecting group "P” of formulas VII, V, IV, and II are each tert-butoxy carbonyl (Boc) groups.
  • 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.
  • compound of formula X is reacted with bromoacetyl bromide (compound of formula IXa) in the presence of A1C1 3 and dichloromethane.
  • compound of formula Vila 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.
  • compound of formula Vila 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.
  • Boc anhydride di-t-butyl dicarbonate
  • the conversion of compound of formula IVa to compound of formula Ilia is carried out at a temperature of 85 °C-110 °C for a period of 10 hours to 20 hours.
  • deprotection of compound of formula Ilia to get compound of formula II is carried out using methanolic HC1.
  • 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.
  • Example 1 Preparation of l-(biphenyl-4-yl)ethanone (formula X): A reaction vessel was charged with A1C1 3 (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.
  • a reaction vessel was charged with AICI 3 (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.
  • 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 l-(4'- acetylbiphenyl-4-yl)-2-bromoethanone was isolated as a solid with the aid of isopropyl ether.
  • a reaction vessel was charged with 2-[2-(4'-acetylbiphenyl-4-yl)-2-oxoethyl] 1-tert-butyl pyrrolidine- 1 ,2-dicarboxylate (formula Vila, 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
  • 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.
  • a reaction vessel was charged with 2-[2-(4'-acetylbiphenyl-4-yl)-2-oxoethyl] 1-tert-butyl pyrrolidine- 1 ,2-dicarboxylate (formula Vila, 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.
  • 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.
  • 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.
  • 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).
  • reaction vessel was charged with 2,2'-[biphenyl-4,4'-diylbis(2-oxoethane-2,l-diyl)] 1, l'-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.
  • the reaction mass was cooled to below about 60 °C and toluene (-400 mL) was distilled off under vacuum.
  • a reaction vessel was charged with di-tert-butyl (2S,2'S)-2,2'-[biphenyl-4,4'-diylbis(lH- imidazole-5,2-diyl)]dipyrrolidine-l-carboxylate (formula Ilia, 220.0 g), methanol (660 mL), and methanolic HC1 (on 100% assay of HC1) (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.
  • a reaction vessel was charged with N-Moc-L-valine (183.9 g), l-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.
  • reaction mixture was stirred for additional 60 minutes at the same temperature and 5,5'-biphenyl-4,4'-diylbis ⁇ 2-[(2S)-pyrrolidin-2-yl]-lH-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 HC1 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.

Abstract

La présente invention concerne un nouveau procédé de préparation de daclatasvir et de ses sels pharmaceutiquement acceptables, utilisant de nouveaux intermédiaires. Formule (I)
PCT/IN2016/050128 2015-05-07 2016-05-05 Procédé de préparation de daclatasvir WO2016178250A1 (fr)

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WO2018007984A1 (fr) * 2016-07-08 2018-01-11 Lupin Limited Formes cristallines du dichlorhydrate de daclatasvir
WO2018167546A1 (fr) * 2017-03-13 2018-09-20 Optimus Drugs Pvt Ltd Procédé amélioré de préparation de dichlorhydrate de daclatasvir
CN109503557A (zh) * 2018-12-29 2019-03-22 常州吉恩药业有限公司 一种达卡他韦关键中间体的工业化生产方法
CN110878090A (zh) * 2019-12-09 2020-03-13 南通常佑药业科技有限公司 Ns5a蛋白抑制剂-达卡他韦的一锅法制备工艺
US11344858B2 (en) 2019-05-02 2022-05-31 Council Of Scientific & Industrial Research Micro-electrolysis reactor for ultra fast, oxidant free, C—C coupling reaction and synthesis of daclatasvir analogs thereof

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Publication number Priority date Publication date Assignee Title
WO2018007984A1 (fr) * 2016-07-08 2018-01-11 Lupin Limited Formes cristallines du dichlorhydrate de daclatasvir
WO2018167546A1 (fr) * 2017-03-13 2018-09-20 Optimus Drugs Pvt Ltd Procédé amélioré de préparation de dichlorhydrate de daclatasvir
US10392370B2 (en) 2017-03-13 2019-08-27 Optimus Drugs Pvt Ltd Process for the preparation of Daclatasvir dihydrochloride and its intermediates
CN109503557A (zh) * 2018-12-29 2019-03-22 常州吉恩药业有限公司 一种达卡他韦关键中间体的工业化生产方法
US11344858B2 (en) 2019-05-02 2022-05-31 Council Of Scientific & Industrial Research Micro-electrolysis reactor for ultra fast, oxidant free, C—C coupling reaction and synthesis of daclatasvir analogs thereof
CN110878090A (zh) * 2019-12-09 2020-03-13 南通常佑药业科技有限公司 Ns5a蛋白抑制剂-达卡他韦的一锅法制备工艺
CN110878090B (zh) * 2019-12-09 2022-04-12 南通常佑药业科技有限公司 Ns5a蛋白抑制剂-达卡他韦的一锅法制备工艺

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