WO2013016499A1 - Procédés de préparation de composés du thiophène - Google Patents

Procédés de préparation de composés du thiophène Download PDF

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Publication number
WO2013016499A1
WO2013016499A1 PCT/US2012/048270 US2012048270W WO2013016499A1 WO 2013016499 A1 WO2013016499 A1 WO 2013016499A1 US 2012048270 W US2012048270 W US 2012048270W WO 2013016499 A1 WO2013016499 A1 WO 2013016499A1
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WIPO (PCT)
Prior art keywords
compound
palladium
yne
dimetylbut
mol
Prior art date
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PCT/US2012/048270
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English (en)
Inventor
Valdas Jurkauskas
Piero L. RUGGIERO
Stefanie Roeper
David Willcox
Michael Waldo
Dahrika Milfred Yap GUERETTE
Billie J. KLINE
Hoa Q. Luong
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Vertex Pharmaceuticals Incorporated
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Application filed by Vertex Pharmaceuticals Incorporated filed Critical Vertex Pharmaceuticals Incorporated
Publication of WO2013016499A1 publication Critical patent/WO2013016499A1/fr
Priority to US14/163,036 priority Critical patent/US20140206888A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the entire teachings of these applications are incorporated herein by reference.
  • HCV Hepatitis C virus
  • HCV is believed to replicate through the production of a complementary negative-strand RNA template. Due to the lack of efficient culture replication system for the virus, HCV particles were isolated from pooled human plasma and shown, by electron microscopy, to have a diameter of about 50-60 nm.
  • the HCV genome is a single- stranded, positive-sense RNA of about 9,600 bp coding for a polyprotein of 3009-3030 amino- acids, which is cleaved co and post-translationally into mature viral proteins (core, El, E2, p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B). It is believed that the structural glycoproteins, El and E2, are embedded into a viral lipid envelope and form stable heterodimers. It is also believed that the structural core protein interacts with the viral RNA genome to form the nucleocapsid.
  • the nonstructural proteins designated NS2 to NS5 include proteins with enzymatic functions involved in virus replication and protein processing including a polymerase, protease and helicase.
  • HCV infection The main source of contamination with HCV is blood.
  • the magnitude of the HCV infection as a health problem is illustrated by the prevalence among high-risk groups. For example, 60% to 90% of hemophiliacs and more than 80% of intravenous drug abusers in western countries are chronically infected with HCV. For intravenous drug abusers, the prevalence varies from about 28% to 70% depending on the population studied. The proportion of new HCV infections associated with post-transfusion has been markedly reduced lately due to advances in diagnostic tools used to screen blood donors.
  • the present invention generally relates to a method of preparing anti-viral agents, such as Compound (1) or pharmaceutically acceptable salt thereof.
  • the present invention is directed to a method of preparing Compound (1) represented by the following structural formula:
  • the method comprises: a) reacting Compound (A) with 3,3-dimetylbut-l-yne in the presence of one or more palladium catalysts selected from the group consisting of Pd(PPh 3 ) 4 and Pd(PPh 3 ) 2 Cl 2 , and one or more copper catalysts selected from the group consisting of Cul, CuBr, and CuCl, to generate Compound (B);
  • the present invention is directed to a method of preparing Compound (1) or a pharmaceutically acceptable salt thereof.
  • the method comprises: a) reducing the cyclohexanone of Compound (C) to cyclohexanol in the presence of LiAlH(O l Bu)3 in an amount of 1.0 to 1.5 equivalents based on molar amount of
  • the present invention is directed to a method of preparing Compound (1) or a pharmaceutically acceptable salt thereof.
  • the method comprises:
  • the present invention is directed to a method of preparing Compound (B):
  • the method comprises reacting Compound (A) with 3,3-dimetylbut-l-yne in the presence of one or more palladium catalysts selected from the group consisting of Pd(PPh 3 ) 4 and Pd(PPh 3 ) 2 Cl 2 , and one or more copper catalysts selected from the group consisting of Cul, CuBr, and CuCl, to generate Compound (B):
  • NS5B polymerase inhibitors and also described in WO 2008/058393.
  • Compound (1) can be prepared by employing Step 4 of general scheme 1 : reacting Compound (A) with 3,3-dimethylbut-l-yne in the presence of one or more palladium catalysts selected from the group consisting of Pd(PPh 3 ) 4 and Pd(PPh 3 ) 2 Cl 2 , and one or more copper catalysts selected from the group consisting of Cul, CuBr, and CuCl, to generate Compound (B) under suitable conditions, for example in the presence of a base. Any suitable conditions known in the art can be employed for this step.
  • Step 4 is performed in the presence of Et 3 N and/or 1 Pr 2 NH.
  • the palladium catalyst is present in an amount 0.1 mol% to 0.5 mol%, such as 0.15 mol% to 0.3 mol% (e.g., 0.2 mol%).
  • the copper catalyst is present in an amount 1 mol% to 5 mol%, such as 2.5 mol% to 5 mol% or 2.5 mol% to 3.5 mol% (e.g., 3 mol%).
  • the amount of 3,3-dimethylbut-l-yne is in a range of 1 to 1.5 equivalents to Compound (A), such as 1.1 to 1.3 equivalents to Compound (A).
  • Any suitable solvent system can be employed for the reaction of Compound (A) with 3,3-dimethylbut-l-yne.
  • Suitable examples include 2-methyl tetrahydrofuran (2-Me THF), dimethylformamide (DMF), methylethyl ketone (MEK or 2-butanone), ethylacetate (EtOAc), methyl t-butyl ether (MtBE), dichloromethane (DCM), toluene, and a mixture thereof.
  • 2-methyl tetrahydrofuran (2-Me THF) or methyl t-butyl ether (MtBE) is employed.
  • the reaction of Compound (A) with 3,3- dimethylbut-l-yne is performed in the presence of Pd(PPh 3 ) 4 and Cul in 2-methyl
  • reaction of Compound (A) with 3,3-dimethylbut-l- yne is followed by washing the reaction mixture with an aqueous oxalic acid (e.g., 12.6 wt% aqueous oxalic acid and/or 6 wt% aqueous oxalic acid) at least twice.
  • an aqueous oxalic acid e.g., 12.6 wt% aqueous oxalic acid and/or 6 wt% aqueous oxalic acid
  • the washing can be done by: i) adding a first washing of aqueous oxalic acid (e.g., 12.6 wt% aqueous oxalic acid) into the reaction mixture Compound (A) with 3,3-dimethylbut-l-yne while maintain the temperature of the mixture below 20 °C - 25 °C; ii) stirring the resulting mixture of step i) at a temperature of 20 °C - 25 °C; iii) adding a second washing of aqueous oxalic acid (e.g., 6 wt% aqueous oxalic acid) into the resulting mixture of step ii) while maintain the temperature of the mixture below 20 °C - 25 °C; and then iv) subsequently stirring the resulting mixture of step iii) at a temperature of 20 - 25 °C.
  • aqueous oxalic acid e.g., 12.6 wt% aque
  • the oxalic acid washing generally generates a biphasic mixture: organic and aqueous layers.
  • the desired organic layer is further treated with activated carbon.
  • the aqueous oxalic acid washing and the treatment with activated carbon can reduce the level of residual palladium and copper substantially.
  • Step 4 employing the palladium and copper catalysts can be performed at a temperature in a range of 18 °C to 30 °C (e.g., 20 °C to 25 °C).
  • performing the reaction at such a low temperature without heating can prevent any potential decomposition of the Pd and/or copper catalysts, and thus preventing generation of impurities associated with the catalyst decomposition.
  • Step 4 is performed at a temperature in a range of 20 °C to 30 °C, such 20 °C to 25 °C.
  • the methods further comprise reacting Compound (B) with an acid to generate Compound (C), as depicted in Step 5 of general scheme 1.
  • suitable acids include TFA (trifluoroacetic acid) (e.g., TFA (e.g., 3 eq) in MeOH (methanol), acetone, or MTBE (methyl t-butyl ether)), H 2 S0 4 (e.g., H 2 S0 4 (e.g., 3 eq) in acetone/H 2 0), TCA
  • TFA trifluoroacetic acid
  • TFA e.g., TFA (e.g., 3 eq) in MeOH (methanol), acetone, or MTBE (methyl t-butyl ether)
  • H 2 S0 4 e.g., H 2 S0 4 (e.g., 3 eq) in acetone/H 2 0)
  • TCA trifluoroacetic acid
  • TMSC1 trimethylsilyl chloride
  • Amberlyst 15 e.g, Amberlyst 15 (e.g., 25 mg) in MTBE
  • HC1 e.g., HC1 (e.g., 2 eq, 5 eq, 6.5 eq) in dioxane/acetone, dioxane/acetone/H 2 0, or THF/H 2 0
  • ZnCl 2 e.g., ZnCl 2 in THF and/or H 2 0
  • AlCls e.g., AICI3 in THF/H2O
  • acetic acid e.g., AcOH (e.g. ,3 eq) in acetone
  • Additional suitable examples include oxalic acid in MeOH, MIBK (methyl isobutyl ketone), 2-butanol (2-BuOH), or 2-butanone.
  • the acid is HC1, such as aqueous HC1.
  • a typical concentration of aqueous HC1 which can be employed in Step 5 is in a range of IN to 6N, such as 1.6N to 3N (e.g., 2N).
  • the aqueous HC1 is added to a solution of Compound (B) in acetone and/or 2-butanone maintained at a temperature in a range of 50 °C to 65 °C, such as 50 °C to 60 °C, or approximately 55 °C.
  • Compound (B) with HC1 includes: i) adding a first aqueous HC1 solution to a solution of Compound (B) in 2-butanone; ii) stirring the mixture for at least an hour; iii) adding a second aqueous HC1 solution to the resulting mixture of step ii); and iv) stirring the resulting mixture of step iii) for at least an hour.
  • this recharging of a second aqueous HC1 solution once the reaction between Compound (B) and the first aqueous HC1 solution reaches an equilibrium brings the conversion of Compound (B) to Compound (C) over 99%> (e.g., 99.5%> conversion).
  • carrying Compound (B) as an impurity over to the next step can be minimized, which can improve the overall purity of Compound (1).
  • the resulting product of Step 5 can be crystallized from a suitable solvent system.
  • crystallization or “crystallized” includes
  • recrystallization or “recrystallized.” In one example, it is crystallized from a mixture of acetone, 2-butanone, and water (e.g., solution or suspension of Compound (C) in acetone, 2- butanone, and water).
  • water e.g., solution or suspension of Compound (C) in acetone, 2- butanone, and water.
  • the cyclohexanone of Compound (C) can further be reduced to cyclohexanol of Compound (D), as depicted in Step 6 of general scheme 1.
  • Any suitable reducing agent known in the art can be employed for Step 6. Suitable examples include LiAlH(0'Bu) 2 (O i Bu)3, DiBAlH (diisobutylaluminum hydride), LiBH 4 , NaBH 4 , NaBH(OAc) 3 , Bu 4 NBH 4 , ADH005 MeOH/KRED recycle mix A, KRED-130 MeOH/KRED recycle mix A, Al(0'Pr) 3 / 'PrOH, (3 ⁇ 4u) 2 A10'Pr ( l Bu: tert-butyl; 3 ⁇ 4u: iso-butyl; Me: methyl; Ac: acetyl; 'Pr: isopropyl).
  • LiAlH(O t Bu) 3 wherein ' u is ter-butyl.
  • the reduction is performed at a temperature in a range of -70 °C to -35 °C, such as -70 °C to -40 °C or -50 °C to -40 °C.
  • LiAlH(O i Bu)3 is added portion wise into a solution of Compound (C) (e.g., a solution of Compound (C) in THF and/or 2-MeTHF), for example over an hour or 2 hours.
  • Step 6 may further include treating the reaction material resulted from the treatment of Compound (C) with a suitable reducing agent (e.g., LiAlH(O i Bu) 3 ) with an acid, such as tartaric acid or oxalic acid, or a mixture thereof.
  • a suitable reducing agent e.g., LiAlH(O i Bu) 3
  • an acid such as tartaric acid or oxalic acid, or a mixture thereof.
  • the acid is tartaric acid.
  • the acid is oxalic acid.
  • the resulting product of Step 6 can be crystallized (e.g., recrystallization) from a suitable solvent system. In one example, it is crystallized from a mixture of methanol and water (e.g., solution or suspension of Compound (D) in methanol and water).
  • Step 6 employing LiAlH(O i Bu) 3 can generate over 95% of Compound (D) (e.g., over 97%) (as compared to its cis isomer) in solution prior to isolation. Further isolation of Compound (D) from the solution can generate over 99% of the desired Compound (D) (as compared to its cis isomer).
  • Compound (D) can be treated with a base to produce Compound (1).
  • suitable bases for Step 7 include NaOH, LiOH, Bu 4 NOH, NaOMe, KOH, and KOH/Bu 4 NBr, and a combination thereof, wherein Bu is n-butyl and Me is methyl.
  • the base includes NaOH, LiOH, Bu 4 NOH, or NaOMe.
  • the base includes NaOH or Bu 4 NOH.
  • a THF or Me- THF solution of compound (D) is treated with the base.
  • the resulting product of Step 7 can be crystallized (including recrystallization) from a suitable solvent system.
  • the term "crystallization” includes recrystallization also.
  • the resulting product of Step 7 can be crystallized to form Form M of Compound (1).
  • it is crystallized from a solvent system that includes isopropanol, ethyl acetate, n-butyl acetate, methyl acetate, acetone, 2-butanone, or heptane, or a combination thereof to form From M of Compound (1).
  • the crystallization (or recrystallization) of Compound (1) to form Form M of Compound (1) is performed in isopropanol; ethyl acetate; n- butyl acetate; a mixture of n-butyl acetate and acetone; a mixture of n-butyl acetate and methyl acetate; acetone; butanone; a mixture of n-butyl acetate and heptane; a mixture of acetone and heptane; or a mixture of ethyl acetate and heptane.
  • the crystallization of Compound (1) to form Form M of Compound (1) is performed in ethyl acetate; n-butyl acetate; or a mixture of n-butyl acetate and acetone.
  • the crystallization of Compound (1) to form Form M of Compound (1) is performed in isopropanol at a temperature in a range of 10 °C to 47 °C.
  • the crystallization of Compound (1) to form Form M of Compound (1) is performed in ethyl acetate is stirred at a temperature in a range of 45 °C to 47 °C.
  • the crystallization of Compound (1) to form Form M of Compound (1) is performed in n-butyl acetate at a temperature in a range of 35 °C to 47 °C.
  • the crystallization of Compound (1) to form Form M of Compound (1) is performed in a mixture of n-butyl acetate and acetone (e.g., 5 wt% - 95 wt% n-butyl acetate and 5 wt% - 95 wt% acetone, such as 90 wt% n-butyl acetate and 10 wt% acetone) at a temperature in a range of 30 °C to 47 °C.
  • Compound (1) to form Form M of Compound (1) is performed in a mixture of n-butyl acetate and methyl acetate (5 wt% - 95 wt% n-butyl acetate and 5 wt% - 95 wt% methyl acetate, such as 50 wt% /? -butyl acetate and 50 wt% methyl acetate) at a temperature in a range of 25 °C to 47 °C.
  • the crystallization of Compound (1) to form Form M of Compound (1) is performed in acetone at a temperature in a range of 20 °C to 47 °C.
  • the crystallization of Compound (1) to form Form M of Compound (1) is performed in butanone at a temperature in a range of 30 °C to 47 °C.
  • the crystallization of Compound (1) to form Form M of Compound (1) is performed in a mixture of n-butyl acetate and heptane (e.g., 5 wt% - 95 wt% n-butyl acetate and 5 wt% - 95 wt% heptane, such as 50 wt% n-butyl acetate and 50 wt% heptane) at a temperature in a range of 25 °C to 47 °C.
  • Compound (1) to form Form M of Compound (1) is performed in a mixture of acetone and heptane (e.g., 5 wt% - 95 wt% acetone and 5 wt% - 95 wt% heptane, such as 50 wt% acetone and 50 wt% heptane) at a temperature in a range of 25 °C to 47 °C.
  • a mixture of acetone and heptane e.g., 5 wt% - 95 wt% acetone and 5 wt% - 95 wt% heptane, such as 50 wt% acetone and 50 wt% heptane
  • the crystallization of Compound (1) to form Form M of Compound (1) is performed in a mixture of ethyl acetate and heptane (e.g., 5 wt% - 95 wt% ethylacetate and 5 wt% - 95 wt% heptane, such as 50 wt% ethyl acetate and 50 wt% heptane) at a temperature in a range of 25 °C to 47 °C.
  • ethyl acetate and heptane e.g., 5 wt% - 95 wt% ethylacetate and 5 wt% - 95 wt% heptane, such as 50 wt% ethyl acetate and 50 wt% heptane
  • Polymorph Form M of Compound (1) can be characterized by, e.g., its X-ray powder diffraction (XRPD) pattern, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and/or solid state C nuclear magnetic spectroscopy (NMR) spectrum.
  • XRPD X-ray powder diffraction
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • NMR solid state C nuclear magnetic spectroscopy
  • the polymorphic Form M is characterized as having an X-ray powder diffraction pattern (obtained at room temperature using Cu K alpha radiation) with the most intense characteristic peak expressed in 2-theta ⁇ 0.2 at 19.6.
  • the polymorphic Form M is characterized as having an X-ray powder diffraction pattern (obtained at room temperature using Cu K alpha radiation) with characteristic peaks expressed in 2-theta ⁇ 0.2 at the following positions: 19.6, 16.6, 18.1, 9.0, 22.2, and 11.4.
  • the polymorphic Form M is characterized as having an X-ray powder diffraction pattern
  • the polymorphic Form M is characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 230 ⁇ 2 °C.
  • the polymorphic Form M is characterized as having peaks at 177.3, 134.3, 107.4, 56.5, 30.7, and 25.3 in a solid state C 13 nuclear magnetic spectroscopy (NMR) spectrum.
  • the methods of the present invention employ Steps 4-7 of general scheme 1 to prepare Compound (1).
  • the methods further include
  • the methods further include crystallization of Compound (D) from a mixture of methanol and water (e.g., solution or suspension of Compound (D) in a mixture of methanol and water) prior to Step 7.
  • the methods optionally further employ crystallization of Compound (1) in ethylacetate (e.g., solution or suspension of Compound (1) in ethylacetate) or in a mixture of n-butylacetate and acetone (e.g., solution or suspension of Compound (1) in n-butylacetate 5 wt%-95 wt% acetone 5 wt%-95 wt%, such as 90 wt% n-butylacetate and 10 wt% acetone).
  • ethylacetate e.g., solution or suspension of Compound (1) in ethylacetate
  • a mixture of n-butylacetate and acetone e.g., solution or suspension of Compound (1) in n-butylacetate 5 wt%-95 wt% acetone 5 wt%-95 wt%, such as 90 wt% n-butylacetate and 10 wt% acetone.
  • the methods of the present invention employ Steps 3-7 of general scheme 1 to prepare Compound (1).
  • Compound (A) can be prepared by reacting Compound (E) with I 2 (Step 3).
  • I 2 can be added into a solution of Compound (E) maintained at a temperature in a range of -80 °C to -40 °C (e.g., -78 °C to -40 °C, or -50 °C to -40 °C).
  • the reaction of Compound (E) with I 2 is performed in the presence of a base, such as a mixture of 'Pr 2 NH and n BuLi.
  • a base such as a mixture of 'Pr 2 NH and n BuLi.
  • the methods of the present invention employ Steps 2-7 of general scheme 1 to prepare Compound (1).
  • Compound (E) can be prepared by reacting Compound (G) with Compound (F) (either as isolated acid chloride (Step 2(b)) or in situ prepared acid chloride) (Step 2(a)).
  • Compound (E) can be prepared by reacting Compound (G) with Compound (F) (either as isolated acid chloride (Step 2(b)) or in situ prepared acid chloride) (Step 2(a)).
  • Step 2(b) isolated acid chloride
  • Step 2(a) in situ prepared acid chloride
  • Compound (F) is provided in situ by reacting Compound (H) (H) with SOCl 2 .
  • Compound (F) is provided in an isolated form.
  • Any suitable condition known in the art for an amidation of an amine with an acid chloride can be employed for Step 2.
  • the amindation can be performed in the presence of a base, such as pyridine.
  • the methods of the present invention employ Steps 1-7 of general scheme 1 to prepare Compound (1).
  • Compound (G) can be prepared by reacting Compound (J) with Compound (K) (Step 1). Any suitable condition known in the art for an amination of a ketone can be employed for Step 1.
  • Compounds (J) and (K) can be combined with NaBH(OAc) 3 and trichloroacetic acid (where Ac is acetyl).
  • NaBH(OAc) 3 and trichloroacetic acid are combined with Compounds (J) and (K) in Toluene.
  • trichloroacetic acid in toluene is added to a mixture of Compounds (J), (K), and NaBH(OAc) 3 in toluene.
  • the mixture of Compounds (J), (K), NaBH(OAc) 3 is added to a mixture of Compounds (J), (K), NaBH(OAc) 3 , and
  • trichloroacetic acid in toluene is maintained at a temperature in a range of 20 °C to 25 °C.
  • a method of the present invention is directed to a method of preparing Compound (B):
  • Compound (A) can be reacted with 3,3-dimetylbut-l-yne in the presence of one or more palladium catalysts selected from the group consisting of Pd(PPh 3 ) 4 and Pd(PPh 3 ) 2 Cl 2 , and one or more copper catalysts selected from the group consisting of Cul, CuBr, and CuCl, to generate Compound (B), as depicted in Step 4 of general scheme 1.
  • palladium catalysts selected from the group consisting of Pd(PPh 3 ) 4 and Pd(PPh 3 ) 2 Cl 2
  • copper catalysts selected from the group consisting of Cul, CuBr, and CuCl
  • the compounds described herein are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
  • a protecting group has one or more, or specifically all, of the following characteristics: a) is added selectively to a functional group in good yield to give a protected substrate that is b) stable to reactions occurring at one or more of the other reactive sites; and c) is selectively removable in good yield by reagents that do not attack the regenerated, deprotected functional group.
  • the reagents do not attack other reactive groups in the compound. In other cases, the reagents may also react with other reactive groups in the compound. Examples of protecting groups are detailed in Greene, T. W., Wuts, P.
  • nitrogen protecting group refers to an agent used to temporarily block one or more desired nitrogen reactive sites in a multifunctional compound.
  • Preferred nitrogen protecting groups also possess the characteristics exemplified for a protecting group above, and certain exemplary nitrogen protecting groups are also detailed in Chapter 7 in Greene, T.W., Wuts, P. G in "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
  • the term "displaceable moiety” or “leaving group” refers to a group that is associated with an aliphatic or aromatic group as defined herein and is subject to being displaced by nucleophilic attack by a nucleophile.
  • polymorphism is an ability of a compound to crystallize as more than one distinct crystalline or "polymorphic" species.
  • a polymorph is a solid crystalline phase of a compound with at least two different arrangements or polymorphic forms of that compound molecule in the solid state.
  • Polymorphic forms of any given compound are defined by the same chemical formula or composition and are as distinct in chemical structure as crystalline structures of two different chemical compounds.
  • Form M of Compound (1) can be prepared by stirring a mixture of Compound (1) and a solvent system that includes isopropanol, ethyl acetate, n-butyl acetate, methyl acetate, acetone, 2-butanone, or heptane, or a combination thereof, as described above for the crystallization (including recrystallization) of Compound (1) to form Form M of Compound (1).
  • Form H of Compound (1) can be prepared by stirring a solution of Compound (1) at a temperature in a range of 48 °C to 70 °C or 50 °C to 70 °C
  • a mixture of Compound (1) and a solvent system that includes ethyl acetate is stirred at a temperature in a range of 48 °C to 70 °C for a period of time to form Form H.
  • a mixture of Compound (1) and a solvent that includes ethyl acetate is stirred at a temperature of 65 ⁇ 2 °C for a period of time to form Form H.
  • Form P of Compound (1) can be prepared by heating a mixture of Compound (1) and a solvent system that includes a solvent selected from the group consisting of dichloromethane, and
  • tetrahydrofuran THF
  • the mixture of Compound (1) and a solvent system that includes dicholoromethane is stirred at room temperature for a period of time to form Form P.
  • Form X of Compound (1) can be prepared by de-solvating the EtOAc solvate G of Compound (1), for example, in vaccum at an elevated temperature in a range of 50 °C to 65 °C (e.g., 60 °C) to remove EtOAc.
  • Form X is isostructural with the EtOAc solvate G (see the Exemplification section below).
  • Form ZA of Compound (1) can be prepared by heating the n-BuOAc solvate A of Compound (1) to a temperature in a range of 140 °C to 150 °C (e.g., 145 °C) (see the Exemplification section below).
  • co-crystal as used herein means a crystalline material comprised of two or more unique solids at room temperature, each containing distinctive physical characteristics, such as structure, melting point and heats of fusion, with the exception that, if specifically stated, the active pharmaceutical ingredient (API) may be a liquid at room temperature.
  • the co- crystals typically comprise the API and a co-crystal former.
  • the co-crystal former may be H-bonded directly to the API or may be H-bonded to an additional molecule which is bound to the API.
  • Other modes of molecular recognition may also be present including, pi-stacking, guest-host complexation and van der Waals interactions.
  • the additional molecule may be H- bonded to the API or bound ionically or covalently to the API.
  • the additional molecule could also be a different API.
  • Solvates of API compounds that do not further comprise a co-crystal forming compound are not co-crystals according to the present invention.
  • the co-crystals may however, include one or more solvate molecules in the crystalline lattice. That is, solvates of co-crystals, or a co-crystal further comprising a solvent or compound that is a liquid at room temperature, is included in the present invention, but crystalline material comprised of only one solid and one or more liquids (at room temperature) are not included in the present invention, with the previously noted exception of specifically stated liquid APIs.
  • co-crystals comprising Compound (1) include co-crystals of Compound (1) and a co-crystal former selected from the group consisting of urea, nicotinamide, and isonicotinamide, as shown in the Exemplification below.
  • Such co-crystals can be prepared by employing the step of stirring a mixture of Compound (1) and the co-crystal former (urea, nicotinamide, or isonicotinamide) in a suitable solvent at room temperature for a period of time to form the co-crystal.
  • Compound (1) and the co-crystal former are in a 1 : 1 molar ratio.
  • the compounds described herein can exist in free form, or, where appropriate, as salts. Those salts that are pharmaceutically acceptable are of particular interest since they are useful in administering the compounds described above for medical purposes. Salts that are not pharmaceutically acceptable are useful in manufacturing processes, for isolation and purification purposes, and in some instances, for use in separating stereoisomeric forms of the compounds of the invention or intermediates thereof.
  • the term "pharmaceutically acceptable salt” refers to salts of a compound, which are, within the scope of sound medical judgment, suitable for use in humans and lower animals without undue side effects, such as, toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • compositions described herein include those derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds.
  • acid addition salts can be prepared by, for example, 1) reacting the purified compound in its free-base form with a suitable organic or inorganic acid; and 2) isolating the salt thus formed.
  • acid addition salts might be a more convenient form for use and use of the salt amounts to use of the free basic form.
  • Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, o
  • base addition salts can be prepared by, for example, 1) reacting the purified compound in its acid form with a suitable organic or inorganic base and 2) isolating the salt thus formed.
  • base addition salt might be more convenient and use of the salt form inherently amounts to use of the free acid form.
  • Salts derived from appropriate bases include alkali metal (e.g., sodium, lithium, and potassium), alkaline earth metal (e.g., magnesium and calcium), ammonium and N(Ci_ 4 alkyl) 4 + salts. This invention also envisions the
  • Basic addition salts include pharmaceutically acceptable metal and amine salts.
  • Suitable metal salts include the sodium, potassium, calcium, barium, zinc, magnesium, and aluminium.
  • the sodium and potassium salts are usually preferred.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • Suitable inorganic base addition salts are prepared from metal bases which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide and the like.
  • Suitable amine base addition salts are prepared from amines which are frequently used in medicinal chemistry because of their low toxicity and acceptability for medical use.
  • Ammonia ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, dietanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine,
  • dehydroabietylamine N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine and the like.
  • salts derived from amino acids e.g. L-arginine, L- Lysine
  • salts derived from appropriate bases include alkali metals (e.g. sodium, lithium, potassium), alkaline earth metals (e.g. calcium, magnesium), ammonium, NR 4 (where R is Ci _ 4 alkyl) salts, choline and tromethamine salts.
  • the pharmaceutically acceptable salt is a sodium salt.
  • the pharmaceutically acceptable salt is a lithium salt.
  • the pharmaceutically acceptable salt is a potassium salt.
  • the pharmaceutically acceptable salt is a tromethamine salt.
  • the pharmaceutically acceptable salt is an L- arginine salt.
  • the compounds in accordance with the present invention are provided as pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts can be derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toleune-p-sulphonic, tartaric, acetic, trifluoroacetic, citric, methanesulphonic, formic, benzoic, malonic,
  • naphthalene -2-sulphonic and benzenesulphonic acids may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
  • Salts derived from amino acids are also included (e.g. L-arginine, L-Lysine).
  • Salts derived from appropriate bases include alkali metals (e.g. sodium, lithium, potassium), alkaline earth metals (e.g. calcium, magnesium), ammonium, NR 4 + (where R is C 1 4 alkyl) salts, choline and tromethamine.
  • alkali metals e.g. sodium, lithium, potassium
  • alkaline earth metals e.g. calcium, magnesium
  • ammonium NR 4 + (where R is C 1 4 alkyl) salts
  • choline and tromethamine include steline and tromethamine.
  • the pharmaceutically acceptable salt is a sodium salt.
  • the pharmaceutically acceptable salt is a potassium salt.
  • the pharmaceutically acceptable salt is a lithium salt.
  • the pharmaceutically acceptable salt is a tromethamine salt.
  • the pharmaceutically acceptable salt is an L- arginine salt.
  • the methods of the invention can be employed for preparing pharmaceutically acceptable solvates (e.g., hydrates) and clathrates of these compounds.
  • solvate is a solvate of a compound, which are, within the scope of sound medical judgment, suitable for use in humans and lower animals without undue side effects, such as, toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • solvate includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).
  • Specific examples of solvates include hydrates and solvates of organic solvent(s) (e.g., acetone, ethanol, methanol, isopropanol, ethylacetate, 2-methyl THF, or mixtures thereof).
  • hydrate means a compound described herein or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • clathrate means a compound described herein or a salt thereof in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within.
  • a "pharmaceutically acceptable derivative or prodrug” includes any pharmaceutically acceptable ester, salt of an ester, or other derivative or salt thereof, of a compound described herein, which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound described herein or an inhibitorily active metabolite or residue thereof.
  • Particularly favoured derivatives or prodrugs are those that increase the bioavailability of the compounds when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
  • prodrug means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound described herein. Prodrugs may become active upon such reaction under biological conditions, or they may have activity in their unreacted forms.
  • prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of the invention that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • Other examples of prodrugs include derivatives of compounds described herein that comprise -NO, -N0 2 , -ONO, or -ONO 2 moieties.
  • Prodrugs can typically be prepared using well-known methods, such as those described by BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed).
  • a "pharmaceutically acceptable derivative” is an adduct or derivative which, upon administration to a patient in need, is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, esters and salts of such esters.
  • compositions described above include, without limitation, esters, amino acid esters, phosphate esters, metal salts and sulfonate esters.
  • a pharmaceutically acceptable prodrug can be readily prepared using methods known in the art, such as those described in Burger's Medicinal Chemistry and Drug Chemistry, Vol. 1, 172-178 and 949-982, John Wiley & Sons (1995). See also Bertolini et al, J. Med. Chem., 40, 2011-2016 (1997); Shan et al, J. Pharm. Sci., 86(7), 765-767 (1997); Bagshawe, Drug Dev.
  • prodrugs of Compound (1) include those described in
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational) forms of the structure.
  • isomeric e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational
  • the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in this invention, unless only one of the isomers is drawn specifically.
  • a substituent can freely rotate around any rotatable bonds.
  • a substituent can freely rotate around any rotatable bonds.
  • a substituents e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • Such compounds, especially deuterium (D) analogs can also be therapeutically useful.
  • the compounds in accordance with the present invention can contain a chiral center.
  • the compounds of formula may thus exist in the form of two different optical isomers (i.e. (+) or (-) enantiomers). All such enantiomers and mixtures thereof including racemic mixtures are included within the scope of the invention.
  • the single optical isomer or enantiomer can be obtained by method well known in the art, such as chiral HPLC, enzymatic resolution and chiral auxiliary.
  • the compounds in accordance with the present invention are provided in the form of a single enantiomer at least 95%, at least 97% and at least 99% free of the corresponding enantiomer.
  • the compounds in accordance with the present invention are in the form of the (+) enantiomer at least 95% free of the corresponding (-) enantiomer.
  • the compounds in accordance with the present invention are in the form of the (+) enantiomer at least 97% free of the corresponding (-) enantiomer.
  • the compounds in accordance with the present invention are in the form of the (+) enantiomer at least 99% free of the corresponding (-) enantiomer.
  • the compounds in accordance with the present invention are in the form of the (-) enantiomer at least 95% free of the corresponding (+) enantiomer.
  • the compounds in accordance with the present invention are in the form of the (-) enantiomer at least 97% free of the corresponding (+) enantiomer.
  • the compounds in accordance with the present invention are in the form of the (-) enantiomer at least 99% free of the corresponding (+) enantiomer.
  • subject includes an animal and a human (e.g., male or female, for example, a child, an adolescent, or an adult).
  • a human e.g., male or female, for example, a child, an adolescent, or an adult.
  • the "subject,” "host,” or “patient” includes an animal and a human (e.g., male or female, for example, a child, an adolescent, or an adult).
  • the "subject,” "host,” or patient” includes an animal and a human (e.g., male or female, for example, a child, an adolescent, or an adult).
  • the "subject,” "host,” or patient” includes an animal and a human (e.g., male or female, for example, a child, an adolescent, or an adult).
  • the "subject,” "host,” or “patient” includes an animal and a human (e.g., male or female, for example,
  • patient is a human.
  • Compound (1) various polymorphic forms thereof, pharmaceutically acceptable salts thereof, solvates thereof, derivatives or prodrugs thereof, or cocrystals thereof (collectively "the active compounds” hereinafter) can be used for treating or preventing a Flaviviridae viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound according to the invention described herein.
  • the viral infection is chosen from Flavivirus infections.
  • the Flavivirus infection is Hepatitis C virus (HCV), bovine viral diarrhea virus (BVDV), hog cholera virus, dengue fever virus, Japanese encephalitis virus or yellow fever virus.
  • HCV Hepatitis C virus
  • BVDV bovine viral diarrhea virus
  • hog cholera virus dengue fever virus
  • Japanese encephalitis virus yellow fever virus.
  • the Flaviviridea viral infection is hepatitis C viral infection (HCV), such as HCV genotype 1, 2, 3, or 4 infections.
  • HCV hepatitis C viral infection
  • the active compounds can be used for treatment of HCV genotype 1 infection.
  • the HCV can be genotype la or genotype lb.
  • the active compounds can be used for treating or preventing a Flaviviridae viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound according to the invention described herein, and further comprising administering at least one additional agent chosen from viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomudulating agents, antioxidant agents, antibacterial agents, therapeutic vaccines, hepatoprotectant agents, antisense agents, inhibitors of HCV NS2/3 protease and inhibitors of internal ribosome entry site (IRES).
  • at least one additional agent chosen from viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomudulating agents, antioxidant agents, antibacterial agents, therapeutic vaccines, hepatoprotectant agents, antisense agents, inhibitors of HCV NS2/3 protease and inhibitors of internal ribosome entry site (IRES).
  • a method for inhibiting or reducing the activity of viral polymerase in a host comprising administering a therapeutically effective amount of a compound according to the invention described herein.
  • a method for inhibiting or reducing the activity of viral polymerase in a host comprising administering a therapeutically effective amount of a compound according to the invention described herein and further comprising administering one or more viral polymerase inhibitors.
  • viral polymerase is a Flaviviridae viral polymerase.
  • viral polymerase is a RNA-dependant RNA- polymerase.
  • viral polymerase is HCV polymerase.
  • viral polymerase is HCV NS5B polymerase.
  • the compounds described above can be formulated in pharmaceutically acceptable formulations that optionally further comprise a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • a suitable pharmaceutical composition can include the active compound(s) and at least one pharmaceutically acceptable carrier, adjuvant, or vehicle, which includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium
  • side effects encompasses unwanted and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Side effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a therapy (e.g., prophylactic or therapeutic agent) might be harmful or uncomfortable or risky.
  • a pharmaceutically acceptable carrier may contain inert ingredients which do not unduly inhibit the biological activity of the compounds.
  • the pharmaceutically acceptable carriers should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic or devoid of other undesired reactions or side-effects upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed.
  • Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as twin 80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, methylcellulose, hydroxypropyl methylcellulose, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose
  • glycols such a propylene glycol or polyethylene glycol
  • esters such as ethyl oleate and ethyl laurate
  • agar buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • compositions thereof can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • parenteral as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions, can be used for the oral administration.
  • carriers commonly used include, but are not limited to, lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents such as, for example, water or other solvents, solubilizing agents
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin,
  • polyvinylpyrrolidinone, sucrose, and acacia c) humectants such as glycerol, d) disintegrating agents such as agar—agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.
  • disintegrating agents such as agar—agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate
  • e) solution retarding agents such
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions examples include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in microencapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions examples include polymeric substances and waxes.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • Sterile injectable forms may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their
  • oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • a long-chain alcohol diluent or dispersant such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are specifically suppositories which can be prepared by mixing the active compound with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Dosage forms for topical or transdermal administration includes ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
  • transdermal patches which have the added advantage of providing controlled delivery of a compound to the body, can also be used.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the active compounds and pharmaceutically acceptable compositions thereof may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • the active compounds and pharmaceutically acceptable compositions thereof can be formulated in unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form can be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form can be the same or different for each dose.
  • the amount of the active compound in a unit dosage form will vary depending upon, for example, the host treated, and the particular mode of administration, for example, from 0.01 mg/kg body weight/day to 100 mg/kg body weight/day.
  • a suitable dose will be in the range of from about 0.1 to about 750 mg/kg of body weight per day, for example, in the range of 0.5 to 60 mg/kg/day, or, for example, in the range of 1 to 20 mg/kg/day.
  • the desired dose may conveniently be presented in a single dose or as divided dose administered at appropriate intervals, for example as two, three, four or more doses per day.
  • the active compound(s) can be formulated as a pharmaceutical composition which further includes one or more additional agents chosen from viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomudulating agents, antioxidant agents, antibacterial agents, therapeutic vaccines, hepatoprotectant agents, antisense agent, inhibitors of HCV NS2/3 protease and inhibitors of internal ribosome entry site (IRES).
  • additional agents chosen from viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomudulating agents, antioxidant agents, antibacterial agents, therapeutic vaccines, hepatoprotectant agents, antisense agent, inhibitors of HCV NS2/3 protease and inhibitors of internal ribosome entry site (IRES).
  • the pharmaceutical composition may include the active compound(s); one or more additional agents select from non-nucleoside HCV polymerase inhibitors (e.g., HCV-796), nucleoside HCV polymerase inhibitors (e.g., R7128, R1626, and R1479), HCV NS3 protease inhibitors (e.g., VX- 950/telaprevir and ITMN-191), interferon and ribavirin; and at least one pharmaceutically acceptable carrier or excipient.
  • non-nucleoside HCV polymerase inhibitors e.g., HCV-796
  • nucleoside HCV polymerase inhibitors e.g., R7128, R1626, and R147
  • HCV NS3 protease inhibitors e.g., VX- 950/telaprevir and ITMN-191
  • interferon and ribavirin interferon and ribavirin
  • at least one pharmaceutically acceptable carrier or excipient
  • the active compound(s) can be employed as a combination therapy in combination with one or more additional agents chosen from viral serine protease inhibitors, viral NS5A inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomudulating agents, antioxidant agents, antibacterial agents, therapeutic vaccines, hepatoprotectant agents, antisense agent, inhibitors of HCV NS2/3 protease and inhibitors of internal ribosome entry site (IRES).
  • additional agents chosen from viral serine protease inhibitors, viral NS5A inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomudulating agents, antioxidant agents, antibacterial agents, therapeutic vaccines, hepatoprotectant agents, antisense agent, inhibitors of HCV NS2/3 protease and inhibitors of internal ribosome entry site (IRES).
  • the active compounds and additional agent can be administered sequentially.
  • the active compounds and additional agent can be administered simultaneously.
  • the combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier therefore comprise a further aspect of the invention.
  • viral serine protease inhibitor means an agent that is effective to inhibit the function of the viral serine protease including HCV serine protease in a mammal.
  • Inhibitors of HCV serine protease include, for example, those compounds described in WO 99/07733 (Boehringer Ingelheim), WO 99/07734 (Boehringer Ingelheim), WO 00/09558 (Boehringer Ingelheim), WO 00/09543 (Boehringer Ingelheim), WO 00/59929 (Boehringer Ingelheim), WO 02/060926 (BMS), WO 2006039488 (Vertex), WO 2005077969 (Vertex), WO 2005035525 (Vertex), WO 2005028502 (Vertex) WO 2005007681 (Vertex), WO 2004092162 (Vertex), WO 2004092161 (Vertex), WO 2003035060 (Vertex), of WO 03/
  • viral polymerase inhibitors as used herein means an agent that is effective to inhibit the function of a viral polymerase including an HCV polymerase in a mammal.
  • Inhibitors of HCV polymerase include non-nucleosides, for example, those compounds described in: WO 03/010140 (Boehringer Ingelheim), WO 03/026587 (Bristol Myers Squibb); WO
  • inhibitors of HCV polymerase also include nucleoside analogs, for example, those compounds described in: WO 01 /90121 A2 (Idenix), WO 02/069903 A2 (Biocryst Pharmaceuticals Inc.), and WO 02/057287 A2 (Merck/ Isis) and WO 02/057425 A2 (Merck/lsis).
  • viral NS5A inhibitor means an agent that is effective to inhibit the function of the viral NS5A protease in a mammal.
  • Inhibitors of HCV NS5A include, for example, those compounds described in WO2010/117635, WO2010/117977,
  • HCV NS5A inhibitors include: EDP-239 (being developed by Enanta); ACH-2928 (being developed by Achillion); PPI-1301 (being developed by Presido Pharmaceuticals); PPI-461 (being developed by Presido Pharmaceuticals); AZD-7295 (being developed by AstraZeneca); GS-5885 (being developed by Gilead); BMS-824393 (being developed by Bristol-Myers Squibb); BMS-790052 (being developed by Bristol-Myers Squibb)
  • nucleoside or nucleotide polymerase inhibitors such as PSI-661 (being developed by Pharmasset), PSI-938 (being developed by Pharmasset), PSI- 7977 (being developed by Pharmasset), INX-189 (being developed by Inhibitex), JTK-853 (being developed by Japan Tobacco) , TMC-647055 (Tibotec Pharmaceuticals), RO-5303253 (being developed by Hoffmann-La Roche), and IDX-184 (being developed by Idenix
  • nucleoside inhibitors of an HCV polymerase include R1626, R1479 (Roche), R7128 (Roche), MK-0608 (Merck), R1656, (Roche-Pharmasset) and
  • Valopicitabine (Idenix).
  • Specific examples of inhibitors of an HCV polymerase include JTK- 002/003 and JTK- 109 (Japan Tobacco), HCV-796 (Viropharma), GS-9190(Gilead), and PF- 868,554 (Pfizer).
  • viral helicase inhibitors as used herein means an agent that is effective to inhibit the function of a viral helicase including a Flaviviridae helicase in a mammal.
  • Immunomodulatory agent as used herein means those agents that are effective to enhance or potentiate the immune system response in a mammal.
  • Immunomodulatory agents include, for example, class I interferons (such as alpha-, beta-, delta- and omega- interferons, x- interferons, consensus interferons and asialo-interferons), class II interferons (such as gamma- interferons) and pegylated interferons.
  • immunomudulating agents include, but are not limited to: thalidomide, IL-2, hematopoietins, IMPDH inhibitors, for example Merimepodib (Vertex Pharmaceuticals Inc.), interferon, including natural interferon (such as OMNIFERON, Viragen and
  • SUMIFERON Sumitomo, a blend of natural interferon's
  • natural interferon alpha ALFERON, Hemispherx Biopharma, Inc.
  • interferon alpha nl from lymphblastoid cells WELLFERON, Glaxo Wellcome
  • oral alpha interferon Peg-interferon, Peg-interferon alfa 2a (PEGASYS, Roche), recombinant interferon alpha 2a (ROFERON, Roche), inhaled interferon alpha 2b (AERX, Aradigm), Peg-interferon alpha 2b (ALBUFERON, Human Genome Sciences/Novartis, PEGINTRON, Schering), recombinant interferon alfa 2b (INTRON A, Schering), pegylated interferon alfa 2b (PEG-INTRON, Schering, VIRAFERONPEG, Schering), interferon beta- la (REBIF, Serono, Inc. and Pfizer), consensus
  • interferon gamma- lb (ACTIMMUNE, Intermune, Inc.), un-pegylated interferon alpha, alpha interferon, and its analogs, and synthetic thymosin alpha 1 (ZADAXIN, SciClone Pharmaceuticals Inc.).
  • class I interferon as used herein means an interferon selected from a group of interferons that all bind to receptor type 1. This includes both naturally and synthetically produced class I interferons. Examples of class I interferons include alpha-, beta-, delta- and omega- interferons, tau-interferons, consensus interferons and asialo-interferons.
  • class II interferon as used herein means an interferon selected from a group of interferons that all bind to receptor type II. Examples of class II interferons include gamma-interferons.
  • Antisense agents include, for example, ISIS-14803.
  • inhibitors of HCV NS3 protease include BILN-2061
  • ISIS-14803 ISIS-14803
  • the additional agent is interferon alpha, ribavirin, silybum marianum, interleukine-12, amantadine, ribozyme, thymosin, N-acetyl cysteine or cyclosporin.
  • the additional agent is interferon alpha 1A, interferon alpha 1 B, interferon alpha 2 A, or interferon alpha 2B.
  • Interferon is available in pegylated and non pegylated forms. Pegylated interferons include PEGASYSTM and Peg-intronTM.
  • the recommended dose of PEGASYSTM monotherapy for chronic hepatitis C is 180 mg (1.0 mL vial or 0.5 mL prefilled syringe) once weekly for 48 weeks by subcutaneous administration in the abdomen or thigh.
  • the recommended dose of PEGASYSTM when used in combination with ribavirin for chronic hepatitis C is 180 mg (1.0 mL vial or 0.5 mL prefilled syringe) once weekly.
  • Ribavirin is typically administered orally, and tablet forms of ribavirin are currently commercially available.
  • General standard, daily dose of ribavirin tablets e.g., about 200 mg tablets
  • ribavirn tablets are administered at about 1000 mg for subjects weighing less than 75 kg, or at about 1200 mg for subjects weighing more than or equal to 75 kg. Nevertheless, nothing herein limits the methods or combinations of this invention to any specific dosage forms or regime.
  • ribavirin can be dosed according to the dosage regimens described in its commercial product labels.
  • the recommended dose of PEG-lntronTM regimen is 1.0 mg/kg/week subcutaneously for one year. The dose should be administered on the same day of the week.
  • the recommended dose of PEG- lntron is 1.5 micrograms/ kg/ week.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier therefore comprise a further aspect of the invention.
  • the individual components for use in the method of the present invention or combinations of the present invention may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • the additional agent is interferon a 1A, interferon a IB, interferon a 2A, or interferon a 2B, and optionally ribavirin.
  • the dose of each compound may be either the same as or differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • reaction mixture Upon completion of reaction, the reaction mixture was transferred into a solution of K 2 C0 3 (307.7 g, 7.0 eq) in DI water (375 mL, 7.5 vol). The biphasic mixture was stirred and then the phases were separated. The organic phase was washed with aqueous solution of K 2 C0 3 (175.9 g, 4.0 eq) in DI water (375 mL, 7.5 vol), then with aqueous solution of NaCl (20.4 g, 1.1 eq) in DI water (375 mL, 7.5 vol). The organic phase was separated.
  • reactor-1 (acid chloride obtained above) in toluene was added to the reactor-2 over 1 hour.
  • the reaction mixture was heated to 95 - 105°C once the addition had complete.
  • An IPC sample was taken after 24 - 30 h and analyze for Compound G consumption by HPLC.
  • the reaction mixture was then cooled to 25 - 30°C. MeOH (665 mL, 1.9 vol) was added to the reaction mixture over 45 minutes. DI water (1.33 L, 3.8 vol) was then added to the reaction mixture at 25 - 30°C. The mixture was heated to 55 - 60°C then stirred for 1 hour. Stopped agitation and allowed the phases to separate for 10 minutes. The upper organic layer was separated and the aqueous layer was set aside. DI water (1.33 L, 3.8 vol) was added to the reaction mixture at 55 - 60°C then stirred for 1 hour. Stopped agitation and allowed the phases to separate for 10 minutes. The upper organic layer was separated and the aqueous layer was set aside.
  • Solvent switch to toluene was performed: added toluene (1.5 L, 3.0 vol) again then concentrated to 3.0 vol (-1.5 L). Toluene (5.0 L, 10.0 vol) was then added to the resulting concentrate and the mixture was heated to 95 - 100°C until a homogenous solution was obtained. Added heptane (5.0 L, 10.0 vol) at 95 - 100°C to the toluene solution, then the mixture was cooled to 20 - 25°C over 6 hours. The suspension was filtered. The cake was washed twice with heptane (500 mL, 1.0 vol). The solids were dried on the filter under vacuum. The isolated compound A was analyzed by HPLC, GC, and Karl Fischer titration.
  • the batch temperature was then adjusted to 20 - 25 °C and the biphasic mixture was stirred for at least 3 hours at this temperature.
  • the phases were then allowed to separate for at least 30 minutes.
  • the organic phase was then again washed with aqueous oxalic acid dehydrate (6 wt%, 383.6 mL, 6 vol) while maintaining the batch temperature below 20-25 °C.
  • the biphasic mixture was stirred for at least 1 hour at this temperature. Then the phases were split.
  • Activated carbon (6.4 g - 12.8 g, 10- 20 wt% with respect to Compound A) was added to the reaction mixture.
  • the suspension was stirred at 20 - 25°C for not less than 12 hours.
  • the mixture was filtered over celite.
  • the filter cake was washed with MtBE (192 mL, 3 vol) and the filtrate was added to the organic phase. This solution was typically used directly in the next step.
  • Cul for both 99.9% and 98%): with 0.03 equiv of Cul, over 95% conversion into Compound (B) after about 2 hours' reaction time; with 0.025 equiv of Cul, over 90%> conversion into Compound (B) after about 5 hours' reaction time; with 0.02 equiv of Cul, over 90%> conversion into Compound (B) after about 5 hours' reaction time; with 0.015 equiv of Cul, over 90%) conversion into Compound (B) after about 5 hours' reaction time; with 0.01 equiv of Cul, over 75% conversion into Compound (B) after about 5 hours' reaction time;
  • CuCl with 0.03 equiv of CuCl, over 99%> conversion into Compound (B) after about 2 hours' reaction time; with 0.025 equiv of Cul, approximately 100% conversion into Compound (B) after about 2 hours' reaction time; with 0.02 equiv of CuCl, over 90%> conversion into Compound (B) after about 2 hours' reaction time; with 0.015 equiv of CuCl, over 95% conversion into Compound (B) after about 2 hours' reaction time; with 0.01 equiv of CuCl, approximately 100% conversion into Compound (B) after about 20 hours' reaction time;
  • CuBr with 0.03 equiv of CuBr, over 99% conversion into Compound (B) after about 22 hours' reaction time; with 0.025 equiv of CuBr, over 85% conversion into Compound (B) after about 22 hours' reaction time; with 0.02 equiv of CuBr, over 95% conversion into Compound (B) after about 22 hours' reaction time; with 0.015 equiv of CuBr, over 70% conversion into Compound (B) after about 22 hours' reaction time; with 0.01 equiv of CuBr, over 80%
  • a jacketed 1L 4-neck reactor was fitted with a nitrogen inlet then charged with a solution of Compound (B) (22.9 g, 45.65 mmol) in 2-butanone ( ⁇ 250 mL), then heated to 60°C.
  • the reactor was purged with a stream of nitrogen then an aqueous solution of 2N HC1 (175 mL) was added.
  • the mixture was stirred at 60°C for 4 hours.
  • the stirring was stopped and the lower aqueous phase was removed. Agitation was started again followed by the addition of fresh aqueous solution of 2N HC1 (175 mL).
  • the mixture continued to stir at 60°C until the conversion (99% by HPLC) had reached equilibrium (approximately another 2.5 hours).
  • a jacketed 1L 4-neck reactor was fitted with a nitrogen inlet then charged with a solution of Compound (B) (103.3 g, 1.0 eq based on 100%) yield in Step 4) in 2-butanone ( ⁇ 1.03 L, approximately 10 vol total batch volume), then heated to 57 °C - 62 °C (e.g., 60°C).
  • the reactor was purged with a stream of nitrogen then an aqueous solution of 2N HC1 (723 mL, 7 vol based on 103.3g of Compound (B)) was added over about 10 minutes while maintaining the batch temperature at 57 °C - 62 °C (e.g., 60°C).
  • the mixture was stirred at 57 °C - 62 °C (e.g., 60°C) for 5 hours. The stirring was stopped and the lower aqueous phase was removed. Agitation was started again followed by the addition of fresh aqueous solution of 2N HC1 (310 mL, 3 vol based on 103.3g of Compound (B)). The mixture continued to stir at 57 °C - 62 °C (e.g., 60°C) until the conversion (99% by HPLC) had reached equilibrium (approximately another 2.5 hours). After cooling to 20 - 25°C, the agitation was stopped and phases were allowed to separate for at least 30 minutes. An aqueous NH 4 C1 (10 wt%, 517 mL, 5 vol) was then added while
  • Aqueous HC1 solutions were used in methods A and B above for step 5. Other acids than aqueous HC1 could also be used.
  • a summary of the tested acids and conversion (%) is summarized below:
  • LiAlH(OtBu) 3 (960 ml of 1 M in THF, 2.40 vol or 1.1 eq) was added while maintaining not higher than -40 °C batch temperature. The solution was added over 2 hours and 15 minutes. The rate of addition was 1.45 vol/h.
  • MTBE (1197 L, 3 vol) was charged to the batch, then the batch was warmed to 0 °C.
  • the resulting solution was added over about 10-15 minutes to a mixture of aqueous oxalic acid (or tartaric acid) which was prepared by cooling a mixture of oxalic acid (or tartaric acid) (9% w/w, 2394 L, 6 vol) and MTBE (7 L, 2 vol) to 8-10 °C.
  • the batch temperature was adjusted to 15-25 °C and the resulting mixture was stirred for 30-60 minutes.
  • the batch was then cooled 15 - 25 °C at approximately 5 °C / hour, and was held for not less than (NLT) 4 hours at 15 - 25 °C.
  • the filter cake was washed with 1 volume (based on compound 5 charge) of 50 volume% methanol/ water
  • the material was dried for at least 12 hours under vacuum with nitrogen bleed at 55-65 °C.
  • the batch could be recrystallized by charging dry Compound (D) (1 equiv) and methanol (2 vol, relative to Compound (D) charge) to a reactor and heating the batch to 60-65 °C until all solids dissolved. The batch would then be cooled to -20 °C over a 3 hour period. The resulting solids would be filtered and dried for at least 12 hours under vacuum with nitrogen bleed at 55-65 °C.
  • Method B Reducing reagents other than LiAlH(OtBu)3 Reducing reagents other than LiAlH(OtBu)3 that gave predominantly the desired isomer were: LiAlH(OzBu) 2 (Ot5 M ) 3 , DiBAlH, LiBH4, NaBH4, NaBH(OAc) 3 , Bu 4 NBH 4 , ADH005
  • MeOH/KRED recycle mix A KRED-130 MeOH/KRED recycle mix A, Al(Oz ' -Pr) 3 / z-PrOH, and (z-Bu) 2 A10zPr.
  • the batch volume was reduced to 3 volumes (based on compound (D) charge) via vacuum distillation at a maximum temperature of 35 °C. Then dry Me-THF (3 vol, based on compound (D) charge) was added. The water content was determined by Karl Fisher titration. The batch is deemed dry if residual water level is ⁇ 1.0%.
  • the final product of Compound (1) can be recrystallized either in EtOAc or in a mixture of nBuOAc and acetone via solvent switch described below to form Form M of
  • a solvent switch from 2-Me-THF to nBuOAc was performed by first reducing the batch volume to 2-3 volumes (based on compound (D) charge) by vacuum distillation at a maximum temperature of 45 °C.
  • nBuOAc (3 vol, based on compound (D) charge) was added and the batch volume was reduced to 2-3 volumes (based on compound (D) charge) via vacuum distillation at a maximum temperature of 45 °C.
  • the batch volume was then adjusted to a total of 5-6 volumes by addition of nBuOAc.
  • the solution was analyzed for residual 2-Me-THF in content in nBuOAc. This cycle was repeated until less than 1% of 2-Me-THF with respect to nBuOAc remained, as determined by GC analysis.
  • a solvent switch from 2-Me-THF to EtOAc was performed by first reducing the batch volume to 2-3 volumes (based on compound (D) charge) by vacuum distillation at a maximum temperature of 35 °C.
  • EtOAc (10 vol, based on compound (D) charge) was added and the batch volume was reduced to 2-3 volumes (based on compound (D) charge) via vacuum distillation at a maximum temperature of 35 °C.
  • the solution was analyzed for residual 2-Me-THF in content in EtOAc. This cycle was repeated until less than 1% of Me-THF with respect to EtOAc remained, as determined by GC analysis.
  • the batch temperature was adjusted to 40 - 45 °C.
  • Compound 1 seed (1.0% by weight with respect to the total target weight of compound (1)) was added.
  • the batch was agitated at 40 - 45 °C for 12 hours.
  • a flat floor / flat bottomed reactor (not conical) should be used.
  • the recrystallization progress is monitored by X-ray powder diffraction (XRPD). If spectrogram matched that of required form, then the batch was cooled from 40 - 45 °C to 1 1 - 14 °C at rate of 5 °C/hour.
  • Polymorphic Form A of Compound (1) can be prepared by following the steps described below:
  • Compound (1) formed.
  • the solids of Compound (1) were filtered. 20 g of acetone at 25 °C was added to the solids of Compound (1). The mixture of acetone and Compound (1) was stirred for 1 hour and the resulting solids were filtered. The filtered solids were dried at 75 °C for 12 hours.
  • Polymorphic Form M of Compound (1) can be prepared by following the steps described below:
  • Example 2 10 g of Compound (1) prepared according to the procedures depicted in Example 2 was charged to a reactor. 50 g of ethyl acetate was then charged to the reactor. The reactor was heated to 45 °C and the mixture was stirred for 1 - 2 days until Form M was observed. Then, the reactor was cooled to 25 °C, and left until solids of Compound (1) formed. The solids of Compound (1) were filtered and the filtered solids were dried at 35 °C for 24 hours.
  • polymorphic Form M of Compound (1) can be prepared in the following
  • Polymorphic Form H of Compound (1) can be prepared by following the steps described below:
  • Example 2 10 g of Compound (1) prepared according to the procedures depicted in Example 2 was charged to a reactor. 50 g of ethyl acetate was then charged to the reactor. The reactor was heated to 65 °C and the mixture was stirred for 1 - 2 days until Form H was observed. If desired, a seed(s) of Form H could be added into the reactor for a large scale production. Then, the reactor was cooled to 25 °C, and left until solids of Compound (1) formed. The solids of Compound (1) were filtered and the filtered solids were dried at 65 °C for 24 hours.
  • Polymorphic Form P of Compound (1) can be prepared by following the steps described below: Method A:
  • Example 2 20 mg of Compound (1) prepared according to the procedures depicted in Example 2 was charged to a vial. 0.5 mL of dicholormethane was then charged to the vial. The mixture was stirred at room temperature for 3 weeks until solids of Compound (1) were formed. The solids of Compound (1) were filtered and the filtered solids were dried at room temperature for 1 hour.
  • Example 2 500 mg of Compound (1) prepared according to the procedures depicted in Example 2 was charged to a vial. 6 mL of dicholormethane was then charged to the vial. The mixture was stirred at room temperature for 4 days until solids of Compound (1) were formed. The solids of Compound (1) were filtered and the filtered solids were dried at room temperature for 1 hour.
  • Polymorphic Form X of Compound (1) can be prepared by following the steps described below:
  • EtOAc Solvate G 50 mg was placed into an open 20 mL vial in a vacuum oven at 60°C for 24 hours. After 24 hours the vial was removed and the powder was analyzed by XRPD. Form X was isostructural with EtOAc Solvate G so the location of the peaks listed in the xrpd patterns were within 0.2 degrees 2-theta of each other.
  • Polymorphic Form ZA of Compound (1) can be prepared by following the steps described below:
  • n-BuOAc solvate A of Compound (1) was placed into an aluminum DSC pan. The sample was heated at a rate of 10°C per minute to 145°C to remove n-BuOAc from n-BuOAc solvate A.
  • Characteristics of Form ZA of Compound (1) Certain representative XRPD peaks of Form ZA of Compound (1) are summarized in Table 4C below. Table 4C: Certain representative XRPD Peaks of Form ZA
  • Urea co-crystals of Compound (1) can be prepared by following the steps described below:
  • urea co-crystals of Compound (1) can be prepared by following the steps described below:
  • Nicotinamide Co-crystal Nicotinamide co-crystals of Compound (1) can be prepared by following the steps described below:
  • Isonicotinamide co-crystals of Compound (1) can be prepared by following the steps described below:
  • RT refers to the LCMS retention time, in minutes, associated with the compound.
  • NMR and Mass Spectroscopy data of certain specific compounds are summarized in Table 8.
  • DSC was conducted on a TA Instruments model Q2000 V24.3 calorimeter (Asset Tag V014080). Approximately 1-2 mg of solid sample was placed in an aluminum hermetic DSC pan with a crimped lid with a pinhole. The sample cell was heated under nitrogen purge at 10 °C per minute to 300 °C.
  • the XRPD patterns were acquired at room temperature in reflection mode using a Bruker D8 Discover diffractometer (Asset Tag V012842) equipped with a sealed tube source and a Hi-Star area detector (Bruker AXS, Madison, WI).
  • the X-Ray generator was operating at a voltage of 40 kV and a current of 35 mA.
  • the powder sample was placed in an aluminum holder. Two frames were registered with an exposure time of 120 s each. The data were subsequently integrated over the range of 4°-40° 2 ⁇ with a step size of 0.02° and merged into one continuous pattern.
  • Hydrate A of Compound (1) can be prepared by following the steps described below:
  • Hydrate B of Compound (1) can be prepared by following the steps described below:
  • Methanol solvates of Compound (1) can be prepared by following the steps described below:
  • Ethanol/Isopropanol solvates_of Compound (1) (94.7 vol% EtOH/ 5.3 vol% IP A) can be prepared by following the steps described below: A slurry containing 100 mg of Compound (1) in EtOH/IPA (95.7% EtOH / 4.7% IPA) in a 2 mL vial was stirred at room temperature overnight to form Compound (1) ⁇ . The solvent was decanted off, giving the remaining wet-cake which was analyzed by XRPD.
  • Acetone solvates of Compound (1) (Compound (1) ⁇ 1 acetone) can be prepared by following the steps described below:
  • Crystals of acetone solvate of Compound (1) (1 : 1 stoichiometry) were grown by slow evaporation from a solution of Compound (1) in acetone. The crystals were collected and analyzed by XRPD. TGA data indicated an acetone solvate with a stoichiometry of
  • 2-MeTHF (91.38 mL) was added and the batch was distilled down to 3 vol .
  • the batch was distilled down to 3 volume.
  • 2-MeTHF (91.38 mL) was added and the batch was distilled down to 3 vol EtOAc (304.6 mL) was charged and the batch was distilled down to 2-3 volumes.
  • the batch was adjusted to 10 volumes by adding 7-8 volumes of EtOAc.
  • the batch was distilled down to 2-3 volumes.
  • the batch was adjusted to 10 volumes by adding 7-8 volumes of EtOAc.
  • the batch was distilled down to 2-3 volumes.
  • the batch was adjusted to 10 volumes by adding 7-8 volumes of EtOAc.
  • Characteristics of isopropylacetate solvate of Compound (1) XRPD data of isopropylacetate solvate of Compound (1) showed that the ethyl acetate Form A solvate of Compound (1) and isopropylacetate solvate of Compound (1) were isostructural to each other, sharing the same representative XRPD peaks summarized in Table 20 below.
  • n-Butylacetate solvates A-C of Compound (1) (Compound (1) ⁇ nBuOAc) can be prepared by following the steps described below:
  • Heptane solvates A-D of Compound (1) (Compound (1) ⁇ Heptane can be prepared by following the steps described below:
  • amorphous Compound (1) 106 mg was added to a solvent mixture of 0.5 mL EtOAc and 0.5 mL heptane. The suspension was agitated for 7 days at 20°C. The solids were isolated by centrifugation filtration and analyzed.
  • a slurry in 1 mL of heptane was made by addition of approximately 50 mg of Compound (1).
  • the material was stirred for 60 days at 20°C.
  • the material was then filtered and analyzed by XRPD.
  • a slurry in 1 mL of heptane was made by addition of approximately 50 mg of Compound (1).
  • the material was stirred for 60 days at 25°C.
  • the material was then filtered and analyzed by XRPD.
  • MEK solvates of Compound (1) (Compound (1) ⁇ MEK can be prepared by following the steps described below:
  • Compound (1) 400 mg was added to 1 mL of MEK (methylethyl ketone (2-butanone)) in a vial. A thick slurry was obtained after vortexing the vial for 1 minute. The resulting mixture was then stirred for 4 hours. The solids from the wet slurry were analyzed by 13 C SSNMR.
  • MEK methylethyl ketone (2-butanone
  • MeOAc solvates of Compound (1) (Compound (1) ⁇ MeOAc can be prepared by following the steps described below:
  • 200 mg Form A capsules were prepared as follows. 50 mg Form A capsules were prepared in a similar manner as described below for 200 mg capsules. The formulation compositions for both the wet granulation and capsules blends of the active capsule are described in Tables 35a and 35b.
  • Table 35b Po mor hic Form A of Com ound 1 200m Ca sule Composition
  • the actual weights of each ingredient for the final capsule blend of the 200mg capsule strength batch can be determined based on the yield calculations of the wet granulation (internal Phase). Sample calculation below:
  • Monohydrate, Poloxamer 188, Sodium Lauryl Sulfate, and Povidone K29/32 were weighed and transferred to a V-Shell blender (PK lcu.ft.).
  • Crosscarmellose Sodium, Magnesium Stearate, and milled granulation were weighed and transferred to a V-Shell blender (PK lcu.ft), except the magnesium stearate.
  • Example 6 Preparation of Tablets Comprising Polymorphic Form M of Compound (1) a. Tablets A
  • Tables 36a and 36b The formulation compositions for both the wet granulation and tablet blends of the active tablets are described in Tables 36a and 36b.
  • the overall composition specification of the tablets is described in Table 36c.
  • Table 36b Form M (250mg) Tablet Composition Component Amount % W/W
  • a V-Shell blender was set up and the materials from step 3 were transferred into a blender.
  • V-Shell blender The contents of the V-Shell blender were emptied into LDPE bags (Bulk Wet Granulation blend).
  • Stage 1 77% of the total amount of water required for the wet granulation was used to granulate the material at the prescribed process parameters. Once the water addition was complete, the granulation was stopped. The walls, impeller, and chopper of the high shear granulator were scraped and the granulation was verified to determine if the visual endpoint was reached. If YES moved on to step 10, if NO proceeded to stage 2
  • the granulation was stopped and the walls, impeller, and chopper of the high shear granulator were scraped and the granulation was verified to determine if the visual endpoint was reached. If YES moved on to step 10, if NO continued to granulate at the preceding process parameters with 2ml portions of water until the end-point was reached. Once the granulation end point was achieved, the material (Wet granulation blend) was screened through a #20 (850 ⁇ ) mesh screen and the screened material was transferred into a suitable container.
  • the screened material from step 10 was dried in an oven according to the prescribed drying parameters (overall drying temperature: 30°C -45°C).
  • Crosscarmellose Sodium, Magnesium Stearate, and milled granulation were weighed. The materials were transferred into a V-Shell blender, except the magnesium stearate. 5. The materials in the V-Shell blender were blended for lOmins at the set speed (typically 25RPM).
  • V-Shell blender The materials in the V-Shell blender were blended for lmin at the set speed (typically 25RPM).
  • a GlobePharma tablet press with the modified caplet tooling (size 0.30" x 0.60") was set up.
  • the formulation composition for the pre granulation blend is given in Table 38a.
  • Table 38b gives the composition of the granulation binder solution.
  • the theoretical compression blend composition is given in Table 38c.
  • the composition and approximate batch size of the film coating suspension (including 50%> overage for line priming and pump calibration) is given in Table 38d.
  • the overall specification of the tablets B composition is summarized in Table 7e.
  • the target amount of the film coating is 3.0% w/w of the core tablet weight.
  • the binder solution included the Povidone, SLS, and Poloxamer.
  • the solution was prepared based on 9% w/w water content of the final dry granulation. An excess amount of 100% was prepared for pump calibration, priming lines, etc. 1.
  • the required amount of Poloxamer 188, Sodium Lauryl Sulfate, Povidone K12, and purified (DI) water were weighed.
  • Compound (1) weighed out Compound (1), lactose, and avicel were delumped respectively at 4000 rpm in the U5, or 2800 rpm in the U10 into bags or directly into the Meto 200 L blender.
  • step 3 The materials were transferred from step 2 into a Meto 200 L bin blender.
  • the materials were charged into a loss in weight powder feeder directly from the blend shell, or into a LDPE bag.
  • the dry blend was fed into the extruder using a K-Tron loss in weight feeder.
  • the binder fluid was injected into the extruder using a calibrated K-Tron liquid pump.
  • the pump was calibrated using the actual fluid prior to operation.
  • the weight ratio of solution feed rate over powder feed rate was 0.215 to have the proper final composition.
  • the solution feed rate was 35.91 g min "1 .
  • the wet granules coming out of the twin screw was milled using an inline U5 Comil at 1000 rpm with square 4mm screen and round bar impeller.
  • the wet milled granules were collected and dried.
  • the water content was NMT 3.0%.
  • composition was weighed.
  • the granules and Cab-O-Sil was added directly to the 200 L Meto bin blender and blended for 8 minutes at 15 RPM.
  • the blend was then passed through a U10 Comil with a 40G screen and round bar impeller at 600 rpm directly into the 600 L Meto bin blender or into double LDPE bags.
  • a film coating was applied to the core tablets in a Vector VPC 1355 pan coater as a 20wt % Opadry II white # 85F18378 aqueous suspension.
  • the target coating was 3.0% w/w of the core tablet weight, with an acceptable range of 2.5% to 3.5%. To accomplish this, an amount of coating suspension equivalent to a 3.2% weight gain was sprayed, which would give a 3.0% coating assuming a coating efficiency of 95%>.
  • the film coating process was performed as follows:
  • the actual weights of each ingredient for the final tablet blend of the 250mg tablet strength batch can be determined based on the yield calculations of the wet granulation (internal Phase). Sample calculation below High shear wet granulation process flow
  • step 4 The materials from step 3 were transferred into a V-Shell blender. 5. The materials in the V-Shell blender were blended for 5mins at the set speed (typically 25RPM).
  • the blend was granulated.
  • the wet granulation process was performed in two stages:
  • Stage 1 77% of the total amount of water required for the wet granulation was used to granulate the material at the prescribed process parameters. Once the water addition was complete, the granulation was stopped, and the walls, impeller, and chopper of the high shear granulator were scraped and the granulation was verified to determine if the visual endpoint was reached. If YES moved on to step 10, if NO proceeded to stage 2
  • Stage 3 The material was granulated at the prescribed process parameters using just the impellor and chopper for -30 seconds. The granulation was stopped, and the walls, impeller, and chopper of the high shear granulator were scraped and the granulation was verified to determine if the visual endpoint was reached. If YES moved on to next step, if NO continued to granulate at the preceding process parameters (Stage 2) with 2ml portions of water until the end-point was reached. Once the granulation end point was achieved, the material (Wet granulation blend) was screened through a #10 mesh screen and the screened material was transferred into a suitable container.
  • Magnesium Stearate, and milled granulation were weighed.
  • V-Shell blender 15. The materials in the V-Shell blender were blended for 5mins at the set speed (typically 25RPM). 16. Magnesium stearate was then added into the V-shell blender.
  • the final blend was compressed using a GlobePharma tablet press according to the prescribed tablet compression process parameters. During the compression process, the individual and average tablet weights, hardness, thickness, and friability were monitored.
  • WFI Water for Injection
  • pH 7.0 range: 7.0 to 7.4
  • Phosphoric Acid or 1 M Sodium Hydroxide Solution.
  • the overall composition specification of the tablets is described in Table 42.
  • the tablet formulation was prepared in a similar manner as described above in Example 8 but using roller compaction instead of twin screw wet granulation process.
  • the manufacturing process includes:
  • Compound (1) (Form M), Microcrystalline cellulose, and croscarmellose sodium were individually screened, added to the blender and blended. Magnesium stearate was individually screened, added to the above blend and further blended. The blend was then dry granulated using a roller compactor and milled into granules. The granules were then further blended with individually screened Microcrystalline cellulose, croscarmellose sodium and sodium stearyl stearate. The final blend was then compressed into tablets. The final tablet contained 400 mg of Compound (1). Following the compression, SDD tablets were tested for release and packaged. Table 42: Form M Tablet C Overall Composition
  • the tablet formulation was prepared in a similar manner, using Consigma 1 twin screw granulator with Fluid bed dryer, as described above in Example 8 for Tablet B.
  • the overall Compound (1) granule composition tablet for HPC2.25% is given in Table 43a and 43b.
  • the tablet formulation was prepared in a similar manner, using Consigma 1 twin screw granulator with Fluid bed dryer, as described above in Example 6 for Tablet B.
  • the overall Compound (1) granule composition tablet for HPC 2.25% is given in Table 19a and 19b.
  • Table 44a The formulation composition and batch size for the pre granulation blend was given in Table 44a.
  • Tables 44b, c, d, e, f and g gave the composition and batch size of the granulation binder solutions.
  • the batch size of the binder solutions included a 100% overage for pump calibration and priming of solution lines.
  • the binder solution included the HPC binder.
  • the solution was prepared based on 48, 53, and 58% w/w water content of the final dry granulation. An excess amount of 100% was prepared for pump calibration, priming lines, etc. 1. Weigh out the required amounts (Table 44b, c, d, e, f, and g) of HPC, and purified (DI) water.
  • a partial vacuum can be pulled on the solution tank for up to an hour to degas the solution.
  • the weight ratio of solution feed rate over powder feed rate varies from one

Abstract

L'invention concerne un procédé de préparation du composé (1) : ou d'un sel de qualité pharmaceutique de celui-ci. Ce procédé consiste : a) à faire réagir le composé (A) avec du 3,3-diméthylbut-1-yne en présence d'un ou de plusieurs catalyseurs à base de palladium choisis dans le groupe constitué par Pd(PPh3)4 et Pd(PPh3)2Cl2, et d'un ou de plusieurs catalyseurs à base de cuivre choisis dans le groupe constitué par CuI, CuBr et CuCl, pour générer le composé (B); b) à traiter le composé (B) par un acide pour générer le composé (C) : c) à réduire la cyclohexanone du composé (C) en cyclohexanol pour générer le composé (D); d) à faire réagir le composé (D) avec une base pour générer le composé (1), les composés (A), (B), (C) et (D) étant chacun tels que représentés par les présentes.
PCT/US2012/048270 2011-07-26 2012-07-26 Procédés de préparation de composés du thiophène WO2013016499A1 (fr)

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Cited By (2)

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EP2762124A1 (fr) 2013-01-31 2014-08-06 IP Gesellschaft für Management mbH Emballage comprenant des unités d'administration de polymorphes, formes amorphes ou solvates
WO2022010367A1 (fr) * 2020-07-10 2022-01-13 Aquafortus Technologies Limited Solution de séchage par solvant et processus s'y rapportant

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