WO2015095430A1 - Procédés et intermédiaires pour la préparation de macrolactames - Google Patents

Procédés et intermédiaires pour la préparation de macrolactames Download PDF

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WO2015095430A1
WO2015095430A1 PCT/US2014/071007 US2014071007W WO2015095430A1 WO 2015095430 A1 WO2015095430 A1 WO 2015095430A1 US 2014071007 W US2014071007 W US 2014071007W WO 2015095430 A1 WO2015095430 A1 WO 2015095430A1
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alkyl
group
independently selected
groups
cycloalkyl
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PCT/US2014/071007
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English (en)
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Michael Williams
Mark Mclaughlin
Jongrock Kong
Yan Jin
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Merck Sharp & Dohme Corp.
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    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D498/22—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 four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D498/12—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 three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • the present disclosure relates to synthetic processes useful in the preparation of macrolactams that inhibit hepatitis C virus (HCV), and specifically inhibit HCV NS3 protease activity.
  • Such macrolactams and processes to prepare them have application in the treatment of conditions caused by HCV, as well as therapeutic and research applications.
  • the present disclosure also encompasses intermediates useful in the disclosed synthetic processes and the methods of their preparation.
  • HCV infection is a major health problem. HCV infection leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals.
  • NS3 metalloprotease
  • NS3 serine protease
  • NS3 a helicase
  • NS5B RNA- dependent RNA polymerase
  • the NS3 protease is located in the N-terminal domain of the NS3 protein.
  • NS4A provides a cofactor for NS3 activity.
  • the present invention includes methods and intermediates for preparing macrolactams.
  • One use of the methods and intermediates described herein is in the production of macrolactam compounds able to inhibit HCV NS3 protease activity.
  • HCV NS3 inhibitory compounds have therapeutic and research applications.
  • A is a rin selected from the group consisting of
  • R A is selected from H and Ci-C 6 alkyl groups
  • R and R are each selected from the group consisting of H and Ci-Cg alkyl, or are optionally taken together with the carbon atoms to which they are attached to form a 3- to 6- membered cycloalkyl ring;
  • R 3 is selected from the group consisting of H, Ci-Cg alkyl, C 3 -Cg cycloalkyl, and C 3 -Cg cycloalkyl(Ci-Cg)alkyl groups, wherein when R 3 is not H, said R 3 is substituted with 0 to 3 substituents independently selected from the group consisting of halogen atoms, -OR 10 , -SR 10 , -N(R 10 ) 2 , -N(Ci-C 6 alkyl)0(Ci-C 6 alkyl), Ci-C 6 alkyl, Ci-C 6 haloalkyl, halo(Ci-C 6 alkoxy), -N0 2 , -CN, -CF 3 , -S0 2 (Ci-C 6 alkyl), -S(0)(Ci-C 6 alkyl), -NR 10 SO 2 R 6 , -S0 2 N(R 6 ) 2 , -NHCOOR 6 ,
  • each R 5 is independently selected from the group consisting of halogen atoms, -OH, Ci-C 6 alkoxy, Ci-C 6 alkyl, -CN, -CF 3 , -OCF 3 , -C(0)OH, -C(0)CH 3 , -SR 10 , -S0 2 (Ci-C 6 alkyl), C 3 -Cg cycloalkyl, C 3 -Cg cycloalkoxy, Ci-C 6 haloalkyl, -N(R 7 ) 2 , phenyl, naphthyl, -O-phenyl, -O-naphthyl, heteroaryl and heterocyclyl groups; wherein:
  • R 5 heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy groups are substituted with 0 to 4 substituents independently selected from the group consisting of halogen atoms, -OR 10 , -SR 10 , -N(R 10 ) 2 , -N(Ci-C 6 alkyl)0(Ci-C 6 alkyl), Ci-C 6 alkyl, Ci-C 6 haloalkyl, halo(Ci-C 6 alkoxy), -N0 2 , -CN, -CF 3 , -S0 2 (Ci-C 6 alkyl), -S(0)(Ci-C 6 alkyl), -NR 10 SO 2 R 6 , -S0 2 N(R 6 ) 2 , -NHCOOR 6 , -NHCOR 6 , -NHCONHR 6 , -C0 2 R 10 , -C(0)R 10 , and -CON(
  • R 6 is selected from the group consisting of Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 5 )alkyl, phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(Ci-C4 alkyl), heterocyclyl, and heterocyclyl(Ci-Cg alkyl) groups, wherein
  • R F and R G are each independently selected from the group consisting of H and Ci-Cg alkyl groups, with a catalyst selected from the group of ring-closing metathesis catalysts.
  • A is selected from the group consisting of
  • R 5 is substituted by 0 or 1 substituent R 5 , and R 5 is selected from the group consisting of H, -F, -I, -Br, -CI, -CN, phenyl, -O-phenyl, -OCF 3 , -OCH 3 , -OH, Ci-C 6 alkoxy, Ci-C 6 alkyl, -CF 3 , -C(0)OH, and -C(0)CH 3 ; m is 1, 2 or 3; n is 1, 2 or 3; R A is selected from H and Ci-C 3 alkyl
  • R and R ⁇ are taken together with the carbon atoms to which they are attached to form a 3- to 6-membered cycloalkyl ring;
  • R 3 is selected from the group consisting of H, Ci-Cg alkyl and C 3 -Cg cycloalkyl groups;
  • R F is selected from the group consisting of H and Ci-C 3 alkyl groups;
  • R is selected from the group consisting of H and C 1 -C3 alkyl groups; and the catalyst is a phosphine-free metathesis catalyst.
  • the metathesis catalyst is selected from:
  • A is where R 5 is -OCH 3 ; m is 1, 2 or 3, and n is 1, 2 or 3, such that m + n is 3; R A is -CH 3 ; R B and R* are taken together with the carbon atoms to which they are attached to form a 3-membered st is
  • Functional groups that can be modified include a different heterocycle group, a different alkyl in place of the tert-butyl group, and alteration of the cyclopropylsulfonyl functional group and the cyclopropyl amide moiety (e.g., with an ethyl group replacing the ethylene and/or a methylcyclopropyl group replacing the cyclopropyl group).
  • Liverton et al. WO 2009/010804; Liverton et al., WO 2008/057209; Liverton et al.,
  • WO 2013/028471 and Xu et al, WO 2013/028470 describe methods and intermediates for making Compound A, and Beutner et al, WO 2013/028465 describes crystal forms of
  • macrocycles such as Compound A
  • the methods described herein include enantioselective methods of preparing the functionalized cyclopropane moiety having high yields.
  • the use of a green, chemoenzymatic Baeyer-Villiger oxidation allows for simple and quick access of the cyclopropanol precursor.
  • the side chain elaboration is accomplished via an amide coupling, introduction of the olefin by the use of a Lindlar reduction and salt formation to yield a crystalline intermediate.
  • any variable is as defined in the first instance where the variable occurs, unless otherwise indicated.
  • any variable occurs more than one time in any constituent, compound or Formula, its selection on each occurrence is independent of its selection at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • Compound A may be prepared utilizing ring-closing metathesis (RCM).
  • RCM ring-closing metathesis
  • the method of certain embodiments includes a ring-closing metathesis step that is operationally simple to run, high-yielding, incorporates low catalyst loading, and can utilize a variety of diverse N-heterocyclic carbene (NHC) containing metathesis precatalysts.
  • NOC N-heterocyclic carbene
  • Particular instances of these embodiments include methods of preparing the quinoxaline moiety, which have high yields and allow for regioselective introduction of the homoallyl side chain. The hydroxyproline moiety can then be introduced without the need for selective ⁇ ⁇ ⁇ chemistry, which lowers impurities and regioisomers therefore decreased reaction sensitivity.
  • each R 5 is independently selected from the group consisting of halogen atoms
  • R 6 is selected from the group consisting of Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(Ci-C 5 )alkyl, phenyl, naphthyl, phenyl(Ci-C 4 )alkyl, naphthyl(Ci-C 4 )alkyl, heteroaryl, heteroaryl(Ci-C 4 alkyl), heterocyclyl, and heterocyclyl(Ci-Cg alkyl) groups, wherein each R 6 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 6 heteroaryl is attached through a ring atom selected from C and N, and each R 6 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S
  • R F is selected from the group consisting of H and Ci-C 8 alkyl groups.
  • Formula B or salts thereof by a method comprising (i) reacting R F with a leaving agent
  • R F where LG is selected from H, CI, Br, I, F, Ci-C 6 alkyl sulfonate groups, phenyl sulfonate groups, tolyl sulfonate groups and trifluoromethyl sulfonate groups; (ii) reacting
  • Scheme A illustrates a general, overall scheme that can be used to prepare quinoxaline moieties, and different intermediates.
  • Each of the variables set forth in Scheme A are as defined above.
  • Each of the individual steps of Scheme A provides for additional embodiments. Further embodiments include steps upstream and downstream from a particular step.
  • Alkene compounds and their salts are useful intermediates for preparing
  • alkene compounds useful for preparing Compound A and analogues thereof include compounds of Formula D:
  • R 3 is selected from the group consisting of H, Ci-C 8 alkyl, C 3 -C 8 cycloalkyl, and C 3 -C 8 cycloalkyl(Ci-Cg)alkyl groups, wherein when R 3 is not H, said R 3 is substituted with 0 to 3 substituents independently selected from the group consisting of halogen atoms, -OR 10 , -SR 10 , -N(R 10 ) 2 , -N(Ci-C 6 alkyl)0(Ci-C 6 alkyl), Ci-C 6 alkyl, Ci-C 6 haloalkyl, halo(Ci-C 6 alkoxy),
  • Scheme B illustrates a general, overall scheme that can be used to prepare compounds such as 2-methylpropane-2-amine (5)-3,3-dimethyl-2-((((li?,2i?)-2-((Z)-pent-2-en-l- yl)cyclopropoxy)carbonyl)amino)butanoate salts thereof, and different intermediates. Any proportions or amounts are intended to be non-limiting and merely illustrious of additional embodiments.
  • Each of the variables set forth in Scheme B are as defined above.
  • Each of the individual steps of Scheme B provide for additional embodiments. Further embodiments include steps upstream and downstream from a particular step.
  • Scheme B 1 illustrates a specific embodiment of a process according to Scheme B. Any proportions or amounts are intended to be non-limiting and merely illustrious of additional embodiments. Each of the individual steps of Scheme B 1 provides for additional embodiments. Further embodiments include steps upstream and downstream from a particular step.
  • R 5 heteroaryl is selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms
  • R 5 heterocyclyl is selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 5 heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy groups are substituted with 0 to 4 substituents independently selected from the group consisting of halogen atoms, -OR 10 , -SR 10 , -N(R 10 ) 2 , -N(Ci-C 6 alkyl)0(Ci-C 6 alkyl), Ci-C 6 alkyl, Ci-C 6 haloalkyl, halo(Ci-C 6 alkoxy), -N0 2 , -CN, -CF 3 , -S0 2 (Ci-C 6 alkyl), -S(0)(C C 6 alkyl), -NR 10 SO 2 R 6 ,
  • the compound of Formula E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe
  • the compound of Formula (I) may be converted to compounds of Formula (I) by the methods discussed above.
  • compounds of Formula (I) can be converted to compounds of Formula (II):
  • R E is selected from H and C3 ⁇ 4 and il is selected from a single and a double bond.
  • R E is H; and il is a double bond.
  • R E is H; and il is a single bond.
  • Scheme C illustrates a general overall scheme that can be used to prepare compounds such as Compound A, and different intermediates. Any proportions or amounts are intended to be non-limiting and merely illustrious of additional embodiments.
  • Each of the variables set forth in Scheme C are as defined above.
  • Each of the individual steps of Scheme C provide for additional embodiments. Further embodiments include steps upstream and downstream from a particular step.
  • Scheme C 1 illustrates a specific embodiment of a process according to Scheme C Any proportions or amounts are intended to be non-limiting and merely illustrious of additional embodiments. Each of the individual steps of Scheme C 1 provides for additional embodiments. Further embodiments include steps upstream and downstream from a particular step. Scheme C 1
  • variables n, m, R A , R B , R c , R E , R F , R G , R 3 , R 5 , LG, PG and X are each as defined above.
  • step (ix) reacting with MeMgCl to form with enating and reacting with fert-butyl amine to form t of step (vi), to
  • the method for preparing Compound A (ii) to form ; (iv) chlorinating to form
  • Terminal alkene TBA salts, and analogues thereof are also useful intermediates for preparing Compound A and analogues thereof.
  • Particular terminal alkene TBA salts useful for preparing Compound A and analogues thereof include certain embodiments of the compounds of Formula D, an ex d of Formula F:
  • Scheme D 1 illustrates a specific embodiment of a process according to Scheme D, which can be used to prepare terminal (i?)-2-((((li?,2i?)-2-allylcyclopropoxy)carbonyl)amino)- 3,3-dimethylbutanoic acid salts thereof, and different intermediates. Any proportions or amounts are intended to be non-limiting and merely illustrious of additional embodiments.
  • Each of the individual steps of Scheme D 1 provide for additional embodiments. Further embodiments include steps upstream and downstream from a particular step.
  • Substituted quinoxaline salts, and analogues thereof are also useful intermediates for preparing Compound A and analogues thereof.
  • Particular substituted quinoxaline salts useful for preparing Compound A and analogues thereof include compounds of Formula B:
  • R salt is selected from the group consisting of HF, HCl, HBr, HI, H 3 P0 4 , H 2 S0 4 , TFA and R J S0 3 H, and R J is selected from Ci-C 6 alkyl, phenyl and tolyl groups, to prepare R salt.
  • PG is a protecting group selected from the group consisting of -OSiR 8 3 , -OR 8 , -OS(0) 2 R 8 , -C(0)OR 8 and -C(0)R 8 where R 8 is independently selected from the group consisting of Ci alkyl, C cycloalkyl, aryl and heteroaryl groups, and the acid is R J S0 3 H, and R J is selected from Ci-C 6 alkyl, phenyl and tolyl groups. In specific embodiments, the acid is CH 3 S0 3 H.
  • Scheme E illustrates a general, overall scheme that can be used to prepare compounds of Formula B and salts thereof. Any proportions or amounts are intended to be non- limiting and merely illustrious of additional embodiments.
  • Each of the variables set forth in Scheme E are as defined above.
  • Each of the individual steps of Scheme E provide for additional embodiments. Further embodiments include steps upstream and downstream from a particular step.
  • Scheme E 1 illustrates a specific embodiment of a process according to Scheme E, which can be used to prepare 2-butenylquinoxaline salts. Any proportions or amounts are intended to be non-limiting and merely illustrious of additional embodiments. Each of the individual steps of Scheme E 1 provides for additional embodiments. Further embodiments include steps upstream and downstream from a particular step.
  • Particular compounds useful for preparing Compound A and analogues thereof include compounds of Formula (II)
  • a ring closing reaction on in the presence a catalyst selected from the group of ring closing metathesis catalysts, where , m, n, A, R 3 , R A , and R are as described above.
  • Scheme F illustrates a generic overall scheme that can be used to prepare amide formation and ring closing metathesis utilizing a terminal olefin, where one of R F and R G is hydrogen. Any proportions or amounts are intended to be non-limiting and merely illustrious of additional embodiments.
  • Each of the variables set forth in Scheme F are as defined above.
  • Each of the individual steps of Scheme F provide for additional embodiments. Further embodiments include steps upstream and downstream from a particular step.
  • Olefin metathesis catalysts include the Ruthenium-based species disclosed in the following: F. Miller et al, 118 J. AM. CHEM. SOC. 9606 (1996); G. Kingsbury et al, 121 J. AM. CHEM. SOC. 791 (1999); H. Scholl et al, 1 ORG. LETT. 953 (1999); U.S. Patent Application Publication US2002/0107138; K. Furstner et al, 64 J. ORG. CHEM. 8275 (1999).
  • the utility of these catalysts in ring-closing metathesis is well known in the literature (e.g. Trnka and Grubbs, 34 Acc. CHEM. RES. 18 (2001).
  • alkyl refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range.
  • Ci_ 6 alkyl refers to any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and tert-butyl, n- and iso-propyl, ethyl, and methyl.
  • Ci_ 4 alkyl refers to n-, iso-, sec- and tert-butyl, n- and isopropyl, ethyl, and methyl.
  • cycloalkyl refers to any monocyclic ring of an alkane having a number of carbon atoms in the specified range.
  • C 3 _ 8 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fiuoro, chloro, bromo, and iodo or F, CI, Br and I).
  • haloalkyl refers to an alkyl group as defined above in which one or more of the hydrogen atoms have been replaced with a halogen (i.e., F, CI, Br or I).
  • a halogen i.e., F, CI, Br or I.
  • Ci_ 6 haloalkyl or “Ci-C 6 haloalkyl” refers to a Ci to C 6 linear or branched alkyl group as defined above with one or more halogen substituents.
  • fluoroalkyl has an analogous meaning except the halogen substituents are restricted to fiuoro. Suitable fluoroalkyls include the series (CH 2 )o- 4 CF 3 (i.e. , trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.).
  • aryl as a group or part of a group means phenyl or naphthyl.
  • heteroaryl as a group or part of a group means a 5- or 6-membered aromatic ring having 1 , 2 or 3 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen.
  • groups include pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl and tetrazolyl.
  • any alkyl group, cycloalkyl group, aryl group or heteroaryl group may be substituted by 0, 1 , 2, 3 or 4 substituents independently selected from the group consisting of Ci_ 6 alkyl, Ci_ 6 alkenyl, Ci_ 6 alkynyl, aryl, halogen, -NH 2 or -OH.
  • the atoms in a compound described herein may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of described herein.
  • different isotopic forms of hydrogen (H) include protium (1H) and deuterium ( 2 H).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds described herein can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples provided herein using appropriate isotopically-enriched reagents and/or intermediates.
  • compositions for treating patients can be used with compounds for treating patients.
  • Non-pharmaceutical salts may, however, be useful in the preparation of intermediate compounds.
  • Pharmaceutically acceptable salts are suitable for administration to a patient, preferably, a human.
  • Suitable salts include acid addition salts which may, for example, be formed by mixing a solution of a compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid.
  • Compounds carrying an acidic moiety can be mixed with suitable pharmaceutically acceptable salts to provide, for example, 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.
  • suitable organic ligands such as quaternary ammonium salts.
  • pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.
  • compositions described herein having therapeutic applications can be administered to a patient infected with HCV.
  • administration and variants thereof (e.g., “administering” a compound) means providing the compound to the individual in need of treatment.
  • administration and its variants are each understood to include concurrent and sequential provision of the compound or salt and other agents.
  • composition is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combining the specified ingredients.
  • pharmaceutically acceptable is meant the ingredients of the pharmaceutical composition must be compatible with each other and are suitable to the recipient thereof.
  • an effective amount indicates a sufficient amount to exert a therapeutic or prophylactic effect.
  • an effective amount is sufficient to achieve one or more of the following effects: reduce the ability of HCV to replicate, reduce HCV load, and increase viral clearance.
  • an effective amount is sufficient to achieve one or more of the following: a reduced susceptibility to HCV infection, and a reduced ability of the infecting virus to establish persistent infection for chronic disease.
  • the compounds can be administered by means that produces contact of the active agent with the agent's site of action. They can be administered by conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but typically are
  • a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • Compounds can, for example, be administered by one or more of the following routes: orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation (such as in a spray form), or rectally, in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and pharmaceutically-acceptable carriers (e.g., a carrier suitable for administration to a human patient), adjuvants and vehicles.
  • pharmaceutically-acceptable carriers e.g., a carrier suitable for administration to a human patient
  • Liquid preparations suitable for oral administration e.g., suspensions, syrups, elixirs and the like
  • media such as water, glycols, oils, alcohols and the like.
  • Solid preparations suitable for oral administration can be prepared according to techniques known in the art and can employ solid excipients as such starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like.
  • Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as solubility aids.
  • injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose.
  • Therapeutic compounds can be administered orally in a dosage range of 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per day in a single dose or in divided doses.
  • mammal e.g., human
  • One dosage range is 0.01 to 500 mg/kg body weight per day orally in a single dose or in divided doses.
  • Another dosage range is 0.1 to 100 mg/kg body weight per day orally in single or divided doses.
  • the compositions can be provided in the form of tablets or capsules containing 1.0 to 500 mg of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, and 750 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • HCV NS3 activity The ability of a compound to inhibit HCV NS3 activity, HCV replicon activity, and HCV replication activity can be evaluated using techniques well-known in the art. (See, for example, Carroll et al. , J. Biol. Chem. 275: 11979-11984, 2003.)
  • One such assay is a HCV NS3 protease time -resolved fluorescence (TRF) assay as described below and in Mao et al, Anal. Biochem. 573: 1-8, 2008 and Mao et al.,
  • a NS3 protease assay can be performed, for example, in a final volume of 100 ⁇ assay buffer containing 50 mM HEPES, pH 7.5, 150 mM NaCl, 15% glycerol, 0.15% TRITON X- 100, 10 mM DTT, and 0.1 % PEG 8000.
  • NS3 and NS4A are pre-incubated with various concentrations of inhibitors in DMSO for 30 min. The reaction is initiated by adding the TRF peptide substrate (final concentration 100 nM).
  • NS3 mediated hydrolysis of the substrate is quenched after 1 h at RT with 100 ⁇ of 500 mM MES, pH 5.5.
  • Product fluorescence is detected using either a VICTOR V2 or FUSION fluorophotometer (Perkin Elmer Life and Analytical Sciences) with excitation at 340 nm and emission at 615 nm with a 400 delay. Testing concentrations of different enzyme forms are selected to result in a signal to background ratio (S/B) of 10-30.
  • S/B signal to background ratio
  • IC 50 values are derived using a standard four-parameter fit to the data.
  • IQ values are derived from IC 50 values using the following formula,
  • DIPEA DIE Diisopropyl ethyl amine (Hunig's base)
  • Ra-Ni Sponge metal catalyst also known as Raney nickel®
  • X Refers to the number of times a process is iterated (e.g., "washed
  • reaction mixture was stirred at RT for 30 min and then cooled to 5°C with ice bath, stirred for 20 min.
  • the precipitate was collected by filtration, rinsed with 20% IPA/MTBE (30 ml, 2X), dried under vacuum and N 2 sweep overnight to yield desired product (6.82 g, 66% isolated yield) as an off white solid.
  • the reaction mixture was stirred at -70°C for 2 h when NMR showed full conversion.
  • the reaction was quenched with saturated NH 4 C1 (354 ml), water (70 ml), and MTBE (700 ml), and temperature went up to -40°C.
  • the reaction was allowed to warm up to RT.
  • R. erythropolis agar colonies were used to inoculate 2 L non-baffled shake flasks containing sterilized culture medium (10 g soybean peptone, 0.5 g yeast extract and 5 g NaCl containing 2 g D-glucose (sterilized separately)). The cultures were maintained at 28°C/120 rpm for 48 h. Cyclohexanol was added (0.05 % v/v) and cultures maintained for a further 24 h. The cells were harvested by centrifugation (5000 rpm/10 min) at 20°C. Cell pellets were washed twice with sterilized 350 mL potassium phosphate buffer, pH 7.5, with centrifugation (5000 rpm/10 min) at 20°C.
  • the washed cell pellets were assessed for coloration, orange cell biomass was prepared for reactions and pale biomass discarded.
  • R. erythropolis cell pellets were resuspended in sterilized 0.1M potassium phosphate buffer, pH 7.5 (500 mL), and the biomass was agitated gently whilst the substrate (0.5 mL/flask) was added drop wise.
  • the reactions were allowed to progress to greater than 90% conversion as determined by GC (typically after 2-6 d, but optimally after 48 h).
  • Rhodococcus erythropolis (strain number DSM 1069) has been deposited under the Budapest Treaty, in the culture collection of the Sammlung von Mikroorganismen und Zellkulturen GmbH at Inhoffenstrape 7B, 38124 Branschweig, Germany by Klatt et al. in 1995, and was assigned DSM Patent Deposit Designation DSM 1069.
  • the purification was carried out by dry vacuum column chromatography using DCM and DCM + 1 % MeOH as eluent.
  • the purified fractions were combined and concentrated under reduced pressure (-170 mbar) on a rotary evaporator with a bath temperature of 10°C.
  • the overall yield is typically in the region of 50 %.
  • ⁇ , ⁇ -carbonyldiimidazole (3.09 g, 17.71 mmol, 1.1 equiv., 93% purity) as a solid, the reaction mixture was stirred (1 h), and deemed complete by HPLC. The mixture was quenched with the dropwise addition (10 min) of water (44.4 ml, 8X), and allowed to warm to RT (30 min).
  • the reaction mixture was transferred to a separatory funnel using EtOAc (27.8 ml, 5X) and water (27.8 ml, 5X), and the layers were separated, with the yellow color remaining in the aqueous layer.
  • the aqueous layer was extracted with EtOAc (27.8 ml, 5X), and the organic layers were combined, dried over MgS0 4 , and then concentrated (50 mm Hg in a 30° - 35°C water bath) to yield dark yellow-brown oil.
  • EtOAc 100 mL
  • alkyne acid (6.5062 g, 16.42 mmol, 1.0 eq,
  • Example 13 Amide Coupling of TBA Salt of c/s-Alkene Acid and Quinaxoline pTSA Salt
  • Neolyst M2 catalyst tricyclohexylphospine- [3 -phenyl- 1H- inden- 1 -ylidene] [ 1 ,3-bis(2,4,6-trimethylphenyul)-4,5-dihydroimidazol-2-ylidene] ruthenium (II) dichloride, 15.3 mg), degassed toluene (7.25 mL), and the system was sonicated and stirred until no solid remained.
  • Neolyst M2 catalyst tricyclohexylphospine- [3 -phenyl- 1H- inden- 1 -ylidene] [ 1 ,3-bis(2,4,6-trimethylphenyul)-4,5-dihydroimidazol-2-ylidene] ruthenium (II) dichloride, 15.3 mg
  • degassed toluene (7.25 mL)
  • Neolyst M2 catalyst 3.05 mg, 3.21 ⁇ , 0.002 eq
  • toluene 1.450 ml
  • the reaction mixture was sampled (3 h), deemed complete via HPLC analysis, cooled to RT, diluted with MeCN and assayed via HPLC analysis.
  • the diluted crude mixture contained trans-RCM product (683 mg, 1.21 mmol, 75% yield) and cis-RCM product (109 mg, 0.193 mmol, 12% yield) which was carried on to the Example 15 as a mixture without further purification.
  • the mixture was concentrated (-4.6 mL, 5X), 2-propanol (9.1 mL, 10X) was charged, and again the mixture was concentrated (-4.6 mL, 5X) in the same manner.
  • the mixture was seeded heated to 40°C to 50°C for 30 min.
  • the mixture was then cooled to RT, heptane (4.6 mL, 5X) was slowly charged which initiated crystallization.
  • the mixture was heated to 40°C to 50°C (20 min), and the mixture was allowed to cool to RT. Additional heptane (4.6 mL, 5X) was slowly charged, and the resulting slurry was allowed to stir (20 min) where it was filtered.
  • the reaction was then allowed to warm to RT over approximately 20 min and then heated to an internal temperature of 55°C overnight. The mixture was then refluxed (4 h); the reaction was deemed complete by HPLC analysis and then cooled to 10°C, where it was quenched with half-saturated NH 4 C1 (160 mL). The layers were then separated, and the organic layer was washed 10% NaCl (2 x 50 mL) and then concentrated. The combined aqueous layers were then combined and back-extracted with EtOAc (50 mL). The layers were separated, and the organic layer was washed with 10% NaCl (20 mL). The final organic layers were combined and concentrated to yield a crude oil.
  • the crude product was further purified via silica gel chromatographed (eluted with hexanes: EtOAc 1st 70: 30 then 50:50) to yield the desired product (8.01 g, 77% yield) upon concentration and flushing with THF.
  • MeMgCI 35.0mL, 105 mmol; 3M
  • Example 21 Fe-Catalyzed Cross-Coupling of Chloroquinoxaline and 3- Butenylma nesium Bromide
  • Boc Proline quinoxaline (20.0 g, 44.8 mmol, 1.0 eq)
  • ferric acetylacetonate 0.790 g, 2.238 mmol, 0.05 eq
  • the reaction mixture was cooled between 0°C and 10°C, and then 3-butenylmagnesium bromide (94 ml, 47.0 mmol, 1.05 eq) was charged dropwise to the reaction mixture keeping the internal temperature between 0°C and 10°C, causing a color change from red to brown to black upon addition.
  • the mixture was allowed to stir, then sampled (30 min), and deemed complete by HPLC analysis.
  • the reaction was then quenched with 1 M HCl (100 ml, 5X) and MTBE (100 ml, 5X) keeping the internal temperature below 25°C, where it was transferred to a separatory funnel, and the layers were separated.
  • the resulting organic layer (dark black-red colored) was extracted with water (100 ml, 5X) and then 10 wt% brine (100 ml, 5X). The organic layer was assayed by HPLC and found to yield the desired product (18.0 g, 39.2 mmol, 88% yield). The resulting organic layer was concentrated to yield orange opaque oil, which was carried on to the next reaction without further purification.
  • the reaction mixture was allowed to warm and stir at RT over the weekend, where it was sampled (87 h), deemed complete by HPLC analysis, quenched with 10 wt% citric acid (54.5 ml) and MTBE (54.5 ml). The layers were separated, and the aqueous layer was extracted with MTBE (54.5 ml). The organic layers were combined, washed with 10 wt% citric acid (2 x 54.5 ml), 10 wt% NaCl (54.5 ml), dried over MgS0 4 , filtered, and concentrated to yield brown oil.
  • the crude brown oil was purified via gradient silica gel chromatography (Biotage 100 g SNAP Si gel column; 5 to 40% EtOAc in Hex, then ramp to 75% EtOAc in Hex, detected by TLC-UV) to yield the RCM precursor (6.029 g, 7.40 mmol, 107% yield) as a light yellow oil.
  • Example 20 To a 50 mL 2-neck RB flask with reflux condenser and needle for N 2 bubbling was charged the product of Example 20 (1.034 g, 0.869 mmol, 1.0 eq), toluene (20.68 ml, 20X), and the resulting solution was degassed with N 2 .
  • Hoveyda-Grubbs 2 nd generation catalyst (10.90 mg, 0.017 mmol) was charged to the pot, and the system was heated to 80°C with constant sparge of N 2 , with color change from green to reddish. The reaction was sampled (5 h) and assay by HPLC to be approximately 80% converted. The system was removed from the heat and allowed to stir at RT overnight under N 2 .

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des procédés de synthèse utiles dans la préparation de macrolactames qui inhibent le virus de l'hépatite C (VHC), spécifiquement des composés à base de macrolactame qui inhibent l'activité de la protéase NS3 du VHC et ont une application dans le traitement d'états provoqués par le VHC. L'invention concerne également des intermédiaires utiles dans les procédés de synthèse décrits et les procédés pour leur préparation.
PCT/US2014/071007 2013-12-20 2014-12-18 Procédés et intermédiaires pour la préparation de macrolactames WO2015095430A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2014370125B2 (en) * 2013-12-23 2017-11-16 Gilead Pharmasset Llc Synthesis of a macrocyclic HCV NS3 inhibiting tripeptide
CN111018795A (zh) * 2019-12-25 2020-04-17 上海彩迩文生化科技有限公司 一种碱性条件下合成喹喔啉-3-酮的方法

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WO2010011566A1 (fr) * 2008-07-22 2010-01-28 Merck & Co., Inc. Composés de quinoxaline macrocycliques en tant qu'inhibiteurs de protéase ns3 du virus de l'hépatite c (hcv)
WO2012040040A1 (fr) * 2010-09-21 2012-03-29 Merck Sharp & Dohme Corp. Inhibiteurs de protéase ns3 du vhc
WO2012082672A2 (fr) * 2010-12-14 2012-06-21 Merck Sharp & Dohme Corp. Procédé et intermédiaires pour la préparation de macrolactames

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Publication number Priority date Publication date Assignee Title
WO2010011566A1 (fr) * 2008-07-22 2010-01-28 Merck & Co., Inc. Composés de quinoxaline macrocycliques en tant qu'inhibiteurs de protéase ns3 du virus de l'hépatite c (hcv)
WO2012040040A1 (fr) * 2010-09-21 2012-03-29 Merck Sharp & Dohme Corp. Inhibiteurs de protéase ns3 du vhc
WO2012082672A2 (fr) * 2010-12-14 2012-06-21 Merck Sharp & Dohme Corp. Procédé et intermédiaires pour la préparation de macrolactames

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2014370125B2 (en) * 2013-12-23 2017-11-16 Gilead Pharmasset Llc Synthesis of a macrocyclic HCV NS3 inhibiting tripeptide
US10030033B2 (en) 2013-12-23 2018-07-24 Gilead Sciences, Inc. Synthesis of an antiviral compound
CN111018795A (zh) * 2019-12-25 2020-04-17 上海彩迩文生化科技有限公司 一种碱性条件下合成喹喔啉-3-酮的方法
CN111018795B (zh) * 2019-12-25 2023-03-28 上海彩迩文生化科技有限公司 一种碱性条件下合成喹喔啉-3-酮的方法

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