WO2017019581A1 - Procédé de production de composés de promédicaments nucléosidiques contenant du phosphore - Google Patents

Procédé de production de composés de promédicaments nucléosidiques contenant du phosphore Download PDF

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WO2017019581A1
WO2017019581A1 PCT/US2016/043806 US2016043806W WO2017019581A1 WO 2017019581 A1 WO2017019581 A1 WO 2017019581A1 US 2016043806 W US2016043806 W US 2016043806W WO 2017019581 A1 WO2017019581 A1 WO 2017019581A1
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Prior art keywords
alkylene
alkyl
compound
cycloalkyl
formula
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PCT/US2016/043806
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English (en)
Inventor
Jamie M. MCCABE DUNN
Robert K. Orr
Andrew F. Nolting
Rebecca T. Ruck
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Merck Sharp & Dohme Corp.
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Publication of WO2017019581A1 publication Critical patent/WO2017019581A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/213—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids containing cyclic phosphate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/02—Phosphorylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/11—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids containing cyclic phosphate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide

Definitions

  • the present invention is directed to a process for making Phosphorus-Containing Nucleoside Prodrug Compounds which may be useful for the treatment or prophylaxis of HCV infection.
  • HCV infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, and is estimated to affect approximately 2-15% of the world's population. Once infected, about 20% of people clear the virus, but the rest harbor HCV the rest of their lives. Ten to twenty percent of chronically infected individuals eventually develop liver-destroying cirrhosis or cancer. HCV is transmitted parenterally by contaminated blood and blood products, contaminated needles, sexually or vertically from infected mothers or carrier mothers to their off-spring.
  • HCV NS5B polymerase Inhibition of HCV NS5B polymerase prevents formation of the double-stranded HCV RNA and therefore constitutes an attractive approach to the development of HCV-specific antiviral therapies.
  • nucleoside phosphoramidate compounds which may be useful in the treatment of infection by HCV and in the treatment, prophylaxis, or delay in the onset or progression of HCV infection.
  • Representative nucleoside phosphoramidate compounds that may be useful for treating HCV infection are described, for example, in International Patent Publication Nos. WO 2013/177219 and WO 2014/058801.
  • nucleoside analogs that inhibit HCV NS5B polymerase are disclosed, for example, in WO 2011/035231, WO 2005/003147, WO 2010/0081628, U.S. 7,879,815, WO 2010/075517, WO 2010/002877, and WO 2009/132123.
  • prodrugs which have the 5' -OH group masked as a phosphoramidate moiety (also referred to as "McGuigan" prodrugs).
  • the present invention is directed to a process for making Phosphorus-Containing Nucleoside Prodrug Compounds of Formula (IV) which may be useful for the treatment and prophylaxis of HCV infection. More particularly, the present invention includes a process (alternatively referred to herein as "Process A") for preparing a compound of Formula (IV):
  • B is a natural or non-natural purine or pyrimidine base, or B is selected from one of the following
  • X is O, N, S or CH 2 ;
  • R 1 is H, C1-C3 alkyl, C 2 -C 3 alkenyl or C 2 -C 3 alkynyl;
  • R 2 is selected from H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, -CN, -N 3 , - N(R 1 ) 2 , Ci-C 6 haloalkyl, Ci-C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and C3-C7 cycloalkyl;
  • R 3 is selected from C1-C6 alkyl, C3-C7 cycloalkyl, phenyl or benzyl, wherein said C3-C7 cycloalkyl group, said phenyl group and the phenyl moiety of said benzyl group can be optionally substituted with one or more R 5 groups;
  • R 4 is selected from C1-C6 alkyl, C2-C6 alkenyl, -(C1-C3 alkylene) m -(C 3 -Ci4 cycloalkyl) and -(C1-C3 alkylene) m -(C6-Cio aryl);
  • each occurrence of R 5 is independently selected from -C1-C6 alkyl, halo, -OR 6 , - C(0)R 6 , -CO2R 6 , -SR 6 , -Ci-C 6 hydroxyalkyl, -Ci-C 6 haloalkyl, -N(R 6 ) 2 , -S(0)R 6 , -S(0) 2 R 6 , -CN and -N0 2 ;
  • each occurrence of R 6 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -(C1-C3 alkylene) m -(C3-C 7 cycloalkyl), -(C1-C3 alkylene) m -(C 6 -Ci 0 aryl), -(C1-C3 alkylene) m -(4 to 7-membered heterocycloalkyl), -(C1-C3 alkylene) m -(5- or 6-membered monocyclic heteroaryl) or -(C1-C3 alkylene) m -(9- or 10-membered bicyclic heteroaryl);
  • R 7 , R 8 and R 9 are each independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, C3-C7 cycloalkyl, halo, -OR 10 , -SR 10 , -S(0)R 10 , -S(0) 2 R 10 , -S(O) 2 N(R 10 ) 2i - NHC(0)OR 10 , -NHC(0)N(R 14 ) 2 , Ci-C 6 haloalkyl, Ci-C 6 hydroxyalkyl, -0-(d-C 6 haloalkyl), - CN, -NO2, -N(R 10 ) 2 , -NH(Ci-C 6 alkylene)-(5- or 6-membered monocyclic heteroaryl), -NH(C C 6 alkylene)-(9- or 10-membered bicyclic heteroaryl), -C(0)R 10 , -C(0)OR
  • each occurrence of R 10 is independently selected from H, C1-C10 alkyl, C1-C6 haloalkyl, Ci-C 6 hydroxyalkyl, -(C1-C3 alkylene)n-(C 3 -C 7 cycloalkyl), -(C1-C3 alkylene) n -(C 6 -Cio aryl), -(C1-C 3 alkylene) n -(4 to 7-membered heterocycloalkyl), -(C1-C 3 alkylene) n -(5- or 6- membered monocyclic heteroaryl) and -(C1-C 3 alkylene) n -(9- or 10-membered bicyclic heteroaryl);
  • R 11 is selected C6-C1 0 aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10- membered bicyclic heteroaryl, wherein said C6-C1 0 aryl group, said 5 or 6-membered
  • monocyclic heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can be optionally substituted with one or more R 5 groups;
  • R 12 is selected from -0-(C6-Cio aryl), -0-(5 or 6-membered monocyclic heteroaryl) and -S-(C6-Cio aryl), wherein said 5 or 6-membered monocyclic heteroaryl group or any of said C6-C1 0 aryl groups can be optionally substituted with up to 5 groups, each independently selected from C1-C6 alkyl, -N0 2 , halo and C1-C6 haloalkyl;
  • R 13 is selected from H and C1-C6 alkyl
  • each occurrence of m is independently 0 or 1; and each occurrence of n is independently 0 or 1.
  • the present invention is directed to a process for making Phosphorus-Containing Nucleoside Prodrug Compounds of Formula (I) which may be useful for inhibiting HCV NS5B polymerase, inhibiting the replication of HCV and for the treatment or prophylaxis of HCV infection.
  • C ⁇ -Ce alkyl refers to an aliphatic hydrocarbon group, having from 1 to 6 carbon atoms wherein one of its hydrogen atoms is replaced with a bond.
  • a C1-C6 alkyl group may be straight or branched.
  • Non-limiting examples of C1-C6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl.
  • a C1-C6 alkyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH 2 , -NH(alkyl), - N(alkyl) 2 , -NH(cycloalkyl), -0-C(0)-alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl, -C(0)OH and - C(0)0-alkyl.
  • a C1-C6 alkyl group is linear.
  • a Ci- e alkyl group is branched. Unless otherwise indicated, a C1-C6 alkyl group is unsubstituted
  • alkenyl refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and having one of its hydrogen atoms replaced with a bond.
  • An alkenyl group may be straight or branched and contain from about 2 to about 15 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkenyl group contains from about 2 to about 6 carbon atoms.
  • Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3- methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
  • An alkenyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH 2 , -NH(alkyl), - N(alkyl) 2 , -NH(cycloalkyl), -0-C(0)-alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl, -C(0)OH and - C(0)0-alkyl.
  • C2-C6 alkenyl refers to an alkenyl group having from 2 to 6 carbon atoms. Unless otherwise indicated, an alkenyl group is unsubstituted.
  • alkylene refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a bond.
  • alkylene groups include -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, - CH(CH 3 )CH 2 CH 2 -, -CH(CH 3 )- and -CH 2 CH(CH 3 )CH 2 -.
  • an alkylene group has from 1 to about 6 carbon atoms.
  • an alkylene group is branched.
  • an alkylene group is linear.
  • an alkylene group is - CH 2 -.
  • C1-C6 alkylene refers to an alkylene group having from 1 to 6 carbon atoms.
  • C1-C3 alkylene refers to an alkylene group having from 1 to 3 carbon atoms.
  • C6-C10 aryl refers to phenyl and naphthyl. In one embodiment, an aryl group is phenyl.
  • cycloalkyl refers to a non-aromatic monocyclic or multicyclic ring system comprising from about 3 to about 14 ring carbon atoms.
  • 3 to 7-membered cycloalkyl refers to a monocyclic cycloalkyl group having from about 3 to about 7 ring carbon atoms.
  • Examples of “3 to 7-membered cycloalkyl” groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • 7 to 14-membered cycloalkyl refers to a multicyclic cycloalkyl group having from about 7 to about 14 ring carbon atoms.
  • Examples of “7 to 14-membered cycloalkyl” groups include, but are not limited to adamantyl and octahydro indene.
  • a cycloalkyl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • a cycloalkyl group is unsubstituted.
  • One or more ring carbon atoms of a cycloalkyl may be functionalized as a carbonyl group.
  • An illustrative example of such a cycloalkyl (also referred to herein as a "cycloalkanoyl” group) includes, but is not limited to, cyclobutanoyl:
  • halo refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).
  • 5 or 6-membered monocyclic heteroaryl refers to an aromatic monocyclic ring system comprising about 5 to about 6 ring atoms, wherein from 1 to 4 of the ring atoms is independently O, N or S and the remaining ring atoms are carbon atoms.
  • a 5 or 6-membered monocyclic heteroaryl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • a 5 or 6-membered monocyclic heteroaryl group is joined via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
  • 5 or 6-membered monocyclic heteroaryl also encompasses a 5 or 6-membered monocyclic heteroaryl group, as defined above, which is fused to a benzene ring.
  • Non-limiting examples of 5 or 6-membered monocyclic heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, imidazolyl, benzimid
  • 9 or 10-membered bicyclic heteroaryl refers to an aromatic bicyclic ring system comprising about 9 to about 10 ring atoms, wherein from 1 to 4 of the ring atoms is independently O, N or S and the remaining ring atoms are carbon atoms.
  • a 9 or 10-membered bicyclic heteroaryl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • a 9 or 10-membered bicyclic heteroaryl group is joined via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
  • Non-limiting examples of 9 or 10-membered bicyclic heteroaryls include imidazo[l ,2-a]pyridinyl, imidazo[2, l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, benzimidazolyl, quinazolinyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, benzothiazolyl, and the like, and all isomeric forms thereof. Unless otherwise indicated, a 9 or 10-membered bicyclic heteroaryl group is unsubstituted.
  • heterocycloalkyl refers to a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to about 11 ring atoms, wherein from 1 to 4 of the ring atoms are independently O, S, N or Si, and the remainder of the ring atoms are carbon atoms.
  • a heterocycloalkyl group can be joined via a ring carbon, ring silicon atom or ring nitrogen atom.
  • a heterocycloalkyl group is monocyclic and has from about 3 to about 7 ring atoms.
  • a heterocycloalkyl group is monocyclic has from about 4 to about 7 ring atoms.
  • a heterocycloalkyl group is bicyclic and has from about 7 to about 11 ring atoms. In still another embodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms. In one embodiment, a heterocycloalkyl group is monocyclic. In another embodiment, a heterocycloalkyl group is bicyclic. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Any -NH group in a heterocycloalkyl ring may exist protected such as, for example, as an -N(BOC), -N(Cbz), -N(Tos) group and the like; such protected heterocycloalkyl groups are considered part of this invention.
  • heterocycloalkyl also encompasses a heterocycloalkyl group, as defined above, which is fused to an aryl (e.g. , benzene) or heteroaryl ring.
  • a heterocycloalkyl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • the nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Non-limiting examples of monocyclic heterocycloalkyl rings include oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, delta-lactam, delta-lactone and the like, and all isomers thereof.
  • a ring carbon atom of a heterocycloalkyl group may be functionalized as a carbonyl group.
  • An illustrative example of such a heterocycloalkyl group is:
  • a heterocycloalkyl group is a 5-membered monocyclic heterocycloalkyl. In another embodiment, a heterocycloalkyl group is a 6-membered monocyclic heterocycloalkyl.
  • the term "3 to 6-membered monocyclic heterocycloalkyl” refers to a monocyclic heterocycloalkyl group having from 3 to 6 ring atoms.
  • the term "4 to 7- membered monocyclic heterocycloalkyl” refers to a monocyclic heterocycloalkyl group having from 4 to 7 ring atoms.
  • 7 to 1 1-membered bicyclic heterocycloalkyl refers to a bicyclic heterocycloalkyl group having from 7 to 1 1 ring atoms. Unless otherwise indicated, a heterocycloalkyl group is unsubstituted. Unless expressly stated to the contrary in a particular context, any of the various cyclic rings and ring systems described herein may be attached to the rest of the compound of which they are a part at any ring atom (i.e., any carbon atom or any heteroatom) provided that a stable compound results.
  • any variable occurs more than one time in a compound involved in the process of the invention (e.g., R5 or m)
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • combinations of substituents and/or variables are permissible only if such combinations result in a stable compound.
  • substitution by a named substituent is permitted on any atom in a ring (e.g., cycloalkyl, aryl, or heteroaryl) provided such ring substitution is chemically allowed and results in a stable compound.
  • a “stable” compound is one whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow its use in the processes of the invention.
  • a “stable” compound is a compound which can be prepared in accordance with the present invention and then isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for its intended purpose; e.g., for use as a synthetic intermediate to make compounds capable of inhibiting HCV NS5B polymerase, and to make medicinally useful compounds, such as compounds useful for treating HCV infection in a subject.
  • protecting groups When a functional group in a compound is termed "protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.
  • the Phosphorus-Containing Nucleoside Prodrug Compounds can form salts which are also within the scope of this invention.
  • the term "salt(s)”, as used herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • a Phosphorus-Containing Nucleoside Prodrug Compound contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts”) may be formed and are included within the term "salt(s)" as used herein.
  • the salt is a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt.
  • the salt is other than a pharmaceutically acceptable salt.
  • Salts of the Compounds of Formula (II) may be formed, for example, by reacting a Phosphorus-Containing Nucleoside Prodrug Compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, t-butyl amine, choline, and salts with amino acids such as arginine, lysine and the like.
  • alkali metal salts such as sodium, lithium, and potassium salts
  • alkaline earth metal salts such as calcium and magnesium salts
  • salts with organic bases for example, organic amines
  • organic bases for example, organic amines
  • amino acids such as arginine, lysine and the like.
  • Basic nitrogen- containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g., methyl, ethyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g., dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g., decyl, lauryl,
  • acid salts and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
  • the acid salts and base salts of the invention are intended to be pharmaceutically acceptable salts within the scope of the invention.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well-known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • Sterochemically pure compounds may also be prepared by using chiral starting materials or by employing salt resolution techniques.
  • some of the Phosphorus-Containing Nucleoside Prodrug may also be prepared by using chiral starting materials or by employing salt resolution techniques.
  • Atropisomers e.g., substituted biaryls
  • Enantiomers can also be directly separated using chiral chromatographic techniques, such as chiral HPLC.
  • Phosphorus-Containing Nucleoside Prodrug Compounds may exist in different tautomeric forms, and all such stable forms are embraced within the scope of the invention.
  • all stable keto-enol and imine-enamine forms of the compounds are included in the invention.
  • All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds including those of the salts, solvates, hydrates and esters of the compounds), such as those which may exist due to the presence of asymmetric carbon or phosphorus atoms, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention.
  • a Phosphorus-Containing Nucleoside Prodrug Compound incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • the use of the terms "salt”, “solvate”, “ester”, and the like, is intended to apply equally to the salt, solvate and ester of enantiomers, diastereomers, rotamers, tautomers or racemates of the inventive compounds.
  • the present invention is directed to a process for making Phosphorus-Containing
  • Nucleoside Prodrug Compounds of Formula (IV) which may be useful for inhibiting the replication of HCV and for the treatment or prophylaxis of HCV infection.
  • One aspect of the present invention is the process for making Compounds of Formula (IV) as set forth above in the Summary of the Invention ("Process A"):
  • B is a natural or non-natural purine or pyrimidine base, or B is selected from one of the following groups:
  • X is O, N, S or CH 2 ;
  • R 1 is H, C1-C3 alkyl, C 2 -C 3 alkenyl or C 2 -C 3 alkynyl;
  • R 2 is selected from H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, -CN, -N 3 , N(R 1 ) 2 , Ci-C 6 haloalkyl, Ci-C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and C3-C7 cycloalkyl;
  • R 3 is selected from C1-C6 alkyl, C3-C7 cycloalkyl, phenyl or benzyl, wherein said C3-C7 cycloalkyl group, said phenyl group and the phenyl moiety of said benzyl group can be optionally substituted with one or more R 5 groups;
  • R 4 is selected from C1-C6 alkyl, C2-C6 alkenyl, -(C1-C3 alkylene) m -(C 3 -Ci4 cycloalkyl) and -(C1-C3 alkylene) m -(C6-Cio aryl);
  • each occurrence of R 5 is independently selected from -C1-C6 alkyl, halo, -OR 6 , - C(0)R 6 , -CO2R 6 , -SR 6 , -Ci-C 6 hydroxyalkyl, -Ci-C 6 haloalkyl, -N(R 6 ) 2 , -S(0)R 6 , -S(0) 2 R 6 , -CN and -N0 2 ;
  • each occurrence of R 6 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -(C1-C3 alkylene) m -(C3-C 7 cycloalkyl), -(C1-C3 alkylene) m -(C 6 -Ci 0 aryl), -(C1-C3 alkylene) m -(4 to 7-membered heterocycloalkyl), -(C1-C3 alkylene) m -(5- or 6-membered monocyclic heteroaryl) or -(C1-C3 alkylene) m -(9- or 10-membered bicyclic heteroaryl);
  • R 7 , R 8 and R 9 are each independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, C3-C7 cycloalkyl, halo, -OR 10 , -SR 10 , -S(0)R 10 , -S(0) 2 R 10 , -S(O) 2 N(R 10 ) 2i - NHC(0)OR 10 , -NHC(0)N(R 14 ) 2 , Ci-C 6 haloalkyl, Ci-C 6 hydroxyalkyl, -0-(d-C 6 haloalkyl), - CN, -NO2, -N(R 10 ) 2 , -NH(Ci-C 6 alkylene)-(5- or 6-membered monocyclic heteroaryl), -NH(C C 6 alkylene)-(9- or 10-membered bicyclic heteroaryl), -C(0)R 10 , -C(0)OR
  • each occurrence of R 10 is independently selected from H, C1-C10 alkyl, C1-C6 haloalkyl, Ci-C 6 hydroxyalkyl, -(C1-C3 alkylene)n-(C 3 -C 7 cycloalkyl), -(C1-C3 alkylene) n -(C 6 -Cio aryl), -(C1-C 3 alkylene) n -(4 to 7-membered heterocycloalkyl), -(C1-C 3 alkylene) n -(5- or 6- membered monocyclic heteroaryl) and -(C1-C 3 alkylene) n -(9- or 10-membered bicyclic heteroaryl);
  • R 11 is selected C6-C1 0 aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10- membered bicyclic heteroaryl, wherein said C6-C1 0 aryl group, said 5 or 6-membered
  • monocyclic heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can be optionally substituted with one or more R 5 groups;
  • R 12 is selected from -0-(C6-Cio aryl), -0-(5 or 6-membered monocyclic heteroaryl) and -S-(C6-Cio aryl), wherein said 5 or 6-membered monocyclic heteroaryl group or any of said C6-C1 0 aryl groups can be optionally substituted with up to 5 groups, each independently selected from C1-C6 alkyl, -N0 2 , halo and C1-C6 haloalkyl;
  • R 13 is selected from H and C1-C6 alkyl
  • each occurrence of m is independently 0 or 1; and each occurrence of n is independently 0 or 1.
  • Step A organic solvent A is selected from ethyl acetate, NMP, THF, 2-methyl THF, DMF, DCM, acetonitrile, IP AC, DME, DMSO and mixtures thereof.
  • Step A organic solvent A is THF.
  • Step A organic solvent A is a mixture of THF and DMF.
  • Step A organic solvent A is a mixture of ethyl acetate and NMP.
  • Process A, Step A can be conducted in any organic solvent.
  • the non-nucleophilic base used in Process A, Step A is an organic amine base.
  • non-nucleophilic base used in Process A, Step A is selected from DBU, TMG, DBN, MTBD and DMAP.
  • non-nucleophilic base used in Process A, Step A is
  • the non-nucleophilic base used in Process A, Step A is DBU and organic solvent A is THF.
  • Process A, Step A is conducted at a temperature in a range of from about -20°C to about 70°C.
  • Process A is conducted at a temperature in a range of from about -10°C to about 40°C.
  • Process A is conducted at a temperature in a range of from about 0°C to about 30°C.
  • Process A is conducted at a temperature in a range of from about 0°C to about 15°C.
  • Process A, Step A is conducted at a reaction about 0°C.
  • the non-nucleophilic base used in Process A, Step A is used in an amount of about 1 to about 1.5 molar equivalents.
  • non-nucleophilic base used in Process A, Step A is used in an amount of about 1 to about 1.3 molar equivalents. In another embodiment, the non-nucleophilic base used in Process A, Step A is used in an amount of about 1 to about 1.2 molar equivalents.
  • non-nucleophilic base used in Process A, Step A is used in an amount of about 1 to about 1.1 molar equivalents.
  • non-nucleophilic base used in Process A, Step A is used in an amount of about 1 molar equivalent.
  • Step A For Process A, Step A:
  • the organic solvent A is THF, DMF, EtOAc, NMP or a mixture thereof;
  • the base used is selected from DBU, TMG, DBN, MTBD and DMAP; and the process is conducted at a temperature in a range of from about -20°C to about
  • Step A In another embodiment, for Process A, Step A:
  • the organic solvent A is THF or a solvent mixture comprising THF; the base used is DBU;
  • the process is conducted at a temperature in a range of from about -10°C to about
  • R 12 is -O-phenyl, -O-pyridyl or -S-phenyl wherein said phenyl or pyridyl groups can each be optionally substituted with up to 5 groups, each independently selected from C1-C6 alkyl, -N0 2 , halo and Ci-C 6 haloalkyl;
  • R 3 is -Ci-C 6 alkyl
  • R 4 is -Ci-C 6 alkyl.
  • the organic solvent A is THF
  • the base used is DBU
  • the process is conducted at a temperature in a range of from about -10°C to about 40°C;
  • the compound of formula (I) used has the formula (la ' ), (la"), (lb') or (lb"):
  • R is pentafluorophenoxy
  • R 3 is -Ci-C 6 alkyl
  • R 4 is -Ci-C 6 alk l.
  • Step A In another embodiment, for Process A, Step A:
  • the organic solvent A is THF
  • the base used is DBU
  • the process is conducted at a temperature in a range of from about 0°C to about
  • the compound of formula (I) used has the formula (la ' ), (la"), (lb') or (lb"):
  • R is pentafluorophenoxy
  • R 3 is methyl
  • R 4 isopropyl
  • organic solvent B is selected from DMF, 2-methyl-THF, CPME, acetonitrile, NMP, THF and mixtures thereof.
  • organic solvent B is acetonitrile.
  • organic solvent B is a mixture of DMF and 2-methyl-THF.
  • Process A, Step B can be conducted in any organic solvent.
  • the non-nucleophilic base used in Process A, Step B is an organic amine base.
  • non-nucleophilic base used in Process A, Step B is an alkali metal alkoxide base.
  • non-nucleophilic base used in Process A, Step B is a silyl-containing amide base.
  • non-nucleophilic base used in Process A, Step B is selected from DBU, DBN, TMG, TMP, ⁇ , ⁇ -dicyclohexylmethyl amine, NaOMe, NaOtBu, KOtBu and LiHMDS. In another embodiment, the non-nucleophilic base used in Process A, Step B is
  • the non-nucleophilic base used in Process A, Step B is DBU and organic solvent B is acetonitrile.
  • the non-nucleophilic base used in Process A, Step B is DBU and organic solvent B is a mixture of DMF and 2-methyl-THF.
  • the non-nucleophilic base used in Process A, Step B is used in an amount of about 1.5 to about 5 molar equivalents.
  • non-nucleophilic base used in Process A, Step B is used in an amount of about 2 to about 4 molar equivalents.
  • the non-nucleophilic base used in Process A, Step B is used in an amount of about 2.5 to about 3.5 molar equivalents.
  • the non-nucleophilic base used in Process A, Step B is used in an amount of about 3 to about 3.5 molar equivalents.
  • the non-nucleophilic base used in Process A, Step B is used in an amount of about 2 molar equivalents.
  • non-nucleophilic base used in Process A, Step B is used in an amount of about 2.5 molar equivalents.
  • non-nucleophilic base used in Process A, Step B is used in an amount of about 3 molar equivalents.
  • non-nucleophilic base used in Process A, Step B is used in an amount of about 3.5 molar equivalents.
  • Process A, Step B is conducted at a temperature in a range of from about -20°C to about 70°C.
  • Process A, Step B is conducted at a temperature in a range of from about -10°C to about 40°C.
  • Process A, Step B is conducted at a temperature in a range of from about 0°C to about 30°C.
  • Process A, Step B is conducted at a temperature in a range of from about 0°C to about 15°C.
  • Process A, Step B is conducted at a reaction about 0°C.
  • Step B the organic solvent B is selected from DMF, 2-methyl-THF, CPME, acetonitrile, NMP, THF and mixtures thereof ;
  • the base used is an organic amine
  • the process is conducted at a temperature in a range of from about -20°C to about 70°C.
  • Step B In another embodiment, for Process A, Step B:
  • the organic solvent B is selected from DMF, 2-methyl-THF, CPME, acetonitrile, NMP, THF and mixtures thereof;
  • the base used is selected from DBU, DBN, TMG, TMP, N,N-dicyclohexylmethyl amine, NaOMe, NaOtBu, KOtBu and LiHMDS; and
  • the process is conducted at a temperature in a range of from about -10°C to about
  • Step B
  • the organic solvent A is a mixture of DMF and 2-methyl-THF;
  • the base used is DBU, DBN, TMG, TMP, ⁇ , ⁇ -dicyclohexylmethyl amine, NaOMe, NaOtBu, KOtBu and LiHMDS;
  • the process is conducted at a temperature in a range of from about 0°C to about 20°C.
  • Step B In another embodiment, for Process A, Step B:
  • the organic solvent A is a mixture of DMF and 2-methyl-THF;
  • the base used is DBU
  • the process is conducted at a temperature in a range of from about 0°C to about
  • the base is present in an amount of from about 2.5 molar equivalents to about 3.5 molar equivalents.
  • X is O.
  • B is a natural or non-natural pyrimidine base. In another embodiment, B is:
  • R 1 is selected from C1-C6 alkyl and C2-C6 alkynyl.
  • R 1 is C1-C3 alkyl.
  • R 1 is methyl
  • R 1 is -C ⁇ CH.
  • R 2 is selected from C2-C6 alkenyl, -CI, -F, -CN, -N 3 and -
  • R 2 is -C ⁇ CH.
  • R 2 is -CI.
  • R 2 is -F.
  • R 2 is -CN.
  • R 2 is -N 3 .
  • R 2 is -NH 2 .
  • R 1 is methyl and R 2 is selected from C2-C6 alkenyl, -CI, -F, - CN, -N 3 and -NH 2 .
  • R 1 is methyl and R 2 is -CI.
  • R 1 is methyl and R 2 is -F.
  • R 1 is methyl and R 2 is -CN.
  • R 1 is methyl and R 2 is -N 3 .
  • R 1 is methyl and R 2 is -NH 2 .
  • R 3 is Ci-Ce alkyl.
  • R 4 is Ci-Ce alkyl.
  • R 3 and R 4 are each independently Ci-Ce alkyl. In another embodiment, R 3 is methyl.
  • R 4 isopropyl
  • R 3 is methyl and R 4 isopropyl.
  • R 8 is H.
  • R 11 is C6-C1 0 aryl, which can be optionally substituted as set forth in formula (I) of Process A.
  • R 11 is unsubstituted phenyl.
  • R 11 is unsubstituted phenyl, R 3 is methyl and R 4 isopropyl.
  • R 12 is -0-(C6-Cio aryl), which can be optionally substituted with up to 5 groups, each independently selected from -NO2 and halo.
  • R 12 is -0-(5 or 6-membered monocyclic heteroaryl), which can be optionally substituted with up to 5 groups, each independently selected from halo.
  • R 12 is -S-(C6-Cio aryl), which can be optionally substituted with up to 5 groups, each independently selected from halo.
  • R 12 is -O-phenyl or -O-pyridyl, each of which can be optionally substituted with up to 5 groups, each independently selected from F, CI and -N0 2 .
  • R 12 is pentafluorophenoxy.
  • R 12 is:
  • R 11 is unsubstituted phenyl
  • R 12 is pentafluorophenyl
  • R 3 is methyl
  • R 4 isopropyl
  • R 1 is methyl
  • R 2 is selected from C2-C6 alkenyl, -CI, -F, -CN, -N 3 and -NH 2
  • X is O
  • B is:
  • R 1 is methyl
  • R 2 is selected from C2-C6 alkenyl, -CI, -F, - CN, -N3 and -NH2
  • R 3 and R 4 are each independently Ci-Ce alkyl
  • X is O
  • B is:
  • R 1 is methyl; R 2 is selected from C2-C6 alkenyl, -CI,
  • R 3 and R 4 are each independently C1-C6 alkyl;
  • X is O; and
  • B is:
  • R 1 is methyl; R 2 is selected from C2-C6 alkenyl, -CI, -F,
  • R 3 and R 4 are each independently C1-C6 alkyl; R n is phenyl; X is O; and B is:
  • R 1 is methyl
  • R 2 is selected from C2-C6 alkenyl, -CI, F, -CN, -N 3 and -NH 2
  • R 3 and R 4 are each independently Ci-C 6 alkyl
  • R 11 is phenyl
  • R 12 is pentafluorophenoxy
  • X is O
  • B is:
  • the compound of formula (I) used in Process A has the formula (la) or (lb):
  • R 3 is -Ci-C 6 alkyl
  • R 4 is -Ci-C 6 alkyl
  • R 12 is selected from -0-(C6-Cio aryl), -0-(5 or 6-membered monocyclic heteroaryl) and -S-(C6-Cio aryl), wherein said 5 or 6-membered monocyclic heteroaryl group or any of said C6-C1 0 aryl groups can be optionally substituted with up to 5 groups, each independently selected from C1-C6 alkyl, -N0 2 , halo and C1-C6 haloalkyl.
  • the compound of formula (I) used in Process A has the formula (la'), (la"), (lb') or (lb"):
  • R 3 is -Ci-C 6 alkyl
  • R 4 is -Ci-C 6 alkyl; and R is selected from -0-(C6-Cio aryl), -0-(5 or 6-membered monocyclic heteroaryl) and -S-(C6-Cio aryl), wherein said 5 or 6-membered monocyclic heteroaryl group or any of said C6-C10 aryl groups can be optionally substituted with up to 5 groups, each independently selected from C1-C6 alkyl, -N0 2 , halo and C1-C6 haloalkyl.
  • the compound of formula (I) used in Process A is selected from:
  • the compound of formula (I) used in Process A is:
  • the compound of formula (II) used in Process A is a compound of formula (Ila):
  • the present invention provides a process (“Process B") for making a compound of formula (III):
  • B is a natural or non-natural purine or pyrimidine base, or B is selected from of the following
  • X is O, N, S or CH 2 ;
  • R 1 is H, C1-C3 alkyl, C 2 -C 3 alkenyl or C 2 -C 3 alkynyl;
  • R 2 is selected from H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, -CN, -N 3 , - N(R 1 ) 2 , Ci-C 6 haloalkyl, Ci-C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and C3-C7 cycloalkyl;
  • R 3 is selected from C1-C6 alkyl, C3-C7 cycloalkyl, phenyl or benzyl, wherein said C3-C7 cycloalkyl group, said phenyl group and the phenyl moiety of said benzyl group can be optionally substituted with one or more R 5 groups;
  • R 4 is selected from C1-C6 alkyl, C 2 -C6 alkenyl, -(C1-C3 alkylene) m -(C 3 -Ci4 cycloalkyl) and -(C1-C3 alkylene) m -(C6-Cio aryl);
  • each occurrence of R 5 is independently selected from -C1-C6 alkyl, halo, -OR 6 , - C(0)R 6 , -C0 2 R 6 , -SR 6 , -Ci-C 6 hydroxyalkyl, -Ci-C 6 haloalkyl, -N(R 6 ) 2 , -S(0)R 6 , -S(0) 2 R 6 , -CN and -N0 2 ;
  • each occurrence of R 6 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -(C1-C 3 alkylene) m -(C 3 -C7 cycloalkyl), -(C1-C 3 alkylene) m -(C 6 -Cio aryl), -(C1-C 3 alkylene) m -(4 to 7-membered heterocycloalkyl), -(C1-C 3 alkylene) m -(5- or 6-membered monocyclic heteroaryl) or -(C1-C 3 alkylene) m -(9- or 10-membered bicyclic heteroaryl); R 7 , R 8 and R 9 are each independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, C3-C7 cycloalkyl, hal
  • each occurrence of R 10 is independently selected from H, C1-C1 0 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -(C1-C3 alkylene) n -(C 3 -C7 cycloalkyl), -(C1-C3 alkylene) n -(C 6 -Cio aryl), -(C1-C3 alkylene) n -(4 to 7-membered heterocycloalkyl), -(C1-C3 alkylene) n -(5- or 6- membered monocyclic heteroaryl) and -(C1-C3 alkylene) n -(9- or 10-membered bicyclic heteroaryl);
  • R 11 is selected C6-C10 aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10- membered bicyclic heteroaryl, wherein said C6-C1 0 aryl group, said 5 or 6-membered
  • monocyclic heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can be optionally substituted with one or more R 5 groups;
  • R 12 is selected from -0-(C6-Cio aryl), -0-(5 or 6-membered monocyclic heteroaryl) and -S-(C6-Cio aryl), wherein said 5 or 6-membered monocyclic heteroaryl group or any of said C6-C1 0 aryl groups can be optionally substituted with up to 5 groups, each independently selected from C1-C6 alkyl, -N0 2 , halo and C1-C6 haloalkyl;
  • R 13 is selected from H and C1-C6 alkyl
  • m is independently 0 or 1 ;
  • n is independently 0 or 1.
  • organic solvent A is selected from ethyl acetate, NMP, THF, 2-methyl THF, DMF, DCM, acetonitrile, IP AC, DME, DMSO and mixtures thereof.
  • organic solvent A is THF.
  • organic solvent A is a mixture of THF and
  • organic solvent A is a mixture of ethyl acetate and NMP.
  • Process B can be conducted in any organic solvent.
  • the non-nucleophilic base used in Process B is an organic amine base.
  • the non-nucleophilic base used in Process B is selected from DBU, TMG, DBN, MTBD and DMAP.
  • the non-nucleophilic base used in Process B is DBU.
  • the non-nucleophilic base used in Process B is DBU and organic solvent A is THF.
  • Process B is conducted at a temperature in a range of from about -20°C to about 70°C.
  • Process B is conducted at a temperature in a range of from about -10°C to about 40°C.
  • Process B is conducted at a temperature in a range of from about 0°C to about 30°C.
  • Process B is conducted at a temperature in a range of from about 0°C to about 15°C.
  • Process B is conducted at a temperature of about 0°C.
  • the non-nucleophilic base used in Process B is used in an amount of about 1 to about 1.5 molar equivalents.
  • the non-nucleophilic base used in Process B is used in an amount of about 1 to about 1.3 molar equivalents.
  • the non-nucleophilic base used in Process B is used in an amount of about 1 to about 1.2 molar equivalents.
  • the non-nucleophilic base used in Process B is used in an amount of about 1.1 molar equivalents.
  • the non-nucleophilic base used in Process B is used in an amount of about 1 molar equivalent.
  • the organic solvent A is THF, DMF, EtOAc, NMP or a mixture thereof;
  • the base used is selected from DBU, TMG, DBN, MTBD and DMAP; and the process is conducted at a temperature in a range of from about -20°C to about
  • Process B for Process B:
  • the organic solvent A is THF or a solvent mixture comprising THF; the base used is DBU;
  • the process is conducted at a temperature in a range of from about -10°C to about
  • R is -O-phenyl, -O-pyridyl or -S-phenyl wherein said phenyl or pyridyl groups can each be optionally substituted with up to 5 groups, each independently selected from C1-C6 alkyl, -N0 2 , halo and C1-C6 haloalkyl;
  • R 3 is -Ci-C 6 alkyl
  • R 4 is -Ci-C 6 alkyl.
  • the organic solvent A is THF
  • the base used is DBU
  • the process is conducted at a temperature in a range of from about -10°C to about
  • the compound of formula (I) used has the formula (la'), (la"), (lb') or (lb"):
  • R 12 is pentafluorophenoxy
  • R 3 is -Ci-C 6 alkyl
  • R 4 is -Ci-C 6 alkyl.
  • the organic solvent A is THF
  • the base used is DBU
  • the process is conducted at a temperature in a range of from about 0°C to about
  • the compound of formula (I) used has the formula (la'), (la"), (lb') or (lb"):
  • R is pentafluorophenoxy
  • R 3 is methyl
  • R 4 isopropyl
  • the present invention provides an altemate method ("Process C") for makin mpound of formula (IV):
  • B is a natural or non-natural purine or pyrimidine base, or B is selected from of the following groups:
  • X is O, N, S or CH 2 ;
  • R 1 is H, C1-C3 alkyl, C 2 -C 3 alkenyl or C 2 -C 3 alkynyl;
  • R 2 is selected from H, d-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, -CN, -N 3 , N(R 1 ) 2 , Ci-C 6 haloalkyl, Ci-C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and C3-C7 cycloalkyl;
  • R 3 is selected from C1-C6 alkyl, C3-C7 cycloalkyl, phenyl or benzyl, wherein said
  • R 4 is selected from C1-C6 alkyl, C 2 -C6 alkenyl, -(C1-C3 alkylene) m -(C 3 -Ci4 cycloalkyl) and -(C1-C3 alkylene) m -(C6-Cio aryl);
  • each occurrence of R 5 is independently selected from -C1-C6 alkyl, halo, -OR 6 , - C(0)R 6 , -C0 2 R 6 , -SR 6 , -Ci-C 6 hydroxyalkyl, -Ci-C 6 haloalkyl, -N(R 6 ) 2 , -S(0)R 6 , -S(0) 2 R 6 , -CN and -N0 2 ;
  • each occurrence of R 6 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -(C1-C3 alkylene) m -(C3-C 7 cycloalkyl), -(C1-C3 alkylene) m -(C 6 -Ci 0 aryl), -(C1-C3 alkylene) m -(4 to 7-membered heterocycloalkyl), -(C1-C3 alkylene) m -(5- or 6-membered monocyclic heteroaryl) or -(C1-C3 alkylene) m -(9- or 10-membered bicyclic heteroaryl);
  • R 7 , R 8 and R 9 are each independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, C3-C7 cycloalkyl, halo, -OR 10 , -SR 10 , -S(0)R 10 , -S(0) 2 R 10 , -S(O) 2 N(R 10 ) 2i - NHC(0)OR 10 , -NHC(0)N(R 14 ) 2 , Ci-C 6 haloalkyl, Ci-C 6 hydroxyalkyl, -0-(Ci-C 6 haloalkyl), - CN, -NO2, -N(R 10 ) 2 , -NH(Ci-C 6 alkylene)-(5- or 6-membered monocyclic heteroaryl), -NH(C C 6 alkylene)-(9- or 10-membered bicyclic heteroaryl), -C(0)R 10 , -C(0)
  • each occurrence of R 10 is independently selected from H, C1-C10 alkyl, C1-C6 haloalkyl, Ci-C 6 hydroxyalkyl, -(C1-C3 alkylene)n-(C 3 -C 7 cycloalkyl), -(C1-C3 alkylene) n -(C 6 -Cio aryl), -(C1-C3 alkylene) n -(4 to 7-membered heterocycloalkyl), -(C1-C3 alkylene) n -(5- or 6- membered monocyclic heteroaryl) and -(C1-C3 alkylene) n -(9- or 10-membered bicyclic heteroaryl);
  • R 11 is selected C6-C10 aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10- membered bicyclic heteroaryl, wherein said C6-C10 aryl group, said 5 or 6-membered
  • monocyclic heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can be optionally substituted with one or more R 5 groups;
  • R 12 is selected from -0-(C6-Cio aryl), -0-(5 or 6-membered monocyclic heteroaryl) and -S-(C6-Cio aryl), wherein said 5 or 6-membered monocyclic heteroaryl group or any of said C6-C10 aryl groups can be optionally substituted with up to 5 groups, each independently selected from C1-C6 alkyl, -N0 2 , halo and C1-C6 haloalkyl;
  • R 13 is selected from H and C1-C6 alkyl
  • m is independently 0 or 1 ;
  • n is independently 0 or 1.
  • organic solvent C is selected from ethyl acetate, acetonitrile, NMP, THF, 2-methyl THF, DMF, DCM, acetonitrile, IP AC, DME, DMSO and mixtures thereof.
  • organic solvent C is selected from acetonitrile, NMP, THF, 2-methyl THF, DMF and mixtures thereof.
  • organic solvent C is a mixture of 2- methyl-THF and DMF.
  • organic solvent C is acetonitrile. In yet another embodiment, for Process C, can be conducted in any organic solvent.
  • the non-nucleophilic base used is an organic amine base.
  • the non-nucleophilic base used is selected from DBU, TMG, DBN, MTBD and DMAP.
  • the non-nucleophilic base used is DBU.
  • the non-nucleophilic base used is DBU and organic solvent C is THF.
  • Process C is conducted at a temperature in a range of from about -30°C to about 50°C.
  • Process C is conducted at a temperature in a range of from about -20°C to about 40°C.
  • Process C is conducted at a temperature in a range of from about -15°C to about 20°C.
  • Process C is conducted at a temperature in a range of from about -15°C to about 0°C.
  • Process C is conducted at a temperature in a range of from about -10°C to about 10°C.
  • Process C is conducted at a reaction about -15°C.
  • Process C is conducted at a reaction about 0°C.
  • the non-nucleophilic base used in Process C is used in an amount of about 1.5 to about 5 molar equivalents.
  • the non-nucleophilic base used in Process C is used in an amount of about 2 to about 4 molar equivalents.
  • the non-nucleophilic base used in Process C is used in an amount of about 2.5 to about 3.5 molar equivalents.
  • the non-nucleophilic base used in Process C is used in an amount of about 3 to about 3.5 molar equivalents.
  • the non-nucleophilic base used in Process C is used in an amount of about 2 molar equivalents.
  • non-nucleophilic base used in Process C is used in an amount of about 2.5 molar equivalents. In another embodiment, the non-nucleophilic base used in Process C is used in an amount of about 3 molar equivalents.
  • the non-nucleophilic base used in Process C is used in an amount of about 3.5 molar equivalents.
  • the organic solvent C is selected from acetonitrile, NMP, THF, 2-methyl THF, DMF and mixtures thereof;
  • the base used is an organic amine
  • the process is conducted at a temperature in a range of from about -30°C to about
  • the organic solvent C is acetonitrile
  • the base used is selected from DBU, TMG, DBN, MTBD and DMAP;
  • the process is conducted at a temperature in a range of from about -20°C to about
  • the organic solvent C is acetonitrile
  • the base used is DBU
  • the process is conducted at a temperature in a range of from about -15°C to about
  • the compound of formula (I) used has the formula (la'), (la"), (lb') or (lb"):
  • R 12 is pentafluorophenoxy
  • R 3 is -Ci-C 6 alkyl
  • R 4 is -Ci-C 6 alkyl.
  • the compound of formula (IV) that is made by Process A or Process C is selected from:
  • the compound of formula (II) that is made by Process A or Process B is selected from:
  • Methyl-THF (2.0 mL) was cooled to 0 °C, then to the cooled mixture was added a solution of compound 2 (1.0 g, 1.8 mmol) in a mixture of DMF (1.2 mL) and 2-Methyl-THF (0.9 mL).
  • the internal reaction temperature was kept below 5 °C during addition and then the reaction was allowed to warm to room temperature and allowed to stir overnight.
  • the reaction was then quenched by addition of 0.5 M citric acid and diluted with EtOAc.
  • the organic layer was removed and the aqueous layer was back extracted twice with EtOAc. The combined organic layers were washed with 10% aqueous LiCl twice and then concentrated in vacuo.

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Abstract

La présente invention se réfère à des procédés de production de composés représentés par la formule (IV) : (IV), et à des sels de ceux-ci. Dans la formule, B, X, R1, R2, R3 et R4 sont tels que définis dans la description.
PCT/US2016/043806 2015-07-29 2016-07-25 Procédé de production de composés de promédicaments nucléosidiques contenant du phosphore WO2017019581A1 (fr)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2023081105A1 (fr) * 2021-11-02 2023-05-11 Ligand Pharmaceuticals Incorporated Composés phosphoramidates cycliques

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US8772503B2 (en) * 2009-12-07 2014-07-08 Mapi Pharma Ltd. Processes for the preparation of deferasirox, and deferasirox polymorphs
US20140205566A1 (en) * 2012-11-30 2014-07-24 Novartis Ag Cyclic nucleuoside derivatives and uses thereof

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Publication number Priority date Publication date Assignee Title
US20100298257A1 (en) * 2009-05-20 2010-11-25 Pharmasset, Inc. Nucleoside phosphoramidates
US8772503B2 (en) * 2009-12-07 2014-07-08 Mapi Pharma Ltd. Processes for the preparation of deferasirox, and deferasirox polymorphs
US20140205566A1 (en) * 2012-11-30 2014-07-24 Novartis Ag Cyclic nucleuoside derivatives and uses thereof

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TONN, VC ET AL.: "Solid-Phase Synthesis of (Poly)phosphorylated Nucleosides and Conjugates.", CHEMISTRY, A EUROPEAN JOURNAL, vol. 17, 2011, pages 9832 - 9842, XP055058215 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023081105A1 (fr) * 2021-11-02 2023-05-11 Ligand Pharmaceuticals Incorporated Composés phosphoramidates cycliques

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