US20070244334A1 - Processes and intermediates for preparing steric compounds - Google Patents

Processes and intermediates for preparing steric compounds Download PDF

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US20070244334A1
US20070244334A1 US11/724,002 US72400207A US2007244334A1 US 20070244334 A1 US20070244334 A1 US 20070244334A1 US 72400207 A US72400207 A US 72400207A US 2007244334 A1 US2007244334 A1 US 2007244334A1
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optionally substituted
compound
formula
cyclopropyl
acid
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Gerald Tanoury
Minzhang Chen
Young Jung
Raymond Forslund
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Vertex Pharmaceuticals Inc
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Vertex Pharmaceuticals Inc
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Assigned to VERTEX PHARMACEUTICALS INCORPORATED reassignment VERTEX PHARMACEUTICALS INCORPORATED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHEN, MINZHANG, JUNG, YOUNG CHUN, TANOURY, GERALD J., FORSLUND, RAYMOND E.
Publication of US20070244334A1 publication Critical patent/US20070244334A1/en
Priority to US12/806,014 priority patent/US8383858B2/en
Priority to US13/740,707 priority patent/US20130131359A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/16—Preparation of optical isomers
    • C07C231/20—Preparation of optical isomers by separation of optical isomers
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated
    • C07C247/06—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated and containing rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
    • C07D301/14—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with organic peracids, or salts, anhydrides or esters thereof
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general
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    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • This invention relates to processes and intermediates for the preparation of protease inhibitors, in particular, serine protease inhibitors.
  • HCV hepatitis C virus
  • protease inhibitors and in particular serine protease inhibitors, useful in the treatment of HCV infections are disclosed in WO 02/18369. Also disclosed therein are processes and intermediates for the preparation of these compounds. There remains however, a need for economical processes for the preparation of these compounds.
  • This invention relates to processes and intermediates for the preparation of an alpha-amino beta-hydroxy acid of Formula 1 wherein the variables R 1 , R′ 1 and R 2 are defined herein and the compound of Formula 1 has an enantiomeric excess (ee) of 55% or greater.
  • the process comprises the steps of oxidizing an unsaturated amide or ester to form the corresponding epoxide, forming an alpha-hydroxy, beta-amino acid with an appropriate aminating reagent and resolving the amino-alcohol amide.
  • the invention features processes and intermediates used in the preparation of the serine protease inhibitor of Formula 3.
  • the term “enantimoeric excess (ee) of 55% or greater” means that one enantiomer is present 55% or more than the other in a chemical substance.
  • the enantiomer can be a result of either the carbon center to which the amino group is bonded (shown with an asterisk) in Formula 1 or the carbon center to which the hydroxyl group is bonded (also shown with an asterisk) in Formula 1, or both carbon centers.
  • the compound can be (2S,3S), (2S,3R), (2R, 3R) or (2R, 3S) in these two carbon centers.
  • trialkylamines e.g. diethylisopropylamine, triethylamine, N-methylmorpholine and the like
  • heteroaryl amines e.g. pyridine, quinoline, and the like.
  • aliphatic encompasses alkyl, alkenyl, and alkynyl.
  • an “alkyl” group refers to a saturated aliphatic hydrocarbon group containing 1-8 (e.g., 1-6 or 1-4) carbon atoms.
  • An alkyl group can be straight or branched. Examples of an alkyl group include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, and 2-ethylhexyl.
  • An alkyl group can be optionally substituted with one or more substituents such as cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy (two alkoxy groups on the same atom or adjacent atoms may form a ring together with the atom(s) to which they are bound), aroyl, heteroaroyl, alkoxycarbonyl, alkylcarbonyloxy, acyl, sulfonyl (such as alkylsulfonyl or arylsulfonyl), sulfinyl (such as alkylsulfinyl), sulfanyl (such as alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl.cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroary
  • an “alkenyl” group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl.
  • An alkenyl group can be optionally substituted with one or more substituents such as cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy (two alkoxy groups on the same atom or adjacent atoms may form a ring together with the atom(s) to which they are bound), aroyl, heteroaroyl, alkoxycarbonyl, alkylcarbonyloxy, acyl, sulfonyl (such as alkylsulfonyl or arylsulfonyl), sulfinyl (such as alkylsulfinyl), sulfanyl (such as alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl.cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, hetero
  • an “alkynyl” group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and has at least one triple bond.
  • An alkynyl group can be straight or branched. Examples of an alkynyl group include, but are not limited to, propargyl and butynyl.
  • An alkynyl group can be optionally substituted with one or more substituents such as cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy (two alkoxy groups on the same atom or adjacent atoms may form a ring together with the atom(s) to which they are bound), aroyl, heteroaroyl, alkoxycarbonyl, alkylcarbonyloxy, acyl, sulfonyl (such as alkylsulfonyl or arylsulfonyl), sulfinyl (such as alkylsulfinyl), sulfanyl (such as alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy
  • an “amino” group refers to —NRXRY wherein each of RX and RY is independently hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, or heteroaralkyl each of which are defined herein and are optionally substituted.
  • RX has the same meaning as defined above.
  • an “aryl” group used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refers to phenyl, naphthyl, or a benzofused group having 2 to 3 rings.
  • a benzofused group includes phenyl fused with one or two C4-8 carbocyclic moieties, e.g., 1, 2, 3, 4-tetrahydronaphthyl, indanyl, or fluorenyl.
  • An aryl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloal
  • an “aralkyl” group refers to an alkyl group (e.g., a C 1-4 alkyl group) that is substituted with an aryl group. Both “alkyl” and “aryl” are defined herein. An example of an aralkyl group is benzyl. An “heteroaralkyl” group refers to an alkyl group that is substituted with a heteroaryl. Both “alkyl” and “heteroaryl” are defined herein. As used herein, a “cyclcoaliphatic” group encompasses a “cycloalkyl” group and a “cycloalkenyl” group.
  • a “cycloalkyl” group refers to a saturated carbocyclic mono- or bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbon atoms.
  • Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, and bicyclo[3.3.2.]decyl, and adamantyl.
  • a “cycloalkenyl” group refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bond.
  • Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, bicyclo[2.2.2]octenyl, and bicyclo[3.3.1]nonenyl.
  • a cycloalkyl or cycloalkenyl group can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkyl
  • heterocycloaliphatic encompasses a heterocycloalkyl group and a heterocycloalkenyl group.
  • heterocycloalkyl refers to a 3- to 10-membered mono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom, e.g., N, O, or S.
  • heterocycloalkyl group examples include piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuryl, dioxolanyl, oxazolidinyl, isooxazolidinyl, morpholinyl, octahydro-benzofuryl, octahydro-chromenyl, octahydro-thiochromenyl, octahydro-indolyl, octahydro-pyrindinyl, decahydro-quinolinyl, octahydro-benzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, anad 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl.
  • a monocyclic heterocycloalkyl group may be fused with a phenyl moiety such as tetrahydroisoquinoline.
  • a “heterocycloalkenyl” group refers to a mono- or bicylic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom, e.g., N, O, or S.
  • a heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl (such as a benzimidazolidinyl), (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy (two alkoxy groups on the same atom or adjacent atoms may form a ring together with the atom(s) to which they are bound), cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alky
  • a “heteroaryl” group refers to a monocyclic, bicyclic, or tricyclic ring structure having 4 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom, e.g., N, O, or S and wherein one or more rings of the bicyclic or tricyclic ring structure is aromatic.
  • a heteroaryl group includes a benzofused ring system having 2 to 3 rings.
  • a benzofused group includes phenyl fused with one or two C 4-8 heterocyclic moieties, e.g., indolinyl and tertahydroquinolinyl.
  • heteroaryl examples include azetidinyl, pyridyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, and benzo[1,3]dioxole.
  • a heteroaryl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloal
  • heteroaryl group refers to an alkyl group (e.g., a C 1-4 alkyl group) that is substituted with a heteroaryl group. Both “alkyl” and “heteroaryl” have been defined above.
  • cyclic moiety includes cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, each of which has been defined previously.
  • an “acyl” group refers to a formyl group or alkyl-C( ⁇ O)— where “alkyl” has been defined previously. Acetyl and pivaloyl are examples of acyl groups.
  • a “carbamoyl” group refers to a group having the structure —O—CO—NRxRy or —NRx—CO—O-Rz wherein Rx and Ry have been defined above and Rz can be alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl.
  • a “carboxy” and a “sulfo” group refer to —COOH or —COOR X and —SO 3 H or —SO 3 R X , respectively.
  • alkoxy refers to an alkyl-O— group where “alkyl” has been defined previously.
  • a “sulfoxy” group refers to —O—SO—R X or —SO—O—R X , where R X has been defined above.
  • a “sulfonyl” group refers to —S(O) 2 —R X , wherein R X has been defined above.
  • sulfinyl refers to —S(O)—R X , wherein R X has been defined above.
  • sulfanyl group refers to —S—R X , wherein R X has been defined above.
  • halogen or “halo” group refers to fluorine, chlorine, bromine or iodine.
  • haloaliphatic refers to an aliphatic group substituted with 1-3 halogen.
  • haloalkyl includes the group —CF 3 .
  • a “sulfamoyl” group refers to the structure —S(O) 2 —NR x R y or —NR x , —S(O) 2 —Rz wherein Rx, Ry, and Rz have been defined above.
  • sulfamide refers to the structure —NR X —S(O) 2 —NR Y R Z wherein R X , R Y , and R Z have been defined above.
  • a “carbonylamino” group used alone or in connection with another group refers to an amido group such as —C(O)—NR X —, —NR X —C(O)—, and —C(O)—N(R X ) 2 .
  • an alkylcarbonylamino includes alkyl-C(O)—NR X — and alkyl-NR X —C(O)—.
  • urea refers to the structure —NR X —CO—NR Y R Z and a “thiourea” group refers to the structure —NR X —CS—NR Y R Z .
  • R X , R Y , and R Z have been defined above.
  • an alkyl group may be substituted with alkylsulfanyl and the alkylsulfanyl may be optionally substituted with one to three of halo, cyano, alkoxy, hydroxyl, nitro, haloalkyl, and alkyl.
  • the cycloalkyl portion of a (cycloalkyl)carbonylamino may be optionally substituted with one to three of halo, cyano, alkoxy, hydroxyl, nitro, haloalkyl, and alkyl.
  • substituted refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
  • Specific substituents are described above in the definitions and below in the description of compounds and examples thereof.
  • an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • a ring substituent such as a heterocycloalkyl
  • substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.
  • stable or chemically feasible refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • bicyclic fused ring system or “bicyclic ring system” refers to two rings which share two atoms. Either ring may be saturated, partially unsaturated, or aromatic. Each ring also may contain 1 to 3 heteroatoms.
  • tricyclic fused ring system or “tricyclic ring system” refers to a bicyclic ring system in which a third ring is fused to the bicyclic ring system such that the third ring shares at least two atoms with the bicyclic ring system. In some embodiments, all three rings share at least one common atom. Any of the rings in the tricyclic ring system may be saturated, partially unsaturated, or aromatic. Each of the rings may include 1 to 3 heteroatoms.
  • aliphatic groups, alkyl groups, aryl groups, heterocyclic groups, carbocyclic groups, and bicyclic or tricyclic ring systems contain one or more substituents.
  • the substituents are selected from those that will be stable under the reaction conditions of the present process, as would be generally known to those skilled in the art.
  • substituents include halogen, -Q 1 , —OQ 1 , —OH, protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NHQ 1 , —N(Q 1 ) 2 , —NHCOQ 1 , —NHCONHQ 1 , —NQ 1 CONHQ 1 , —NHCON(Q 1 ) 2 , —NQ 1 CON(Q 1 ) 2 , —NQ 1 COQ 1 , —NHCO 2 Q 1 , —NQ 1 CO 2 Q 1 , —CO 2 Q 1 , —COQ 1 , —CONHQ 1 , —CON(Q 1 ) 2 , —S(O) 2 Q 1 , —SONH 2 , —S(O)Q 1 , —SO 2 NHQ 1 , —SO 2 N(Q 1 ) 2 ,
  • nitrogen atoms on a heterocyclic ring may be optionally substituted. Suitable substituents on the nitrogen atom include Q 2 , COQ 2 , S(O) 2 Q 2 , and CO 2 Q 2 , where Q 2 is an aliphatic group or a substituted aliphatic group.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.
  • substantially pure refers to the stereochemical purity of a compound that is greater than 90%. In some embodiments, the stereochemical purity of a compound is greater than 95%. And in still others, the stereochemical purity of a compound is 99% or greater.
  • selective crystallization means crystallization of a substantially pure isomer from a solvent containing a mixture of isomers.
  • dynamic crystallization means crystallization of a substantially pure isomer from a solvent containing a mixture of isomers under conditions which cause isomerization of the mixture of isomers to an isomer which selectively crystallizes.
  • isomerization of the more soluble enantiomer to the less soluble isomer results in crystallization of the less soluble isomer as the equilibrium between the isomers is driven by crystallization toward the less soluble enantiomer.
  • a specific example of dynamic crystallization may include the epimerization of an anomeric carbon in a solvent under conditions which selectively crystallizes one substantially pure enantiomer.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • amine capping groups may be used in the methods of this invention.
  • examples of amine capping groups or protecting groups include, but are not limited to, -Q 7 , —C(S)Q 7 , —C(O)OQ 7 , —SOQ 7 , —SO 2 Q 7 , —SO 3 Q 7 , —SO 2 N(Q 7 ) 2 , —C(O)C(O)Q 7 , —C(O)C(O)OQ 7 , —C(O)CH 2 C(O)Q 7 , —C(O)N(Q 7 ) 2 , —(CH 2 ) 0-2 NHC(O)Q 7 , —C( ⁇ NH)N(Q 7 ) 2 , —C(O)N(OQ 7 )Q 7 , —C( ⁇ NOQ 7 )Q 7 , —P(O)(Q 7 ) 2 , and —P(O)(Q 7 ) 2 , and
  • Q 7 is C 1-12 aliphatic, C 3-10 cycloaliphatic, (C 3-10 cycloaliphatic)-C 1-12 aliphatic, C 6-10 aryl, (C 6-10 aryl)-(C 1-12 aliphatic)-, C 3-10 heterocyclyl, (C 6-10 heterocyclyl)-C 1-12 aliphatic, C 5-10 heteroaryl, or (C 5-10 heteroaryl)-(C 1-12 aliphatic)-.
  • lewis acid refers to moiety capable of sharing or accepting an electron pair.
  • lewis acids include, but are not limited to, BF 3 -etherates and metal halides, alkoxides, and mixed halide/alkoxides (e.g., Al(O-alkyl) 2 Cl, Al(O-alkyl)Cl 2 ).
  • the metals can be aluminum, titanium, zirconium, magnesium, copper, zinc, iron, tin, boron, ytterbium, lanthanum, and samarium.
  • EDCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
  • HOBt is 1-hydroxybenzotriazole.
  • HOSuc is N-hydroxysuccinimide.
  • THF is tetrahydrofuran.
  • TFA is trifluoroacetic acid.
  • DCM is dichloromethane.
  • DMAP is 4-dimethylaminopyridine.
  • DIPEA is diisopropylethylamine.
  • DMF is dimethylformamide.
  • TFA is trifluoroacetic acid.
  • CBZ is benzyloxycarbonyl. 1 H NMR is proton nuclear magnetic resonance.
  • TLC is thin layer chromatography.
  • TEMPO is 2,2,6,6-Tetramethylpiperidinyloxy free radical.
  • this invention relates to processes for and intermediates used in the preparation of steric-specific compounds.
  • R 3 is RW— or a P4-L3-P3-L2-P2-;
  • R 4 is —NH—CR 1 R′ 1 —CH(OH)C(O)—NHR 2 ;
  • Each W is independently a bond, —NR 4 , —O— or —S—;
  • Each of P2, P3 and P4 is independently a bond, H, an optionally substituted aliphatic, an optionally substituted heteroaliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted alkoxy, an optionally substituted alkylsufanyl, an optionally substituted aralkoxy, an optionally substituted aralkylsulfanyl, an optionally substituted mono- or dialkylamino, an optionally substituted mono- or diarylamino or an optionally substituted mono- or diheteroarylamino, provided that when L2 is absent and P3 is H, that L3 and P4 are absent;
  • P3 when P3 is not a terminal group, that P3 is bound to L2, if present, or P2, if L2 is absent, and P3 is also bound to L3, if present, or P4, if L3 is absent;
  • Each L2 or L3 is independently a bond, —C(O)— or —SO 2 —;
  • Each R 1 and R′ 1 is independently H, an optionally substituted aliphatic, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaliphatic or an optionally substituted heteroaralkyl, or each R 1 and R′ 1 together with the atom to which they are attached may form a 3 to 7 membered optionally substituted cycloaliphatic ring.
  • R 3 is P2-, which is represented by the structure: wherein
  • Each T is independently a bond, H, —C(O)—, —O—C(O)—, —NHC(O)—, —C(O)C(O)— or —SO 2 —;
  • Each R is independently H, an optionally substituted aliphatic, an optionally substituted heteroaliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocyclic, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl or an optionally substituted heteroaryl; and
  • Each R 5 and R 6 is independently H, an optionally substituted aliphatic, an optionally substituted heteroaliphatic, an optionally substituted heteroaryl, an optionally substituted phenyl, an optionally substituted aralkyl or an optionally substituted heteroarylalkyl, or
  • R 5 and the adjacent R 6 taken together with the atoms to which they are attached form a 5- to 7-membered, optionally substituted monocyclic heterocycle, or a 6- to 12-membered, optionally substituted bicyclic heterocycle, in which each heterocycle ring optionally contains an additional heteroatom selected from —O—, —S— or —NR 4 —; and
  • Each R 7 is independently H, an optionally substituted aliphatic, an optionally substituted heteroaliphatic, an optionally substituted heteroaryl, or an optionally substituted phenyl.
  • R 1 is P3-L2-P2 which is represented by the structure:
  • R 3 is P4-L3-P3- L2-P2 which is represented by the structure: wherein
  • Each T is independently a bond, H, —C(O)—, —O—C(O)—, —NHC(O)—, —C(O)C(O)— or —SO 2 —;
  • Each R is independently H, an optionally substituted aliphatic, an optionally substituted heteroaliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocyclic, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl or an optionally substituted heteroaryl;
  • Each R 5 , R 6 , R 7 and R 8 is independently H, an optionally substituted aliphatic, an optionally substituted heteroaliphatic, an optionally substituted heteroaryl, an optionally substituted phenyl, an optionally substituted aralkyl or an optionally substituted heteroarylalkyl, or
  • R 7 and the adjacent R 6 together with the atoms to which they are attached may form a 5 to 7 membered, optionally substituted monocyclic heterocycle, a 5 to 7 membered, optionally substituted monocyclic aryl, a 6 to 12 membered, optionally substituted bicyclic heterocycle, or a 6 to 12 membered, optionally substituted bicyclic aryl, in which each heterocycle or aryl ring optionally contains an additional heteroatom selected from —O—, —S— or —NR 4 —;
  • R 8 and the adjacent R 6 together with the atoms to which they are attached may form a 5 to 7 membered, optionally substituted monocyclic heterocycle, a 5 to 7 membered, optionally substituted monocyclic heteroaryl, a 6 to 12 membered, optionally substituted bicyclic heterocycle, or a 6 to 12 membered, optionally substituted bicyclic heteroaryl, in which each heterocycle or heteroaryl ring optionally contains an additional heteroatom selected from —O—, —S— or —NR 4 —;
  • R 8 and R together with the atoms to which they are attached may form a 5 to 7 membered, optionally substituted monocyclic heterocycle, a 5 to 7 membered, optionally substituted monocyclic aryl, a 6 to 12 membered, optionally substituted bicyclic heterocycle, or a 6 to 12 membered, optionally substituted bicyclic aryl, in which each heterocycle or aryl ring optionally contains an additional heteroatom selected from —O—, —S— or —NR 4 —;
  • R 7 and the ring system formed by R 5 and R 6 may form an 8- to 14-membered optionally substituted bicyclic fused ring system, wherein the bicyclic fused ring system is optionally further fused with an optionally substituted phenyl to form an optionally substituted 10- to 16-membered tricyclic fused ring system.
  • HCV protease inhibitors of Formula 2 is the compound of Formula 3 shown below.
  • the invention provides processes and intermediates for producing an x-hydroxy- ⁇ -amino acid derivative of Formula 1, which is useful in producing protease inhibitors:
  • R 1 and R′ 1 are each independently H, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted arylaliphatic, optionally substituted heteroaliphatic or optionally substituted heteroarylaliphatic and R 2 is H, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted arylaliphatic, optionally substituted heteroaliphatic or optionally substituted heteroarylaliphatic and the amino-alcohol amide of Formula 1 has an enantiomeric excess (ee) of greater than 55% (for the definition of ee see, e.g., Jerry March, Advanced Organic Chemistry , John Wiley and Sons, Inc., 1992, p. 125).
  • ee enantiomeric excess
  • the invention provides a process and intermediates for preparing a compound of Formula 1 as outlined in Scheme 1.
  • R 1 and R′ 1 are as previously described;
  • R′ 2 is —NHR 2 or —OE wherein R 2 is as previously described and E is C 1 -C 5 alkyl or optionally substituted benzyl.
  • the unsaturated compound i is converted the epoxide ii (step a) using known methods, e.g., oxidation with a peracid such as, for example, meta-chlorperbenzoic acid or peracetic acid (see, e.g., R. S. Porto, M. L. A. A. Vasconcellos, E. Ventura, F.
  • urea-hydrogen peroxide also called urea hydroperoxide
  • the epoxide ii may be obtained by using a glycidic ester condensation (see, e.g., M. Ballester, Chem. Revs. 55, 283-300 (1955); D. M. Burness, Organic Synthesis, Collective Volume 4, p. 649).
  • the epoxidation may be performed to provide optically enriched epoxides (see, e.g., H. Kakei, R. Tsuji, T. Ohshima, M. Shibasaki, J. Am. Chem. Soc., 2005, 127, 8962-8963; M. Marigo, J. Franzen, T. B. Poulsen, W. Zhuang, K. A. Jorgensen, J. Am. Chem. Soc., 2005, 127, 6284-6289; M. Shibisaki, et. al., U.S. Pat. No. 6,833,442 (BINOL Ars complex); R. Kino, K. Daikai, T.
  • the ester is subsequently converted to an amide. It is within the scope of the invention that formation of the amide can be performed at any stage of the process using known methods and protecting groups where appropriate.
  • Suitable amination reagents are those which may be converted to the amino compound III.
  • suitable amination reagents include azide, phthalimide and an optionally substituted benzyl amine.
  • step c the mixture of amino alcohols of Formula iii is resolved to provide the optically active compound of Formula iv.
  • Suitable methods for resolving the mixture iii include, for example, formation of a salt with a suitable optically active organic acid.
  • Suitable optically active organic acids include, but are not limited to, tartaric acid, malic acid, di-isopropylidenegulonic acid and deoxycholic acid.
  • R′ 2 of Formula i is —NHR 2
  • the epoxidation of i is performed using tert-butyl hydroperoxide in the presence of a base such as, for example, sodium hydroxide or butyl lithium.
  • the epoxidation is performed using potassium monopersulfate, ethylenediamine tetraacetic acid and an optionally optically active ketone.
  • the amino-alcohol of Formula iii has a trans configuration.
  • the compound of Formula iv has a 2-(S), 3(S) configuration.
  • the amination of ii to give the amino alcohol iii is performed by reaction of ii with sodium azide followed by reduction of the intermediate azide with hydrogen in the presence of a palladium on carbon catalyst.
  • the resolution of iii to iv is performed by forming a salt with an optically active acid and crystallizing the thus obtained salt.
  • the optically active organic acid is tartaric acid.
  • the optically active organic acid is deoxycholic acid.
  • R 1 is C 1 -C 6 alkyl and R′ 1 is H.
  • R 2 is C 1 -C 6 alkyl or C 1 -C 6 cycloalkyl.
  • R 2 is cyclopropyl
  • amino-hydroxy compounds of formula iii may be prepared according to methods described in U.S. Pat. Nos. 6,020,518, 6,087,530 and 6,639,094, each of which is incorporated herein in its entirety by reference.
  • this invention provides a process and intermediates for preparing a compound of Formula 3.
  • Removing the protecting group Z in the tripeptide of Formula 9 provides the free amino-tripeptide of Formula 10.
  • the desired protease inhibitor may be derived by attaching the appropriate P 2 , P 2 —P 3 , or P 2 —P 3 —P 4 moiety.
  • a coupling of an amine with such a moiety may be carried out using the corresponding carboxylic acid, or reactive equivalent thereof, under standard amide bond-forming or coupling conditions.
  • a typical coupling reaction includes a suitable solvent, the amine in a concentration ranging from about 0.01 to 10 M, preferably about 0.1 to 1.0 M, the requisite carboxylic acid, a base and a peptide coupling reagent.
  • the coupling may be carried out in situ in the solvent of the reaction mixture used in the preparation of the amine, or in a different solvent.
  • the requisite carboxylic acid may be added and the reaction maintained at a temperature in the range of about 0 to 100° C., preferably between about 20 to about 40° C.
  • the base and peptide coupling reagent are then added to the mixture, which is maintained at a temperature in the range of from about 0 to about 60° C., preferably between about 20 to about 40° C.
  • the base is typically a tertiary amine base, such as triethylamine, diisopropylethylamine, N-methylmorpholine, DBU, DBN, N-methylimidazole, preferably triethylamine or diisopropylethylamine.
  • the amount of base used is generally up to about 20 equivalents per equivalent of the amine, preferably at least about 3 equivalents of base.
  • peptide coupling reagents examples include DCC (dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide), di-p-toluoylcarbodiimide, BDP (1-benzotriazole diethylphosphate-1-cyclohexyl-3-(2-morpholinylethyl)carbodiimide), EDC (1-(3-dimethylaminopropyl-3-ethyl-carbodiimide hydrochloride), cyanuric fluoride, cyanuric chloride, TFFH (tetramethyl fluoroformamidinium hexafluorophosphosphate), DPPA (diphenylphosphorazidate), BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate), HBTU (O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl
  • EDC, HOAT, BOP—Cl and PyBrOP are preferred peptide coupling reagents.
  • the amount of peptide coupling reagent is in the range of about 1.0 to about 10.0 equivalents.
  • Optional reagents that may be used in the amide bond-forming reaction include DMAP (4-dimethylaminopyridine) or active ester reagents, such as HOBT (1-hydroxybenzotriazole), HOAT (hydroxyazabenzotriazole), HOSu (hydroxysuccinimide), HONB (endo-N-hydroxy-5-norbornene-2,3-dicarboxamide), in amounts ranging from about 1.0 to about 10.0 equivalents.
  • —C( ⁇ O)X 1 is a group that is more reactive than COOH in the coupling reaction.
  • Acid and amine protecting groups as used herein are known in the art (see, e.g., T. W. Greene & P. G. M Wutz, Protective Groups in Organic Synthesis, 3 rd Edition, John Wiley & Sons, Inc. (1999) and the earlier editions of this book).
  • P 3 —P 2 portion of the protease inhibitor.
  • Examples of such P 3 —P 2 — groups are included in U.S. Application No. 60/709,964, which is also incorporated hereto by reference in its entirety.
  • Example 1 A flask equipped with a stir bar, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with the acid of Example 1 (5.0 g, 38 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI; 8.1 g, 42 mmol), 1-hydroxybenzotriazole hydrate (HOBt; 5.7 g, 42 mmol) and N,N-dimethylformamide (DMF; 50 mL) then cooled to 0 ⁇ 5° C.
  • the addition funnel was charged with NMM (5.9 mL, 54 mmol) which was then added to the reaction mixture maintaining the temperature at 0 ⁇ 5° C.
  • the reaction mixture washed by adding hydrochloric acid (500 mL, 1.0 N) and the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the washing procedure repeated.
  • Sodium hydroxide 500 mL, 1.0 N was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and base wash procedure repeated.
  • Water 500 mL was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the wash procedure repeated.
  • the combined organic phases were concentrated under reduced pressure to 1 ⁇ 3 original volume then IPAc (600 mL) was added; this was repeated two times when a white precipate formed.
  • Example 4 (19.80 g, 130 mmol) in THF (20 mL) was added maintaining the temperature at 0 ⁇ 5° C. after which the temperature was increased to 25 ⁇ 5° C. and the reaction stirred for 12 hours.
  • IPAc 200 mL
  • saturated aqueous sodium hydrosulfite 200 mL
  • the layers were separated and the aqueous layer extracted with IPAc (twice, 75 mL each).
  • the combined organic phases were dried over sodium sulfate (Na 2 SO 4 ), filtered and concentrated under reduced pressure to provide the title compound (21.87 g, 99%).
  • the reaction mixture was then again cooled to 0° C. and quenched by adding saturated NaHCO 3 (5 vol.) slowly and stirring for 30 minutes.
  • the organic layer was separated, and the aqueous layer was extracted with CH 2 Cl 2 (50 mL, 5 vol).
  • the combined organic layer was dried and evaporated to afford 10.0 g (90%) of the crude the product, N-cyclopropyl-3-propyloxirane-2-carboxamide, as a pale yellow oil.
  • the crude product was used for the next step without further purification.
  • Example 7 The azide of Example 7 (15.1 g, 71.3 mmol), Pd/C (1.5 g, 5 wt %, 50% wet) and MeOH (150 mL) was charged to a pressure vessel then purged with nitrogen gas for 5 min. The vessel was sealed, pressurized to 1 bar with nitrogen gas then released three times. The same was repeated with hydrogen gas. After the third purge with hydrogen the vessel was charged with 3 bar of hydrogen. Agitation was begun and a temperature of 25 ⁇ 5° C. was maintained. Reaction was stirred in this manner for 14 hours after which time the reaction mixture was filtered through a pad of Celite 545 and the solvent removed to provide crude amino-alcohol (8.48 g) as a yellow solid.
  • the sultam shown above vi is prepared by known methods such as those described in Y. Elemes and U. Ragnarsson, J. of Chem. Soc., Perkin 1, 1996, 6, p. 537; W. Oppolzer, et. al., Helv. Chim. Acta., 1994, 25: 2363), by using the corresponding unsubstituted sultam and propyl iodide.
  • Step b Preparation of (S)-2-(benzyloxycarbonylamino)-Pentanoic Acid (Compound viii Shown Above)
  • Compound vii (15.39 g, 32.1 mmol) is combined with THF (100 mL) and 1N HCl (50 mL). The resulting emulsion is stirred overnight at the room temperature and then concentrated under reduced vacuum to provide a thick oil. The oil is dissolved in THF (100 mL), water (25 mL) and LiOH (3.08 g, 128 mmol) is added. The resultant solution is stirred overnight at the room temperature and then concentrated to remove the THF, resulting a hazy light yellow emulsion. The emulsion is diluted with water (25 mL) and extracted with CH 2 Cl 2 (3 ⁇ 50 mL).
  • the aqueous phase is diluted with THF (200 mL) and then cooled to 0° C. while stirring rapidly and CBZ-Cl (7.6 mL, 54 mmol) is added dropwise over 15 minutes. After 1 hour at 0° C., the THF is removed in vacuo and the residue is acidified by addition of 50 mL of 1 N HCl. This is extracted with EtOAc (3 ⁇ 100 mL) and the organic phase is dried over Na 2 SO 4 and concentrated to provide an oil. The residue is dissolved in EtOAc (25 mL) and heptane (150 mL), seeded and stirred overnight at the room temperature.
  • Step d Preparation of (S)-benzyl 1-(methoxy(methyl)amino)-1-oxo-2-pentan-2-ylcarbamate
  • Step d the Cbz-protected amino acid of Step d is converted to the title compound. Specifically, into a flask containing 1.0 eq. of (S)-benzyl 1-(methoxy(methyl)amino)-1-oxo-2-pentan-2-ylcarbamate (810 mg, 2.75 mmol) in 10 mL of dry THF maintained at 0° C. (in an ice bath) is added slowly 1.7 eq. of a solution of lithium borohydride (1.0M) (4.67 mL). After about 10 minutes, the ice bath is removed and the reaction continue for an hour. The reaction solution is quenched at 0° C.
  • Step f Preparation of benzyl (3S)-1-(cyclopropylamino)-2-hydroxy-1-oxo-hexan-3-ylcarbamate.
  • Cyclopropyl isocyanide is prepared according to the scheme shown below.
  • Step g Preparation of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide
  • Step h Preparation of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((35)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide
  • the title compound is prepared from the hydroxy-amino amide product of Step g by condensation with the appropriate acid in the presence of a coupling reagent such as, e.g., EDCI and HOSu. Specifically, in a flask containing 1.2 eq. of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (1.59 g) in 20 mL of DMF, is added 2.5 eq.
  • a coupling reagent such as, e.g., EDCI and HOSu.
  • Step i Preparation of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)-N—((S)-1-(cyclopropylamino)-1,2-dioxo-hexan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide
  • the title compound is prepared by oxidation of the product of Step h with a suitable oxidizing reagent such as Dess-Martin periodinane or TEMPO and sodium hypochlorite.
  • a suitable oxidizing reagent such as Dess-Martin periodinane or TEMPO and sodium hypochlorite.
  • a suitable oxidizing reagent such as Dess-Martin periodinane or TEMPO and sodium hypochlorite.
  • the stirring is stopped and the organic layer is separated and the aqueous layer is extracted with EtOAc (3 vol ⁇ 3).
  • the organic layers are combined and concentrated in vacuo until the total volume becomes 3 vol.
  • the resulting solution was extracted with 1 N NaOH (3 vol ⁇ 3) and the remaining organic layer was discarded.
  • the combined aqueous solution was acidified with 6 N HCl until the pH became 1.0.
  • the solution is extracted with CH 2 Cl 2 (3 vol ⁇ 5).
  • the combined organic layer are dried over MgSO 4 and concentrated to get the product (i.e., compound 4).
  • the reaction mixture is washed with 1 N NaOH (3 vol ⁇ 2), 1N HCl (3 vol ⁇ 2), and brine solution (3 vol), and water (3 vol).
  • the organic layer is dried over MgSO 4 and concentrated to afford the crude product as oil.
  • the crude product is dissolved with heptane (5 vol) and cooled to ⁇ 78° C. with stirring.
  • the precipitated solid is filtered and dried to give the product (i.e., compound 5).
  • reaction mixture is filtered through a pad of Celite® to afford a clear solution.
  • the product is isolated by concentrating the solution at 20 ⁇ 5° C. until 3 vol of the solution remains. The solid is collected by filtration, washed (IPAC, 3 vol), and dried to give the product (i.e., compound 8).

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050197299A1 (en) * 2000-08-31 2005-09-08 Babine Robert E. Peptidomimetic protease inhibitors
US20070225297A1 (en) * 2006-03-16 2007-09-27 Perni Robert B Deuterated hepatitis C protease inhibitors
US7964624B1 (en) 2005-08-26 2011-06-21 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases
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