MXPA02001944A - Synthetic routes for the preparation of rhinovirus protease inhibitors and key intermediates. - Google Patents

Synthetic routes for the preparation of rhinovirus protease inhibitors and key intermediates.

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Publication number
MXPA02001944A
MXPA02001944A MXPA02001944A MXPA02001944A MXPA02001944A MX PA02001944 A MXPA02001944 A MX PA02001944A MX PA02001944 A MXPA02001944 A MX PA02001944A MX PA02001944 A MXPA02001944 A MX PA02001944A MX PA02001944 A MXPA02001944 A MX PA02001944A
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group
formula
compound
cycloalkyl
independently
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MXPA02001944A
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Spanish (es)
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Tian Qingping
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Agouron Pharma
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    • 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
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    • B01J19/2415—Tubular reactors
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    • 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
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    • B01J19/2475—Membrane reactors
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    • 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
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    • 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
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    • 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
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    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Pyrrole Compounds (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Efficient synthetic routes for the preparation of rhinovirus protease inhibitors of formula (I), as well as key intermediates usefull in those synthetic routes. These compounds of formula (I), as well as pharmaceutical compositions that contain these compounds, are suitable for treating patients or hosts infected with one or more picornaviruses.

Description

SYNTHETIC ROUTES FOR THE PREPARATION OF RHINOVIRUS PROTEASE INHIBITORS TECHNICAL FIELD AND INDUSTRIAL APPLICABILITY OF THE INVENTION: The present invention relates to an improved process for the preparation of ethyl-3-. { . { 5 '-methylisoxazole-3'-carbonyl) -L-Val? (C0CH2) -L- (4-F-Phe) -L- ((S) -Pyrrole-Ala)} -E- propanoate, (also known as AG7088), its analogs and pharmaceutically acceptable salts thereof. The present invention also includes a novel group of key intermediates to be used in the above process.
BACKGROUND OF THE INVENTION: Picornaviruses are a family of viruses that contain positive-stranded, unenveloped, tiny RNAs that infect humans and other animals. These viruses include human pnovirus, human poliovirus, human coxsacquievirus, human ecovirus, human and bovine enterovirus, encephalomyocarditis virus, meningitis virus, foot and mouth virus, hepatitis A virus, and others. Human rhinoviruses are the main cause of the common cold.
REF: 135728 sff 3C proteolytic enzymes are required for the natural ripening of picornaviruses. In this way, the inhibition of the activity of these 3C proteolytic enzymes should represent an important method for the treatment and cure of viral infections of this nature, including the common cold.
Recently, some small molecule inhibitors of the enzymatic activity of 3C picornaviral protease (ie compounds 10 antipicornaviral drugs). See, for example: U.S. Patent Application No. 08 / 850,398, filed May 2, 1997, by Webber et al .; U.S. Patent Application No. 08 / 991,282, filed December 16, 1997, by Dragovich et al .; Patent Application 15 United States No. 08 / 991,739, filed on December 16, 1997, by Webber et al. Those applications for US patents, the descriptions of which are incorporated herein by reference, describe certain antipicornaviral compounds and methods for their synthesis.
More recently, an especially potent group of antipicornaviral agents has been discovered as set forth in U.S. Patent Application No. 60 / 098,354 (application? 354), filed on August 28, 1998, by Dragovich et al., Which is incorporated herein by reference. This application describes, inter alia, a group of antipicornaviral agents of the general formula I. A particularly promising compound, AG7088, which falls within the scope of this group, exhibits excellent antiviral properties against a large number of Rinoviral serotypes and is currently in trials. clinical with humans. The application? 354 also describes methods and intermediates useful for synthesizing those compounds. For example, General Method V, where a general method for synthesizing compounds of formula I is described, which involves subjecting a carboxylic acid of general formula BB to an amide-forming reaction with an amine of general formula P to provide a product final CC, as shown below.
DC The application? 354 further describes methods for synthesizing the intermediates of the general formulas BB and P, and teaches methods for carrying out the amide formation reaction referred to above. Thus, the application? 354 teaches suitable methods for synthesizing the compounds of general formula I from a carboxylic acid BB (within the scope of the compounds of the general formula II referred to below) and the compounds of general formula P (the same as the compounds of general formula III to which reference is made below). Similarly, two recent publications by Dragovich et al. Describe antipicornavirus agents and synthetic methods suitable for their synthesis. See Structure-Based. Design, Syn thesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Proteases Inhibitors, 3. Activity Structure and Studies of Ketomethylene-With taining Peptidomimetics, Dragovich et al., Journal of Medicinal Chemistry, ASAP, 1999; and Structure-Based Design, Syn thesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Proteases Inhibitors, 4. Incorporation of Pl Lactam Moieties as L-Glutamine Replacements, Dragovich et al., Journal of Medicinal Chemistry, ASAP, 1999, Those items mentioned above are incorporated herein by reference in their entirety.
However, there is still a desire to discover improved, more efficient processes and novel intermediates to be used in the synthesis of the compounds of the group of antipicornaviral agents. In particular, there is a need for improved methods for synthesizing the compounds of the general formulas II and III.
SUMMARY OF THE INVENTION: The present invention relates to the discovery of a cheap and effective process for the ^^ ^ ^ ^ ^ ^ ^ -. ^^. f ^^^. ^^ í ^ Repair of antipicornaviral agents of formula I, such as the compound AG7088, as well as intermediates that are useful in that synthesis.
The antipicornaviral agents of formula comprise: wherein Ri is H, F, an alkyl group, OH, SH, or an O-alkyl group; R2 and R3 are each independently H; where n is an integer from 0 to 5, Ai is CH or N, A2 and each A3 are independently selected from C (R4?) (R41), N (R4?), S, S (0), S (0 ) 2 and O, A4 is NH or NR41, where each R41 is independently H or lower alkyl, provided that no more than two heteroatoms occur consecutively in the ring described above formed by Ai, A2, (A3) n, A4 and C = 0, and at least R2 and R3 is R4 is R5 and R6 are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; R7 and R8 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -0r 7 -SRu, - ruris, - R19R17R18, or -NR17OR18, where RI7, R1 and R19 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 R7 and R1 is an alkyl group, a group aryl, a heteroaryl group, -OR17, -SR17, -NR? 7R18, -NR? 9R? 7R? 8, or -NR? 7OR? 8; ili fii .i i ^ ai ^ R9 is a five-membered heterocycle having from one to three heteroatoms selected from O, N, and S; Y Z and Zi are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, [-C (0) R2i, -C02R2 ?, CN, -C (0) NR2? R22, -C (O) NR21R22, -C (S) NR2 ?, -C (S) NR2? R22, -N02, -SOR2 ?, -S02R21, -S02NR21R22, -SO (NR2X) (OR22), -SO3R21, -PO (OR2 ') 2, -PO (R22), -PO (NR21R22) oR 23, -PO (R22 NR2?) (NR23R24), "C (0) NR22R23 or NR2 (R2?)?. - C (S) NR21NR22R23. where R? if R22. R23, and P24 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a tiacilo group , or where either of R2, R22, R23, and R24, together with the atoms to which they are attached, form a heterocycloalkyl group, provided that Z and Zi are not both H; or Zi and Ri, together with the atom to which they are attached, form a cycloalkyl or heterocycloalkyl group, wherein Zx and Ri are as defined above, except for the portions which can not form the cycloalkyl or heterocycloalkyl group; or Z and Zi, together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl group, where Z and Zi are as defined above, except for the portions which can not form the cycloalkyl or hete bcycloalkyl group.
As discussed below, the antipicornaviral agents of formula I can be synthesized by subjecting a compound of general formula II together with a compound of general formula III to a suitable amide formation reaction. The process of the present invention not only reduces the number of steps required to synthesize the compounds of formula III, but, more importantly, also employs less expensive starting materials and reagents. Those objects, advantages and features of the present invention will be more fully understood and appreciated by reference to the written specification.
DETAILED DESCRIPTION OF A PREFERRED MODE OF THE INVENTION: As used in the present application, the following definitions apply: According to a convention used in the art, ^ 'is used in structural formulas here for É ^^ he_tá _ ^^^ LM ^. A ¿^^ _ fc «_itft, -aatt É ^ j. | describe the link that is the junction point of the portion or substituents to the core of a central structure.
Where chiral carbons are included in the chemical structures, unless a particular orientation is described, it is intended that both stereoisomeric forms be encompassed.
An "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 can not be substituted (ie, contain only carbon and hydrogen) ) or substituted by one or more suitable substituents as defined below (eg, one or more halogens, such as F, Cl, Br, or I, with F and Cl being preferred). It is intended that a "lower alkyl group" means 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, monocyclic or tricyclic radical containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms in the ring. carbon, each of which can be saturated or unsaturated, and which may be Substituted or unsubstituted by one or more suitable substituents as defined below, and which may be fused one or more heterocycloalkyl groups, aryl groups, or heteroaryl groups, which may themselves be unsubstituted or substituted by one or more substituents Illustrative examples of cycloalkyl groups include the following portions: A "heterocycloalkyl 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 atoms in the carbon ring, which include 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen and sulfur, where the radical is unsubstituted or substituted by one or more suitable substituents as defined below, and to which one or more cycloalkyl groups, aryl groups, heteroaryl groups, may be fused, which may themselves be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of heterocycloalkyl groups include the following portions: An "aryl group" is intended to mean a monovalent monocyclic monocyclic, aromatic monocyclic, radical containing 6, 10, 14 or 18 carbon atoms in the ring, which may be unsubstituted or substituted.
? - ^^ T "*? Substituted by one or more suitable substituents as defined below, and in which one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups may be fused, which may themselves be unsubstituted or substituted by one or more suitable substituents Illustrative examples of aryl groups include the following portions: A "heteroaryl group" is intended to mean a monovalent monocyclic or aromatic monocyclic, monocyclic radical, containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 atoms in the ring, 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 one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups are fused, which may themselves be unsubstituted or substituted by one or more suitable substituents. The Illustrative examples of heteroaryl groups include the following portions: It is intended that a "heterocycle" means a heteroaryl or heterocycloalkyl group (each of which, as defined above, are optionally substituted). It is intended that an "acyl group" means a radial -C (0) -R, where R is a substituent as defined, below. A "thioacyl group" is intended to mean a radial -C (S) R, where R is a substituent as defined below. A "sulfonyl group" is intended to mean a radial -S02R, where R is a substituent as defined below. It is intended that a "hydroxy group" means the -OH radical. It is intended that an "amino group" means the radical -NH2. An "alkylamino group" is intended to mean the radical -NHRa, where Ra is an alkyl group. A "dialkylamino group" is intended to mean the radical -NRaR, where Ra and Rb are each independently an alkyl group. An "alkoxy group" is intended to mean the radical -ORa, where Ra is an alkyl group. Exemplary alkoxy groups include methoxy, ethoxy, propoxy and the like. An "alkoxycarbonyl group" is intended to mean the radical -C (0) ORa, where Ra is an alkyl group.
It is intended that an "alkylsulfonyl group" means the radical -S02Ra, where Ra is an alkyl group. It is intended that an "alkylaminocarbonyl group" Mean the radical -C (0) NHRa, where Ra is an alkyl group. A "dialkylaminocarbonyl group" is intended to mean the radical -C (0) NRaRb, where Ra and Rb are each independently an alkyl group. It is intended that a "mercapto group" means the radical -SH. An "alkylthio group" is intended to mean the radical -SRa, where Ra is an alkyl group. It is intended that a "carboxy group" means the radical -C (0) 0H. It is intended that a "carbamoyl group" means the radical -C (0) NH2. An "aryloxy group" is intended to mean the radical -ORc, where Rc is an aryl group. A "heteroaryloxy group" is intended to mean the radical -ORd, where Rd is a heteroaryl group. It is intended that an "arylthio group" means the radical -SRC where Rc is an aryl group. A "heteroarylthio group" is intended to mean the radical -SRd, where Rd is a heteroaryl group. It is intended that a "leaving group" (Lv) means any suitable group that can be displaced by a substitution reaction. One skilled in the art will know that any conjugate base of a strong acid can act with a leaving group. Illustrative examples of suitable leaving groups include, but are not limited to, -F, -Cl, -Br, alkyl chloride, alkyl bromides, alkyl iodides, alkyl sulfonates, alkyl benzenesulfonates, alkyl p-toluenesulfonates, alkyl methanesulfonates, triflate, and any groups having a bisulfate, methyl sulfate, sulfate 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 will understand that the compounds listed within each group can be used interchangeably; for example, a compound listed under "reagents and solvents" can be used as a protecting group, and so on. In addition, one skilled in the art will know other possible protective groups, reagents and solvents; they are intended to be within the scope of this invention.
Table 1 Protective Groups Ada Adamantan Acetyl Aloe Allyloxycarbonyl Table 1 Protective Groups Allyl Allyl ester Boc tert-butyloxycarbonyl Bzl Benzyl Cbz Benzyloxycarbonyl Fmoc Fluorenylmethyloxycarbonyl Obzl Benzyl ester OEt Ethyl ester Orne Methyl ester Cough (Tosyl) p-Toluenesulfonyl Trt Tryphenylmethyl Reagents and Solvents ACN Acetonitrile AcOH Acetic acid Ac.sub2 O Acetic acid anhydride AdacOH Adamantan acetic acid AIBN 2,2-azobisisobutyronitrile Alloc-Cl Allyloxycarbonyl Chloride BHT 2, 6-di-tert-butyl-4-methylphenol Boc. sub.2 O di-tert-butyl dicarbonate CDl 1,1 '-carbonyldiimidazole DIEA Diisopropylethylamine DIPEA N, N-diisopropylethylamine DMA Dimethylacetamide '_ ^. ^^. ?? ^^ á ^^? ^^^ ^ É k.? I Table 1 Protective Groups DMF dimethylformamide DMSO Dimethyl sulfoxide EDTA acid etilendia intetracético Et.sub.3 N Triethylamine EtOAc Ethyl acetate FDH formate dehydrogenase of FmocOSu 9-fluorenylmethyloxy carbonyl N-hydroxysuccinimide ester HATU N-oxide hexafluorophosphate N- [(dimethylamino) -1H 1, 2, 3-triazolo [4, 5-b] piridiilmetileño] -N-methylmethanaminium HOBT 1-hydroxybenzotriazole HF hydrofluoric acid LDH lactate dehydrogenase LiHMDS lithium bistrimethylsilylamide MeOHMethanol Month (Mesii; Methanesulfonyl MTBE t-butyl methyl ether NAD Nicotinamide adenine dmucleotide NADH Hydroperoxide oxidoreductase NaHMDS Nitrate sodium bistrimethylsilamide NMP l-methyl-2-pyrrolidinone ninhydrin Table 1 Protective Groups i-PrOH Iso-propanol Pip Piperidine PPL Lipase PTSA Monohydrate p-toluenesulfonic acid Pyr Pyridine TEA Triethylamine TET Triethylenetetramine TFA Trifluoroacetic acid THF Tetrahydrofuran Triflate (Tf) tri fluomethanesulfonyl The term "suitable organic portion" is intended to mean any recognizable organic portion, such as by routine testing, by those skilled in the art that does not adversely affect the inhibitory activity of the compounds of the invention. organic suitable 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, alkylamino groups, dialkylamino groups, carbamoyl groups, arylthio groups, heteroarylthio groups, and the like The term "substituent" or "suitable substituent" is intended to mean any suitable substituent that can be recognized or selected, such as through routine, by those skilled in the art, illustrative examples of suitable substituents s 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, of alkylamino, carbamoyl groups, aryloxy groups, heteroaryloxy groups, arylthio groups, heteroarylthio groups and the like. It is intended that the term "optionally substituted" expressly indicates that the specified group is not substituted or substituted by one or more suitable substituents, unless the optional substituents are specifically specified, in which case the term indicates that the group is unsubstituted or substituted with the specified substituents. As defined above, different groups may be unsubstituted or substituted (that is, they are optionally substituted) to unless otherwise indicated here (for example, indicating that the specified group is replaced). A "prodrug" is intended to mean a compound either converted under physiological conditions or by solvolysis or metabolically to a specified compound is pharmaceutically active. A "pharmaceutically active metabolite" is intended to mean a pharmacologically active product produced through the metabolism in the body of a specified compound. A "solvate" is intended to mean a pharmaceutically acceptable solvate of a specified compound that retains the biological effectiveness of such a compound. Examples of 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 compounds and that is not biologically undesirable in other circumstances. Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisufatos, sulfites, bisulfites, phosphates, monohidrofosfatos, dihidrofosfatos, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, . ir * os, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butin-1, 4-dioates, hexin-1, 6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylene sulphonates, filacetates, phenylpropionates, filbutyrates, citrates, lactates,? -hydroxybutyrates, glycolates, tartrates, methansulfonates, propansulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates and mandelates. The present invention further provides synthetic methods which 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. In this way, the synthetic method can be only the synthetic step or have additional synthetic steps that may be associated with it. A synthetic method may have a few additional synthetic steps or may have numerous additional synthetic steps. If the antipicornaviral agent of the formula I formed from the process of the present invention is a base, the desired salt can be prepared by any suitable method known in the art, including treatment where the free base with an organic acid, such as the acid i ^ __ ^ i ^ - MÉk -. ^ - í- & í ^ ^ & í_ _? . . Hydrochloric; 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; gLioaLiao 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 similar. If the antipicornaviral agent of formula I is formed from the process of the present invention is an acid, a desired salt can be prepared by any suitable method known in the art, including the treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary); an alkali metal hydroxide or alkaline earth metal hydroxide; or similar. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary and tertiary amines; 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.In the case of compounds, salts or solvates that are solid, it should be understood by those skilled in the art. that the compounds of formula I and the intermediates used in the process of the present invention, salts and solvates thereof, may exist in different crystalline forms, all of which are intended to be within the scope of the present invention and the specified formulas. The antipicornaviral agents of formula I and the intermediates used in the process of the present invention can exist as single stereoisomers, racemates, and / or mixtures of enantiomers and / or diastereomers It is intended that all stereoisomers, racemates and mixtures thereof be Within the broad scope of the present invention, preferably, however, the intermediate compounds used in the process of The present invention is used in optically pure form. As generally understood by those skilled in the art, an optically pure compound is one that is enantiomerically pure. As used herein, the term "optically pure" is intended to mean a compound comprising at least a sufficient amount of a single enantiomer to produce a compound having the desired pharmacological activity. Preferably, "optically pure" is meant to mean a compound comprising at least 90% of a single isomer (80% enantiomeric excess (hereinafter later "ee")), more preferably at least 95% (90% ee), even more preferably at least 97.5% (95% ee), and more preferably at least 99% (98% ee). Preferably, the antipicornaviral agents of formula I formed from a process of the present invention are optically pure. The present invention relates to a process for preparing antipicornaviral agents of formula I: in which Rj. is H, F, an alkyl group, OH, SH, or an O-alkyl group; R2 and R3 are each independently H; where n is an integer from 0 to 5, Ai is CH or N, A2 and each A3 is independently selected from C (R4?) ..A ^ i ^ Míi ^ ^ M. ^ M? L • (R1), N (R4?), S, S (0), S (0), O, and A4 is NH or NR41, where each R4 ? is independently H or a lower alkyl, provided that no more than two heteroatoms occur consecutively in the ring described above formed by Ax, A2, (A3) n, A and C = 0, and at least one of R2 and R3 is R4 is R5 and R6 are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; R and R8 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR17, -SR17, -NR1R18 -NR? 9NR: 7Ri8 / or -NR17OR? 8, wherein Ri7, R8 and 19 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 Rv and R8 is an alkyl group , an aril group, a group 7R8, -NR? 9NR? 7R? 8, or -NR? 7OR18; R9 is a five-membered heterocycle having one or three heteroatoms selected from 0, N, and S; and Z and Zi are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -C (0) R2 ?, -CO2R21, CN, -C (0) NR21R22, -C (0) NR2? 0R22, -C (S) R2? -C) S) NR21R22, -N02, -SOR21, -SO2R21, -SO2NR21R22, -S0 (NR2i) (0R22), -SONR21, -SO3R21, -P0 (0R2?) 2, -P0 (R2?) (R22), -P0 (NR2? R22) (0R23), -P0 (NR21R22) (0R23), -P0 (NR2? R22) ) (NR23R24), -C (0) NR2? NR22R2, OR -C (S) NR2? NR22R23, wherein R2i, R22, R23 and R24 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a group thioacyl, or where either of two of R2i, R22, R23 and R24, together with the atoms to which they are attached, form a heterocycloalkyl group, provided that Z and Zi are both H; or Zi and Ri, together with the atoms to which they are attached, form a cycloalkyl, or heterocycloalkyl group, wherein Zi and Ri are as defined above, except for portions which can not form the cycloalkyl or heterocycloalkyl group; or Z and Zi, together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl group, where Z and Zi are as defined above except for the portions that can not form the cycloalkyl or heterocycloalkyl group. The present invention discloses that the compounds of formula I can be prepared by subjecting a compound of formula II and a compound of formula III to an amide formulation reaction: The amide formation reaction can be achieved by any suitable method, reagents and reaction conditions. Preferably, any of the methods described in the application is used? 354. For example, a compound of formula II can be reacted with a compound of formula III in the presence of HATU, DIPEA, CH3CN and H20 to produce the desired compound of formula I. Any suitable purification method can be used to further purify the compound of Formula I. More preferably, the compound of formula I is prepared by an amide-forming reaction comprising the steps of: the compound of formula II with a compound of formula IIIA in the presence of N-methylmorpholine to form a reaction mixture; Y F3CCOOH-H2N (IIIA) (b) adding a compound of formula Lv-X to the reaction mixture to form a compound of formula I, wherein x is any suitable halide. Preferably, the method for preparing a compound of formula I that utilizes the most preferable amide formation reaction utilizes some or all of the reagents and reaction conditions described below. In this way, preferably, the compound of formula II and the compound of formula IIIA in DMF are combined in any suitable vessel. The suitable container preferably a single-neck flask which is then covered with any suitable stopper and covered with a temperature probe. Nitrogen gas is used to form the suitable vessel before the N-methylmorpholine is added to the reaction mixture. Most preferably, the N-methylmorpholine is added via a syringe in a single portion and the reaction mixture is cooled to a ¡¿¿¿¿¿^ __É_.2 _S__. "TO* ""';. í j *,? __, _!,. ____ !. Li _ '.:, Mi.i «. approximately between -5 ° C and 5 ° C. Most preferably, the reaction mixture is cooled to about 0 ° C. Next, a solution of the compound of formula Lv-X is added to the reaction mixture. More preferably, the solutions of the compound of formula Lv-X is a solution of a compound of formula L-X in DMF. Even more preferably, the compound of formula Lv-X is CDMT. The solution of the compound of formula Lv-X is added to the reaction mixture by any suitable method to maintain the reaction mixture at a constant temperature. For example, the solution of a compound of Lv-X can be added to the reaction mixture by dripping using the syringe. After completing the addition of the solution of the compound of formula Lv-X, the reaction mixture is allowed to warm to about room temperature. The progress of the reaction can be followed by verifying the disappearance of the compound of formula II by thin-layer chromatography (hereinafter "TLC"). When the reaction is at least substantially complete, the compound of formula I can be precipitated from the solution for form a suspension by the slow addition of water to the reaction mixture. The compound of formula I can then be removed from the suspension by any suitable methods known to those skilled in the art. For example, the compound of formula I can be removed from the suspension by filtration.
Any purification method known to a person skilled in the art can be used to purify the compound of formula I. More preferably, the compound of formula I is purified by recrystallization. The present invention also describes two alternative processes for the synthesis of the compound of formula III and acid addition salts thereof. Of those two routes, and the second process is currently preferred because it offers a cheaper cost on 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.
(IV) (V) One skilled in the art will recognize that the compounds of formula IV are a subgenus of those of formula III.
The compound of formula V can be prepared from commercially available β-benzyl ester of Boc L-glutamic acid. Any suitable method for preparing the compound of formula V can be used. Preferably, the method described in US Patent Application No. 08 / 991,739 is used. U.S. Patent Application No. 08 / 991,739 is incorporated herein by reference in its entirety. The process of the present invention comprises the steps of: (a) cyanomethylation of a compound of formula V using bis (trimethylsilyl) amide and bromoacetonitrile to produce a compound of formula VI; OR (b) reduction, cyclization and deprotection of compound VI in that respective order to produce a compound of formula VII; Y (c) oxidation and olefination of the compound of formula VII by the reaction of the compound with a S03-pyridine complex to produce a reaction mixture and reacting the reaction mixture with a phosphorane of formula VIII.
According to the present invention, and as described above, the preparation of compound V from N-Boc glutamic acid β-benzyl ester can be carried out by any method known in the art. In addition, the cyanomethylation of the compound of formula V can be carried out using any suitable method, reagents and reaction conditions. Preferably, the method described below and the use of all or some of the reactants and reaction conditions are used. Thus, it is preferred that the compound of formula V be added dropwise to a stirred solution of NaHMDS in THF at -70 ° C under a nitrogen atmosphere for 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 gives the compound of formula VI together with its epimer in a 5: 1 ratio. Nevertheless, the compound can be purified by any suitable method. Preferably, the compound of formula VI is purified by filtration and chromatography, followed by titration. Under these preferred conditions, a total yield of 60% of the compound of formula VI having >is achievable99% diastereomeric purity. The three steps of the reduction, cyclization and deprotection reaction of step (b) to convert the compound of formula VI to the compound of formula VII can be carried out using any suitable reagents and reaction conditions. Preferably, the method described below is used, using all or some of the reactants and reaction conditions. Therefore, preferably, the compound of formula VI is reduced by the addition of a solution of cobalt chloride (II) 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. Next, p-toluenesulfonic acid monohydrate is added to the solution of crude material in methanol and allowed to react for at least 18 hours at room temperature. After removal of the solvent, the residue dissolved in ethyl acetate and washed. Any suitable washing agent can be used. Most 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 raw product can be removed from a solution by any suitable method. For example, the crude product can be removed by filtration and the concentrated filtrate in a rotary evaporator. The product is then dissolved in ethyl acetate, dried, filtered and concentrated to the crude compound of formula VII. More preferably, the product is dried over MgSO4. The crude compound of formula VII can be purified by any suitable purification process. More preferably, the crude compound of formula VII is purified through a titration process using ethyl acetate and hexane 1: 1. A total yield of at least about 95% crude compound of formula VII is achievable if the reaction in three steps is used, preferably the reduction, cyclization and deprotection described above.
Any suitable methods, reagents and reaction conditions can be used in subsequent oxidation and olefination using a complex of S03 pyridine and the phosphone of formula VIII to produce the compound of formula IV. Preferably, the method described below and all or some of the reactants and reaction conditions are used. Accordingly, trimethylamine is preferably 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 removal the source used to cool the solution to about 5 ° C, the reaction is stirred for at least about 1 additional hour. Then (Carboethoxymethylenetriphenyl) -phosphorane is added and the reaction mixture is stirred at room temperature for at least about 3 hours. Then, the reaction mixture is stopped and extracted with ethyl acetate. More preferably, the reaction is stopped by the addition of saturated brine. The combined organic phases are then washed, dried, filtered and concentrated to give the crude compound of formula IV. Most preferably, the combined organic phases are washed with saturated brine and dried over MgSO4. The compound of formula IV can be purified by any suitable method. Preferably, the purification techniques by chromatography and grinding are used. If the preferable purification technique is used, the achievable yields range from 55% to 60%. The second process for the preparation of the compound of formula IV, and its acid addition salts, together with the present invention comprises the steps of: (a) the dianionic alkylation of a compound of formula IX using a bromoacetonitrile to produce a compound of formula X: (b) hydrogenation of the compound of formula X to produce an amine of formula XI; (c) reacting the amine of formula XI with ET3N to produce a lactam ester of formula XII; (d) reducing the lactam ester of formula XII through a suitable reduction procedure to produce a compound of formula XIII; (e) oxidation and olefination of the compound of formula XIII to produce a compound of formula XIV by reaction with a compound of formula XV; Y * - *. • } j_ 40 Z PPh. (XV z_ (f) converting the compound of formula XIV to the compound of formula IV In addition, one skilled in the art will recognize that the method described below can be used to prepare the compound of formula XIV.Specifically, steps (a) - (e) describe a process for preparing a compound of formula XIV The compound of formula IX can be prepared by any suitable method known in the art For example N-Boc L- (+) - glutamic acid dimethyl ester can be prepared from the commercially available dimethyl ester of L-glutamic acid or L-glutamic acid 5-methyl ester commercially available according to the methods of the literature, for example, Shimamoto et al, J. Org. Chem. 1991, 56 , 4167 and Duralski et al, Tetrahedron Lett, 1998, 30, 3585. These references are incorporated herein by reference in their entirety.
Preferably, the dianionic alkylation reaction is carried out using the method and all or some of the reactants and reaction conditions described below. Therefore, preferably, the compound of formula IX is first dissolved in THF to form a solution which is added dropwise to a stirred solution of LiHMDS at -78 ° C under an Argon atmosphere. The resulting reaction mixture is then stirred at about -78 ° C for two hours before freshly distilled bromoacetonitrile is added dropwise over a period of one hour. The reaction mixture is stirred at about -78 ° C for an additional 2 hours. The reaction is then stopped. More preferably, the reaction is stopped by the addition of 0.5 M HCl and H20. The resulting aqueous layer is separated and 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 can be hydrogenated to the amine of formula XI by any desired method known in the art. Preferably, the hydrogenation is carried out in the presence of 5% Pd / C. More preferably, the hydrogenation reaction is carried out according to the method, using all the reagents and reaction conditions described below. According to this preferred hydrogenation method, the compound of formula IX is dissolved in HOAc and stirred with 5% Pd on C under H2 gaseous at a pressure of 50 psi (344.73 kPa), for 3 days. The mixture is then filtered over celite. The filtrate can 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 Et3N can be achieved using any suitable conditions. Preferably, the methods and all or some of the reactants and reaction conditions described below are used. Accordingly, preferably, the amine of formula XI is dissolved in MeOH / THF 1: 1, before Et3N is added to the solution. The resulting mixture is stirred at about 45 ° C for about 10 hours or until the initial material has disappeared. The presence of the initial material can be verified by the 1H NMR. After removing the solvent, methyl tert-butyl ether is added. The precipitate is then filtered. 0.5 M HCl is added to the filtrate diluted with H20. After separating the phases, the aqueous phase can 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 MgSO4. The phases can be concentrated on a rotary evaporator. Flash chromatography affords the lactam ester of formula XII.
Any suitable reduction method can be used to convert the lactam ester of formula XII to the compound of formula XIII. Preferably, LiBH4 is used as a reducing agent. More preferably, the method, or any portion thereof, and any or all of the reactants and reaction conditions described herein may be used. Thus, more preferably, LiBH4 is added to a stirred solution of the lactam ester of formula XII in THF. The LiBH4 is added in several portions at 0 ° C in an Argon atmosphere. The reaction mixture was stirred at 0CC for 10 minutes, then allowed to warm to room temperature and stirred for an additional 2 hours. Next, the reaction is stopped. Even more preferably, the reaction is stopped by the dropwise addition of 0.5 M HCl while cooling using an ice bath. The solution is diluted with ethyl acetate and H20. After separation of the phases, the aqueous phase can 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 MgSO4. The phases can be concentrated in a rotary evaporator. Flash chromatography provides a compound of formula XII.
Any suitable oxidation and olefinization method can be used to prepare the compound of formula XIV from the compound of formula XIII. Preferably, the method, or any part thereof, and all or some of the reactants and reaction conditions described below are used. Thus, in accordance with the present invention, benzoic acid, (carboethoxymethylenetriphenyl) phosphorane and DMSO are added to a solution of the compound of formula XIII in CH2C12. Dess-Martin periodinane is added to the solution in several portions, and the reaction mixture is then stirred for about 5 hours at room temperature until the compound of formula XIII disappears substantially. The presence of the compound of formula XIII can be verified by 1 H NMR. Saturated NaHCO 3 solution is added before the mixture is stirred for 30 minutes to produce a precipitate. The precipitate is filtered before the organic phase of the filtrate is separated, washed, and concentrated to produce a crude compound of formula XIV. More preferably, the filtrate is washed with brine and concentrated in a rotary evaporator. Any suitable method can be used to purify the crude compound of formula XIV. More preferably, the crude compound of formula XIV is purified by flash chromatography, then dissolved in ethyl acetate. Then excess hexane is gradually added to the solution with stirring to produce a precipitate. The precipitate is filtered and dried to give 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 solely for illustrative purposes of the present invention and should not be read as limiting the scope of protection of the present invention, as defined by the appended claims.
EXAMPLES: The following illustrates an example of amide reaction and formation between two compounds that fall within the scope of formulas II and III to prepare a compound that falls within the scope of formula I. Specifically, this example, as described in Reaction Scheme I, illustrates the reaction of 1 with 2 to prepare the protease inhibitor AG7088.
Reaction Scheme 1 1A AG7088 The following examples describe the preparation of a compound 1 that falls within the scope of formula IV. The first example, as described in Reaction Scheme 2 below, illustrates the use of the cyanomethylation path described above. The second example, described in Reaction Scheme 3 below, illustrates the second most preferable and inexpensive route to prepare the same compound.
Reaction Scheme 2 3, N-Acyloxazolidinone 1. NaBH4, CoCl2.6H20 MEOH: THF, 0 ° C-ta. 47% during 3 steps HCI 0.5M, .EtOAc 2. pTSA, MeOH, 18h 3. EtOAc, MeOH a) 'A. Hexane / EtOAc 1 * 1 _ * i? _ * l.'i i, - iL.A_a._i. , Jtt__ > > ..x_í _ ^? ¿aiMÍ_¿íS ^? ^^ ^ Reaction Scheme 3 NHBoc H2, 50 psi (344 7 kPa), Pd / C, H3C0 OCH, HOAc, ta, 3 days Preparation of 4 (Reaction Scheme 2) A solution of 3 (1.0 kg, 2.34 mol, 1.0 equiv.) In THF (8.0 L) is added dropwise to a solution with stirring of NaHMDS in THF (1M in THF, 2.96 L , 1.28 equiv.) At -70 ° C in a nitrogen atmosphere for a period of 5 hours. The resulting solution was stirred at -70 ° C for 0.5 hour and then bromoacetonitplo (320 mL, 2.0 equiv.) Was added dropwise over a period of 25 minutes. Mix The reaction was stopped until the initial material disappeared. The reaction was stopped by the addition of saturated ammonium chloride solution (7.0 L), and extracted with methyl tertiary butyl ether (24 L). ). The organic phase was washed with brine (3X6.0 L). The solvent was removed under reduced pressure to give a dark brown oil (1.5 kg). This crude product was dissolved in methylene chloride (8.0 L) and passed over a bed of silica gel (600 g) and activated carbon (250 g). After rinsing the cake with methylene chloride (4.0 L), the filtrate was concentrated on a rotary evaporator to give a light brown oil (1.28 Kg), which was then dissolved in ethyl acetate (2.5 L). To the resulting solution, excess hexane (14.5 L) was added under vigorous stirring and a white solid precipitated in 30 minutes. The suspension was cooled with an ice-water bath and stirred for 4.5 hours, followed by filtration to give 4 as a light brown solid (662 g, 60%). XH NMR (CDC13) d 1.46 (s, 3 H), 1.49 (s, 9 H), 1.59 (s, 3 H), 1.75-1.95 (m, 1 H), 2.15-2.31 (, 1 H), 2.55 -3.15 (m, 3 H), 3.36 (d, J = 10.8 Hz, 1 H), 3.62-4.10 (m, 3 H), 4.13-4.32 (m, 3 H), 4.70 (m, 1 H), 7.15-7.42 (m, 5 H).
* Preparation of 6 (Reaction Scheme 3) Compound 6 was prepared from L-glutamic acid dimethyl ester hydrochloride (commercially available from Lancaster) or L-glutamic acid 5-methyl ester (commercially available from Aldrich) of according to the procedures of the literature.
Preparation of 7 (Reaction Scheme 3) A solution of N-Boc L- (+) - glutamic acid dimethyl ester (6.10 g, 36.3 mmol, 1 equiv.) In THF (100 mL) was added dropwise to a stirred solution of LiHMDS (77 mL, 1 M in THF, 77.0 mmol, 2.1 equiv.) at -78 ° C under 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 an additional 2 hours and the disappearance of the initial material (6) was confirmed by analysis by TLC. The reaction was stopped by the addition of HCl (120mL, 0.5M) and H20 (200mL). The layers were separated, and the aqueous layer was further extracted with methyl tert-butyl ether (3 x 200 mL). The combined organic extracts were washed with saturated NaHCO3 (2 x 250 mL)brine (2 x 250 mL), dried over MgSO4 and filtered. The solvent was evaporated under reduced pressure to give a brown oil (15.2 g). Flash chromatography on silica gel (hexane / ethyl acetate 3: 1) gave a colorless oil (7.67 g, 10.8 mmol, 58%): XH NMR (CDC13) d 1.46 (s, 9 H), 2.12- 2.24 (m, 2 H), 2.77-2.82 (m, 2 H), 2.85-2.91 (m, 1 H), 3.78 (s, 3 H), 3.79 (s, 3 H), 4.32-4.49 (m, 1 H), 5.13 (d, J = 6.0 Hz, 1 H); 13C NMR (CDC13) d 19.4, 28.6, 34.3, 38.6, 49.8, 53.1, 80.9, 117.5, 155.9, 172.4, 172.8; HRMS m / z 314.1481 (calculated for C12H22N2O3, 314.1486).
Preparation of 8 (Reaction Scheme 3) Compound 7 (4.60 g, 14.6 mmol) was dissolved in HOAc (120 mL) and stirred with 5% Pd on C (20 g) under H2 gaseous (50 psi (344.7 kPa) ) for 3 days. The mixture was filtered on Celite The filtrate was evaporated under reduced pressure and the residue was repeatedly evaporated from methyl tert-butyl ether to produce a light pink solid (8, 8.32 g), which was used directly in the next step. XH NMR (CD30D) d 1.47 (s, 9 H), 1.85-2.10 (M, 4 H), 2.60-2.62 (m, 1 H), 2.92-2.96 (m, 2 H), 3.74 (s, 3 H) ), 3.77 (s, 3 H), 4.22-4.26 (m, 1 H): Note: Experiments have shown that less than 5% Pd on C can drive the reaction to its conclusion; that is, 1 g of 5% of Pd on C was efficient for the reduction of 2 g of 7.
Preparation of 9 (Reaction Scheme 3) Crude product 8 was dissolved in MeOH / THF (40 L) and Et3N (7 mL) was added to the solution. The resulting mixture was stirred at 45 ° C for 10 hours until the disappearance of the initial material verified by XH NMR. After separation of the solvent in a rotary evaporator, methyl tert-butyl ether (200 mL) was added and a white solid precipitated. The solid precipitate was removed by filtration. The filtrate was diluted with 200 mL of H20 followed by the addition of 0.5 M HCl (5 mL). The phases were separated, and the aqueous phase was extracted with ethyl acetate (4 x 200 mL). The combined organic phases were washed with brine (2x700 mL), dried over MgSO4, filtered and concentrated in a rotary evaporator to give a light brown oil. Flash chromatography afforded a white solid (9, 2.5 g, 8.74 mmol, 60%): XH NMR (CDC13) 6 1.37 (s, 9 H), 1.75-1.80 (m, 2 H), 2.04-2.09 (m, 1 H), 2.39-2.42 (m, 2 H), 3.25-3.29 (, 2 H), 3.67 (s, 3 H), 4.23-4.26 (m, 1 H), 5.47 (d, J = 8.0 Hz, 1 H), 6.29 (s, 1 H); 13C NMR (CDC13) d 28.5, 28.6, 34.5, 38.5, 40.7, 52.7, 52.8, 80.3, 156.1, 173.3, 180.0; HRMS m / z 286.1564 (calculated for Ci3H22N2? 5, 286.1587).
Preparation of 5 from 4 (Reaction Scheme 2) To a solution of 4 (400 g, 0.85 mol, 1 equiv.) In tetrahydrofuran (3.0 L) was added a solution of cobalt (II) chloride hexahydrate (200 g, 0.85 mol, 1 equiv.) in methanol (3.0 L). The resulting solution was cooled to 0 ° C and sodium borohydride (130 g, 3.51 mol, 4.4 equiv.) Was added in portions over a period of 7 hours. The reaction mixture was allowed to warm to room temperature and was stirred for 20 hours while it was verified by TLC for the disappearance of the starting material (4). The reaction was cooled to 0 ° C and stopped by the 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 separated, washed with brine (1X3.0 L), concentrated in a rotary evaporator to give the crude material (440 g), which was used directly in the next hydrolysis reaction. To a solution of the crude material (440 g, 1 equiv.) In methanol (800 mL) was added p-toluenesulfonic acid monohydrate (4.0 g, 0.015 equiv.). The reaction was stirred at room temperature overnight. The solvent was removed on a rotary evaporator and the residue was dissolved in ethyl acetate (2.0 L), washed with saturated sodium carbonate (2X100 mL). The combined aqueous phases were extracted with ethyl acetate (2X200 mL). All organic phases were combined, concentrated, concentrated in a rotary evaporator to give 275 g of the crude product, which was charged with a 2.5% methanol solution (20 mL) in water (780 mL) and stirred at room temperature during the night. The granular solid (chiral auxiliary) was removed by filtration and the filtrate was concentrated in a rotary evaporator. The residue was dissolved in ethyl acetate (1.5L), dried over MgSO4, filtered and concentrated to give a viscous oil. The oil was further purified through a trituration process using ethyl acetate (1 L) and hexane (1 L) 1: 1 to give 5 as a white solid (104 g, 47% total yield from 4) .
Preparation of 5 from 9 (Reaction Scheme 3) To a stirred solution of 9 (1.75 g, 6.10 mmol) in THF (40 mL) was added LiBH4 (270 mg, 12.2 mmol, 2 equiv.) In several portions at 0 ° C in an Argon atmosphere. The reaction mixture was stirred at 0 ° C for 10 minutes, then allowed to warm to room temperature and stirred for an additional 2 hours. The reaction is stopped by the dropwise addition of 0.5 M HCl (24 mL) with cooling in an ice bath (Note: gas formation was observed). The solution was diluted with ethyl acetate (100 L) and H20 (50 mL). The phases were separated, and the aqueous layer was extracted with ethyl acetate (6 x 150 mL). The combined organic phases were dried over MgSO4, filtered and concentrated in a rotary evaporator to provide a light brown oil. Flash chromatography gave a white solid (5, 1308 g, 5.06 mmol, 83%): XH NMR (CDC13) d 1.46 (s, 9 H), 1.61-1.67 (m, 1 H), 1. 82-1.91 (m, 1 H), 1.94-2.00 (m, 1 H), 2.43-2.48 (m, 1 H), 2. 49-2.55 (m, 1 H), 3.32-3.34 (m, 3 H), 3.58-3.66 (m, 2 H), 3. 68-3.79 (m, 2 H), 5.47 (d, J = 7.0 Hz, 1 H), 6.24 (s, 1 H); 13 C NMR (CDCl 3) d 28.8, 32.9, 38.4, 40.8, 51.5, 66.3, 79.8, 157.0, 181.3; HRMS m / z 258.1652 (calculated for C13H22N2? 5, 258.1650).
Preparation of 1 from 5 Procedure A (Reaction Scheme 2) a solution of 5 (50.0 g, 184 mol, 1 equiv.) Ethyl sulfoxide (500 mL) added triethylamine (116 mL). The resulting solution was cooled to 5 ° C with an ice bath, followed by the addition of sulfur trioxide-pyridine complex (132 g). The reaction was stirred at room temperature for 15 minutes. The cold bath was removed and the reaction was stirred for an additional 1 hour. (Carboethoxymethylenetriphenyl) -phosphorane (112 g) was added in one batch and the reaction was stirred at room temperature for 3 hours. The reaction was stopped by the addition of saturated brine (3.0 L), extracted with ethyl acetate (3X1.5 L). The combined organic phases were washed with saturated brine (3X1.5 L), dried over MgSO4, filtered and concentrated to give a dark red oil. The oil was purified by chromatography, followed by a trituration process using ethyl acetate (60 mL) and excess hexane (240 mL). 1 was obtained as a white solid (36.0 g, 60%).
Procedure B (Reaction Scheme 3) To a solution of 5 (1.0 g, 3.87 mmol, 1 equiv.) In CH 2 Cl 2 (80 mL) was added benzoic acid (1.89 g, 15.5 mmol, 4 equiv.), (Carboethoxymethylenephenyl) phosphorane (5.39 g, 15.5 mmol, 4 equiv.) And DMSO (4.8 mL). Dess-Martin periodinane (4.1 g, 9.17 mmol, 2.5 equiv.) Was added in several portions to the solution, and the reaction mixture was then stirred for 5 hours at room temperature until the disappearance of the initial material 5. Solution was added saturated with NaHCO3, and the mixture was stirred for 30 minutes. A white solid precipitated, which was then filtered. The organic phase of the filtrate was separated, washed with brine (250 mL), and concentrated in a rotary evaporator to give a brown oil, which was purified by flash chromatography to produce a light brown foam (0.956 g). The foam was dissolved in ethyl acetate (3 mL). An excess of hexane (12 mL) was gradually added to the solution with stirring and a white solid precipitated. The solid was filtered and dried under vacuum overnight to give 1 (0.69 g, 2.11 mmol, 55%). Chiral CLAP: purity of 97%, 98% of and 100% of E isomer: XH NMR (CDC13) d 1.22 (t, J = 7.2 Hz, 3 H), 1.38 (s, 9 H), 1.53-1.58 (m , 1 H), 1.66-1.84 (m, 1 H), 1.85- 2.00 (m, 1 H), 2.30-2.50 (m, 2 H), 3.20-3.37 (m, 2 H), 4.13 (c, J) = 7.2 Hz, 2 H), 4.20-4.35 (m, 1 H), 5.13 (d, J = 7.5 Hz, 1 H), 5.68 (s, 1 H), 5.90 (dd, J = 1.8, 15.6 Hz, 1 H), 6.80 (dd, J = 5.1, 15.6 Hz, 1 H); HRMS m / z 326.1846 (calculated for C? 6H26 2? 6, 326.1840).
Preparation of? G7088 from 1 and 2 (Reaction Scheme) 1) . 751 mg of compound 1 was dissolved in DCM (10 mL / g of 1) in a single-neck spherical bottom flask and covered with a stopper. The flask was then purged with nitrogen followed by the addition of 1.4 mL of TFA via a syringe while the solution was being stirred. The progress of the reaction was verified by TLC using 5% MeOH in DCM until after approximately 4 hours the initial material disappeared. Solvent and excess TFA were removed under vacuum at a pressure of <50 m Torr @ 45 ° C. The product, compound A, was used immediately in the step set forth below. Compounds 1A and 2 were dissolved in DMF (5 mL / g of 2) in a single neck flask covered with a stopper and equipped with a temperature probe. The flask was purged with nitrogen. The resulting solution was divided into two portions. In a first portion, 1.6 mL of n-methylmorpholine was added via a syringe and cooled to 0 ° C + 5 ° C. In a second portion of the solution 281 mg of CDMT was dissolved. This CDMT solution was then added by drip via a syringe to the first portion of the solution, maintaining the reaction temperature of 0 ° C + 5 ° C. The resulting reaction mixture was then allowed to warm to room temperature. The reaction was checked for approximately 1 hour by TLC (hexane: EtOAc: IPA 7: 3: 1) until compound 2 disappeared. Once the reaction was completed, the AG7088 product was precipitated from the solution by the slow addition of water to the solution. reaction mixture. The resulting suspension was filtered to obtain a yield of > 85% white granular crystals of compound AG7088 having a purity of > 97%. The product was then recrystallized by dissolving it in hot MeOH: EtOAc 1: 1 followed by the slow addition of hexane (2 volumes). It should be understood that the foregoing description is exemplary and explanatory in nature, and is intended to illustrate the invention and its preferred embodiments. Through routine experimentation, the expert will recognize the obvious modifications and variations that can be made without departing from the spirit of the invention. Thus, it is intended that the invention be defined not by the above description, but by the following claims and their equivalents. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (25)

  1. Having described the invention as above, the content of the following claims is claimed as property: 1. A useful process for synthesizing antipicornaviral compounds, characterized in that it comprises: (a) effecting the cyanomethylation of a compound of formula V using bis (trimethylsilyl) amide and bromoacetonitpyl to produce a compound of formula VI; (b) effecting the reduction, then the cyclization, and then the deprotection of compound VI to produce a compound of formula VII; Y (c) effecting the oxidation and olefination of the compound of formula VII by reacting the compound of formula VII with a complex of S03-pyridine to produce a reaction mixture and reacting the reaction mixture with a compound of formula VIII to form a compound of formula IV: where Ri is H, F, an alkyl group, OH, SH, or an O-alkyl group; wherein each R4i is independently H or lower alkyl; and X is any suitable protecting group by nitrogen. 2. The process according to claim 1, characterized in that the compound of formula V is prepared from β-benzyl ester of N-Boc L glutamic acid. 3. The process according to claim 1, characterized in that X is a Boc group. 4. The process according to claim 1, characterized in that R4? is H 5. The process according to claim 1, characterized in that Zi is H. 6. The process according to claim 1, characterized in that Z is -COOEt .. yiw 7. A useful process for synthesizing antipicornaviral compounds according to claim 1, characterized in that it further comprises the steps of: (d) deprotecting the compounds of formula IV to produce a compound of formula IV A: and (e) subjecting the compound of formula II and the compound of formula IV A to an amide-forming reaction to produce a compound of formula IA: where R2 and R3 are each independently H; ) n where n is an integer from 0 to 5, Ai is CH or N, A2 and each A3 is independently selected from C (R4?) (R4?), N (R41), S, S (O), S (0 ) 2, O, and A4 is HN or NR41, where each R4? is independently H or a lower alkyl, provided that no more than two heteroatoms occur consecutively in the ring described above formed by Ai, A2, (A3) n, A4 and C = 0, and at least one of R2 and R3 is u d-ii-.aa-H-i - "*" " R5 and R6 are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aplo group, or a heteroaryl group; R7 and R8 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -ORi7, -SR? , -NR? 7Rs, -R19NR17R18, or -NR? 70Ri8, where Ri7, Ris and R19 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group acyl, provided that at least one of R? and Rs are an alkyl group, an aplo group, a hetero group, -0Ri7, -SR? 7, -NR? 7R8, -NR19NR17R? 8, or -NR? 70R18; Rg is a five-membered heterocycle having one or three heteroatoms selected from O, N, and S; and Z and Zi are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -C (0) R2 ?, -CO2R21, CN, -C (0) NR2? R22, -C (O) NR2? OR22, -C (S) R2 ?, -C (S) NR21R22, -N02, -SOR21, -S02R21, -S02NR21R22, -SO (NR21) (OR22), - SONR21, -S03R2 ?, -PO (OR2?) 2, -PO (R21) (R2), -PO (NR21R22) (OR23), -PO (NR2? R22) (NR23R24), -C (O) NR2? NR22R23, or -C (S) NR21NR22R23, where R21, R22, R23 and ^ 2. are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or where either of R2, R22, R23 and R24. together with the atoms to which they are attached, they form a heterocycloalkyl group, provided that Z and Zi are both H; or Zi and Ri, together with the atoms to which they are attached, form a cycloalkyl, or heterocycloalkyl group, where Zx and Ri are as defined above, except for portions which can not form the cycloalkyl or heterocycloalkyl group; or Z and Zi, together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl group, where Z and Zi are as defined above except for the portions which can not form the cycloalkyl or heterocycloalkyl group. 8. The process according to claim 7, characterized in that X is a Boc group. 9. The process according to claim 7, characterized in that the compound IV is * & fc. l * * 10. The process according to claim 7, characterized in that the compound II is 11. The process according to claim 7, characterized in that the compound IV A is ? ÁáM á ^ m ^, ..... ^^, .. ^ _ .. ^^ J, ^ ^ á ^ .mfe ^ JUL 12. The process according to claim 7, characterized in that the compound IA is 13. A useful process for synthesizing antipicornaviral compounds, characterized in that it comprises: (a) effecting the dianionic alkylation of a compound of formula IX using bromoacetonitrile to produce a compound of formula X: (b) effecting the hydrogenation of the compound of formula X to effect an amine of formula XI; OR (c) reacting the compound of formula XI on ET3N to produce a lactam ester of formula XII; The concentration of the lactam ester of formula XII to produce a compound of formula XIII: (e) effecting the oxidation and olefmation of the compound of formula XIII to produce a compound of formula XIV by reacting it with a compound of formula XV: Z PPh. (XV) Z. wherein each R41 is independently H or lower alkyl; . ,? ^,, ^ ^,., ^^ ^? Z and Zi are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -C (0) R2 ?, -CO2R21, CN, -C (0) NR2 R22, -C (0) NR2? OR22, -C ('S) R21, -C (S) NR2? R22. "N02, -S0R2 ?, -S02R2 ?, -S02NR21R22, -SO (NR2i) (OR22), -SONR21, -SO3R21 -PO (OR2?) 2, -P0 (R2X) (R22), -PO (NR2? R22) (OR23), -PO (NR2? R22) (NR23R24), -C (0) NR2? NR22R23, or -C (S) NR2? NR22R23, where R2 ?, R22, R23 and R4 are each independently H , an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or where either of R2, R22, R23 and R24, together with the which are joined, form a heterocycloalkyl group, provided that Z and Zi are both H; or Zi and Zi, together with the atoms to which they are attached, form a cycloalkyl group, or heterocycloalkyl, where Zi and Zx are as defined above, except for portions which can not form the cycloalkyl or heterocycloalkyl group, and X is a protective group suitable for nitrogen 14. The process useful in the synthesis of antipicornaviral compounds according to claim 13, characterized p or it also includes: μ jf- ifc L a ^ prepare a compound of formula IV to convert the compound of formula XIV to produce the compound of formula IV: where Ri is H, F, an alkyl group, OH, SH, or an O-alkyl group. 15. The process useful for synthesizing antipicornaviral compounds according to claim 14, characterized in that it further comprises: Step A: deprotecting the compound of formula IV to produce a compound of formula IV A: tí? á-i? í - á Íl, kéí_. - * - • * JUfeM ** - í, • Step B: subjecting the compound of formula II and the compound of formula IV A to an amide forming reaction to produce a compound of formula IA: where R2 and R3 are each independently H; where n is an integer from 0 to 5, Ai is CH or N, A2 and each A3 are independently selected from C (R4?) (R4?), N (R4X), S, S (O), S (0 ) 2, O, and A4 is NH or NR4 ?, where each R41 is independently H or a lower alkyl, provided that no more than two heteroatoms occur consecutively in the ring described above formed by Ai, A2, (A3) n, A4 and C = 0, and at least one of R2 and Rs be R4 is Rs and Re are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; R7 and R8 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR? , -SR17, -NR? 7Re, -NR? 9NR? 7Ri8, or -NR? 7OR? 8, where Ri7, R? 8 and R19 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 R7 and Rs is an alkyl group, an aryl group, a heteroaryl group, -ORi7, -SRi7, -NR? R18, -R19NR17R18, or -NR? 7OR? 8; Rg is a five-membered heterocycle having one or three heteroatoms selected from O, N, and S; and Z and Zi are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -C (0) R2X, -CO2R21, CN, -C (0) NR2 ? R22. -C (O) NR2? OR22, -C (S) R2 ?, -C (S) NR2? R22, -N02, -SOR2 ?, -S02R21, -S02NR2? R22, -SO (NR2X) (OR22), -SONR2 ?, -SO3R21, -PO (OR2?) 2, -PO (R2i) (R22), -PO (NR2? R22) (OR23), -PO (NR2? R22) (NR23R24), -C (0 ) NR2iNR22R23, O -C (s') NR21NR22R23, where R2 ?, R22, R23 and R24 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group , or a thioacyl group, or where any two of R21, R22, R23 and R24, together with the atoms to which they are attached, form a heterocycloalkyl group, provided that Z and Zi are both H; or Zi and Ri, together with the atoms to which they are attached, form a cycloalkyl, or heterocycloalkyl group, wherein Zx and R2 are as defined above, except for portions which can not form the cycloalkyl or heterocycloalkyl group; or Z and Zi, together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl group, where Z and Zi are as defined above except for the portions which can not form the cycloalkyl or heterocycloalkyl group. 16. The process according to claim 13, characterized in that X is a Boc group. 17. The process according to claim 13, characterized in that R4? is H. 18. The process according to claim 13, characterized in that Zi is H. The process according to claim 13, characterized in that Z is -COOEt. 20. The process according to claim 14, characterized in that Ri is H. 21. A process useful for the synthesis of a compound of formula IA ', and acid salts thereof: characterized in that it comprises the steps of: Step A: preparing a compound of formula IV comprising: ? The cyanomethylation of a compound of formula V using bis (trimethylsilyl) amide and bromoacetonitrile is carried out to produce a compound of formula VI ': (b) effecting the reduction, then cyclization, and then deprotection of the compound of formula VI 'to produce a compound of formula VII', and ií (c) effecting the oxidation and olefination of the compound of formula VII by reacting the compound with a S03-pyridine complex before the resulting reaction mixture is reacted with Ph3P = CHC02Et; Step B: Deprotection of the compound of formula IV to produce a compound of formula IV: Step C: subject a compound of formula II 'and the compound of formula IV A' to an amide-forming reaction; _ __ _ ___ __íá ____ ^ 22. The process according to claim 21, characterized in that the compound of formula V is prepared from acid? -benzyl ester N-Boc L glutamic 23. A useful process for synthesizing antipicornaviral compounds, characterized in that it comprises: (a) effecting the diamionic alkylation of a compound of formula IX 'using bromoacetonitrile to prepare a compound of formula X': O O (b) effecting the hydrogenation of the compound of formula X 'to produce an amine of formula XI'; (c) reacting the compound of formula XI 'on ET3N to produce a lactam ester of formula XII'; (d) effecting the reduction of the lactam ester of formula XII, to produce a compound of formula XIII ': (e) effecting the oxidation and olefination of the compound of formula XIII 'to produce a compound of formula XIV by reacting it with Ph3P = CHC02Et; 24. The process useful for the synthesis of antipicornaviral compounds according to claim 23, characterized in that it further comprises: converting the compound of formula XIV to the compound of formula IV: 25. The process useful for the synthesis of antipicornaviral compounds according to claim 24, characterized in that it further comprises: Step A: Deprotection of the compound of formula IV to produce a compound of formula IV: -. - ^ - * ^ "• i ^ lj ^^^^ gjg lí ^ j and Step C: submit a compound of formula II 'and the compound of formula IVA' to an amide-forming reaction; | ^^^^ and ^ jgcjj ^ aagstii- BgQMEH OF THE INVENTION Efficient synthetic routes for the preparation of rhinovirus protease inhibitors of formula (I), as well as useful intermediates in those synthetic routes. Those compounds of formula (I), as well as the pharmaceutical compositions containing those compounds, are suitable for treating patients or hosts infected with one or more picornaviruses. 02 w?
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