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`\..
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`03956.054600.5
`Bruce S. Ross
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`NUCLEOSTDE PHOSPHORAMTDA TES
`
`Priority
`
`This application is a continuation-in-part of U.S. Patent Application No.
`
`5
`
`12/783,680 filed on May 20, 2010, which claims priority to US 61/179,923, filed May 20,
`
`2009 and US 61/319,513, filed on March 31, 2010. Priority is claimed to US 61/319,513,
`
`filed on March 31, 2010 and US 61/319,548, filed March 31, 2010.
`
`Field of the Invention
`
`Disclosed herein are nucleoside phosphoramidates and their use as agents for
`
`treating viral diseases. These compounds are inhibitors of RNA-dependent RNA viral
`
`replication and are useful as inhibitors ofHCV NS5B polymerase, as inhibitors ofHCV
`
`replication and for treatment of hepatitis C infection in mammals.
`
`10
`
`15
`
`Background
`
`Hepatitis C virus (HCV) infection is a major health problem that leads to chronic
`
`liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of
`
`20
`
`infected individuals, estimated to be 2-15% of the world's population. There are an
`
`estimated 4.5 million infected people in the United States alone, according to the U.S.
`
`Center for Disease Control. According to the World Health Organization, there are more
`
`than 200 million infected individuals worldwide, with at least 3 to 4 million people being
`
`infected each year. Once infected, about 20% of people clear the virus, but the rest can
`
`25
`
`harbor HCV the rest of their lives. Ten to twenty percent of chronically infected
`
`individuals eventually develop liver-destroying cirrhosis or cancer. The viral disease is
`
`transmitted parenterally by contaminated blood and blood products, contaminated
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`needles, or sexually and vertically from infected mothers or carrier mothers to their
`
`offspring. Current treatments for HCV infection, which are restricted to immunotherapy
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`30 with recombinant interferon-a alone or in combination with the nucleoside analog
`
`ribavirin, are of limited clinical benefit. Moreover, there is no established vaccine for
`
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`Docket No. 60137.0045USI1
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`HCV. Consequently, there is an urgent need for improved therapeutic agents that
`
`effectively combat chronic HCV infection.
`
`The HCV virion is an enveloped positive-strand RNA virus with a single
`
`oligoribonucleotide genomic sequence of about 9600 bases which encodes a polyprotein
`
`5
`
`of about 3,010 amino acids. The protein products of the HCV gene consist of the
`
`structural proteins C, El, and E2, and the non-structural proteins NS2, NS3, NS4A and
`
`NS4B, and NS5A and NS5B. The nonstructural (NS) proteins are believed to provide the
`
`catalytic machinery for viral replication. The NS3 protease releases NS5B, the RNA(cid:173)
`
`dependent RNA polymerase from the polyprotein chain. HCV NS5B polymerase is
`
`10
`
`required for the synthesis of a double-stranded RNA from a single-stranded viral RNA
`
`that serves as a template in the replication cycle ofHCV. Therefore, NS5B polymerase is
`
`considered to be an essential component in the HCV replication complex (K. Ishi, et al,
`
`Heptology, 1999, 29: 1227-1235; V. Lohmann, et al., Virology, 1998, 249: 108-118).
`
`Inhibition ofHCV NS5B polymerase prevents formation of the double-stranded HCV
`
`15
`
`RNA and therefore constitutes an attractive approach to the development ofHCV(cid:173)
`
`specific antiviral therapies.
`
`HCV belongs to a much larger family of viruses that share many common
`
`features.
`
`Flaviviridae Viruses
`
`20
`
`The Flaviviridae family of viruses comprises at least three distinct genera:
`
`pestiviruses, which cause disease in cattle and pigs;jlavivruses, which are the primary
`
`cause of diseases such as dengue fever and yellow fever; and hepaciviruses, whose sole
`
`member is HCV. The flavivirus genus includes more than 68 members separated into
`
`groups on the basis of serological relatedness (Calisher et al., J Gen. Viral, 1993,70,37-
`
`25
`
`43). Clinical symptoms vary and include fever, encephalitis and hemorrhagic fever
`
`(Fields Virology, Editors: Fields, B. N., Knipe, D. M., and Howley, P. M., Lippincott(cid:173)
`
`Raven Publishers, Philadelphia, PA, 1996, Chapter 31, 931-959). Flaviviruses of global
`
`concern that are associated with human disease include the Dengue Hemorrhagic Fever
`
`viruses (DHF), yellow fever virus, shock syndrome and Japanese encephalitis virus
`
`30
`
`(Halstead, S. B., Rev. Infect. Dis., 1984, 6, 251-264; Halstead, S. B., Science, 239:476-
`
`481, 1988; Monath, T. P., New Eng. J Med, 1988, 319, 64 1-643).
`
`2
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`Docket No. 60137.0045USI1
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`The pestivirus genus includes bovine viral diarrhea virus (BVDV), classical swine
`
`fever virus (CSFV, also called hog cholera virus) and border disease virus (BDV) of
`
`sheep (Moennig, V. et al. Adv. Vir. Res. 1992, 41, 53-98). Pestivirus infections of
`
`domesticated livestock ( cattle, pigs and sheep) cause significant economic losses
`
`5 worldwide. BVDV causes mucosal disease in cattle and is of significant economic
`
`importance to the livestock industry (Meyers, G. and Thiel, H.J., Advances in Virus
`
`Research, 1996, 47, 53-118; Moennig V., et al, Adv. Vir. Res. 1992, 41, 53-98). Human
`
`pestiviruses have not been as extensively characterized as the animal pestiviruses.
`
`However, serological surveys indicate considerable pestivirus exposure in humans.
`
`10
`
`Pestiviruses and hepaciviruses are closely related virus groups within the
`
`Flaviviridae family. Other closely related viruses in this family include the GB virus A,
`
`GB virus A-like agents, GB virus-Band GB virus-C (also called hepatitis G virus, HGV).
`
`The hepacivirus group (hepatitis C virus; HCV) consists of a number of closely related
`
`but genotypically distinguishable viruses that infect humans. There are at least 6 HCV
`
`15
`
`genotypes and more than 50 subtypes. Due to the similarities between pestiviruses and
`
`hepaciviruses, combined with the poor ability of hepaciviruses to grow efficiently in cell
`
`culture, bovine viral diarrhea virus (BVDV) is often used as a surrogate to study the HCV
`
`virus.
`
`The genetic organization of pestiviruses and hepaciviruses is very similar. These
`
`20
`
`positive stranded RNA viruses possess a single large open reading frame (ORF) encoding
`
`all the viral proteins necessary for virus replication. These proteins are expressed as a
`
`polyprotein that is co- and post-translationally processed by both cellular and virus(cid:173)
`
`encoded proteinases to yield the mature viral proteins. The viral proteins responsible for
`
`the replication of the viral genome RNA are located within approximately the carboxy-
`
`25
`
`terminal. Two-thirds of the ORF are termed nonstructural (NS) proteins. The genetic
`
`organization and polyprotein processing of the nonstructural protein portion of the ORF
`
`for pestiviruses and hepaciviruses is very similar. For both the pestiviruses and
`
`hepaciviruses, the mature nonstructural (NS) proteins, in sequential order from the
`
`amino-terminus of the nonstructural protein coding region to the carboxy-terminus of the
`
`30 ORF, consist of p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B.
`
`3
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`Docket No. 60137.0045USI1
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`The NS proteins of pestiviruses and hepaciviruses share sequence domains that
`
`are characteristic of specific protein functions. For example, the NS3 proteins of viruses
`
`in both groups possess amino acid sequence motifs characteristic of serine proteinases
`
`and ofhelicases (Gorbalenya et al., Nature, 1988, 333, 22; Bazan and Fletterick Virology,
`
`5
`
`1989, 171, 637-639; Gorbalenya et al., Nucleic Acid Res., 1989, 17, 3889-3897).
`
`Similarly, the NS5B proteins of pestiviruses and hepaciviruses have the motifs
`
`characteristic of RNA-directed RNA polymerases (Koonin, E.V. and Dolja, V.V., Crir.
`
`Rev. Biochem. Malec. Biol. 1993, 28, 375-430).
`
`The actual roles and functions of the NS proteins of pestiviruses and
`
`10
`
`hepaciviruses in the lifecycle of the viruses are directly analogous. In both cases, the NS3
`
`serine proteinase is responsible for all proteolytic processing of polyprotein precursors
`
`downstream of its position in the ORF (Wiskerchen and Collett, Virology, 1991, 184,
`
`341-350; Bartenschlager et al., J Viral. 1993, 67, 3835-3844; Eckart et al. Biochem.
`
`Biophys. Res. Comm. 1993,192, 399-406; Grakoui et al., J Viral. 1993, 67, 2832-2843;
`
`15 Grakoui et al., Proc. Natl. Acad Sci. USA 1993, 90, 10583-10587; Hijikata et al., J Viral.
`
`1993, 67, 4665-4675; Tome et al., J Viral., 1993, 67, 4017-4026). The NS4A protein, in
`
`both cases, acts as a cofactor with the NS3 serine protease (Bartenschlager et al., J Viral.
`
`1994, 68, 5045-5055; Failla et al., J Viral. 1994, 68, 3753-3760; Xu et al., J Viral.,
`
`1997, 71 :53 12-5322). The NS3 protein of both viruses also functions as a helicase (Kim
`
`20
`
`et al., Biochem. Biophys. Res. Comm., 1995, 215, 160-166; Jin and Peterson, Arch.
`
`Biochem. Biophys., 1995, 323, 47-53; Warrener and Collett, J Viral. 1995, 69,1720-
`
`1726). Finally, the NS5B proteins of pestiviruses and hepaciviruses have the predicted
`
`RNA-directed RNA polymerases activity (Behrens et al., EMBO, 1996, 15, 12-22;
`
`Lechmann et al., J Viral., 1997, 71, 8416-8428; Yuan et al., Biochem. Biophys. Res.
`
`25
`
`Comm. 1997, 232, 231-235; Hagedorn, PCT WO 97/12033; Zhong et al, J Viral., 1998,
`
`72, 9365-9369).
`
`Currently, there are limited treatment options for individuals infected with
`
`hepatitis C virus. The current approved therapeutic option is the use of immunotherapy
`
`with recombinant interferon-a alone or in combination with the nucleoside analog
`
`30
`
`ribavirin. This therapy is limited in its clinical effectiveness and only 50% of treated
`
`4
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`Docket No. 60137.0045USI1
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`
`patients respond to therapy. Therefore, there is significant need for more effective and
`
`novel therapies to address the unmet medical need posed by HCV infection.
`
`A number of potential molecular targets for drug development of direct acting
`
`antivirals as anti -HCV therapeutics have now been identified including, but not limited
`
`5
`
`to, the NS2-NS3 autoprotease, the N3 protease, the N3 helicase and the NS5B
`
`polymerase. The RNA-dependent RNA polymerase is absolutely essential for replication
`
`of the single-stranded, positive sense, RNA genome and this enzyme has elicited
`
`significant interest among medicinal chemists.
`
`Inhibitors ofHCV NS5B as potential therapies for HCV infection have been
`
`10
`
`reviewed: Tan, S.-L., et al., Nature Rev. Drug Discov., 2002, 1, 867-881; Walker, M.P. et
`
`al., Exp. Opin. Investigational Drugs, 2003, 12, 1269-1280; Ni, Z-J., et al., Current
`
`Opinion in Drug Discovery and Development, 2004, 7, 446-459; Beaulieu, P. L., et al.,
`
`Current Opinion in Investigational Drugs, 2004, 5, 838-850; Wu, J., et al., Current Drug
`
`Targets-Infectious Disorders, 2003, 3, 207-219; Griffith, R.C., et al, Annual Reports in
`
`15 Medicinal Chemistry, 2004, 39, 223-237; Carrol, S., et al., Infectious Disorders-Drug
`
`Targets, 2006, 6, 17-29. The potential for the emergence ofresistant HCV strains and the
`
`need to identify agents with broad genotype coverage supports the need for continuing
`
`efforts to identify novel and more effective nucleosides as HCV NS5B inhibitors.
`
`Nucleoside inhibitors of NS5B polymerase can act either as a non-natural
`
`20
`
`substrate that results in chain termination or as a competitive inhibitor which competes
`
`with nucleotide binding to the polymerase. To function as a chain terminator the
`
`nucleoside analog must be taken up by the cell and converted in vivo to a triphosphate to
`
`compete for the polymerase nucleotide binding site. This conversion to the triphosphate
`
`is commonly mediated by cellular kinases which imparts additional structural
`
`25
`
`requirements on a potential nucleoside polymerase inhibitor. Unfortunately, this limits
`
`the direct evaluation of nucleosides as inhibitors ofHCV replication to cell-based assays
`
`capable of in situ phosphorylation.
`
`In some cases, the biological activity of a nucleoside is hampered by its poor
`
`substrate characteristics for one or more of the kinases needed to convert it to the active
`
`30
`
`triphosphate form. Formation of the monophosphate by a nucleoside kinase is generally
`
`viewed as the rate limiting step of the three phosphorylation events. To circumvent the
`
`5
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`Docket No. 60137.0045USI1
`U.S. Patent Application filed March 31, 2011
`
`need for the initial phosphorylation step in the metabolism of a nucleoside to the active
`
`triphosphate analog, the preparation of stable phosphate prodrugs has been reported.
`
`Nucleoside phosphoramidate prodrugs have been shown to be precursors of the active
`
`nucleoside triphosphate and to inhibit viral replication when administered to viral
`
`5
`
`infected whole cells (McGuigan, C., et al., J Med. Chem., 1996, 39, 1748-1753; Valette,
`
`G., et al., J Med. Chem., 1996, 39, 1981-1990; Balzarini, J., et al., Proc. National Acad
`
`Sci USA, 1996, 93, 7295-7299; Siddiqui, A. Q., et al., J Med. Chem., 1999, 42, 4122-
`
`4128; Eisenberg, E. J., et al., Nucleosides, Nucleotides and Nucleic Acids, 2001, 20,
`
`1091-1098; Lee, W.A., et al., Antimicrobial Agents and Chemotherapy, 2005, 49, 1898);
`
`10 US 2006/0241064; and WO 2007/095269.
`
`Also limiting the utility of nucleosides as viable therapeutic agents is their
`
`sometimes poor physicochemical and pharmacokinetic properties. These poor properties
`
`can limit the intestinal absorption of an agent and limit uptake into the target tissue or
`
`cell. To improve on their properties prodrugs of nucleosides have been employed. It has
`
`15
`
`been demonstrated that preparation of nucleoside phosphoramidates improves the
`
`systemic absorption of a nucleoside and furthermore, the phosphoramidate moiety of
`
`these "pronucleotides" is masked with neutral lipophilic groups to obtain a suitable
`
`partition coefficient to optimize uptake and transport into the cell dramatically enhancing
`
`the intracellular concentration of the nucleoside monophosphate analog relative to
`
`20
`
`administering the parent nucleoside alone. Enzyme-mediated hydrolysis of the phosphate
`
`ester moiety produces a nucleoside monophosphate wherein the rate limiting initial
`
`phosphorylation is unnecessary. To this end, U.S. Patent Application 12/053,015, which
`
`corresponds to WO 2008/121634 and US 2010/0016251, discloses a number of
`
`phosphoramidate nucleoside prodrugs, many of which show activity in an HCV assay.
`
`25
`
`Several compounds disclosed in US 2010/0016251 were tested as a potential clinical
`
`candidate for approval by the FDA.
`
`Summary of the Invention
`
`Disclosed herein is a compound represented by formula 4 and its respective
`
`30
`
`phosphorus-based diastereomers represented by formulas Sp-4 and Rp-4.
`
`6
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`Docket No. 60137.0045USI1
`U.S. Patent Application filed March 31, 2011
`
`0
`
`)lNH
`l __ A
`~
`H
`* 1? ~OyN o
`\__/_-
`0 HN-p-o
`\.
`~
`.
`.
`m:f
`I "
`-;.F
`OPh
`
`4
`
`0
`
`0
`
`H
`
`~
`HN..._p-o
`
`0
`,)lNH
`l __ A
`1? ~O yN o
`\__/_-
`m:f°
`\
`
`/ " Phcf
`
`Brief Description of the Drawings
`
`5
`
`10
`
`Figure 1.
`
`High resolution XRD diffractogram of 4.
`
`Figure 2.
`
`High resolution XRD diffractogram of Rp-4.
`
`Figure 3.
`
`High resolution XRD diffractogram of Sp-4 (Form 1).
`
`Figure 4.
`
`High resolution XRD diffractogram of Sp-4 (Form 1 ).
`
`15
`
`Figure 5.
`
`High resolution XRD diffractogram of Sp-4·CH2Cb (Form 2).
`
`Figure 6.
`
`High resolution XRD diffractogram of Sp-4·CHCh (Form 3).
`
`Figure 7.
`
`High resolution XRD diffractogram of Sp-4 (Form 4).
`
`20
`
`Figure 8.
`
`High resolution XRD diffractogram of Sp-4 (Form 5).
`
`Figure 9.
`
`High resolution XRD diffractogram of Sp-4 (amorphous).
`
`25
`
`Figure 10.
`
`X-Ray Crystal Structure for Sp-4 (Form 1)
`
`Figure 11.
`
`X-Ray Crystal (Isotropic) Structure for Sp-4·CH2Cb (Form 2)
`
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`Figure 12.
`
`X-Ray Crystal (Anisotropic) Structure for Sp-4·CH2Clz (Form 2)
`
`Figure 13.
`
`X-Ray Crystal Structure for Sp-4·CHCh (Form 3)
`
`5
`
`Figure 14.
`
`FT-IR spectrum of 4.
`
`Figure 15.
`
`FT-IR spectrum of Rp-4.
`
`10
`
`Figure 16.
`
`FT-IR spectrum of Sp-4
`
`Figure 17.
`
`TGA and DSC analysis of 4.
`
`Figure 18.
`
`TGA and DSC analysis of Rp-4.
`
`Figure 19.
`
`TGA and DSC analysis of Sp-4.
`
`Figure 20A. X-Ray Crystal Structure for 8 (Sp-isomer) (molecule no. 1 of the
`asymmetric unit).
`
`Figure 20B. X-Ray Crystal Structure for 8 (Sp-isomer) (molecule no. 2 of the
`asymmetric unit).
`
`Figure 21._ High resolution XRD diffractogram of Sp-4 (Form 6).
`
`Figure 22A. X-Ray Crystal Structure for (S)-isopropyl 2-(((S)(cid:173)
`(perfluorophenoxy)(phenoxy)phosphoryl)amino )propanoate (molecule no. 1 of the
`asymmetric unit).
`
`Figure 22B. X-Ray Crystal Structure for (S)-isopropyl 2-(((S)(cid:173)
`(perfluorophenoxy)(phenoxy)phosphoryl)amino )propanoate (molecule no. 2 of the
`asymmetric unit).
`
`15
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`20
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`25
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`30
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`35 Detailed Description of the Invention
`
`Definitions
`
`The phrase "a" or "an" entity as used herein refers to one or more of that entity;
`
`for example, a compound refers to one or more compounds or at least one compound. As
`
`such the terms "a" (or "an") "one or more" and "at least one" can be used
`'
`'
`'
`interchangeably herein.
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`The terms "optional" or "optionally" as used herein means that a subsequently
`
`described event or circumstance may but need not occur, and that the description includes
`
`instances where the event or circumstance occurs and instances in which it does not. For
`
`example, "optional bond" means that the bond may or may not be present, and that the
`
`5
`
`description includes single, double, or triple bonds.
`
`The term "P*" means that the phosphorus atom is chiral and that it has a
`
`corresponding Cahn-Ingold-Prelog designation of "R" or "S" which have their accepted
`
`plain meanings.
`
`The term "purified," as described herein, refers to the purity of a given compound.
`
`10
`
`For example, a compound is "purified" when the given compound is a major component
`
`of the composition, i.e., at least 50% w/w pure. Thus, "purified" embraces at least 50%
`
`w/w purity, at least 60% w/w purity, at least 70% purity, at least 80% purity, at least 85%
`
`purity, at least 90% purity, at least 92% purity, at least 94% purity, at least 96% purity, at
`
`least 97% purity, at least 98% purity, at least 99% purity, at least 99.5% purity, and at
`
`15
`
`least 99.9% purity, wherein "substantially pure" embraces at least 97% purity, at least
`
`98% purity, at least 99% purity, at least 99.5% purity, and at least 99.9% purity
`
`The term "metabolite," as described herein, refers to a compound produced in
`
`vivo after administration to a subject in need thereof.
`
`The term "about" ( also represented by ~) means that the recited numerical value is
`
`20
`
`part of a range that varies within standard experimental error.
`
`The expression "substantially as shown in ... " a specified XRPD pattern means
`
`that the peak positions shown in the XRPD pattern are substantially the same, within
`
`visual inspection or resort to selected peak listings(± 0.2 °28). One of ordinary skill
`
`understands that the intensities can vary depending on the sample.
`
`25
`
`The term "substantially anhydrous" means that a substance contains at most 10%
`
`by weight of water, preferably at most 1 % by weight of water, more preferably at most
`
`0.5% by weight of water, and most preferably at most 0.1 % by weight of water.
`
`A solvent or anti-solvent (as used in reactions, crystallization, etc. or lattice and/or
`
`adsorbed solvents) includes at least one of a C1 to Cs alcohol, a C2 to Cs ether, a C3 to C1
`
`30
`
`ketone, a C3 to C1 ester, a C1 to C2 chlorocarbon, a C2 to C1 nitrile, a miscellaneous
`
`solvent, a C5 to C 12 saturated hydrocarbon, and a C6 to C 12 aromatic hydrocarbon.
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`The C1 to Cs alcohol refers to a straight/branched and/or cyclic/acyclic alcohol
`
`having such number of carbons. The C1 to Cs alcohol includes, but is not limited to,
`
`methanol, ethanol, n-propanol, isopropanol, isobutanol, hexanol, and cyclohexanol.
`
`The C2 to Cs ether refers to a straight/branched and/or cyclic/acyclic ether having
`
`5
`
`such number of carbons. The C2 to Cs ether includes, but is not limited to, dimethyl
`
`ether, diethyl ether, di-isopropyl ether, di-n-butyl ether, methyl-t-butyl ether (MTBE),
`
`tetrahydrofuran, and dioxane
`
`The C3 to C7 ketone refers to a straight/branched and/or cyclic/acyclic ketone
`
`having such number of carbons. The C3 to C7 ketone includes, but is not limited to,
`
`10
`
`acetone, methyl ethyl ketone, propanone, butanone, methyl isobutyl ketone, methyl butyl
`
`ketone, and cyclohexanone.
`
`The C3 to C7 ester refers to a straight/branched and/or cyclic/acyclic ester having
`
`such number of carbons. The C3 to C7 ester includes, but is not limited to, ethyl acetate,
`
`propyl acetate, n-butyl acetate, etc.
`
`15
`
`The C1 to C2 chlorocarbon refers to a chlorocarbon having such number of
`carbons. The C1 to C2 chlorocarbon includes, but is not limited to, chloroform,
`
`methylene chloride (DCM), carbon tetrachloride, 1,2-dichloroethane, and
`
`tetrachloroethane.
`
`A C2 to C7 nitrile refers to a nitrile have such number of carbons. The C2 to C7
`
`20
`
`nitrile includes, but is not limited to, acetonitrile, propionitrile, etc.
`
`A miscellaneous solvent refers to a solvent commonly employed in organic
`
`chemistry, which includes, but is not limited to, diethylene glycol, diglyme ( diethylene
`
`glycol dimethyl ether), 1,2-dimethoxy-ethane, dimethylformamide, dimethylsulfoxide,
`
`ethylene glycol, glycerin, hexamethylphsphoramide, hexamethylphosphorous triame, N-
`
`25 methyl-2-pyrrolidinone, nitromethane, pyridine, triethyl amine, and acetic acid.
`
`The term Cs to C12 saturated hydrocarbon refers to a straight/branched and/or
`
`cyclic/acyclic hydrocarbon. The Cs to C12 saturated hydrocarbon includes, but is not
`
`limited to, n-pentane, petroleum ether (ligroine ), n-hexane, n-heptane, cyclohexane, and
`
`cycloheptane.
`
`30
`
`The term C6 to C12 aromatic refers to substituted and unsubstituted hydrocarbons
`
`having a phenyl group as their backbone. Preferred hydrocarbons include benzene,
`
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`xylene, toluene, chlorobenzene, o-xylene, m-xylene, p-xylene, xylenes, with toluene
`
`being more preferred.
`
`The term "halo" or "halogen" as used herein, includes chloro, bromo, iodo and
`
`fluoro.
`
`5
`
`The term "blocking group" refers to a chemical group which exhibits the
`
`following characteristics. The "group" is derived from a "protecting compound." Groups
`
`that are selective for primary hydroxyls over secondary hydroxyls that can be put on
`
`under conditions consistent with the stability of the phosphoramidate (pH 2-8) and impart
`
`on the resulting product substantially different physical properties allowing for an easier
`
`10
`
`separation of the 3'-phosphoramidate-5'-new group product from the unreacted desired
`
`compound. The group must react selectively in good yield to give a protected substrate
`that is stable to the projected reactions (see Protective Groups in Organic Synthesis, 3nd
`
`ed. T. W. Greene and P. G. M. Wuts, John Wiley & Sons, New York, N.Y., 1999).
`
`Examples of groups include, but are not limited to: benzoyl, acetyl, phenyl-substituted
`
`15
`
`benzoyl, tetrahydropyranyl, trityl, DMT (4,4'-dimethoxytrityl), MMT (4-
`
`monomethoxytrityl), trimethoxytrityl, pixyl (9-phenylxanthen-9-yl) group, thiopixyl (9-
`
`phenylthioxanthen-9-yl) or 9-(p-methoxyphenyl)xanthine-9-yl (MOX), etc.; C(O)-alkyl,
`
`C(O)Ph, C(O)aryl, CH2O-alkyl, CH2O-aryl, SO2-alkyl, SO2-a