WO2012145932A1 - A novel process for the preparation of peramivir and intermediates thereof - Google Patents

A novel process for the preparation of peramivir and intermediates thereof Download PDF

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Publication number
WO2012145932A1
WO2012145932A1 PCT/CN2011/073575 CN2011073575W WO2012145932A1 WO 2012145932 A1 WO2012145932 A1 WO 2012145932A1 CN 2011073575 W CN2011073575 W CN 2011073575W WO 2012145932 A1 WO2012145932 A1 WO 2012145932A1
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Prior art keywords
compound
formula
alkyl
nitrogen
protecting group
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PCT/CN2011/073575
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French (fr)
Inventor
Ping Chen
Yinqiang LI
Shaoping Peng
Shengli JIANG
Zhenwei CAI
Rongcang AN
Weihua Wang
Xuejun DONG
Original Assignee
Pharmaresources (Shanghai) Co., Ltd.
Kaiyuan Hengtai Pharma Co., Ltd.
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Priority to CN201180070519.1A priority Critical patent/CN103827082B/en
Priority to PCT/CN2011/073575 priority patent/WO2012145932A1/en
Publication of WO2012145932A1 publication Critical patent/WO2012145932A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/16—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated

Abstract

The present invention relates to a novel process for preparing peramivir formula (I) or a pharmaceutically acceptable salt thereof, and to intermediates used therein.

Description

A NOVEL PROCESS FOR THE PREPARATION OF PERAMIVIR AND
INTERMEDIATES THEREOF
Field of the Invention
[0001] The present invention relates to a novel process for the preparation of peramivir or a pharmaceutically acceptable salt thereof, and to novel intermediates thereof. In particular, this invention relates to a more efficient process for the preparation of peramivir or a pharmaceutically acceptable salt thereof, comprising highly diastereoselective reactions by utilizing less reaction steps to obtain peramivir.
Background of the Invention
[0002] Peramivir has the chemical name of
(1^,2^,3^, 4R)-3-[(llS)-l-acetamido-2-ethyl-butyl] -4-(diaminomethylideneamino)- 2-hydroxy-cyclopentane-l-carboxylicacid, and has the following structure:
Figure imgf000003_0001
(I)
[0003] Peramivir is currently being developed as an antiviral drug, and in particular, for treatment of influenza. Acting as a neuraminidase inhibitor, peramivir can efficiently inhibit the replication of all type of influenza viruses. Peramivir can be administered via injection, and is known to be well-tolerated and cause only mild adverse effect.
[0004] Several processes relating to the preparation of peramivir are disclosed in CN1227466, CN1282316, and WO01/00577A1.
[0005] As shown in Scheme 1, CN 1227466 discloses a process comprising ring-opening of chiral 2-azabicyclo [2.2.1] hept-5-en-3-one, followed by
amino-protecting reaction, Diel- Alder conjugate cycloaddition, reduction, acetylation, guanidylation and finally hydrolyzation to yield peramivir. The major drawback of this process is the use of highly expensive starting material 1. In addition, this process is not suitable for scale-up.
Scheme 1
Figure imgf000004_0001
[0006] WO2009021404 discloses a method comprising reacting
N-Boc-protected chiral 2-azabicyclo [2.2.1] hept-5-en-3-one and
2-ethylbutylaldehyde as starting material to prepare peramivir as illustrated in Scheme 2.
Scheme 2
Figure imgf000005_0001
eram v r
[0007] The major disadvantages of this process are long synthetic route, low yield and high production cost.
[0008] The present invention relates to a more efficient process for the preparation of peramivir, which comprises shorter synthetic route and higher overall yield. The process is free of chromatographic purification, and suitable for large scale production.
Summary of the Invention
[0009] In one aspect, the present invention provides a process for preparing peramivir (I),
Figure imgf000006_0001
comprising:
(a) reacting a compound of formula (II), or a pharmaceutically acceptable salt thereof,
Figure imgf000006_0002
wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen,
with an amidine compound of formula (III),
NR3
R2HN R4 (in)
wherein R2 and R3 are each independently a nitrogen-protecting group, and R4 is a leaving group,
to provide a compound of formula (IV):
Figure imgf000006_0003
wherein Ri, R2 and R3 are defined as hereinabove;
(b) reacting the compound of formula (IV) with a compound of formula
(V) N.
OH
ci (V)
to produce a compound of formula (VI),
Figure imgf000007_0001
wherein Ri, R2 and R3 are defined as hereinabove;
(c) reducing the compound of formula (VI) using a reducing
followed by acetylation to provide a compound of formula (VII),
Figure imgf000007_0002
wherein Ri, R2 and R3 are defined as hereinabove;
(d) hydrolyzing the compound of formula (VII), wherein Ri is not H, with a base or an acid to provide a compound of formula (VIII),
Figure imgf000007_0003
wherein R2 and R3 are defined as hereinabove;
(e) removing the nitrogen-protecting group (R2 and R3) in the compound of formula (VII), wherein Ri is H, or in the compound of formula (VIII), to provide peramivir (I).
[0010] In another aspect, the present invention provides a process for preparing a compound of formula (IV):
Figure imgf000008_0001
wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen; R2 and R3 are each independently a nitrogen-protecting group,
the process comprising reacting a compound of formula (II), or a
pharmaceutically acceptable salt thereof,
Figure imgf000008_0002
wherein Ri is defined as hereinabove,
with an amidine compound of formula (III),
NR3
R2HN R4 (m)
wherein R2 and R3 are defined as hereinabove, and R4 is a leaving group, to provide the compound of formula (IV).
[0011] In yet another aspect, the present invention provides a process for preparing a compound of formula (VI):
Figure imgf000009_0001
wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen; R2 and R3 are each independently a nitrogen-protecting group,
the process comprising reacting a compound of formula (IV),
Figure imgf000009_0002
wherein Ri, R2 and R3 are defined as hereinabove,
with a compound of formula (V
Figure imgf000009_0003
to produce the compound of formula (VI).
[0012] In a further aspect, the present invention provides a compound of formula (IV),
Figure imgf000009_0004
wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen; and R2 and R3 are each independently a nitrogen-protecting group.
[0013] In another aspect, the present invention provides a compound of formula (VI),
Figure imgf000010_0001
wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen; R2 and R3 are each independently a nitrogen-protecting group.
Brief Description of the Drawings
[0014] Figure 1 depicts ^-NMR for compound 13.
[0015] Figure 2 depicts ^-NMR for compound 15.
[0016] Figure 3 depicts ^-NMR for compound 16.
[0017] Figure 4 depicts ^-NMR for compound 17.
[0018] Figure 5 depicts ^-NMR for compound peramivir.
Detailed Description of the Invention
[0019] The present invention relates to a novel process for preparation of peramivir (I), or a pharmaceuticall acceptable salt thereof:
Figure imgf000010_0002
Peramivir (I) (I)-
[0020] The process comprises: (a) reacting a compound of formula (II), or a pharmaceutically acceptable salt thereof,
Figure imgf000011_0001
wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen, with an amidine compound of formula (III),
NR3
R2HN R4 (in)
wherein R2 and R3 are each independently a nitrogen-protecting group, and R4 is a leaving group, to provide a compound of formula (IV)
Figure imgf000011_0002
wherein Ri, R2 and R3 are defined as hereinabove;
(b) reacting the compound of formula IV) with a compound of formula (V)
Figure imgf000011_0003
to produce a compound of formula (VI),
Figure imgf000012_0001
wherein Ri, R2 and R3 are defined as hereinabove;
(c) reducing the compound of formula (VI) using a reducing agent, followed by acetylation to provide a compound of formula (VII),
Figure imgf000012_0002
wherein Ri, R2 and R3 are defined as hereinabove;
(d) hydrolyzing the compound of formula (VII), wherein Ri is not H, with a base or an acid to provide a compound of formula (VIII),
Figure imgf000012_0003
wherein R2 and R3 are defined as hereinabove;
(e) removing the nitrogen-protecting group (R2 and R3) in the compound of formula (VII), wherein Ri is H, or in the compound of formula (VIII), to provide peramivir (I).
[0021] Starting material compound (II) can be conveniently synthesized according to known literature procedure.
[0022] In certain embodiments, Ri is hydrogen, (Ci-C4)alkyl, (C3-C7)cycloalkyl, phenyl, or (Ci-C4)alkyl-phenyl, in which said (Ci-C4)alkyl is optionally substituted with one or more halogen.
[0023] In certain embodiments, the leaving group is alkylthio, arylthio, pyrazolyl, imidazole, cyano or triazolyl. In certain other embodiments, the leaving group is (Ci-C4)alkylthio, phenylthio, pyrazolyl, imidazole, cyano or triazoly l
[0024] In certain other embodiments, the reducing agent is selected from: (1) alkali metal borohydride in combination with transition metal chloride, transition metal sulfate, or transition metal phosphate; (2) Pt02/H2, Raney Ni/ H2, Pd/C/H2, or Rh/ H2; (3) transition metal such as Zn and Fe in acids such as acetic acid; (4) Red-Al; and (5) NaBH4/Me2S04.
[0025] In yet other embodiments, the alkali metal borohydride is selected from NaBH4, KBH4, LiBH4, NaBH3CN, and NaBH(OAc)3.
[0026] In yet other embodiments, the transition metal chloride is selected from NiCl2, CoCl2, and ZnCl2.
[0027] In certain embodiments, the acetylation step is achieved using acetic anhydride, acetyl chloride, or acetyl mixed anhydrides (e.g. acetic formic
anhydride). In certain other embodiments, the acetylation step is achieved using a carboxylic anhydride of formula Ra(C=0)0(C=0)Rb, wherein Ra and Rb may be same or different and are each independently H or (Ci-C4)alkyl.
[0028] In another aspect, the present invention provides a process for preparing a compound of formula (IV):
Figure imgf000014_0001
wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen; R2 and R3 are each independently a nitrogen-protecting group,
the process comprising reacting a compound of formula (II), or a
pharmaceutically acceptable salt thereof,
Figure imgf000014_0002
wherein Ri is defined as hereinabove,
with an amidine compound of formula (III),
Figure imgf000014_0003
wherein R2 and R3 are defined as hereinabove, and R4 is a leaving group, to provide the compound of formula (IV).
[0029] In certain embodiments, Ri is hydrogen, (Ci-C4)alkyl, (C3-C7)cycloalkyl, phenyl, or (Ci-C4)alkyl-phenyl, in which said (Ci-C4)alkyl is optionally substituted with one or more halogen.
[0030] In certain embodiments, the leaving group is alkylthio, arylthio, pyrazolyl, imidazole, cyano or triazol L In certain other embodiments, the leaving group is (Ci-C4)alkylthio, phenylthio, pyrazolyl, imidazole, cyano or iriazolyl. In certain embodiments, R2 and R3 are defined as hereinabove.
[0031] As described herein, for the synthesis of intermediate IV, the reaction solvent can be selected from, but not limited to ace!xmitrile, dichloroethane, tetrahydrofiiran or other suitable solvents. The reaction temperature can be from room temperature to about 80°C, If R4 represents alky! or aryi sulfide, the reaction rate and yield can be improved by elevated temperature or addition of sulfide precipitation reagent such as ! IgCh. AgNO:, and so on. If R4 represents pyrazolyl or triazolyl, the reaction rate and yield can be improved by addition of an organic base such as trimethylamine, triethylamine, tributylamine,
N. -diisopropyle -thylamine, N-methylpiperidme, pyridine, N,N-dimethylaniline, DBU and so on.
[0032] At the end of the reaction, compound (IV) can be obtained by general purification methods, such as extraction, washing, crystallization, re-crystallization and so on.
[0033] In certain embodiments, the process further comprises reacting the compound of formula (IV) with a com ound of formula (V)
Figure imgf000015_0001
to produce a compound of formula (VI),
Figure imgf000015_0002
(VI) wherein Ri, R2 and R3 are defined as hereinabove.
[0034] In yet another aspect, the present invention provides a process for preparing a compound of formula (VI):
Figure imgf000016_0001
wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen; R2 and R3 are each independently a nitrogen-protecting group,
the process comprising reacting a compound of formula (IV),
Figure imgf000016_0002
wherein Ri, R2 and R3 are defined as hereinabove,
with a compound of formula (V)
Figure imgf000016_0003
to produce the compound of formula (VI).
[0035] Compound (V) can be conveniently prepared by known literature procedure. As used herein, the reaction solvent can be selected from toluene, tetraliydrofuran or other suitable organic solvents. The reaction temperature for UK: synthesis of compound (Vij can be from room temperature to about 100°C. The reaction can be carried out under basic conditions, for example, in presence of trimethylamine, triethylamine, tributylamine, N,N~diisopropylethylaniirie, N-methylpiperidine, pyridine, Ν,Ν-dimethylaniline, DBU and so on.
[0036] Applicants have surprisingly found that the formation of diasteromeric side-product of formula (VI-1) is greatly reduced, if a bulky group is used for R2 and/or R3. For example, when teri-butyloxycarbonyl group is used for both R2 and/or R3, the formation of the side-product is significantly reduced. Without being bound by a particular theory, it is believed that the steric hindrance of the teri-butyloxycarbonyl group helps minimize the formation of the undesired side-product. Compound (VI) can be obtained by general purification methods, such as extraction, washing, crystallization, re~erysta11 zation and so on.
Figure imgf000017_0001
[0037] In certain embodiments, the process further comprises reducing the compound of formula (VI) using a reducing agent, followed by acetylation to provide a compound of formula (VII),
Figure imgf000017_0002
wherein Ri, R2 and R3 are defined as hereinabove.
[0038] In certain embodiments, the reducing agent is selected from: (1) alkali metal borohydride in combination with transition metal chloride, transition metal sulfate, or transition metal phosphate; (2) Pt02/H2, Raney Ni/ H2, Pd/C/H2, or Rh/ H2; (3) transition metal such as Zn and Fe in acids such as acetic acid; (4) Red-Al; and (5) NaBH4/Me2S04.
[0039] In certain embodiments, the alkali metal borohydride is selected from NaBH4, KBH4, LiBH4, NaBH3CN, and NaBH(OAc)3. In certain other
embodiments, the transition metal chloride is selected from NiCl2, CoCl2, and ZnCl2.
[0040] When using alkali metal borohydride and transition metal chloride as a reductive system, the reaction solvent is selected from, but not limited to, protic solvents such as methanol, ethanol and so on. The reaction temperature can be from about -78°C to room temperature, for example at 0°C.
[0041] The resulting reductive reaction mixture can be directly quenched with an acetylation reagent. The molar equivalent ratio between acetylating reagent and compound (VI) can be ranged from about 1 to about 50, for example at about 5 molar equivalents, 10 molar equivalents, 15 molar equivalents, or 20 molar equivalents. The reaction temperature can be from about -78°C to room
temperature, for example at about 0°C.
[0042] In certain embodiments, the acetylation step is achieved using acetic anhydride, acetyl chloride, or acetyl mixed anhydrides (e.g. acetic formic anhydride). In certain other embodiments, the acetylation step is achieved using a carboxylic anhydride of formula Ra(C=0)0(C=0)Rb, wherein Ra and Rb may be same or different and are each independently H or (Ci-C4)alkyl.
[0043] Compound (VII) can be obtained by general purification methods, such as extraction, washing, crystallization, re-crystallization and so on.
[0044] In certain embodiments, the process further comprises hydrolyzing the compound of formula (VII), wherein Ri is not H, with a base or an acid to provide a compound of formula (VIII),
Figure imgf000019_0001
wherein R2 and R3 are defined as hereinabove.
[0045] In certain embodiments, the process further comprises removing the nitrogen-protecting group (R2 and R3) in the compound of formula (VII), wherein Ri is H; or removing the nitrogen-protecting group (R2 and R3) in the compound of formula (VIII), to provide peramivir (I):
Figure imgf000019_0002
[0046] In certain embodiments, the nitrogen-protecting group used herein is t-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl,
9-fluorenylmethoxycarbonyl, 9-(2-sulfo)fluorenylmethoxycarbonyl,
9-(2,7-dibromo)fluorenylmethoxycarbonyl, 17-tetrabenzo[a,c,g,i]fluorenylmethoxycarbonyl,
2-chloro-3-indenylmethoxycarbonyl, benz[f]inden-3-ylmethoxycarbonyl,
2,7-di-t-butyl-[9-( 10, 10-dioxo- 10, 10, 10, 10-tetrahydrothioxanthyl)] methoxycarbon yl, 1, 1 -dioxobenzo[b]thiophene-2-ylmethoxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl,
2-phenylethoxycarbonyl, 1 -( 1 -adamantyl)- 1 -methylethoxycarbonyl,
2-chloroethoxycarbonyl, 1 , 1 -dimethyl-2-haloethoxycarbonyl,
1 , 1 -dimethyl-2,2-dibromoethoxycarbonyl,
1 , 1 -dimthyl-2,2,2-trichloroethoxycarbonyl,
1 , 1 -methyl- 1 -(4-biphenylyl)ethoxycarbonyl,
1- (3,5-di-t-butylphenyl)-l-methylethoxycarbonyl, 2-(2'- and
4'-pyridyl)ethoxycarbonyl, 2,2-bis(4'-nitrophenyl)ethoxycarbonyl,
N-(2-pivaloylamino)- 1 , 1 -dimethylethoxycarbonyl,
2- [(2-nitrophenyl)dithio]- 1 -phenylethoxycarbonyl,
2-(2-(N,N-dicyclohexylcarboxamido) ethoxycarbonyl, t-butyloxycarbonyl, 1 -adamantyloxycarbonyl, 2-adamantyloxycarbonyl, vinyloxycarbonyl,
allyloxycarbonyl, 1 -isopropylallyloxycarbonyl, cinnamyloxycarbonyl,
4-nitrocinnamyloxycarbonyl, 3-(3'-pyridyl)prop-2-enyloxycarbonyl,
8-quinolyloxycarbonyl, N-hydroxypiperdinyl, alkyldithiooxycarbonyl,
benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-chlorobenzyloxycarbonyl,
2,4-dichlorobenzyloxycarbonyl, 4-methylsulfmylbenzyloxycarbonyl, 9-anthrylmethyloxycarbonyl, diphenylmethyloxycarbonyl, N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl,
N-3-phenylpropionyl, N-4-pentenoyl, N-picolinoyl, N-3-pyridylcarboxamido, N-benzoylphenylalanyl, N-benzoyl, or N-p-phenylbenzoyl.
[0047] In certain other embodiments, the nitrogen-protecting group is
t-butyloxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, substituted
benzyloxycarbonyl (e.g., p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-chlorobenzyloxycarbonyl,
2,4-dichlorobenzyloxycarbonyl, 4-methylsulfmylbenzyloxycarbonyl),
allyloxycarbonyl, trimethylsilylethoxycarbonyl, acetyl, substituted acetyl (e.g., N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, or N-phenylacetyl),
N-benzoyl, or N-p-phenylbenzoyl. In yet other embodiments, the
nitrogen-protecting group is t-butyloxycarbonyl.
[0048] In certain embodiments, the nitrogen-protecting group is removed using an organic or inorganic acid, or a mixture thereof. In certain other embodiments, the nitrogen-protecting group is removed using TFA/Et3SiH, HC1, HBr, or a mixture thereof.
[0049] Peramivir can be obtained by general purification methods, such as extraction, washing, crystallization, re-crystallization and so on, for example, re-crystallization from mixture of alcohol and water. In certain embodiments, the re-crystallization solvent is a mixture of methanol and water.
[0050] In a further aspect, the present invention provides a compound of formula (IV),
Figure imgf000022_0001
wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen; R2 and R3 are each independently a nitrogen-protecting group. In certain embodiments, Ri is hydrogen, (Ci-C4)alkyl, (C3-C7)cycloalkyl, phenyl, or (Ci-C4)alkyl-phenyl, in which said (Ci-C4)alkyl is optionally substituted with one or more halogen.
[0051] In certain embodiments, the nitrogen-protecting group (R2 and R3 in formula IV) is described as hereinabove.
[0052] In certain embodiments, the present invention provides a compound of formula
Figure imgf000022_0002
[0053] In another aspect, the present invention provides a compound of formula (VI),
Figure imgf000022_0003
wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen; R2 and R3 are each independently a nitrogen-protecting group. In certain embodiments, Ri is hydrogen, (Ci-C4)alkyl, (C3-C7)cycloalkyl, phenyl, or (Ci-C4)alkyl-phenyl, in which said (Ci-C4)alkyl is optionally substituted with one or more halogen.
[0054] In certain embodiments, the nitrogen-protecting group (R2 and R3 in formula VI) is described as hereinabove.
[0055] In certain embodiments, the present invention provides a compound of
formula
Figure imgf000023_0001
Definition
[0056] Throughout the present application, unless otherwise noted, the term "alkyl" whether used alone or as part of a substituent group, includes straight and branched chains containing one to eight carbon atoms, preferably one to three carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, i-butyl, «-pentyl and the like.
[0057] The term "cycloalkyl" means cyclic aliphatic groups containing three to eight carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
[0058] The term "aryl" means non-substituted aromatic groups, such as phenyl, naphthyl, and the like, preferably phenyl.
[0059] The term "Ar-alkyl" means any alkyl group substituted with an aryl group, such as benzyl, phenylethyl, and so on.
[0060] As used herein, unless otherwise noted, substituents on the aryl or Ar-alkyl group are one or more, preferably one or two of halogen.
[0061] In certain embodiments, the present invention provides a process for the preparation of peramivir (I) as shown in Scheme 3 :
Scheme 3
Figure imgf000024_0001
Figure imgf000024_0002
[0062] Certain specific aspects and embodiments of present invention are described in further detail by the examples below. The illustrated examples are not intended to limit the scope of this invention.
EXAMPLES
Example 1
1 (liS',4J/?)-methyl-4-(2,3-bis(ieri-butoxycarbonyl)guanidino)cyclopent-2-ene- carboxylate (13)
Figure imgf000024_0003
11 12 13 [0063] To a mixture of (lS^R^methyl 4-aminocyclopent-2-enecarboxylate tartaric acid salt 11 ( 7.29 g, 25 mmol) in dichloromethane (150 mL), was added Et3N (9 mL, 65 mmol) at 0 °C, and the resulting mixture was stirred for 15 min. To this, tert-butyl (lH-pyrazol-l-yl)methylenedicarbamate 12 was added. After addition, the reaction was monitored for completion by TLC ( PE: EtOAc=5 : 1 ) . The organic layers were washed with water and brine and dried over anhydrous Na2S04. The mixture was filtered and concentrated to give 13 as a white solid, which was used in the next step without further purification.
[0064] MS (M+l ) : 384.
[0065] 'H NMR (400 MHz, CDC13) δ 11.49 (s, 1H), 8.53 (d, J= 8.4 Hz, 1H), 5.94 - 5.83 (m, 2H), 5.38 - 5.31 (m, 1H), 3.73 (s, 3H), 3.56 - 3.44 (m, 1H), 2.60 (dt, J= 14.0, 8.5 Hz, 1H), 1.94 (dt, J= 13.9, 4.7 Hz, 1H), 1.50 (d, J= 7.4 Hz, 18H) (See attached Chart 1)
Example 2
2 (3aJ/?,4J/?,6iS',6aiS -methyl-4-(2,3-bis(ieri-butoxycarbonyl)guanidino)-3-(pentan -3-yl)-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-6-carboxylate (5)
Figure imgf000025_0001
14 85% a) Preparation of 2-Ethyl-N-hydroxybutanimidoyl chloride (14):
[0066] Hydroxylamine hydrochloride (7.2g, 0.1 mol) was dissolved in water (7 mL). Toluene (27 mL) was added, followed by addition of 2-ethylbutylraldehyde (lOg, 0.1 mol). The two-phase mixture was stirred vigorously while cooling.
Sodium hydroxide solution (ca.30%, 14.6g, O. l lmol) was added slowly (addition is very exothermic) to maintain a temperature between 15-25 °C. The mixture was stirred for 60 min, then allowed to stand to separate the layers. The organic extract was washed with water and brine, dried over Na2S04, and directly used in the next step.
[0067] N-Chlorosuccinimide (NCS) (13.3g, 0.1 mol) was suspended in dimethylformamide (DMF) (17ml) and cooled to about 10 °C. The toluene solution prepared above (3 .15 mol) was added dropwise with sufficient cooling to maintain the reaction temperature betweenlO-25°C. After addition, the reaction was monitored by TLC until completion of the reaction. Water (100ml) was added slowly (slightly exothermic) while maintaining the temperature at 15-25 °C. The two-phase mixture was stirred for 15 min at 15-25 °C and the layers were separated. The water layer was extracted with toluene (10ml) and the organic layer washed with water (3 X 20ml) and brine, dried over Na2S04, and directly used in the next step. b)
Preparation of (3aJ/?,4J/?,6iS',6aiS -methyl-4-(2,3-bis(ieri-butoxycarbonyl)-guan idine)-3 -(pentan-3 -yl)-4,5,6,6a-tetrahy dro-3 aH-cy clopenta [d] is oxazole-6- carboxylate (15)
[0068] 13 (from example 1, 9.2g, 0.024 mol) was dissolved in toluene (100 mL) and triethylamine (10. Og, 0.099 mol) and the reaction mixture was heated to 60-70 °C. 2- Ethyl-N-hydroxylbutanimidoyl chloride 14 (from example 2a, 14.8 g, 0.099 mol) in toluene (40 mL) was added to the above solution. A white solid
(triethylammonium chloride) was formed. After addition, the reaction was
monitored for completion by TLC ( PE: EtOAc=3 : 1. The reaction mixture was cooled to 20-25 °C, the precipitate was removed by filtration and the filter cake was washed with toluene (50 g). The organic filtrate was washed with water, brine, and dried over anhydrous Na2S04. The mixture was filtered and concentrated by rotary evaporation. The resulting residue was purified by silica gel flash column
chromatography using PE/EtOAc (30 : 1-4: 1, v/v) to give 15 as a white solid.
[0069] Yield : 10.0 g (85%).
[0070] MS (M+l ) :497.
[0071] 'H NMR (400 MHz, CDC13) δ 11.29 (s, 1H), 8.55 (d, J= 6.4 Hz, 1H), 5.30 (dd, J= 9.1, 1.5 Hz, 1H), 4.53 (d, J= 4.8 Hz, 1H), 3.78 (s, 3H), 3.70 (d, J = 9.1 Hz, 1H), 3.25 (t, J= 5.4 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.20 (dd, J= 7.6, 3.7 Hz, 2H), 1.87 - 1.60 (m, 4H), 1.49 (d, J= 5.0 Hz, 18H), 0.95 (t, J= 7.4 Hz, 3H), 0.87 (t, J= 7.5 Hz, 3H). (See attached Chart 2)
Example 3 3. (1^,2^,3^,4^)-ιη6ίΗγ1-3-(1-306ίαιηΐάο-2-6ίΗγ1 υίγ1)-4-(2,3- Ϊ8(ί^ί- butoxycarb -onyl) guanidino)-2-hydroxycyclopentanecarboxylate (16):
Figure imgf000028_0001
[0072] Compound 15 ( from example 2, 5.0 g, 10.08 mmol) and nickel chloride hexahydrate (2.5g, 10.5 mmol) were dissolved in methanol (40 mL). The green solution was cooled to -15 °C, while a suspension formed. Sodium borohydride
( 0.456 g, 12 mmol) was added to the reaction mixture at -10 to -5 °C (reaction is highly exothermic). A black suspension was formed along with gas evolution.
After complete addition of the sodium borohydride solution, the reaction mixture was stirred until TLC showed 15 was fully consumed. A solution of acetic
anhydride ( 15g, 0.13 mol) was added slowly and maintained the reaction temperature at 0-5 °C, the reaction mixture was stirred for 2-12 h at 0 °C (The black solution change into green solution ), The pH of the mixture was adjusted to ~9 by addition of 25% aq. ammonium hydroxide. The mixture was concentrated by rotary evaporator. The resulting residue was diluted with water (30 mL) and extracted with EtOAc (50 mL><3). The combined organic extracts were washed with water and brine and dried over anhydrous Na2S04. The mixture was filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography using DCM/Methanol (100:0 to 100:2, v/v) to give 16 as a white solid. [0073] Yield: 3.8 g (71%).
[0074] MS (M+l ) : 543.
[0075] 'H NMR (400 MHz, CDC13) δ 11.39 (s, 1H), 8.72 (d, J= 9.9 Hz, 1H), 8.59 (d, J= 8.5 Hz, 1H), 4.53 - 4.39 (m, 1H), 4.26 (d, J= 16.4 Hz, 2H), 3.96 (t, J = 10.2 Hz, 1H), 3.71 (s, 3H), 2.90 - 2.75 (m, 1H), 2.53 (dt, J= 13.6, 8.8 Hz, 1H), 2.10 (s, 3H), 2.03 (d, J= 6.3 Hz, 1H), 1.90 - 1.76 (m, 1H), 1.38 (dd, J= 73.9, 7.9 Hz, 18H), 1.25 (ddd, J= 15.2, 13.1, 7.3 Hz, 4H), 0.79 (t, J= 7.3 Hz, 3H), 0.75 (dd, J = 14.1, 6.9 Hz, 3H). (See attached Chart 3)
Example 4
4. (1^,2^,3^,4^)-3-(1-306ίαιηΐάο-2-6ίΗγ1 υίγ1)-4-(2,3- Ϊ8(ί^ί- butoxycarbonyl)gu -anidino)-2-hydroxycyclopentanecarboxylic acid (17)
Figure imgf000029_0001
[0076] To a mixture of compound 16 ( from example 3, 2.0 g, 3.69 mmol) in MeOH/THF (1 : 1, v/v, 12 mL), was added aq. NaOH (IN, 7 mL) at room
temperature. After completion of the reaction (monitored by TLC,
DCM:MeOH=10: l, the mixture was concentrated by rotary evaporation. The resulting solution was neutralized to pH 7 using ice-cold 1 N HCl aq. solution and quickly extracted with EtOAc twice. The combined organic extracts were washed with water, brine, and dried over anhydrous Na2S04. The mixture was filtered and the filtrate was concentrated by rotary evaporation. The resulting white foam was washed triturated by hexane, filtered, dried to give 17 as a white solid
[0077] Yield: 1.6 g (84%).
[0078] MS (M+l ) : 529 o
[0079] 'H NMR (400 MHz, CDC13) δ 11.41 (s, 1H), 8.80 (d, J= 9.8 Hz, 1H), 8.62 (d, J= 8.3 Hz, 1H), 4.43 (dd, J= 23.3, 14.3 Hz, 2H), 4.00 (t, J= 9.8 Hz, 1H), 2.83 (s, 1H), 2.53 (dt, J= 16.9, 8.4 Hz, 1H), 2.14 (s, 3H), 1.91 (dd, J= 12.5, 6.0 Hz, 1H), 1.46 (dd, J = 30.1, 9.5 Hz, 18H), 1.47 - 1.14 (m, 6H), 0.97 - 0.69 (m, 6H). (See attached Chart 4)
Example 5
5. (1^,2^,3^,4^)-3-(1-306ίαιηΐάο-2-6ίΗγ1 υίγ1)-4^υαηΐ(1ΐηο-2- hydroxycyclopent -anecarboxylic acid (Peramivir I)
Figure imgf000030_0001
[0080] Compound 17 ( from example 4, 1.1 g, 2 mmol) was dissolved in aq. HC1 ( 6N, 6 mL, 36 mmol) at 0 °C. The mixture was stirred at room temperature overnight. The resulting solution was neutralized to pH 6-7 using ice-cold 1 N NaOH aq. solution. The mixture was concentrated to 1.5 ml by rotary evaporation. To this, methanol (20 mL) was added. The precipitate was filtered, and the filtrate was concentrated. The resulting white solid was recrystallized from
methanol/water (1 : 1, v/v) to give Peramivir I as a white solid.
[0081] Yield: 500 mg (73%).
[0082] MS (M+l ) : 329.
[0083] H NMR (400 MHz, D20) δ 4.21 (d, J= 10.6 Hz, 2H), 3.70 (dd, J= 14.6, 9.0 Hz, 1H), 2.57 (d, J= 4.8 Hz, 1H), 2.40 (dt, J= 17.7, 8.9 Hz, 1H), 2.14 - 2.01 (m, 1H), 1.81 (s, 3H), 1.75 - 1.58 (m, 1H), 1.31 (s, 3H), 0.78 (ddd, J= 21.6, 18.6, 6.8 Hz, 8H). (See attached Chart 5)

Claims

WE CLAIM:
1. A process for preparing a compound of formula (IV):
Figure imgf000032_0001
wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen; R2 and R3 are each independently a nitrogen-protecting group,
the process comprising reacting a compound of formula (II), or a
pharmaceutically acceptable salt thereof,
Figure imgf000032_0002
wherein Ri is defined as hereinabove,
with an amidine compound of formula (III),
NR3
R2HN R4 (in^
wherein R2 and R3 are defined as hereinabove, and R4 is a leaving group, to provide the compound of formula (IV).
2. The process of claim 1, wherein said leaving group is alkylthio, arylthio, pyrazolyl, imidazole, cyano, or triazolyl.
3. The process of claim 1 or 2, further comprising reacting the compound of formula (IV) with a compound of formula V)
Figure imgf000032_0003
(V) to produce a compound of formula (VI),
Figure imgf000033_0001
wherein Ri, R2 and R3 are defined as hereinabove.
4. A process for preparing a compound of formula (VI):
Figure imgf000033_0002
wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen; R2 and R3 are each independently a nitrogen-protecting group,
the process comprising reacting a compound of formula (IV),
Figure imgf000033_0003
wherein Ri, R2 and R3 are defined as hereinabove,
with a compound of formula (V
Figure imgf000033_0004
to produce the compound of formula (VI).
5. The process of claim 3 or 4, further comprising reducing the compound of formula (VI) using a reducing agent, followed by acetylation to provide a compound of formula (VII),
Figure imgf000034_0001
wherein Ri, R2 and R3 are defined as hereinabove.
6. The process of claim 5, wherein said reducing agent is selected from: (1) alkali metal borohydride in combination with transition metal chloride, transition metal sulfate, or transition metal phosphate; (2) Pt02/H2, Raney Ni/ H2, Pd/C/H2, or Rh/ H2; (3) transition metal such as Zn and Fe in acids such as acetic acid; (4) Red-Al; and (5) NaBH4/Me2S04.
7. The process of claim 6, wherein said alkali metal borohydride is selected from NaBH4, KBH4, LiBH4, NaBH3CN, and NaBH(OAc)3.
8. The process of claim 6 or 7, wherein said transition metal chloride is selected from NiC12, CoC12, and ZnC12.
9. The process of claim 5, wherein said acetylation is achieved using acetic anhydride, acetyl chloride, or acetyl mixed anhydrides.
10. The process of any one of claims 5-9, further comprising hydro lyzing the compound of formula (VII), wherein Rl is not H, with a base or an acid to provide a compound of formula (VIII),
Figure imgf000035_0001
wherein R2 and R3 are defined as hereinabove.
11. The process of any one of claims 5-10, further comprising removing the nitrogen-protecting group (R2 and R3) in the compound of formula (VII), wherein Ri is H; or removing the nitrogen-protecting group (R2 and R3) in the compound of formula (VIII), to provide peramivir (I)
Figure imgf000035_0002
12. The process of any one of claims 1-11, wherein said nitrogen-protecting group is t-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl,
9-fluorenylmethoxycarbonyl, 9-(2-sulfo)fluorenylmethoxycarbonyl,
9-(2,7-dibromo)fluorenylmethoxycarbonyl,
17-tetrabenzo[a,c,g,i]fluorenylmethoxycarbonyl,
2-chloro-3-indenylmethoxycarbonyl, benz[fJinden-3-ylmethoxycarbonyl,
2,7-di-t-butyl-[9-( 10, 10-dioxo- 10, 10, 10, 10-tetrahydrothioxanthyl)]
methoxycarbonyl, 1 , 1 -dioxobenzo[b]thiophene-2-ylmethoxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl,
2-phenylethoxycarbonyl, 1 -( 1 -adamantyl)- 1 -methylethoxycarbonyl, 2-chloroethoxycarbonyl, 1 , 1 -dimethyl-2-haloethoxycarbonyl,
1 , 1 -dimethyl-2,2-dibromoethoxycarbonyl,
1 , 1 -dimthyl-2,2,2-trichloroethoxycarbonyl,
1 , 1 -methyl- 1 -(4-biphenylyl)ethoxycarbonyl,
1- (3,5-di-t-butylphenyl)-l-methylethoxycarbonyl, 2-(2'- and
4'-pyridyl)ethoxycarbonyl, 2,2-bis(4'-nitrophenyl)ethoxycarbonyl,
N-(2-pivaloylamino)- 1 , 1 -dimethylethoxycarbonyl,
2- [(2-nitrophenyl)dithio]- 1 -phenylethoxycarbonyl,
2-(2-(N,N-dicyclohexylcarboxamido) ethoxycarbonyl, t-butyloxycarbonyl, 1 -adamantyloxycarbonyl, 2-adamantyloxycarbonyl, vinyloxycarbonyl,
allyloxycarbonyl, 1 -isopropylallyloxycarbonyl, cinnamyloxycarbonyl,
4-nitrocinnamyloxycarbonyl, 3-(3'-pyridyl)prop-2-enyloxycarbonyl,
8- quinolyloxycarbonyl, N-hydroxypiperdinyl, alkyldithiooxycarbonyl,
benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-chlorobenzyloxycarbonyl,
2,4-dichlorobenzyloxycarbonyl, 4-methylsulfmylbenzyloxycarbonyl,
9- anthrylmethyloxycarbonyl, diphenylmethyloxycarbonyl, N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl,
N-3-phenylpropionyl, N-4-pentenoyl, N-picolinoyl, N-3-pyridylcarboxamido, N-benzoylphenylalanyl, N-benzoyl, or N-p-phenylbenzoyl.
13. The process of claim 11 or 12, wherein the nitrogen-protecting group is removed using an organic or inorganic acid, or a mixture thereof.
14. The process of claim 11 or 12, wherein the nitrogen-protecting group is removed using TFA/Et3SiH, HC1, HBr, or a mixture thereof.
15. A process for preparing Peramivir (I),
Figure imgf000037_0001
comprising:
(a) reacting a compound of formula (II), or a pharmaceutically acceptable salt thereof,
Figure imgf000037_0002
wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen,
with an amidine compound of formula (III),
NR3
R2HN R4 (in)
wherein R2 and R3 are defined as hereinabove, and R4 is a leaving group, to provide a compound of formula (IV):
Figure imgf000037_0003
wherein Ri, R2 and R3 are defined as hereinabove; (b) reacting the compound of formula IV) with a compound of formula (V)
Figure imgf000038_0001
to produce a compound of formula (VI),
Figure imgf000038_0002
wherein Ri, R2 and R3 are defined as hereinabove;
(c) reducing the compound of formula (VI) using a reducing agent, followed by acetylation to provide a compound of formula (VII),
Figure imgf000038_0003
wherein Ri, R2 and R3 are defined as hereinabove;
(d) hydrolyzing the compound of formula (VII), wherein Ri is not H, with a base or an acid to provide a compound of formula (VIII),
Figure imgf000038_0004
wherein R2 and R3 are defined as hereinabove; (e) removing the nitrogen-protecting group (R2 and R3) in the compound of formula (VII), wherein Ri is H, or in the compound of formula (VIII), to provide peramivir (I).
16. The process of claim 15, wherein said leaving group is alkylthio, arylthio, pyrazolyl, imidazole, cyano or triazolyl.
17. The process of claim 15 or 16, wherein said reducing agent is selected from: (1) alkali metal borohydride in combination with transition metal chloride, transition metal sulfate, or transition metal phosphate; (2) Pt02/H2, Raney Ni/ H2, Pd/C/H2, or Rh/ H2; (3) transition metal such as Zn and Fe in acids such as acetic acid; (4) Red-Al; and (5) NaBH4/Me2S04.
18. The process of claim 17, wherein said alkali metal borohydride is selected from NaBH4, KBH4, LiBH4, NaBH3CN, and NaBH(OAc)3.
19. The process of claim 17, wherein said transition metal chloride is selected from NiC12, CoCl2, and ZnCl2.
20. The process of any one of claims 15-19, wherein said acetylation is achieved using acetic anhydride, acetyl chloride, or acetyl mixed anhydrides.
21. The process of any one of claims 15-20, wherein said
nitrogen-protecting group is t-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, 9-fluorenylmethoxycarbonyl, 9-(2-sulfo)fluorenylmethoxycarbonyl,
9-(2,7-dibromo)fluorenylmethoxycarbonyl,
17-tetrabenzo[a,c,g,i]fluorenylmethoxycarbonyl,
2-chloro-3-indenylmethoxycarbonyl, benz[fJinden-3-ylmethoxycarbonyl, 2,7-di-t-butyl-[9-( 10, 10-dioxo- 10, 10, 10, 10-tetrahydrothioxanthyl)] methoxycarbon yl, 1, 1 -dioxobenzo[b]thiophene-2-ylmethoxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl,
2-phenylethoxycarbonyl, 1 -( 1 -adamantyl)- 1 -methylethoxycarbonyl,
2-chloroethoxycarbonyl, 1 , 1 -dimethyl-2-haloethoxycarbonyl,
1 , 1 -dimethyl-2,2-dibromoethoxycarbonyl,
1 , 1 -dimthyl-2,2,2-trichloroethoxycarbonyl,
1 , 1 -methyl- 1 -(4-biphenylyl)ethoxycarbonyl,
1- (3,5-di-t-butylphenyl)-l-methylethoxycarbonyl, 2-(2'- and
4'-pyridyl)ethoxycarbonyl, 2,2-bis(4'-nitrophenyl)ethoxycarbonyl,
N-(2-pivaloylamino)- 1 , 1 -dimethylethoxycarbonyl,
2- [(2-nitrophenyl)dithio]- 1 -phenylethoxycarbonyl,
2-(2-(N,N-dicyclohexylcarboxamido) ethoxycarbonyl, t-butyloxycarbonyl, 1 -adamantyloxycarbonyl, 2-adamantyloxycarbonyl, vinyloxycarbonyl,
allyloxycarbonyl, 1 -isopropylallyloxycarbonyl, cinnamyloxycarbonyl,
4-nitrocinnamyloxycarbonyl, 3-(3'-pyridyl)prop-2-enyloxycarbonyl,
8- quinolyloxycarbonyl, N-hydroxypiperdinyl, alkyldithiooxycarbonyl,
benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-chlorobenzyloxycarbonyl,
2,4-dichlorobenzyloxycarbonyl, 4-methylsulfmylbenzyloxycarbonyl,
9- anthrylmethyloxycarbonyl, diphenylmethyloxycarbonyl, N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-4-pentenoyl, N-picolinoyl, N-3-pyridylcarboxamido, N-benzoylphenylalanyl, N-benzoyl, or N-p-phenylbenzoyl.
22. The process of any one of claims 15-20, wherein the
nitrogen-protecting group is removed using an organic or inorganic acid, or a mixture thereof.
23. The process of any one of claims 15-20, wherein the
nitrogen-protecting group is removed using TFA/Et3SiH, HCl, HBr, or a mixture thereof.
24. A compound of formula (IV),
Figure imgf000041_0001
wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen;
R-2 and R3 are each independently a nitrogen-protecting group.
25. The compound of claim 24, wherein said nitrogen-protecting group is t-butyloxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, substituted
benzyloxycarbonyl (e.g., p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-chlorobenzyloxycarbonyl,
2,4-dichlorobenzyloxycarbonyl, 4-methylsulfmylbenzyloxycarbonyl),
allyloxycarbonyl, trimethylsilylethoxycarbonyl, acetyl, substituted acetyl (e.g., N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, or N-phenylacetyl),
N-benzoyl, or N-p-phenylbenzoyl.
26. The compound of claim 24, having the following structure:
Figure imgf000042_0001
NBoc
A compound of formula (VI),
Figure imgf000042_0002
wherein Ri is hydrogen, alkyl, cycloalkyl, aryl, or alkyl-aryl, in which said alkyl is optionally substituted with one or more halogen; R2 and R3 are each independently a nitrogen-protecting group.
28. The compound of claim 27, wherein said nitrogen-protecting group is t-butyloxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, substituted
benzyloxycarbonyl (e.g., p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-chlorobenzyloxycarbonyl,
2,4-dichlorobenzyloxycarbonyl, 4-methylsulfmylbenzyloxycarbonyl),
allyloxycarbonyl, trimethylsilylethoxycarbonyl, acetyl, substituted acetyl (e.g., N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, or N-phenylacetyl),
N-benzoyl, or N-p-phenylbenzoyl.
29. The compound of claim 27, having the following structure:
Figure imgf000042_0003
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