NZ617300B2 - Processes for preparing inhibitors of the hepatitis c virus - Google Patents
Processes for preparing inhibitors of the hepatitis c virus Download PDFInfo
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- NZ617300B2 NZ617300B2 NZ617300A NZ61730012A NZ617300B2 NZ 617300 B2 NZ617300 B2 NZ 617300B2 NZ 617300 A NZ617300 A NZ 617300A NZ 61730012 A NZ61730012 A NZ 61730012A NZ 617300 B2 NZ617300 B2 NZ 617300B2
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- 238000000034 method Methods 0.000 title claims abstract description 72
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- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 229940042397 direct acting antivirals Cyclic amines Drugs 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N ethanolamine Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 125000003106 haloaryl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 108010032844 hepatitis C virus NS3 protein Proteins 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004475 heteroaralkyl group Chemical group 0.000 description 1
- 125000005150 heteroarylsulfinyl group Chemical group 0.000 description 1
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 description 1
- 125000005368 heteroarylthio group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 229940121354 immunomodulators Drugs 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 201000004044 liver cirrhosis Diseases 0.000 description 1
- 201000009673 liver disease Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- 229940113083 morpholine Drugs 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- UMPKMCDVBZFQOK-UHFFFAOYSA-N potassium;iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[K+].[Fe+3] UMPKMCDVBZFQOK-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 101710004466 rgy Proteins 0.000 description 1
- 101710030364 rgy1 Proteins 0.000 description 1
- 101710030359 rgy2 Proteins 0.000 description 1
- 229910001925 ruthenium oxide Inorganic materials 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- GRUMUEUJTSXQOI-UHFFFAOYSA-N vanadium dioxide Chemical compound O=[V]=O GRUMUEUJTSXQOI-UHFFFAOYSA-N 0.000 description 1
- 229910001935 vanadium oxide Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/005—Enzyme inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/36—Extraction; Separation; Purification by a combination of two or more processes of different types
Abstract
Disclosed is a processes for the preparation of compounds of Formula (I) (including boceprevir) that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease and have application in the treatment of conditions caused by HCV. In particular, the present invention relates to oxidation processes useful for preparing compounds of Formula (I) and related compounds, including pharmaceutically acceptable salts, hydrates and solvates thereof, and including stereoisomers thereof. sses useful for preparing compounds of Formula (I) and related compounds, including pharmaceutically acceptable salts, hydrates and solvates thereof, and including stereoisomers thereof.
Description
WO 20121151271
PROCESSES FOR PREPARING INHIBITORS OF THE HEPATITIS C VIRUS
FIELD OF THE INVENTION
S The present invention relates to synthetic processes useful in the preparation of
compounds that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease and have
application in the treatment of conditions caused by HCV. In particular, the present invention
relates to novel oxidation processes useful for preparing compounds of Formula I:
R7 R6
and related compounds, including pharmaceutically acceptable salts, hydrates and solvates
thereof, and including stereo isomers thereof.
BACKGROUND OF THE INVENTION
Hepatitis C virus (HCV) infection is a major health problem that leads to chronic
IS liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected
individuals. Current treatments for HCV infection include immunotherapy with recombinant
interferon-a alone or in combination with the nucleoside analog ribavirin.
Several virally-encoded enzymes are putative targets for therapeutic intervention,
including a metalloprotease (NS2-3), a serine protease (NS3, amino acid residues 1-180), a
helicase (NS3, full length), an NS3 protease cofactor (NS4A), a membrane protein (NS4B), a
zinc metalloprotein (NSSA) and an RNA-dependent RNA polymerase (NSSB). The NS3
protease is located in the N-terminal domain of the NS3 protein, and is considered a prime drug
target because it is responsible for an intramolecular cleavage at the NS3/4A site and for
downstream intermolecular processing at the NS4N4B, NS4B/SA and NSSNSB junctions.
WO 20121151271
U.S. Patent No. 7,012,066 describes compounds that are useful as HCV NS3
inhibitors and useful in the treatment ofHCV and conditions caused by HCV infection. U.S.
Patents No. 7,728,165, 7,723,531, 7,595,419, 7,569,705, 7,528,263, 7,326,795, 7,309,717, and
6,992,220; U.S. Patent Application Publications No. US201110034705, US2010/0256393,
US2010/0145069, US2010/0145013, US2010/0113821, US2009/0326244 US2008/0254128, and
US2008/0193518; and International Patent Application Publication W02009/073380 describe
processes for preparing such compounds. However, there is a continuing need for improved
chemical processes for preparing compounds that are potent inhibitors of intermolecular
cleavage at the NS3/4A site. This disclosure addresses this need.
SUMMARY OF THE INVENTION
The present invention relates to chemical processes useful in the synthesis of
compounds of Formula I and related compounds, including salts, hydrates and solvates thereof,
and including stereoisomers thereof, that are useful as inhibitors of the hepatitis C virus NS3
protease.
The chemical processes of the present invention afford advantages over
previously known procedures and include an efficient route to compounds of Formula I. In
particular, the processes of the present invention afford a halogen-free oxidation process for
preparing compounds of Formula I.
More particularly, the present invention relates to processes for preparing a
compound of Formula I,
H-+---+--H
~~ 1 J~
--~ ~ l' 'R
R3 0
wherein:
A and E are independently selected from the group consisting of a direct bond and
C l-C6alkylene;
WO 20121151271
NJyo ~o\
)lZ)H'1
Rl is -NH(C1-Cgalkyl), or
R2 is C1-Cgalkyl;
R3 is independently selected from the group consisting ofCl-Csalkyl,
C l-Csalkyl(C -Cgcycloalkyl) and substituted C l-Cgalkyl(C -Cgcycloalkyl); or
R4 and R are each independently selected from the group consisting of H,
C1-Cgalkyl, C -Cgcycloalkyl, C1-Cgalkyl(C3-Cgcycloalkyl) and substituted
CI-Cgalkyl(C -C cycloalkyl),
or R4 and R may be taken together to form a C3-Cscycloalkyl;
R6 and R7 are independently H or C1-Cgalkyl;
the process comprising:
reacting a compound of Formula II:
R7 R6
H_ot----t __ H
1 2 3 S 6 7
wherein A, E, R , R , R , R 4, R , R and R are as defined above, with an oxidizing agent
selected from the group consisting ofKMn04, NaMn04, K2Fe04, V20S, RU02, NaN02, Cr03,
K2Cr04, K2Cr207, HSPV2MolO04, peroxides and PhI(OAc)2, in the presence of at least one
catalyst to yield a compound of Formula I. In embodiments, the compounds of Formula I and
Formula II may be present as amorphous compounds, or as pharmaceutically acceptable salts,
hydrates, solvates or stereoisomers thereof.
WO 20121151271
DETAILED DESCRIPTION OF THE INVENTION
A first embodiment of the invention is directed to processes in which R I is
selected from -NHCH , -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2,
-NHCH2CH2CH2CH3, -NHCH(CH )CH CH , -NHCH2CH(CH3)2, -NHC(CH )3,
3 2 3 3
-NHCH2CH2CH2CH2CH3, and -NHCH2CH2CH2CH2CH2CH3. In different aspects ofthis
NJyo ~o\
~ZJH""""J #~ I
embodiment, RI is -NHC(CH3)3, RI is or RI is In all
aspects of this embodiment, all other groups are as provided in the general formula above.
A second embodiment of the invention is directed to processes in which R is
selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH(CH3)CH2CH3,
-CH2CH(CH3h, -C(CH3)3, -CH2CH2CH2CH2CH3, and -CH2CH2CH2CH2CH2CH3. In a
particular aspect of this embodiment, R2 is -C(CH3)3. In all aspects ofthis embodiment, all other
groups are as provided in the general formula above and/or in the first embodiment.
A third embodiment of the invention is directed to processes in which R3 is
selected from the group consisting of -CI-Cgalkyl and -(CH2)I_g(cyclo(C -Cg)alkyl). In aspects of
this embodiment, R3 is -CH CH CH CH3 or OJ In a particular aspect of this
2 2 2
embodiment, R3 is OJ . In all aspects of this embodiment, all other groups are as
in the general formula above and/or in the first or second embodiments.
provided
A fourth embodiment of the invention is directed to processes in which R is
selected from the group consisting ofH, CI-Cgalkyl, C -Cgcycloalkyl, C1-Cgalkyl(C3-Cg
cycloalkyl) and substituted C -Cgalkyl(C -Cgcycloalkyl). In particular aspects of this
embodiment, R4 is H or R4 is cyclopropyl. In all aspects of this embodiment, all other groups are
as provided in the general formula above and/or in the first through third embodiments.
A fifth embodiment of the invention is directed to processes in which R is
selected from the group consisting ofH, C1-Cgalkyl, C -C cycloalkyl, C -C alkyl(C -Cg
cycloalkyl) and substituted CI-Cgalkyl(C3-Cgcyc1oalkyl). In particular aspects of this
WO 20121151271
embodiment, R is H or R is cyclopropyl. In all aspects of this embodiment, all other groups are
as provided in the general formula above and/or in the first through fourth embodiments.
In a sixth embodiment, R4 and R are taken together to form a C3-Cscycloalkyl.
In particular aspects of this embodiment, R4 and R are taken together to form a C -C cycloalkyl.
In all aspects of this embodiment, all other groups are as provided in the general formula above
and/or in the first through third embodiments.
A seventh embodiment of the invention is directed to processes in which R6 is
selected from the group consisting ofH or C1-C4alkyl. In particular aspects of this embodiment,
R6 is H or R6 is methyl. In all aspects of this embodiment, all other groups are as provided in the
general formula above and/or in the first through sixth embodiments.
An eighth embodiment of the invention is directed to processes in which R7 is
selected from the group consisting ofH or C1-C4alkyl. In particular aspects of this embodiment,
R7 is H or R7 is methyl. In all aspects of this embodiment, all other groups are as provided in the
general formula above and/or in the first through seventh embodiments.
A ninth embodiment of the invention is directed to processes in which A and E
are independently selected from the group consisting of a bond and -CH -. In particular aspects
of this embodiment, A and E are each independently a bond. In additional aspects of this
embodiment, A and E are each independently -CH -. In all aspects of this embodiment, all other
groups are as provided in the general formula above and/or in the first through eighth
embodiments.
A tenth embodiment of the invention is directed to processes in which the catalyst
is selected from the group consisting of2,2,6,6-tetramethyl-l-piperidinyloxy free radical
(TEMPO), 4-methoxy-TEMPO, 4-amino-TEMPO, 2-azaadamantane N-oxyl (AZADO), I-Me
AZADO and combinations of one to five catalysts chosen therefrom. In this embodiment, the
catalyst may be any single catalyst selected from the group, or any two, three, four or five
catalysts selected from the group set forth above. In a particular aspect of this embodiment, the
catalyst is TEMPO. In aspects of this embodiment, the catalyst is present in a stoichiometric
amount, with respect to the compound of Formula II. In particular aspects of this embodiment,
0.1 to about 2.0 equivalents,
the at least one catalyst is present in an amount ranging from about
per equivalent of the compound of Formula II. In particular aspects of this embodiment, the at
least one catalyst is present in an amount ranging from about 0.6 to about 1.3 equivalents, per
WO 20121151271
equivalent of the compound of Formula II. In all aspects of this embodiment, all other groups
are as provided in the general formula above andlor in the first through ninth embodiments.
An eleventh embodiment of the invention is directed to processes in which the
oxidizing agent is selected from the group consisting ofKMn04, NaMn0 , Cr03, K Cr04,
K2Cr207, and HSPV2MolO04. In particular aspects of this embodiment, the oxidizing agent is
selected from the group consisting OfKMn04, NaMn04, HSPV2Mol004 and K2Cr207. In
additional aspects of this embodiment, the oxidizing agent is present in an amount ranging from
about 0.5 to about 1.2 equivalents, per equivalent of the compound of Formula II, and in specific
aspects of this embodiment, the oxidizing agent is present in an amount ranging from about 0.6
to about 1.0 equivalents, per equivalent of the compound of Formula II. In all aspects of this
embodiment, all other groups are as provided in the general formula above andlor in the first
through tenth embodiments.
A twelfth embodiment of the invention is directed to processes in which the
reacting is conducted in the presence of an acid. In particular aspects of this embodiment, the
acid is selected from the group consisting of HCI, KHS0 , KH2P04, CICH COOH,
ClzCHCOOH, CH3COOH and HOCH2COOH. In additional aspects of this embodiment, the
acid is provided as a IN to 4N solution. In particular instances of these aspects of this
embodiment, the acid is provided as a 2N to 4N solution. In still further aspects of this
embodiment, the acid is present in an amount ranging from about 1.0 to about 20 equivalents, per
equivalent of the compound of Formula II, and in specific aspects of this embodiment, the acid is
present in an amount ranging from about 3.0 to about 10 equivalents, per equivalent of the
compound of Formula II. In all aspects of this embodiment, all other groups are as provided in
the general formula above andlor in the first through eleventh embodiments.
A thirteenth embodiment of the invention is directed to processes in which the
reacting takes place at a temperature in a range of from about O°C to about 40°C, in particular
aspects ofthis embodiment, in a range of from about 3°C to about 30°C, and in still further
aspects of this embodiment, in a range of from about 5°C to about 25°C. In all aspects of this
embodiment, all other groups are as provided in the general formula above andlor in the first
through twelfth embodiments.
A fourteenth embodiment of the invention is directed to processes in which the
compound of Formula I is a compound of Formula Ia:
WO 20121151271
.:0 ~
yY~yYNH'
~ ~... l... 0 R3 0
R1/1( 'I ~O
o R2 Ia
and the compound of Formula II is a compound of Formula lIa:
In all aspects of this embodiment, all other groups and conditions are as provided in the general
formula above and/or in the first through thirteenth embodiments.
A fifteenth embodiment of the invention is directed to processes in which the
compound of Formula I is a compound of Formula Ib:
~~yYNH'
~ ~ I 0 R3 0
R'/I(Y'O
o ~ Th
and the compound of Formula II is a compound of Formula lib:
WO 20121151271
yY~hNH2
~ ~ I 0 R3 0
Rl/y~O
o R2 lib.
In all aspects of this embodiment, all other groups and conditions are as provided in the general
formula above and/or in the first through thirteenth embodiments.
A sixteenth embodiment of the invention is directed to processes in which the
compound of Formula I is a compound of Formula Ie:
yY~hNH2
~ ~ I 0 R3 0
Rl/y~O
o ~ k
and the compound of Formula II is a compound of Formula lie:
In all aspects of this embodiment, all other groups and conditions are as provided in the general
formula above and/or in the first through thirteenth embodiments.
A seventeenth embodiment of the invention is directed to processes in which the
compound of Formula I is a compound of Formula Id:
WO 20121151271
yY~)yNH2
~ ~... l... 0 R3 0
R1/ Y y ~O
o R2 Id
and the compound of Formula II is a compound of Formula lId:
In all aspects of this embodiment, all other groups and conditions are as provided in the general
formula above and/or in the first through thirteenth embodiments.
An eighteenth embodiment of the invention is directed to processes in which the
compound of Formula I is a compound of Formula Ie:
yY~hNH2
~ ~ I 0 R3 0
R'/ y,,(,o
o ~ k
and the compound of Formula II is a compound of Formula lIe:
WO 20121151271
.:-; "
H H ~~yyNH'
R1/NyN~O 0 R 0
o R2 lIe.
In all aspects of this embodiment, all other groups and conditions are as provided in the general
fonnula above and/or in the first through thirteenth embodiments.
A nineteenth embodiment of the invention is directed to processes in which the
compound of Fonnula I is a compound of Fonnula If:
R .......... y 0
o ~ If
and the compound of Fonnula II is a compound of Fonnula IIf:
In all aspects of this embodiment, all other groups and conditions are as provided in the general
fonnula above and/or in the first through thirteenth embodiments.
A twentieth embodiment of the invention is directed to processes in which the
of F onnula I is a compound of F onnula Ig:
compound
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and the compound of Formula II is a compound of Formula IIg:
~ ".
IIg.
In all aspects of this embodiment, all conditions are as provided in the general formula above
andlor in the first through thirteenth embodiments.
A twenty-first embodiment of the invention is directed to processes in which the
compound of Formula I is a compound of Formula Ib:
and the compound of Formula II is a compound of Formula lIb:
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OH Y
N ~yYNH
//~ Y ~ 0
00 0 ~
IIh.
In all aspects of this embodiment, all conditions are as provided in the general formula above
and/or in the first through thirteenth embodiments.
A twenty-second embodiment of the invention is directed to processes in which
the compound of Formula I is a compound of Formula Ii:
~N H H ~
o ~H H N
: N0 0
and the compound of Formula II is a compound of Formula IIi:
IIi.
In all aspects of this embodiment, all conditions are as provided in the general formula above
and/or in the first through thirteenth embodiments.
A twenty-third embodiment of the invention is directed to a compound of
Formula I or a pharmaceutically acceptable salt thereof, wherein the compound is prepared by
the process according to anyone of the general process above and/or anyone ofthe first through
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twenty-second embodiments. In all aspects of this embodiment, all groups are as provided in the
general process above and/or in any of the first through twenty-second embodiments above.
In a twenty-fourth embodiment of the invention, a compound of the invention is
prepared by process according to anyone of the general process above and/or anyone of the first
through twenty-second embodiments and is selected from the exemplary species depicted in
Examples 2 through 4 shown below.
In the embodiments of processes for preparing the compounds and salts provided
above, it is to be understood that each embodiment may be combined with one or more other
embodiments, to the extent that such a combination provides a stable compound or salt and is
consistent with the description of the embodiments. It is further to be understood that the
embodiments of compositions and methods provided are understood to include all embodiments
of the compounds and/or salts, including such embodiments as result from combinations of
embodiments. Further, each of the embodiments described above, for the compounds of
3 4 5
Formula I and Formula II, variables A, E, Rl, R2, R , R , R , R6 and R7 and reagents, including
the oxidizing agents and catalysts are selected independently from each other.
The present invention also includes a compound of the present invention for use
(i) in, (ii) as a medicament for, or (iii) in the preparation of a medicament for: (a) inhibiting HCV
NS3 activity, or (b) treating HCV infection and/or reducing the likelihood or severity of
symptoms of HCV infection, or ( c) use in medicine. In these uses, the compounds of the present
invention can optionally be employed in combination with one or more second therapeutic
agents selected from HCV antiviral agents, anti-infective agents, and immunomodulators.
Additional embodiments of the invention include the pharmaceutical
compositions, combinations and methods set forth above and the uses set forth in the preceding
paragraph, wherein the compound of the present invention employed therein is a compound of
one of the embodiments, aspects, classes, sub-classes, or features of the compounds described
above. In all of these embodiments, the compound may optionally be used in the form of a
pharmaceutically acceptable salt or hydrate as appropriate.
As used above, and throughout the specification, the following terms, unless
otherwise indicated, shall be understood to have the following meanings:
As used herein, the term "alkyl" refers to any linear or branched chain alkyl group
having a number of carbon atoms in the specified range. Thus, for example, "CI_6alkyl" (or
"CI-C6alkyl") refers to all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and
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t-butyl, n- and isopropyl, ethyl and methyl. Alkyl groups may be substituted as indicated, by
substituents that may be the same or different, each substituent being independently selected
from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio,
amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, carboxy and -C(O)O-alkyl. Non-limiting
examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl,
n-pentyl, heptyl, nonyl, decyl, fluoromethyl, trifluoromethyl and cyclopropylmethyl.
The term "alkoxy" refers to an "alkyl-O-" group. Alkoxy groups may be
substituted as indicated.
The term "cycloalkyl" refers to any cyclic ring of an alkane or alkene having a
1 0 number of carbon atoms in the specified range. Thus, for example, "C _cycloalkyl" (or
"C3-Cscycloalkyl") refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
cyclooctyl. The term "cycloalkoxy" refers to a "cycloalkyl-O-" group. Cycloalkyl groups may
be substituted as indicated.
The term "aryl" (or "aryl ring system") refers to aromatic mono- and poly-
carbocyclic ring systems wherein the individual carbocyclic rings in the polyring systems are
fused or attached to each other via a single bond. As used herein, the term aryl includes aromatic
mono- and poly-carbocyclic ring systems that include from 0 to 4 heteroatoms (non-carbon
atoms) that are independently chosen from N, 0 and S. Suitable aryl groups include phenyl,
naphthyl, biphenylenyl, pyridinyl, pyrimidinyl and pyrrolyl, as well as those discussed below.
Aryl groups may be substituted as indicated. Aryl ring systems may include, where appropriate,
an indication of the variable to which a particular ring atom is attached. Unless otherwise
indicated, substituents to the aryl ring systems can be attached to any ring atom, provided that
such attachment results in formation of a stable ring system.
"Halo" means fluoro, chIoro, bromo, or iodo groups. Preferred are fluoro, chloro
or bromo, and more preferred are fluoro and chIoro. Similarly, "halogen" means fluorine,
chlorine, bromine, or iodine. Preferred are fluorine, chlorine or bromine, and more preferred are
fluorine and chlorine.
"Ring system substituent" means a substituent attached to an aromatic or non
aromatic ring system that, for example, replaces an available hydrogen on the ring system. Ring
system substituents may be the same or different, each being independently selected from the
group consisting of aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl,
heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro,
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cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkyl sulfonyl, arylsulfonyl,
heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio,
heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl,
heterocyclenyl, Y Y N-, YIY2N-alkyl-, Y Y NC(0)- and YIY2NS02-, wherein Yl and Y may
1 2 1 2 2
be the same or different and are independently selected from the group consisting of hydrogen,
alkyl, aryl, and aralkyl.
"Cycloalkylalkyl" means a cycloalkyl-alkyl group in which the cycloalkyl and
alkyl groups are as previously described. The cycloalkyl portion may be optionally substituted
with one or more "ring system substituents." The alkyl portion may be substituted with one or
1 0 more alkyl substituents as defined above.
Unless otherwise specifically noted as only "substituted", a particular group is not
substituted. Preferably, the substituents are selected from the group which includes, but is not
limited to, halo, C1-C20alkyl, -CF3, -NH2, -N(CI-C6 alkyl)2' -N02, oxo, -CN, -N3, -OH,
-0(CI-C6alkyl), C -ClOCycloalkyl, C -C alkenyl, C -C alkynyl, (Co-C alkyl) S(0)0,
3 2 6 2 6 6
aryl-S(0)o, (Co-C6alkyl)S(O)0-2(Co-C6alkyl)-, (C -C6 alkyl)C(O)NH-, H2N-C(NH)-,
-0(C1-C6alkyl)CF3, (Co-C6alkyl)C(0)-, (Co-C6alkyl)OC(0)-, (Co-C alkyl)0(Cl-C6 alkyl)-,
(Co-C6alkyl)C(0)1_2(Co-C6alkyl)-, (Co-C alkyl)OC(O)NH-, aryl, aralkyl, heteroaryl,
heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle and halo-heterocyclyialkyi.
Unless expressly stated to the contrary, all ranges cited herein are inclusive. For
example, a heteroaryl ring described as containing from "0 to 3 heteroatoms" means the ring can
contain 0, 1, 2, or 3 heteroatoms. It is also to be understood that any range cited herein includes
within its scope all of the sub-ranges within that range. The oxidized forms of the heteroatoms N
and S are also included within the scope of the present invention. In addition, the term "or," as
used herein, denotes alternatives that may, where appropriate, be combined; that is, the term "or"
includes each listed alternative separately as well as their combination.
Unless expressly stated to the contrary, substitution by a named substituent is
permitted on any atom provided such substitution is chemically allowed and results in a stable
compound. A "stable" compound is a compound that can be prepared and 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 the purposes described herein (e.g., therapeutic
or prophylactic administration to a subject).
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As a result of the selection of substituents and substituent patterns, certain of the
of the present invention can have asymmetric centers and can occur as mixtures of
compounds
stereoisomers, or as individual diastereomers, or enantiomers. All isomeric forms of these
compounds, whether isolated or in mixtures, are within the scope of the present invention.
The compounds prepared via the present invention may be chiral as a result of
asymmetric centers, chiral axes, or chiral planes as described in: E.L. Eliel and S.H. Wilen,
Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-
1190), and may occur as single optical isomers or as mixtures of any number of the possible
optical isomers, including racemates, racemic mixtures, diastereomers, diastereomeric mixtures,
enantiomers, and enantiomeric mixtures. In certain instances, the compounds disclosed may
exist as tautomers and all tautomeric forms are intended to be encompassed by the scope of the
invention, even though only one tautomeric structure is depicted. That is, for the purposes of the
present invention, a reference to a compound of Formula I is a reference to the compound per se,
or to anyone of its tautomers per se, or to mixtures of two or more tautomers.
Racemic mixtures can be separated into their individual enantiomers by any of a
number of conventional methods. These include chiral chromatography, derivatization with a
chiral auxiliary followed by separation by chromatography or crystallization, and fractional
crystallization of diastereomeric salts.
The compounds of the present invention may be administered in the form of
pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt
that possesses the effectiveness of the parent compound and that is not biologically or otherwise
undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof). Suitable
salts include acid addition salts that may, for example, be formed by mixing a solution of the
compound of the present invention with a solution of a pharmaceutically acceptable acid such as
hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Many of the
compounds of the invention carry an acidic moiety, in which case suitable pharmaceutically
acceptable salts thereof can include alkali metal salts (e.g., sodium or potassium salts), alkaline
earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic
ligands such as quaternary ammonium salts. Also, in the case of an acid (-COOH) or alcohol
group being present, pharmaceutically acceptable esters can be employed to modify the
solubility or hydrolysis characteristics of the compound.
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The tenn "administration" and variants thereof (e.g., "administering" a
compound) in reference to a compound of the invention mean providing the compound or a
prodrug of the compound to the individual in need of treatment. When a compound of the
invention or a prodrug thereof is provided in combination with one or more other active agents
(e.g., antiviral agents useful for treating Hev infection), "administration" and its variants are
of the compound or salt (or
each understood to include concurrent and sequential provision
hydrate) and other agents.
As used herein, the tenn "composition" is intended to encompass a product
comprising the specified ingredients, as well as any product that results, directly or indirectly,
from combining the specified ingredients.
By "pharmaceutically acceptable" is meant that the ingredients of the
pharmaceutical composition must be compatible with each other and not deleterious to the
recipient thereof.
The tenns "subject" (alternatively referred to herein as "patient") and "cell-based
system", as used herein, refer to an animal, preferably a mammal, most preferably a human, who
has been the object of treatment, observation or experiment.
The tenn "pharmaceutically acceptable salts" refers to salts prepared from
pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and
inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium,
calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium,
sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, lithium,
magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable
organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted
amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange
resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl
morpho line, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine,
isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins,
procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine,
and the like.
When the compound of the present invention is basic, salts may be prepared from
pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids
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include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,
mandelic, methanesulfonic, malonic, mucic, nitric, pamoic, pantothenic, phosphoric, propionic,
succinic, sulfuric, tartaric, p-toluenesulfonic acid, trifluoroacetic acid, and the like. Particularly
preferred are citric, fumaric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and
tartaric acids.
The compounds afforded by the instant invention are useful intermediates in the
production ofHCV NS3 inhibitor compounds or are themselves HCV NS3 inhibitor compounds
useful for treating conditions caused by HCV infection or which can be ameliorated by inhibition
ofHCV infection, and/or reduction of the likelihood or severity of symptoms ofHCV infection,
alone or in combination with other active agents. For example, the compounds of this invention
are useful in treating infection by HCV after suspected past exposure to HCV by such means as
blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient
blood during surgery. Treatment is effected by administration of the final product obtained from
the disclosed processes to a mammal in need of such treatment. In addition, these compounds
are useful as ingredients in pharmaceutical compositions alone or in combination with other
active agents.
The following schemes and examples are illustrative of the processes
encompassed by the present invention. As will be readily apparent to those in the field, the
substituents and substitution patterns on the substrates exemplified herein may be modified
without undue experimentation by the choice of readily available starting materials, reagents, and
conventional procedures or variations. As used below and throughout this disclosure, "room
temperature" or "RT" indicates that the reaction was performed at ambient temperature without
the use of any means for cooling or heating. "Room temperature" is about 25°C.
The illustrative examples below, therefore, are not limited by the compounds
listed or by any particular substituents employed for illustrative purposes. Substituent
numbering as shown in the schemes does not necessarily correlate to that used in the claims and
often, for clarity, a single substituent is shown attached to the compound in place of multiple
substituents allowed under the definitions of Formula I defined above.
The processes ofthe instant invention are useful in the preparation of compounds
of Formula I. The compounds of the present invention can be readily prepared according to the
following reaction schemes and examples, or modifications thereof, using readily available
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starting materials, reagents and conventional synthesis procedures. In these reactions, it is also
possible to make use of variants which are themselves known to those of ordinary skill in this art,
but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of
the invention will be readily apparent to the person of ordinary skill in the art in light of the
following reaction schemes and examples. Unless otherwise indicated, all variables are as
defined above. The following reaction schemes and examples serve only to illustrate the
invention and its practice.
EXAMPLES
The following listing defines the abbreviations used herein, both above and in the
Examples below.
ABBREVIATIONS
IHNMR
Proton nuclear magnetic resonance spectrum
Ac Acetyl or -C(O)CH3
AZADO 2-Azaadamantane N-oxyl
Chromium oxide
Cr03
eq. Equivalents
g Grams
Polyoxymetalates
HsPV 2MOlO04
HCI Hydrochloric acid
Acetic acid or CH COOH
HOAc
Cr 0 Potassium dichromate
K 2 7
Potassium chromate
K Cr04
Potassium ferrate
K2Fe04
KBr Potassium bromide
Kilogram
Potassium permanganate
KMn04
L Liter
Molar
Me Methyl or -CH3
mL Milliliters
Millimoles
mmols
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MTBE
Methyl t-butyl ether
N Normal
NaMn04 Sodium permanganate
NaN0
Sodium nitrite
NaOAc Sodium acetate
NaOCl Sodium hypochlorite (bleach)
Phenyl or -C6HS
PW(OAc)2 (Diacetoxyiodo )benzene
rpm Revolutions per minute
Room temperature, approximately 25°C
Ru02 Ruthenium oxide
TEMPO 2,2,6,6-tetramethyl-l-piperidiny loxy free radical (available
from Aldrich and used as received)
Vanadium oxide
Example 1: (lR,2S,5S)-N-( 4-amino-l-cyclobutylhydroxyoxobutanyl)[N-(tert
butylcarbamoyl)methylvalyl]-6,6-dimethylazabicyclo[3.1.0]hexanecarboxamide
(1 R,2S,5S)-N-( 4-amino-l-cyclobutyl-3 -hydroxyoxobutanyl)-3 -[N-(tert
butylcarbamoyl)methylvalyl]-6,6-dimethylazabicyclo[3 .1.0]hexanecarboxamide was
prepared according to the processes disclosed in U.S. Patent Application Publication No.
US2010/5I9485 AI, the disclosures of which are herein incorporated by reference. It will be
appreciated that the processes disclosed therein can be modified without undue experimentation
to prepare specifically desired starting materials.
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Example 2: (lR,2S,5S)-N-(4-amino-l-cyclobutyl-3,4-dioxobutanyl)[N-(tert
butylcarbamoyl)methylvalyIJ-6,6-dimethylazabicyclo[3.1.0Jhexanecarboxamide
The compound of Example 1 (500g), TEMPO (164.7g), methyl tert-butyl ether (4L) and
acetic acid (472g) were charged into a 10-L, 3-necked flask equipped with a mechanical stirrer,
addition funnel and thermometer. The mixture was cooled to between 10°C and 20°C. To the
cooled mixture, pre-diluted NaMn04 (289g of 40% NaMn04 and 1.65L of water) was added
drop-wise while maintaining the temperature between 10°C and 20°C. The mixture was agitated
while maintaining the temperature between 10°C and 20°C until the reaction was complete. The
reaction mixture was cooled to between O°C and 5°C, and 500ml of water was added. The layers
were settled and separated. The organic layer was washed with 2.5L of water and filtered to
remove any solid. The organic layer was washed at 5 to 15°C for about 4 hours with an ascorbic
acid solution prepared from 500g of sodium ascorbate, 1.655L of water and 0.875L of9.9% HCI
solution. After splitting the layers, the organic layer was washed with 2L of 3.0N to 4.0N HCI
solution. After separation oflayers, the organic layer was washed 4 times with 2.5L of water at
between O°C and 10°C. The resulting organic layer was added dropwise to 15L of n-heptane
while keeping the temperature at between -10°C and O°C. The precipitate was filtered and dried
at 35°C to 40°C to give the desired product. The isolated yield of desired product was 73%-90%
by weight. IH NMR, 0 0.84 (d, J= 2.3 Hz, 3H), 0.90-1.02 (m, 9H), 0.99 (d, J= 4.0 Hz, 3H),
1.24 (s, 9H), 1.40-1.86 (m, 7H), 1.90-2.10 (m, 3H), 2.25-2.40 (m, IH), 3.75 (dd, J= 5.3 and lOA
Hz, IH), 4.10 (dd, J= 6.8 and lOA Hz, lH), 4.4 (dd, J= 3.0 and 5.3 Hz, 2H), 5.17 (dddd, J=
4.6,8.1,8.1, and lOA Hz, IH), 5.3 (br s, 2H), 6.71 (d, J= 14.7 Hz, IH), 6.90 (dd, J= 2.3 and
19.0 Hz, IH), and 7.34 (dd, J= 7.1 and 20.2 Hz, IH).
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Example 3: (lR,2S,5S)-N-(4-amino-l-cyclohutyl-3,4-dioxohutanyl)fN-(tert
hutylcarhamoyl)methylvalyIJ-6,6-dimethylazahicyclo{3.1.0Jhexanecarhoxamide
The title compound was prepared according to the procedures in Example 2, using
.0g of the compound of Example 1, and 0.91g ofKMn04, dissolved in 25mL of water, in place
of NaMn04. The isolated yield was about 85% by weight of a product having an identical IH
NMR spectrum to that of the product of Example 2.
Example 4: (lR,2S,5S)-N-(4-amino-l-cyclohutyl-3,4-dioxohutanyl){N-(tert
hutylcarhamoyl)methylvalyIJ-6,6-dimethylazahicyclo{3.1.0Jhexanecarhoxamide
The compound of Example 1 (320kg), TEMPO (106kg), methyl tert-butyl ether
(2560L) and acetic acid (302kg) were charged into a 11000-L, glass-lined reactor that was
equipped with a retreat curve impeller, temperature probes and a temperature control jacket. The
mixture was cooled to a temperature between 11°C and 22°C. To the cooled mixture, pre-diluted
NaMn04 (l81kg of 40% NaMn04 and 1056L of water) was added drop-wise over 2 to 3 hours
while maintaining the temperature between 11°C and 22°C. The mixture was agitated while
maintaining the temperature between 11 °C and 22°C until the reaction was complete. The
reaction mixture was cooled to between O°C and 10°C, and 256L of water was added. The layers
were settled and separated. The organic layer was washed with 1600L of water and filtered to
remove any solid. The organic layer was washed at 5°C to 15°C for about 4 hours with an
ascorbic acid solution prepared from 320 kg of sodium ascorbate, 1060L of water and 560kg of
9.9% HCI solution. After splitting the layers, the organic layer was washed with about 1280L of
3.0 to 4.0N HCI solution. After separation oflayers, the organic layer was washed 4 times with
1600L of water at between O°C and 10°C. The resulting organic layer was precipitated by
mixing it continuously with cold n-heptane (kept between -25°C and 15°C) by use ofa tee mixer
at a volumetric ratio of 1 :4, while maintaining its temperature at between -10°C and O°C. The
precipitate was distilled under vacuum by following the temperature and % batch volume
distilled profile shown in Table 1 to a final volume of lOX. The batch was then filtered and
dried at 35°C to 45°C to give the desired product. The isolated yield of desired product was 88%
by weight.
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Table 1: Distillation profile used in Example 4.
Time (h) Distillation Temperature (OC) % Batch Volume Distilled
.1 to 22.5
0.0 to 2.8
17.7 to 22.5 2.8 to 4.1
16.3 to 22.4
2.8 to 7.0
19.1 to 22.4 7.0 to 8.4
19.2 to 24.2
.9 to 11.4
19.2 to 24.6 11.4 to 14.7
.2 to 24.6 14.7 to 18.8
Comparative Example 1: (lR,2S,5S)-N-(4-amino-l-cyclobutyl-3,4-dioxobutanyl){N-(tert
butylcarbamoyl)methylvalyIJ-6,6-dimethylazabicyclo{3.1.0Jhexanecarboxamide by the
Process of u.s. Patent No. 7,583,263, Example 1
Into a 1L, three-necked flask is placed KEr (lOg, 84mmol), NaOAc (lOg,
122mmol), the compound of Example 1 (50g, 96mmol), and TEMPO (15g, 96mmol), followed
by 500mL ofMTBE. The reaction mixture is stirred at 350-400 rpm, and the temperature is
maintained at a temperature of from lOoC to 20°C. Acetic acid (50mL, 874mmol), and water
(5mL) are added to the reaction mixture and the two phase mixture is agitated for 15 minutes.
Continuously, over a two hour period, to the reaction mixture is added 158mL of a O. 82M
solution ofNaOCI (130mmol). When all of the NaOCI solution is added, the reaction mixture is
stirred for an additional 3 hours while maintaining the temperature. Water (50mL) is added. The
layers are separated and the organic layer is washed twice with water (2 x 250mL). A solution of
ascorbic acid, which is prepared from 50g of sodium ascorbate, 200mL of water, and 50mL of
4N HCI, is added to the organic layer and the mixture is stirred for about 1 hour. After the layers
are separated, the organic layer is washed twice with water (2 x 250mL). The organic layer is
concentrated by distilling off solvent at low temperature (0-5°C) until the total volume is about
350mL. The concentrated organic layer is added dropwise over 30 minutes into a 3L flask
containing 2L of n-heptane at about O°C providing a white precipitate. The white precipitate is
collected by filtration, washed with n-heptane (400 mL) and dried in a vacuum oven (2 hours at
°C, 8 hours at 35°, and 8 hours at 45°C). The product is obtained as a white powder (typically
94-96% yield). lH NMR, () 0.84 (d, J= 2.3 Hz, 3H), 0.90-1.02 (m, 9H), 0.99 (d, J= 4.0 Hz, 3H),
1.24 (s, 9H), 1.40-1.86 (m, 7H), 1.90-2.10 (m, 3H), 2.25-2.40 (m, 1H), 3.75 (dd, J= 5.3 and 10.4
Hz, 1H), 4.10 (dd, J= 6.8 and 10.4 Hz, 1H), 4.4 (dd, J= 3.0 and 5.3 Hz, 2H), 5.17 (dddd, J=
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4.6,8.1,8.1, and lOA Hz, 1H), 5.3 (br s, 2H), 6.71 (d, J= 14.7 Hz, IH), 6.90 (dd, J= 2.3 and
19.0 Hz, IH), and 7.34 (dd, J= 7.1 and 20.2 Hz, IH).
Comparative Example 2: (IR,2S,5S)-N-(4-amino-l-cyclobutyl-3,4-dioxobutanylJ{N-(tert
butylcarbamoyl)methylvalyIJ-6,6-dimethylazabicyclo{3.1.0Jhexanecarboxamide by the
Process of u.s. Patent No. 7,583,263, Example 2
Into a 2L, three necked flask was charged KBr (20g, 168mmol), NaOAc (20g,
243mmol), the compound of Example 1 (IOOg, 192mmol), and TEMPO (30g, 192mmol),
followed by 800mL ofMTBE. The reaction mixture was stirred at 350-400 rpm while the
temperature of the reaction mixture was maintained at a temperature of from 10°C to 20°C.
Acetic acid (70mL, 1223mmol, used as received), was added and the mixture was agitated for 15
minutes additional. Continuously, over a two hour period, 315ml ofa 0.73M solution ofNaOCI
(230mmol) was added to the reaction mixture. When all of the NaOCI solution had been added,
agitation was continued for an additional 3 hours. Water (100mL) was added to the reaction
mixture at the end of 3 hours. The layers were separated and the organic layer was washed once
with water (500mL). A solution of ascorbic acid, which was prepared from 100g of sodium
ascorbate, 456mL of water, and 44mL of36% HCI, was added to the organic layer and the
mixture was stirred for about 2 hours. The layers were separated and then a solution of3.5N
HCL was added and stirred about 30 minutes. After the layers were separated, the organic layer
was washed three times with water (3 x 500mL). This organic layer was then added drop-wise
over 30 minutes into a 5L flask containing 3L ofn-heptane at about -10 to about O°C. The white
precipitate was filtered, washed with n-heptane (600mL) and dried in a vacuum oven (2 hours at
°C, 8 hours at 35°, and 8 hours at 45°C). The product was obtained as a white powder (93%
yield). iHNMR, 80.84 (d, J= 2.3 Hz, 3H), 0.90-1.02 (m, 9H), 0.99 (d, J= 4.0 Hz, 3H), 1.24 (s,
9H), 1.40-1.86 (m, 7H), 1.90-2.10 (m, 3H), 2.25-2.40 (m, IH), 3.75 (dd, J= 5.3 and lOA Hz,
1H), 4.10 (dd, J= 6.8 and lOA Hz, 1H), 404 (dd, J= 3.0 and 5.3 Hz, 2H), 5.17 (dddd, J= 4.6,
8.1,8.1, and 10.4 Hz, IH), 5.3 (br s, 2H), 6.71 (d, J= 14.7 Hz, 1H), 6.90 (dd, J= 2.3 and 19.0
Hz, IH), and 7.34 (dd, J= 7.1 and 20.2 Hz, IH).
Similar yields of 73-90% may be obtained for the procedures of Examples 2-4
and Comparative Examples 1-2 when conducted on a comparable scale, such as using 500g and
100g of the compound of Example I as starting material. However, the procedures of Examples
2-4 provide the desired product without the inclusion of halogenated impurities found in the
WO 20121151271
products of Comparative Examples 1-2. Thus, the claimed procedures provide a process for
producing compounds of Formula I having superior purity when compared to the processes of
U.S. Patent No. 7,583,263.
It will be appreciated that various of the above-discussed and other features and
functions, or alternatives thereof, may be desirably combined into many other different systems
or applications. Also that various presently unforeseen or unanticipated alternatives,
modifications, variations or improvements therein may be subsequently made by those skilled in
the art which are also intended to be encompassed by the following claims.
WO 20121151271
Claims (19)
1. A process for preparing a compound of Formula I, R7 R6 5 wherein: A and E are independently a direct bond; Rl is -NH(CI-Cgalkyl); R2 is CI-Cgalkyl; R3 is independently selected from the group consisting OfCI-Cgalkyl, 10 CI-Cgalkyl(C -Cgcycloalkyl) and substituted CI-Cgalkyl(C -C cycloalkyl); or R4 and R are each independently selected from the group consisting ofH, CI-Cgalkyl, C3-Cgcycloalkyl, C -C alkyl(C -Cgcycloalkyl) and substituted CI-Cgalkyl(C -Cgcycloalkyl), or R4 and R may be taken together to form a C3-Cgcycloalkyl; 15 R6 and R7 are independently methyl; the process comprising: reacting a compound of Formula II: R7 R6 H-.of---+-H - 26- WO 20121151271 3 4 S wherein A, E, RI, R2, R , R , R , R6 and R7 are as defined above, with an oxidizing agent selected from the group consisting ofKMn04, NaMn04, K2Fe04, V 0 RU02, NaN0 , Cr03, 2 S 2 K2Cr04, K2Cr207, HSPV2MoIO04, peroxides and PhI(OAc)2, in the presence of at least one catalyst to yield a compound of Formula I.
2. The process according to claim 1, wherein RI is selected from -NHCH3, -NHCH2CH3, -NHCH2CH CH , -NHCH(CH3)2, -NHCH CH CH CH , -NHCH(CH )CH CH , 3 2 2 2 3 3 3 -NHCH2CH(CH3)2, -NHC(CH )3, -NHCH2CH2CH2CH2CH3, and -NHCH2CH2CH2CH2CH2CH3. 10 3. The process according to claim 1 or claim 2, wherein R2 is selected from -CH , -CH CH , -CH2CH2CH3, CH(CH )2, -CH2CH2CH2CH3, -CH(CH3)CH2CH3,
3 2 3 3 -CH2CH(CH3)2, -C(CH )3, -CH2CH2CH2CH2CH3, and -CH2CH2CH2CH2CH2CH3.
4. The process according to anyone of claims 1-3, wherein R3 is selected 15 from the group consisting of -CI-Csalkyl or -(CH2)I-s(cyclo(C3-Cs)alkyl).
5. The process according to anyone of claims 1-4, wherein R4 and R are independently selected from the group consisting ofH, CI-Csalkyl, C -Cscycloalkyl, C -C alkyl(C -Cscycloalkyl) and substituted CI-Csalkyl(C3-Cscycloalkyl). I s 3
6. The process according to anyone of claims 1-4, wherein R4 and R are taken together to form a C3-Cscycloalkyl.
7. The process according to anyone of claims 1-6, wherein R and R are 25 independently selected from the group consisting ofH and CI-C4alkyl.
8. The process according to claim 1, wherein RI is -NHC(CH )3, R2 is -C( 3)3, R3 is ()--I , R4 is H, R is H, R6 is methyl, and R7 is methyl. - 27- WO 20121151271
9. The process according to anyone of claims 1-8, wherein the at least one catalyst is selected from the group consisting of TEMPO, 4-methoxy-TEMPO, 4-amino TEMPO, AZADO, 1-Me-AZADO and combinations of one to five thereof. 5
10. The process according to claim 1-9, wherein the catalyst is TEMPO.
11. The process according to anyone of claims 1-10, wherein the oxidizing agent is selected from the group consisting ofKMn04, NaMn04, K2Cr207, and HSPV2MoJO04. 10 12.
The process according to anyone of claims 1-11, wherein the oxidizing agent is present in an amount ranging from about 0.5 to about 1.2 equivalents, per equivalent of the compound of Formula II.
13. The process according to anyone of claims 1-12, wherein said reacting is 15 conducted in the presence of an acid.
14. The process according to claim 13, wherein the acid is selected from the group consisting of HCI, KHS0 , KH2P04, CICH2COOH, ChCHCOOH, CH COOH and HOCH COOH.
15. The process according to anyone of claims 1-14, wherein the acid is present in a concentration ranging from about IN to about 4N.
16. The process according to anyone of claims 1-15, wherein the acid is 25 present in a concentration ranging from about 2N to about 4N.
17. The process according to anyone of claims 1-16, wherein the acid is present in an amount ranging from about 1.0 to about 20 equivalents, per equivalent of the compound of Formula II.
18. The process according to anyone of claims 1-17, wherein the reacting takes place at a temperature in a range of from about O°C to about 40°C. - 28- WO 20121151271
19. The process according to anyone of claims 9-18, wherein the compound of Formula I is a compound of Formula Ig: 5 and the compound of Formula II is a compound of Formula IIg: ;: ~ IIg. - 29-
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161482592P | 2011-05-04 | 2011-05-04 | |
US61/482,592 | 2011-05-04 | ||
PCT/US2012/036112 WO2012151271A1 (en) | 2011-05-04 | 2012-05-02 | Processes for preparing inhibitors of the hepatitis c virus |
Publications (2)
Publication Number | Publication Date |
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NZ617300A NZ617300A (en) | 2015-06-26 |
NZ617300B2 true NZ617300B2 (en) | 2015-09-29 |
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