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EP1206450A1 - Voies de synthese permettant de preparer des inhibiteurs de proteases de rhinovirus et intermediaires cles - Google Patents

Voies de synthese permettant de preparer des inhibiteurs de proteases de rhinovirus et intermediaires cles

Info

Publication number
EP1206450A1
EP1206450A1 EP00955831A EP00955831A EP1206450A1 EP 1206450 A1 EP1206450 A1 EP 1206450A1 EP 00955831 A EP00955831 A EP 00955831A EP 00955831 A EP00955831 A EP 00955831A EP 1206450 A1 EP1206450 A1 EP 1206450A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
group
cycloalkyl
yield
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00955831A
Other languages
German (de)
English (en)
Inventor
Qingping Tian
Naresh K. Nayyar
Srinivasan Babu
Junhua Tao
Terence Jarold Moran
Raymond Dagnino, Jr.
Lennert J. Mitchell
Travis Paul Remarchuk
Michael Joseph Parke-Davis MELNICK
Steven Lee Bender
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Agouron Pharmaceuticals LLC
Original Assignee
Agouron Pharmaceuticals LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Agouron Pharmaceuticals LLC filed Critical Agouron Pharmaceuticals LLC
Publication of EP1206450A1 publication Critical patent/EP1206450A1/fr
Withdrawn legal-status Critical Current

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/24—Stationary reactors without moving elements inside
    • B01J19/2415—Tubular reactors
    • B01J19/2435—Loop-type reactors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/24—Stationary reactors without moving elements inside
    • B01J19/2475—Membrane reactors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00049—Controlling or regulating processes
    • B01J2219/00051—Controlling the temperature
    • B01J2219/00074—Controlling the temperature by indirect heating or cooling employing heat exchange fluids
    • B01J2219/00087—Controlling the temperature by indirect heating or cooling employing heat exchange fluids with heat exchange elements outside the reactor
    • B01J2219/00099—Controlling the temperature by indirect heating or cooling employing heat exchange fluids with heat exchange elements outside the reactor the reactor being immersed in the heat exchange medium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00049—Controlling or regulating processes
    • B01J2219/00051—Controlling the temperature
    • B01J2219/00159—Controlling the temperature controlling multiple zones along the direction of flow, e.g. pre-heating and after-cooling

Definitions

  • the present invention relates to an improved process for the preparation of
  • Pyrro/- ⁇ /a) ⁇ -E-propanoate (also referred to as AG7088), its analogs and of 0 pharmaceutically acceptable salts thereof.
  • the present invention also includes a novel group of key intermediate compounds to be used in the above process.
  • Picornaviruses are a family of tiny non-enveloped positive-stranded RNA- containing viruses that infect humans and other animals. These viruses include the human rhinoviruses, human polioviruses, human coxsackieviruses, human echoviruses, human and bovine enteroviruses, encephalomyocarditis viruses, meningitis viruses, foot and mouth viruses, hepatitis A virus, and others. The human rhinoviruses are a major cause of the common cold. Proteolytic 3C enzymes are required for the natural maturation of the picornaviruses. Thus, inhibiting the activity of these proteolytic 3C enzymes should represent an important and useful approach for the treatment and cure of viral infections of this nature, including the common cold.
  • General Method V therein discloses a general method for synthesizing the compounds of formula I involving subjecting a carboxylic acid of general formula BB to an amide-forming reaction with an amine of general formula P to provide a final product CC, as shown below.
  • the '354 application further discloses methods for synthesizing the intermediates of general formulae BB and P, and teaches methods for carrying out the amide-forming reaction referred to above.
  • the '354 application teaches suitable methods for synthesizing the compounds of general formula I from a carboxylic acid BB (within the scope of the compounds of general formula II referred to below) and the compounds of general formula P (the same as the compounds of general formula III referred to below.)
  • two recent publications by Dragovich et al. disclose antipicornavirus agents and suitable synthetic methods for their synthesis. See Structure-Based Design, Synthesis, and Biological Evaluation of Irreversable Human Rhinovirus 3 C Proteases Inhibitors. 3.
  • the present mvention relates to the discovery of a cost effective and efficient process for the preparation of the antipicomaviral agents of formula I, such as compound AG7088, as well as intermediates which are useful in that synthesis.
  • the antipicomaviral agents of formula I comprise:
  • Ri is H, F, an alkyl group, OH, SH, or an O-alkyl group
  • R 2 and R 3 are each independently H
  • n is an integer from 0 to 5
  • A] is CH or N
  • a and each A 3 are independently
  • R 5 and R 6 are each independently H, F, an alkyl group, a cycloalkyl group, a
  • heterocycloalkyl group an aryl group, or a heteroaryl group
  • R 7 and R 8 are each independently H, an alkyl group, a cycloalkyl group, a
  • heterocycloalkyl group an aryl group, a heteroaryl group, -OR ⁇ , -SR 17 , -NR 1 R 18 , -NR ⁇ 9 NR ⁇ 7 Ri8, or -NR ] 7 ORi8, where R 17 , R 18 , and R] are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl
  • R and R 8 are independently alkyl groups, or an acyl group, provided that at least one of R and R 8 is an alkyl group, an
  • R 9 is a five-membered heterocycle having from one to three heteroatoms selected from O, N, and S;
  • Z and Z] are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -C(O)R 2 ⁇ , -CO 2 R 2 ⁇ , CN,
  • R 22 , R 23 , and R 24 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group,
  • antipicomaviral agents of formula I may be any antipicomaviral agents of formula I.
  • alkyl group is intended to mean a straight or branched chain monovalent radical of saturated and/or unsaturated carbon atoms and hydrogen atoms, such as methyl (Me), ethyl (Et), propyl, isopropyl, butyl (Bu), isobutyl, t-butyl (t-Bu), ethenyl, pentenyl, butenyl, propenyl, ethynyl, butynyl, propynyl, pentynyl, hexynyl, and the like, which may be unsubstituted (i.e., containing only carbon and hydrogen) or substituted by one or more suitable sustituents as defined below (e.g., one or more halogens, such as F, Cl, Br, or I, with F and Cl being prefered).
  • suitable sustituents e.g., one or more halogens, such as F, Cl, Br, or I
  • a “lower alkyl group” is intended to mean an alkyl group having from 1 to 4 carbon atoms in its chain.
  • a “cycloalkyl group” is intended to mean a non-aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon ring atoms, each of which may be saturated or unsaturated, and which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more heterocycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more substituents.
  • Illustrative examples of cycloalkyl groups include the following moieties:
  • heterocycloalky group is intended to mean a non-aromatic monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, which includes 1, 2, 3, 4, or 5 heteroatoms selected nitrogen, oxygen, and sulfur, where the radical is unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents.
  • suitable substituents as defined below
  • Illustrative examples of heterocycloalkyl groups include the following moieties:
  • aryl group is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 6, 10, 14 or 18 carbon ring atoms, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents.
  • aryl groups include the following moieties:
  • heteroaryl group is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, including 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents.
  • suitable substituents as defined below
  • Illustrative examples of heteroaryl groups include the following moieties:
  • heterocycle is intended to mean a heteroaryl or heterocycloalkyl group (each of which, as defined above, are optionally substituted).
  • acyl group is intended to mean a -C(O)-R radical, where R is a substituent as defined below.
  • a “thioacyl group” is intended to mean a -C(S)-R radical, where R is a substituent as defined below.
  • a “sulfonyl group” is intended to mean a -SO 2 R radical, where R is a substituent as defined below.
  • a "hydroxy group” is intended to mean the radical -OH.
  • amino group is intended to mean the radical -NH 2 .
  • alkylamino group is intended to mean the radical -NHR a , where R a is an alkyl group.
  • dialkylamino group is intended to mean the radical -NR a Rb, where R a and R b are each independently an alkyl group.
  • alkoxy group is intended to mean the radical -OR a , where R a is an alkyl group.
  • alkoxy groups include methoxy, ethoxy, propoxy, and the like.
  • alkoxycarbonyl group is intended to mean the radical -C(O)OR a , where R a is an alkyl group.
  • alkylsulfonyl group is intended to mean the radical -SO 2 R a , where R a is an alkyl group.
  • alkylaminocarbonyl group is intended to mean the radical -C(O)NHR a , where R a is an alkyl group.
  • a "dialkylaminocarbonyl group” is intended to mean the radical -C(O)NR a R b , where R a and R b are each independently an alkyl group.
  • a “mercapto group” is intended to mean the radical -SH.
  • alkylthio group is intended to mean the radical -SR a , where R a is an alkyl group.
  • a “carboxy group” is intended to mean the radical -C(O)OH.
  • a “carbamoyl group” is intended to mean the radical -C(O)NH 2 .
  • aryloxy group is intended to mean the radical -OR ⁇ , where R c is an aryl group.
  • a "hetero aryloxy group” is intended to mean the radical -OR d , where R d is a heteroaryl group.
  • arylthio group is intended to mean the radical -SR c , where R c is an aryl group.
  • heteroarylthio group is intended to mean the radical -SR d , where R d is a heteroaryl group.
  • a “leaving group” is intended to mean any suitable group that will be displaced by a substitution reaction.
  • any conjugate base of a strong acid can act as a leaving group.
  • suitable leaving groups include, but are not limited to, -F, -Cl, -Br, alkyl chlorides, alkyl bromides, alkyl iodides, alkyl sulfonates, alkyl benzenesulfonates, alkyl p-toluenesulfonates, alkyl methanesulfonates, triflate, and any groups having a bisulfate, methyl sulfate, or sulfonate ion.
  • Typical protecting groups, reagents and solvents such as, but not limited to, those listed below in table 1 have the following abbreviations as used herein and in the claims.
  • One skilled in the art would understand that the compounds listed within each group may be used interchangeably; for instance, a compound listed under "reagents and solvents" may be used as a protecting group, and so on. Further, one skilled in the art would know other possible protecting groups, reagents and solvents; these are intended to be within the scope of this invention.
  • suitable organic moiety is intended to mean any organic moiety recognizable, such as by routine testing, to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds.
  • suitable organic moieties include, but are not limited to, hydroxyl groups, alkyl groups, oxo groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkoxy groups, carboxy groups, amino groups, alkylamino groups, dialkylamino groups, carbamoyl groups, arylthio groups, heteroarylthio groups, and the like.
  • substituted substituent or "suitable substituent” is intended to mean any suitable substituent that may be recognized or selected, such as through routine testing, by those skilled in the art.
  • suitable substituents include hydroxy groups, halogens, oxo groups, alkyl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkyloxy groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, carboxy groups, amino groups, alkylamino groups, dialkylamino groups, carbamoyl groups, aryloxy groups, heteroaryloxy groups, arylthio groups, heteroarylthio groups, and the like.
  • optionally substituted is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more suitable substituents, unless the optional substituents are expressly specified, in which case the term indicates that the group is unsubstituted or substituted with the specified substituents.
  • various groups may be unsubstituted or substituted (i.e., they are optionally substituted) unless indicated otherwise herein (e.g., by indicating that the specified group is unsubstituted).
  • a “prodrug” is intended to mean a compound that is converted under physiological conditions or by solvolysis or metabolically to a specified compound that is pharmaceutically active.
  • a "pharmaceutically active metabolite” is intended to mean a pharmacologically active product produced through metabolism in the body of a specified compound.
  • solvate is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound.
  • solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
  • a "pharmaceutically acceptable salt” is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable.
  • pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophaosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-1,6- dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,
  • the present invention further provides synthetic methods that are comprised of one of the synthetic steps set forth in the present disclosure.
  • a synthetic method is comprised of a synthetic step when the synthetic step is at least part of the final synthetic method.
  • the synthetic method can be only the synthetic step or have additional synthetic steps that may be associated with it.
  • Such a synthetic method can have a few additional synthetic steps or can have numerous additional synthetic steps.
  • a desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid; hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid; and the like, or with an organic acid, such as acetic acid; maleic acid; succinic acid; mandelic acid; fumaric acid; malonic acid; pyruvic acid; oxalic acid; glycolic acid; salicylic acid; pyranosidyl acid, such as glucuronic acid or galacturonic acid; alpha- hydroxy acid, such as citric acid or tartaric acid; amino acid, such as aspartic acid or glutamic acid; aromatic acid, such as benzoic acid or cinnamic acid; sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid; or the like
  • an inorganic acid such as hydrochloric acid; hydrobromic acid; sulfuric acid;
  • a desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary); an alkali metal or alkaline earth metal hydroxide; or the like.
  • an inorganic or organic base such as an amine (primary, secondary, or tertiary); an alkali metal or alkaline earth metal hydroxide; or the like.
  • suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; and cyclic amines, such as piperidine, morpholine, and piperazine; as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • the antipicomaviral agents of formula I, and the intermediates used in the process of the present invention may exist as single stereoisomers, racemates, and/or mixtures of enantiometers and/or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the broad scope of the present invention.
  • the intermediate compounds used in the process of the present invention are used in optically pure form.
  • an optically pure compound is one that is enantiomerically pure.
  • the term "optically pure" is intended to mean a compound comprising at least a sufficient amount of a single enantiomer to yield a compound having the desired pharmacological activity.
  • optically pure is intended to mean a compound that comprises at least 90%) of a single isomer (80% enantiomeric excess (hereinafter "e.e.")), more preferably at least 95%> (90% e.e.), even more preferably at least 97.5% (95%> e.e.), and most preferably at least 99% (98%> e.e.)
  • the antipicomaviral agents of formula I formed from the process of the present invention are optically pure.
  • the present invention relates to a process of preparing antipicomaviral agents of formula I:
  • Rj is H, F, an alkyl group, OH, SH, or an O-alkyl group;
  • R 2 and R 3 are each independently H;
  • n is an integer from 0 to 5
  • At is CH or N
  • a and each A 3 are independently
  • each R 1 is independently H or lower alkyl, provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by Ai, A 2 , (A 3 ) n ,
  • a and C O, and at least one of R and R 3 is
  • R 5 and R 6 are each independently H, F, an alkyl group, a cycloalkyl group, a
  • R 7 and R 8 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR ⁇ , -SR ⁇ , -NR ⁇ 7 R 18 , -NRigNR ⁇ Ris, or -NR ⁇ ORis, where R ⁇ , R ⁇ 8 , and R ⁇ 9 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group, provided that at least one of R 7 and R 8 is an alkyl group, an aryl group, a heteroaryl group, -OR ⁇ , -SR ⁇ , -NR ⁇ 7 R ⁇ 8 , -NR ⁇ 9 NR ⁇ 7 R 18 , or -NR ⁇ 7 OR ⁇ 8 ; Rg is a five-member
  • the amide-forming reaction may be achieved by any suitable method, reagents and reaction conditions. Preferably, any one of the methods disclosed in the '354 application is utilized.
  • a compound of formula II may be reacted with a compound of formula III in the presence of HATU, DIPEA, CH 3 CN and H 2 O to yield desired compound of formula I.
  • Any suitable purification method may be used to further purify the compound of formula I.
  • the compound of formula I is prepared by an amide-forming reaction comprising the steps of:
  • the method for prepa ⁇ ng the compound of formula I utilizing the more preferable amide-forming reaction utilizes some or all of the reagents and reaction conditions disclosed below
  • the compound of formula II and the compound of formula IIIA m DMF are combined in any suitable container
  • the suitable container is preferably a single neck flask which is then covered with any suitable septum and covered with a temperature probe Nitrogen gas is used to purge out the suitable container before N-methylmorphohne is added to the reaction mixture More preferably, the N-methylmorpholme is added via a sy ⁇ nge in one single portion and the reaction mixture cooled to about between -5° C and 5° C More preferably, the reaction mixture is cooled to about 0° C A solution of the compound of formula Lv-X is then added to the reaction mixture More preferably, the solution of the compound of formula Lv-X is
  • any suitable purification method known to one of ordinary skill in the art may be used to purify the compound of formula I. More preferably, the compound of formula I is purified by recrystalization.
  • the present invention also discloses two alternate processes for the synthesis of the compound of formula III and acid addition salts thereof. Of these two routes, the second process is currently preferred because it offers greater cost-effectiveness at a commercial scale.
  • the first of these two processes is for the preparation of a compound of formula IV and its acid addition salts from a compound of formula V.
  • the compound of formula V may be prepared from commercially available N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the process of the present invention comprises the steps of : (a) cyanomethylation of the compound of formula V using bis(trimethysily)amide and bromoacetonitrile to yield a compound of formula VI;
  • the cyanomethylation of the compound of formula V may be carried out using any suitable method, reagents and reaction conditions. Preferably, the method disclosed below and the use of all or some of the reagents and reaction conditions are used. Thus, it is preferable, that the compound of formula V be added dropwise to a stirring solution of NaHMDS in THF at -70°C in a nitrogen atmosphere over a period of at least about 5 hours before being mixed with bromoacetonitrile.
  • This cyanomethylation of the compound of formula V using bis(trimethylsilyl)amide and bromoacetonitrile affords the compound of formula VI along with its epimer in a 5: 1 ratio.
  • the compound may be purified by any suitable method.
  • the compound of formula VI is purified by filtration and chromatography, followed by titration. Under these preferred conditions, a 60% overall yield of the compound of formula VI is attainable having >99% diastereomeric purity.
  • the three step reduction, cyclization, and deprotection reaction of step (b) to convert the compound of formula VI to the compound of formula VII may be carried out using any suitable reagents and reaction conditions. Preferably, the method disclosed below, using all or some of the reagents and reaction conditions are used. Therefore, preferably, the compound of formula VI is reduced by adding a solution of cobalt (II) chloride hexahydrate to a solution of the compound of formula VI in tetrahydrofuran in methanol.
  • the resulting solution is cooled to about 0° C before sodium borohydride is added in portions over a period of at least about 7 hours. Then, / -toluensulfonic acid monohydrate is added to the solution of crude material in methanol and allowed to react for at least about 18 hours at an ambient temperature. After removal of the solvent, the residue is dissolved in ethyl acetate and washed. Any suitable washing agent may be used. More preferably, the washing agent is saturated sodium bicarbonate.
  • the crude product is then charged with a solution of methanol in water. More preferably, a 2.5%) methanol solution is used.
  • the cmde product may be removed from solution by any suitable method.
  • the crude product may be removed by filtration and the filtrate concentrated on a rotary evaporator.
  • the product is then dissolved in ethyl acetate, dried, filtered and concentrated to the cmde compound of formula VII. More preferably, the product is dried over MgSO
  • the cmde compound of formula VII may be further purified by any suitable purification process. More preferably, the cmde compound of formula VII is purified through a titration process using 1 : 1 ethyl acetate and hexanes.
  • any suitable method, reagents and reaction conditions may be used in the subsequent oxidation and olefmation employing a SO 3 -pyridine complex and the phosphorane of formula VIII to yield the compound of formula IV.
  • the method disclosed below and all or some of the reagents and reaction conditions are used.
  • triethylamine is added to a solution of the compound of formula VIII and methylsulfoxide.
  • the resulting solution is cooled to about 5° C, followed by the addition of a sulfur trioxide-pyridine complex.
  • the reaction is stirred at about 5° C for at least about 15 minutes. After removing the source used to cool the solution to about 5°C, the reaction is stirred for at least about an additional 1 hour.
  • the reaction mixture is then added and the reaction mixture stirred at ambient temperature for at least about 3 hours. Then, the reaction is quenched and extracted with ethyl acetate. More preferably, the reaction is quenched by the addition of saturated brine. The combined organic phases are then washed, dried, filtered and concentrated to afford crude compound of formula IV. More preferably, the combined organic phases are washed with saturated brine and dried over MgSO 4 .
  • the compound of formula IV may be purified by any suitable method. Preferably, chromatography purification and titration techniques are used. If the preferable purification technique is used, yields ranging from 55% to 60% are attainable.
  • the second process for preparing the compound of formula IV, and its acid addition salts, disclosed by the present invention comprises the steps of: (a) the dianionic alkylation of a compound of formula IX using bromoacetonitrile to yield a compound of formula X;
  • steps (a)-(e) disclose a process for preparing the compound of formula XIV.
  • the compound of formula IX may be prepared by any suitable method known in the art.
  • N-Boc L-(+)-glutamic acid dimethyl ester may be prepared from commercially available L-glutamic acid dimethyl ester hydrochloride or commercially available L-glutamic acid 5 -methyl ester according to literature procedures. See for example, Shimamoto et al, J. Org. Chem. 1991, 56, 4167 and Duralski et al, Tetrahedron Lett. 1998, 30, 3585. These references are herein incorporated by reference in their entirety.
  • the dianionic alkylation reaction is performed using the method and all or some of the reagents and reaction conditions disclosed below. Therefore, preferably, the compound of formula IX is first dissolved in THF to form a solution which is added dropwise to a stirring solution of LiHMDS at -78°C in an Argon atmosphere. The resulting mixture is then stirred at about -78°C for 2 hours before freshly distilled bromoacetonitrile is added dropwise over a period of 1 hour. The reaction mixture is stirred at about -78°C for additional 2 hours. The reaction is then quenched. More preferably, the reaction is quenched by adding 0.5 M HCl and H 2 0.
  • the resulting aqueous layer is separated and is extracted further with methyl tert-butyl ether.
  • the combined organic extract is washed, dried and filtered. More preferably, the organic extract is washed with saturated NaHCO 3 and brine and dried over MgSO 4 .
  • the solvent is evaporated under reduced pressure.
  • the compound of formula IX may be hydrogenated to the amine of formula XI by any suitable method known in the art.
  • the hydrogenation is performed in the presence of 5% Pd/C. More preferably, the hydrogenation reaction is performed in accordance with the method, using some or all of the reagents and reaction conditions disclosed below.
  • the compound of formula IX is dissolved in HOAc and shaken with 5%o Pd on C under H 2 gas, at 50 psi pressure, for 3 days. The mixture is then filtered over celite. The filtrate may then be evaporated under reduced pressure and the residue repeatedly evaporated from methyl tert-butyl ether.
  • the reaction of the amine of formula XI with Et 3 N may be achieved using any suitable conditions. Preferably, the method and all or some of the reagents and reaction conditions disclosed below are used. Accordingly, preferably, the amine of formula XI is dissolved in 1 :1 MeOH/THF, before Et 3 N is added to the solution.
  • the resulting mixture is stirred at about 45°C for about 10 hours or until the starting material has disappeared.
  • the presence of the starting material may be monitored by ⁇ NMR.
  • methyl tert-butyl ether is added.
  • the precipitate is then filtered.
  • 0.5 M HCl is added to the filtrate diluted with H 2 O.
  • the aqueous phase may be extracted with ethyl acetate.
  • the combined organic phases are washed, dried, filtered and concentrated. More preferably, the combined organic phases are washed with brine and dried over MgSO 4.
  • the phases may be concentrated on a rotovapor. Flash chromatography furnishes the lactam ester of formula XII.
  • any suitable reduction method may be used to convert the lactam ester of formula XII to the compound of formula XIII.
  • LiBH 4 is used as the reducing agent. More preferably, the method, or any portion thereof, and any or all of the reagents and reaction conditions disclosed below are used.
  • LiBH is added to a stirring solution of the lactam ester of formula XII in THF. The LiBH 4 is added in several portions at 0° C in an Argon atmosphere. The reaction mixture is stirred at 0° C for 10 minutes, before being allowed to warm to ambient temperature and stirred for an additional 2 hours. Then, the reaction is quenched.
  • the reaction is quenched by the dropwise addition of 0.5 M HCl while cooling using an ice bath.
  • the solution is diluted with ethyl acetate and H 2 O.
  • the aqueous phase may be extracted with ethyl acetate.
  • the combined organic phases are washed, dried, filtered and concentrated. Even more preferably, the combined organic phases are washed with brine and dried over MgSO 4 .
  • the phases may be concentrated on a rotovapor. Flash chromatography furnishes the compound of formula XII. Any suitable oxidation and olefmation method may be used to prepare the compound of formula XIV from the compound of formula XIII.
  • the method, or any part thereof, and all or some of the reagents and reaction conditions described below are used.
  • benzoic acid, (carboethoxymethylenetriphenyl)phosphorane and DMSO are added to a solution of the compound of formula XIII in CH 2 C1 2 Dess-Martin periodinane is added to the solution in several portions, and the reaction mixture is then stirred for at least about 5 hours at ambient temperature until the compound of formula XIII substantially disappears.
  • the presence of the compound of formula XIII may be monitored by 1H NMR. Saturated NaHCO 3 solution is added before the mixture is stirred for 30 minutes to yield a precipitate.
  • the precipitate is filtered prior to the organic phase of the filtrate being separated, washed, and concentrated to yield the cmde compound of formula XIV. More preferably, the filtrate is washed with brine and concentrated on a rotovapor. Any suitable method may be used to purify the cmde compound of formula XIV. More preferably, the cmde compound of formula XIV is purified by flash chromatography, then dissolved in ethyl acetate. Excess hexanes are then added gradually to the stirring solution to yield a precipitated. The precipitate is filtered and dried to afford the compound of formula XIV. More preferably, the precipitate is dried in a vacuum oven for at least about 12 hours.
  • the following examples are provided merely for illustrative purposes of the present invention and are not to be read as limiting the scope of protection of the present invention, as defined by the appended claims.
  • N-Boc L-(+)-glutamic acid dimethyl ester (6, 10 g, 36.3 mmol, 1 equiv.) in THF (100 mL) was added dropwise to a stirring solution of LiHMDS (77 mL, IM in THF, 77.0 mmol, 2.1 equiv.) at -78°C in an Ar atmosphere.
  • the resulting dark mixture was stirred at -78°C for 2 hours, and then freshly distilled bromoacetonitrile (13. lg, 109.0 mmol, 3 equiv.) was added dropwise over a period of 1 hour.
  • the reaction mixture was stirred at -78°C for additional 2 hours and the disappearance of the starting material (6) was confirmed by TLC analysis.
  • the reaction was quenched by addition of HCl (120mL, 0.5 M) and H 2 O (200 mL). The layers were separated, and the aqueous layer was further extracted with methyl tert- butyl ether (3 x 200 mL). The combined organic extract was washed with saturated NaHC0 3 (2 x 250 mL), brine (2 x 250 mL), dried over MgSO 4 and filtered. The solvent was evaporated under reduce pressure to give a brown oil (15.2 g).
  • the reaction was cooled to 0°C and quenched by addition of 1.0 M HCl (14 L) and ethyl acetate (12 L). The phases were separated and the aqueous phase was charged with 2.0 kg of sodium chloride and 4.0 L of ethyl acetate. The phases were separated, and the organic phases were combined, washed with brine (1X3.0 L), concentrated on a rotary evaporator to afford a cmde material (440 g), which was used directly in the following hydrolysis reaction. To a solution of the cmde material (440 g, 1 equiv.) in methanol (800 mL) was added /?-toluensulfonic acid monohydrate (4.0 g, 0.015 equiv.).

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  • Plural Heterocyclic Compounds (AREA)
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  • Peptides Or Proteins (AREA)
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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

La présente invention concerne des voies de synthèse efficaces qui sont utiles pour préparer des inhibiteurs de protéases de rhinovirus de formule (I) ainsi que des intermédiaires clés utilisés dans ces voies de synthèse. Les composés de formule (I) ainsi que des compositions pharmaceutiques contenant ces composés sont adaptés pour traiter des patients ou des hôtes infectés par un ou plusieurs picornavirus.
EP00955831A 1999-08-24 2000-08-23 Voies de synthese permettant de preparer des inhibiteurs de proteases de rhinovirus et intermediaires cles Withdrawn EP1206450A1 (fr)

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DE60014670T2 (de) 1999-08-04 2006-03-09 Agouron Pharmaceuticals, Inc., San Diego Antipicornavirale verbindungen und zusammensetzungen, ihre pharmazeutische verwendung, und materialien für ihre synthese
PA8507801A1 (es) 1999-12-03 2002-08-26 Agouron Pharma Compuestos y composiciones antipicornavirales, sus usos farmaceuticos y los materiales para su sintesis
PA8515201A1 (es) 2000-04-14 2002-10-24 Agouron Pharma Compuestos y composiciones antipicornavirales; sus usos farmaceuticos y los materiales para su sintesis
JP2004503533A (ja) 2000-06-14 2004-02-05 アグロン・ファーマシュウティカルズ・インコーポレーテッド 抗ピコルナウイルス化合物及び組成物、その医薬的使用、並びにその合成のための物質
CN1309712C (zh) * 2004-04-02 2007-04-11 中国科学院上海有机化学研究所 Ag7088类化合物的关键中间体的前体及其合成方法
JP2021138694A (ja) 2020-03-06 2021-09-16 ファイザー・インク ＳＡＲＳ−ＣｏＶ−２複製を阻害し、コロナウイルス疾患２０１９を処置する方法
CN115260074B (zh) * 2022-08-02 2024-06-21 爱斯特（成都）生物制药股份有限公司 一种口服抗病毒药物Paxlovid中间体的制备方法
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US5962487A (en) * 1997-12-16 1999-10-05 Agouron Pharmaceuticals, Inc. Antipicornaviral compounds and methods for their use and preparation
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