WO2012151271A1 - 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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- WO2012151271A1 WO2012151271A1 PCT/US2012/036112 US2012036112W WO2012151271A1 WO 2012151271 A1 WO2012151271 A1 WO 2012151271A1 US 2012036112 W US2012036112 W US 2012036112W WO 2012151271 A1 WO2012151271 A1 WO 2012151271A1
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- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
Definitions
- 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.
- HCV hepatitis C virus
- the present invention relates to novel oxidation processes useful for preparing compounds of Formula I:
- HCV infection is a major health problem that leads to chronic 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.
- RNA-dependent RNA polymerase RNA-dependent RNA polymerase
- 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 NS4A/4B, NS4B/5A and NS5A/5B junctions.
- U.S. Patent No. 7,012,066 describes compounds that are useful as HCV NS3 inhibitors and useful in the treatment of HCV and conditions caused by HCV infection.
- 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.
- the processes of the present invention afford a halogen-free oxidation process for preparing compounds of Formula I.
- the present invention relates to processes for preparing a compound of Formula I,
- a and E are independently selected from the group consisting of a direct bond and
- R 1 is -NH(Ci-C 8 alk l),
- R 2 is d-Csalk l
- R is independently selected from the group consisting of C]-C 8 alkyl
- R 4 and R 5 are each independently selected from the group consisting of H, Cj-Csalkyl, C 3 -C 8 cycloalkyl, Cj-Csalky Cs-Cgcycloalkyl) and substituted
- R 4 and R 5 may be taken together to form a C3-C 8 cycloalkyl
- R° and R' are independently H or Ci-Cealkyl
- A, E, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above, with an oxidizing agent selected from the group consisting of KMn0 4 , NaMn0 4 , K 2 Fe0 4 , V 2 Os, Ru0 2 , NaN0 2 , Cr0 3 , K 2 Cr04, 2 Cr 2 0 7 , H 5 PV 2 Mo 10 O 4 , peroxides and PhI(OAc) 2 , in the presence of at least one catalyst to yield a compound of Formula I.
- the compounds of Formula I and Formula II may be present as amorphous compounds, or as pharmaceutically acceptable salts, hydrates, solvates or stereoisomers thereof.
- a first embodiment of the invention is directed to processes in which R 1 is selected from -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 ) 2 ,
- R 1 is -NHC(CH 3 ) 3 , R 1 is or R 1 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 2 is selected from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 3 , and -CH 2 CH 2 CH 2 CH 2 CH 3 .
- R is -C(CH 3 ) 3 .
- 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 R is selected from the group consisting of -Ci-C 8 alkyl and -(CH 2 )i -8 (cyclo(C 3 -C 8 )alkyl).
- R J is -CH 2 CH 2 CH 2 CH 3 or In a particular aspect of this embodiment, RR 3J iiss v . In all aspects of this embodiment, all other groups are as provided in the general formula above and/or in the first or second embodiments.
- a fourth embodiment of the invention is directed to processes in which R 4 is selected from the group consisting of H, d-Csalkyl, C 3 -C 8 cycloalkyl, Ci-C 8 alkyl(C 3 -C 8 cycloalkyl) and substituted Ci-Csalky ⁇ Cs-Cscycloalkyl).
- R 4 is selected from the group consisting of H, d-Csalkyl, C 3 -C 8 cycloalkyl, Ci-C 8 alkyl(C 3 -C 8 cycloalkyl) and substituted Ci-Csalky ⁇ Cs-Cscycloalkyl).
- R 4 is H or R 4 is cyclopropyl.
- 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 5 is selected from the group consisting of H, Cj-Csalkyl, C 3 -C 8 cycloalkyl, Ci-C 8 alkyl(C 3 -C 8 cycloalkyl) and substituted d-C 8 alkyl(C 3 -C 8 cycloalkyl).
- R 5 is H or R 5 is cyclopropyl.
- all other groups are as provided in the general formula above and/or in the first through fourth embodiments.
- R 4 and R 5 are taken together to form a C3-C 8 cycloalkyl.
- R 4 and R 5 are taken together to form a C 4 -C 5 cycloalkyl.
- 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 R 6 is selected from the group consisting of H or Ci-C-jalkyl.
- R 6 is H or R 6 is methyl.
- 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 R 7 is selected from the group consisting of H or Ci-C 4 alkyl.
- R is H or R is methyl.
- 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 2 -.
- a and E are each independently a bond.
- a and E are each independently -CH 2 -.
- all other groups are as provided in the general formula above and/or in the first through eighth
- a tenth embodiment of the invention is directed to processes in which the catalyst is selected from the group consisting of 2,2,6,6-tetramethyl-l-piperidinyloxy free radical (TEMPO), 4-methoxy-TEMPO, 4-amino-TEMPO, 2-azaadamantane N-oxyl (AZADO), 1-Me- AZADO and combinations of one to five catalysts chosen therefrom.
- 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.
- the catalyst is TEMPO.
- the catalyst is present in a stoichiometric amount, with respect to the compound of Formula II.
- the at least one catalyst is present in an amount ranging from about 0.1 to about 2.0 equivalents, 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 equivalent of the compound of Formula II. In all aspects of this embodiment, all other groups are as provided in the general formula above and/or 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 of KMn0 4 , NaMn0 4 , Cr0 3 , K 2 Cr0 4 , K 2 Cr 2 0 7 , and H 5 PV 2 Mo 10 O .
- the oxidizing agent is selected from the group consisting of KMn0 4 , NaMn0 4 , H 5 PV 2 Moio0 4 and K 2 Cr 2 0 7 .
- 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 and/or 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.
- the acid is selected from the group consisting of HC1, KHS0 4 , KH 2 P0 4 , ClCH 2 COOH,
- 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 and/or 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 0°C to about 40°C, in particular aspects of this 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.
- all other groups are as provided in the general formula above and/or in the first through twelfth 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 any one of the general process above and/or any one of the first through twenty-second embodiments.
- all groups are as provided in the general process above and/or in any of the first through twenty-second embodiments above.
- a compound of the invention is prepared by process according to any one of the general process above and/or any one of the first through twenty-second embodiments and is selected from the exemplary species depicted in Examples 2 through 4 shown below.
- 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.
- 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.
- alkyl refers to any linear or branched chain alkyl group having a number of carbon atoms in the specified range.
- C 1-6 alkyl (or “Cj-Cealkyl”) refers to all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and 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(0)0-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.
- alkoxy refers to an "alkyl-O-" group. Alkoxy groups may be substituted as indicated.
- cycloalkyl refers to any cyclic ring of an alkane or alkene having a number of carbon atoms in the specified range.
- C 3-8 cycloalkyl or
- Cs-Cgcycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- cycloalkoxy refers to a "cycloalkyl-O-" group. Cycloalkyl groups may be substituted as indicated.
- aryl 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.
- 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, O 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, chloro, bromo, or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro.
- 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, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfmyl, alkylthio, arylthio,
- heteroarylthio aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl,
- heterocyclenyl Y x Y 2 N-, Y ⁇ N-alkyl-, Y x Y 2 NC(0)- and Y ! Y 2 NS0 2 -, wherein Y, and Y 2 may 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 more alkyl substituents as defined above.
- substituents are selected from the group which includes, but is not limited to, halo, C 1 -C 20 alkyl, -CF 3 , -NH 2 , -N(C ! -C 6 alkyl) 2 , -N0 2 , oxo, -CN, -N 3 , -OH,
- C 3 -C 10 cycloalkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 0 -C 6 alkyl) S(O) 0-2 -, aryl-S(O) 0-2 -, (Co-C 6 alkyl)S(0)o -2 (Co-C 6 alkyl)-, (C 0 -C 6 alkyl)C(0)NH-, H 2 N-C(NH)-,
- heterocyclylalkyl halo-aryl, halo-aralkyl, halo-heterocycle and halo-heterocyclylalkyl.
- 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.
- 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.
- 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).
- substituents and substituent patterns certain of the compounds of the present invention can have asymmetric centers and can occur as mixtures of 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.
- 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 any one 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.
- 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.
- 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.
- suitable pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.
- 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.
- administering 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 HCV infection), "administration" and its variants are each understood to include concurrent and sequential provision of the compound or salt (or hydrate) and other agents.
- active agents e.g., antiviral agents useful for treating HCV infection
- 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.
- pharmaceutically acceptable is meant that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.
- subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
- cell-based system refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
- 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, ⁇ , ⁇ '-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine,
- basic ion exchange resins such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morph
- salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
- acids 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 of HCV 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 of HCV infection, and/or reduction of the likelihood or severity of symptoms of HCV infection, alone or in combination with other active agents.
- 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.
- these compounds are useful as ingredients in pharmaceutical compositions alone or in combination with other active agents.
- Example 1 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 NaMn0 4 (289g of 40% NaMn0 4 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 0°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 of 9.9% HC1 solution. After splitting the layers, the organic layer was washed with 2L of 3. ON to 4. ON HC1 solution. After separation of layers, the organic layer was washed 4 times with 2.5L of water at between 0°C and 10°C. The resulting organic layer was added dropwise to 15L of ⁇ -heptane while keeping the temperature at between -10°C and 0°C. The precipitate was filtered and dried at 35°C to 40°C to give the desired product.
- Example 2 The title compound was prepared according to the procedures in Example 2, using 5.0g of the compound of Example 1, and 0.9 lg of KMn0 4 , dissolved in 25mL of water, in place of NaMn0 4 .
- the isolated yield was about 85% by weight of a product having an identical 1H NMR spectrum to that of the product of Example 2.
- Example 1 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 NaMn0 4 (181kg of 40% NaMn0 4 and 1056L of water) was added drop-wise over 2 to 3 hours while maintaining the temperature between 1 1°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 0°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% HC1 solution. After splitting the layers, the organic layer was washed with about 1280L of 3.0 to 4. ON HC1 solution. After separation of layers, the organic layer was washed 4 times with 1600L of water at between 0°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 of a tee mixer at a volumetric ratio of 1 :4, while maintaining its temperature at between -10°C and 0°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 10X.
- 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.
- Table 1 Distillation profile used in Example 4.
- 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 HCl, is added to the organic layer and the mixture is stirred for about 1 hour.
- 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 0°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 25°C, 8 hours at 35°, and 8 hours at 45°C).
- the product is obtained as a white powder (typically 94-96% yield).
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- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Genetics & Genomics (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Enzymes And Modification Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
Claims
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/114,251 US20140058116A1 (en) | 2011-05-04 | 2012-05-02 | Process for preparing inhibitors of the hepatitis c virus |
CN2012800200308A CN103476260A (en) | 2011-05-04 | 2012-05-02 | Processes for preparing inhibitors of the hepatitis C virus |
AU2012250799A AU2012250799A1 (en) | 2011-05-04 | 2012-05-02 | Processes for preparing inhibitors of the hepatitis C virus |
BR112013027652A BR112013027652A2 (en) | 2011-05-04 | 2012-05-02 | process for preparing a compound |
RU2013153533/04A RU2013153533A (en) | 2011-05-04 | 2012-05-02 | METHODS FOR PRODUCING HEPATITIS C VIRUS INHIBITORS |
MX2013012771A MX2013012771A (en) | 2011-05-04 | 2012-05-02 | Processes for preparing inhibitors of the hepatitis c virus. |
KR1020137028743A KR20140022855A (en) | 2011-05-04 | 2012-05-02 | Processes for preparing inhibitors of the hepatitis c virus |
NZ617300A NZ617300B2 (en) | 2011-05-04 | 2012-05-02 | Processes for preparing inhibitors of the hepatitis c virus |
CA2832869A CA2832869A1 (en) | 2011-05-04 | 2012-05-02 | Processes for preparing inhibitors of the hepatitis c virus |
EP12779558.1A EP2704576A4 (en) | 2011-05-04 | 2012-05-02 | Processes for preparing inhibitors of the hepatitis c virus |
JP2014509384A JP2014515764A (en) | 2011-05-04 | 2012-05-02 | Method for preparing hepatitis C virus inhibitor |
SG2013080643A SG194711A1 (en) | 2011-05-04 | 2012-05-02 | Processes for preparing inhibitors of the hepatitis c virus |
IL228601A IL228601A0 (en) | 2011-05-04 | 2013-09-29 | Processes for preparing inhibitors of the hepatitis c virus |
ZA2013/08011A ZA201308011B (en) | 2011-05-04 | 2013-10-29 | Processes for preparing inhibitors of the hepatitis c virus |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161482592P | 2011-05-04 | 2011-05-04 | |
US61/482,592 | 2011-05-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2012151271A1 true WO2012151271A1 (en) | 2012-11-08 |
Family
ID=47108028
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2012/036112 WO2012151271A1 (en) | 2011-05-04 | 2012-05-02 | Processes for preparing inhibitors of the hepatitis c virus |
PCT/US2012/036131 WO2012151283A1 (en) | 2011-05-04 | 2012-05-02 | Drug substances, pharmeceutical compositions and methods for preparing the same |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2012/036131 WO2012151283A1 (en) | 2011-05-04 | 2012-05-02 | Drug substances, pharmeceutical compositions and methods for preparing the same |
Country Status (17)
Country | Link |
---|---|
US (2) | US20140044759A1 (en) |
EP (2) | EP2704570A4 (en) |
JP (2) | JP2014515764A (en) |
KR (2) | KR20140030169A (en) |
CN (2) | CN103476260A (en) |
AR (1) | AR086259A1 (en) |
AU (2) | AU2012250799A1 (en) |
BR (2) | BR112013027652A2 (en) |
CA (2) | CA2832869A1 (en) |
CO (1) | CO6801768A2 (en) |
IL (1) | IL228601A0 (en) |
MX (2) | MX2013012773A (en) |
RU (2) | RU2013153533A (en) |
SG (1) | SG194711A1 (en) |
TW (1) | TW201247668A (en) |
WO (2) | WO2012151271A1 (en) |
ZA (1) | ZA201308011B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8828930B2 (en) | 2009-07-30 | 2014-09-09 | Merck Sharp & Dohme Corp. | Hepatitis C virus NS3 protease inhibitors |
US11351149B2 (en) | 2020-09-03 | 2022-06-07 | Pfizer Inc. | Nitrile-containing antiviral compounds |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2916143C (en) * | 2013-06-19 | 2019-01-29 | Aicuris Anti-Infective Cures Gmbh | Amorphous letermovir and solid pharmaceutical formulations thereof for oral administration |
CA3055019A1 (en) * | 2017-03-07 | 2018-09-13 | Orion Corporation | Manufacture of a crystalline pharmaceutical product |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080221331A1 (en) * | 2007-03-06 | 2008-09-11 | Nissan Chemical Industries Ltd. | Alcohol oxidation catalyst and its preparation process |
US7528263B2 (en) * | 2005-11-14 | 2009-05-05 | Schering Corporation | Oxidation process for the preparation of N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-{N-[(tert-butylamino)carbonyl]-3-methyl-L-valyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide and related compounds |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR044694A1 (en) * | 2003-06-17 | 2005-09-21 | Schering Corp | PROCESS AND INTERMEDIATE COMPOUNDS FOR THE PREPARATION OF (1R, 2S, 5S) - 3 AZABICICLO [3,1,0] HEXANO-2- CARBOXAMIDE, N- [3- AMINO-1- (CYCLLOBUTILMETILE) - 2, 3 - DIOXOPROPIL] -3- [(2S) - 2 - [[[1,1- DIMETHYTILE] AMINO] CARBONYLAMINE] -3,3-DIMETHYL -1- OXOBUTIL] -6.6 DIMETHYL |
CN101495095B (en) * | 2006-04-28 | 2013-05-29 | 默沙东公司 | Process for the precipitation and isolation of 6,6-dimethyl-3-aza-bicyclo [3.1.0] hexane-amide compounds by controlled precipitation and pharmaceutical formulations containing same |
US8420122B2 (en) * | 2006-04-28 | 2013-04-16 | Merck Sharp & Dohme Corp. | Process for the precipitation and isolation of 6,6-dimethyl-3-aza-bicyclo [3.1.0] hexane-amide compounds by controlled precipitation and pharmaceutical formulations containing same |
PL2121605T3 (en) * | 2006-12-20 | 2014-05-30 | Merck Sharp & Dohme | Process for preparing (1r,2s,5s)-n-[(1s)-3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2s)-2-[[[(1,1-dimethylethyl)amino]-carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide |
MX2009008275A (en) * | 2007-02-01 | 2009-08-12 | Tibotec Pharm Ltd | Polymorphic forms of a macrocyclic inhibitor of hcv. |
WO2009038663A1 (en) * | 2007-09-14 | 2009-03-26 | Schering Corporation | Method of treating hepatitis c patients |
DE102009000662A1 (en) * | 2009-02-06 | 2010-08-12 | Evonik Degussa Gmbh | Process for the preparation of aldehydes and ketones from primary and secondary alcohols |
-
2012
- 2012-05-02 CA CA2832869A patent/CA2832869A1/en not_active Abandoned
- 2012-05-02 CN CN2012800200308A patent/CN103476260A/en active Pending
- 2012-05-02 BR BR112013027652A patent/BR112013027652A2/en not_active IP Right Cessation
- 2012-05-02 AU AU2012250799A patent/AU2012250799A1/en not_active Abandoned
- 2012-05-02 AU AU2012250811A patent/AU2012250811A1/en not_active Abandoned
- 2012-05-02 MX MX2013012773A patent/MX2013012773A/en unknown
- 2012-05-02 WO PCT/US2012/036112 patent/WO2012151271A1/en active Application Filing
- 2012-05-02 JP JP2014509384A patent/JP2014515764A/en active Pending
- 2012-05-02 BR BR112013027642A patent/BR112013027642A2/en not_active IP Right Cessation
- 2012-05-02 EP EP12779536.7A patent/EP2704570A4/en not_active Withdrawn
- 2012-05-02 US US14/114,357 patent/US20140044759A1/en not_active Abandoned
- 2012-05-02 EP EP12779558.1A patent/EP2704576A4/en not_active Withdrawn
- 2012-05-02 CA CA2833887A patent/CA2833887A1/en not_active Abandoned
- 2012-05-02 WO PCT/US2012/036131 patent/WO2012151283A1/en active Application Filing
- 2012-05-02 JP JP2014509388A patent/JP2014513127A/en active Pending
- 2012-05-02 SG SG2013080643A patent/SG194711A1/en unknown
- 2012-05-02 RU RU2013153533/04A patent/RU2013153533A/en not_active Application Discontinuation
- 2012-05-02 US US14/114,251 patent/US20140058116A1/en not_active Abandoned
- 2012-05-02 KR KR1020137028709A patent/KR20140030169A/en not_active Application Discontinuation
- 2012-05-02 KR KR1020137028743A patent/KR20140022855A/en not_active Application Discontinuation
- 2012-05-02 MX MX2013012771A patent/MX2013012771A/en unknown
- 2012-05-02 RU RU2013153588/15A patent/RU2013153588A/en unknown
- 2012-05-02 CN CN201280020032.7A patent/CN103501608A/en active Pending
- 2012-05-03 AR ARP120101561A patent/AR086259A1/en not_active Application Discontinuation
- 2012-05-04 TW TW101116053A patent/TW201247668A/en unknown
-
2013
- 2013-09-29 IL IL228601A patent/IL228601A0/en unknown
- 2013-10-29 ZA ZA2013/08011A patent/ZA201308011B/en unknown
- 2013-11-01 CO CO13259875A patent/CO6801768A2/en not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7528263B2 (en) * | 2005-11-14 | 2009-05-05 | Schering Corporation | Oxidation process for the preparation of N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-{N-[(tert-butylamino)carbonyl]-3-methyl-L-valyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide and related compounds |
US20080221331A1 (en) * | 2007-03-06 | 2008-09-11 | Nissan Chemical Industries Ltd. | Alcohol oxidation catalyst and its preparation process |
Non-Patent Citations (1)
Title |
---|
See also references of EP2704576A4 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8828930B2 (en) | 2009-07-30 | 2014-09-09 | Merck Sharp & Dohme Corp. | Hepatitis C virus NS3 protease inhibitors |
US11351149B2 (en) | 2020-09-03 | 2022-06-07 | Pfizer Inc. | Nitrile-containing antiviral compounds |
US11452711B2 (en) | 2020-09-03 | 2022-09-27 | Pfizer Inc. | Nitrile-containing antiviral compounds |
US11541034B2 (en) | 2020-09-03 | 2023-01-03 | Pfizer Inc. | Nitrile-containing antiviral compounds |
Also Published As
Publication number | Publication date |
---|---|
KR20140022855A (en) | 2014-02-25 |
AR086259A1 (en) | 2013-12-04 |
US20140058116A1 (en) | 2014-02-27 |
TW201247668A (en) | 2012-12-01 |
JP2014513127A (en) | 2014-05-29 |
EP2704576A4 (en) | 2014-12-10 |
SG194711A1 (en) | 2013-12-30 |
CO6801768A2 (en) | 2013-11-29 |
AU2012250811A1 (en) | 2013-12-19 |
CA2833887A1 (en) | 2012-11-08 |
RU2013153588A (en) | 2015-06-10 |
CN103501608A (en) | 2014-01-08 |
BR112013027652A2 (en) | 2016-07-26 |
BR112013027642A2 (en) | 2016-07-26 |
IL228601A0 (en) | 2013-12-31 |
MX2013012773A (en) | 2013-11-21 |
JP2014515764A (en) | 2014-07-03 |
ZA201308011B (en) | 2015-05-27 |
EP2704570A4 (en) | 2015-02-18 |
CA2832869A1 (en) | 2012-11-08 |
KR20140030169A (en) | 2014-03-11 |
RU2013153533A (en) | 2015-06-10 |
WO2012151283A1 (en) | 2012-11-08 |
US20140044759A1 (en) | 2014-02-13 |
EP2704570A1 (en) | 2014-03-12 |
MX2013012771A (en) | 2013-11-21 |
AU2012250799A1 (en) | 2013-10-10 |
EP2704576A1 (en) | 2014-03-12 |
NZ617300A (en) | 2015-06-26 |
CN103476260A (en) | 2013-12-25 |
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