AU6797100A - Synthetic routes for the preparation of rhinovirus protease inhibitors and key intermediates - Google Patents

Description

WO 01/14329 PCT/USOO/23033 SYNTHETIC ROUTES FOR THE PREPARATION OF RHINOVIRUS PROTEASE INHIBITORS AND KEY INTERMEDIATES RELATED APPLICATION DATA: 5 This application relates to U.S. Provisional Patent Application Serial No. 60/150,358, filed on August 24, 1999. This application also relates to U.S. Provisional Patent Application Serial No. 60/150,365 (Attorney Docket No. 0125.0027), also filed August 24, 1999, entitled "Efficient Methods For The Preparation Of Rhinovirus Protease Inhibitors, Key 10 Intermediates And A Continuous Membrane Reactor Useful For The Preparation Of The Same" having named as inventors: J. Tao, S. Babu, R. Dagnino, Jr., Q. Tian, T. Remarchuk, K. McGee, N. Nayyar, and T. Moran. The aforementioned application also relates to synthetic routes for the preparation of rhinovirus protease inhibitors, as well as key intermediates useful in their preparation. The above-mentioned 15 applications are relied upon and incorporated herein by reference. TECHNICAL FIELD AND INDUSTRIAL APPLICABILITY OF INVENTION: The present invention relates to an improved process for the preparation of ethyl-3-{(5'-methylisoxazole-3'-carbonyl)-L-Val{(COCH 2 )-L-(4-F-Phe)-L-((S) Pyrrol-Ala)}-E-propanoate, (also referred to as AG7088), its analogs and of 20 pharmaceutically acceptable salts thereof. The present invention also includes a novel group of key intermediate compounds to be used in the above process. BACKGROUND OF THE INVENTION: Picornaviruses are a family of tiny non-enveloped positive-stranded RNA containing viruses that infect humans and other animals. These viruses include the 1 WO 01/14329 PCT/USOO/23033 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. 5 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. Some small-molecule inhibitors of the enzymatic activity of picornaviral 3C 10 protease (i.e., antipicomaviral compounds) have been recently discovered. 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.; and U.S. Patent Application No. 08/991,739, filed December 16, 1997, by Webber et al. These U.S. patent applications, the disclosures of which are incorporated herein 15 by reference, describe certain antipicornaviral compounds and methods for their synthesis. More recently, an especially potent group of antipicomaviral agents have been discovered as set forth in U.S. Patent Application No. 60/098,354, (the '354 application) filed August 28, 1998, by Dragovich et al., which is herein incorporated 20 by reference. This application discloses, inter alias, a group of antipicornaviral agents of general formula I. A particularly promising compound, AG7088, falling within the scope of this group, exhibits excellent antiviral properties against a plethora of Rhinoviral serotypes and is currently in human clinical trials. The '354 application also discloses methods and intermediates useful for synthesizing these compounds. 2 WO 01/14329 PCT/USOO/23033 For example, 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. R7 O R, R2

P

4 N OH + H 2 N Z H OR6 R3 Z, BB P R7 O R2 Z,

P

4 H H 0i R CC 5 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. Thus, the '354 application teaches suitable methods for synthesizing the compounds of general formula I from a carboxylic acid 10 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.) Similarly, two recent publications by Dragovich et al. disclose antipicomavirus agents and suitable synthetic methods for their synthesis. See 3 WO 01/14329 PCT/USOO/23033 Structure-Based Design, Synthesis, and Biological Evaluation of Irreversable Human Rhinovirus 3C Proteases Inhibitors. 3. StructureActivity Studies of Ketomethylene Containing Peptidomimetics, Dragovich et al., Journal of Medicinal Chemistry, ASAP, 1999; and Structure-Based Design, Synthesis, and Biological Evaluation of 5 Irreversable Human Rhinovirus 3C Proteases Inhibitors. 4. Incorporation of Pi Lactam Moieties as L-Glutamine Replacements, Dragovich et al., Journal of Medicinal Chemistry, ASAP, 1999. These aforementioned articles are herein incorporated by reference in their entirety. However, there is still a desire to discover improved, more efficient, processes 10 and novel intermediates for use in the syntheses of the compounds of the group of antipicornaviral agents. In particular, there is a need for improved methods for synthesizing the compounds of general formulae II and III. SUMMARY OF THE INVENTION: The present invention relates to the discovery of a cost effective and efficient 15 process for the preparation of the antipicornaviral agents of formula I, such as compound AG7088, as well as intermediates which are useful in that synthesis. The antipicornaviral agents of formula I comprise: 0 R2 Z RN Z1 H R3 R6 R1 wherein R 1 is H, F, an alkyl group, OH, SH, or an O-alkyl group; 20 R 2 and R 3 are each independently H; 4 WO 01/14329 PCTIUSOO/23033 0 A4 0 or Al (A 3 )n

NH

2

(R

4

)(R

4 ) where n is an integer from 0 to 5, A 1 is CH or N, A 2 and each A 3 are independently selected from C(R 41

)(R

4 1 ), N(R 4 1 ), S, S(O), S(O) 2 , and 0, and A 4 is NH or NR41, where each R41 is independently H or lower alkyl, provided that no more than two 5 heteroatoms occur consecutively in the above-depicted ring formed by A 1 , A 2 , (A 3 )n,

A

4 and C=O, and at least one of R 2 and R 3 is 0

A

4 0 A, (A 3 )n ;or C A 2

NH

2

(R

4 1

)(R

41 )

R

4 is 0 R9 ) N H R 0

R

5 and R 6 are each independently H, F, an alkyl group, a cycloalkyl group, a 10 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 17 , -SR 17 , -NR 17 Ri 8 , 5 WO 01/14329 PCT/USOO/23033

-NR

1 9

NR

1 7 Ri 8 , or -NR 17 0RI 8 , where R 17 , R 18 , and R 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 R 7 and R 8 is an alkyl group, an aryl group, a heteroaryl group, -OR 1 7 , -SR 1 7 , -NR 17 Ri 8 , -NR 19

NR

1 7 Ri 8 , or -NR 1 7 0R 8 ; 5 R 9 is a five-membered heterocycle having from one to three heteroatoms selected from O, N, and S; and Z and Z 1 are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -C(O)R 2 1 , -CO 2

R

21 , CN,

-C(O)NR

21

R

2 2 , -C(O)NR 21 0R 22 , -C(S)R 21 , -C(S)NR 21

R

22 , -NO 2 , -SOR 21 , -S0 2

R

21 , 10 -S0 2

NR

2 1

R

22 , -SO(NR 2 1

)(OR

22 ), -SONR 21 , -S0 3

R

21 , -PO(OR 21

)

2 , -PO(R 21

)(R

22 ),

-PO(NR

2 1

R

22

)(OR

2 3 ), -PO(NR 21

R

22

)(NR

23

R

2 4), -C(O)NR 21

NR

22

R

23 , or

-C(S)NR

21

NR

22

R

23 , where R21, 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, an acyl group, or a thioacyl group, or where any of two of R21, R 22 , R 23 , and R 2 4 , 15 together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and ZI are not both H; or Z 1 and R 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z 1 and R 1 are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group; 20 or Z and Z 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z 1 are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group. As discussed below, these antipicornaviral agents of formula I may be synthesized by subjecting a compound of general formula II together with a compound 6 WO 01/14329 PCT/USOO/23033 of general formula III to a suitable amide-forming 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, it also employs less expensive starting materials and reagents. 5 These 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 EMBODIMENT OF THE INVENTION: As used in the present application, the following definitions apply: In accordance with a convention used in the art, -- is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or 15 substituent to the core or backbone structure. Where chiral carbons are included in chemical structures, unless a particular orientation is depicted, both sterioisomeric forms are intended to 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 20 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 C1 being prefered). A "lower alkyl group" 25 is intended to mean an alkyl group having from 1 to 4 carbon atoms in its chain. 7 WO 01/14329 PCT/USOO/23033 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, 5 and to which may be fused one or more heterocycloalkyl groups, aryl groups, or heteroaiyl groups, which themselves may be unsubstituted or substituted by one or more substituents. Illustrative examples of cycloalkyl groups include the following moieties: , and 10 A "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 15 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. Illustrative examples of heterocycloalkyl groups include the following moieties: 8 WO 01/14329 PCT/USOO/23033 0 D 0) (N) RN NR N 0N N , N R R R R 0 0 0S N N NR NN 0 0 N 0 N and RR R An "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, 5 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. Illustrative examples of aryl groups include the following moieties: and 10 A "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, 9 WO 01/14329 PCTIUSOO/23033 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. Illustrative 5 examples of heteroaryl groups include the following moieties: NN NN N NN-- N' s N N N N 0 0 R N N N N' N' N N a NN N10 N R N N N NN N N NN N N NN R s and N 10 WO 01/14329 PCTIUSOO/23033 A "heterocycle" is intended to mean a heteroaryl or heterocycloalkyl group (each of which, as defined above, are optionally substituted). An "acyl group" is intended to mean a -C(O)-R radical, where R is a 5 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. 10 A "hydroxy group" is intended to mean the radical -OH. An "amino group" is intended to mean the radical -NH 2 . 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 -NRaRb, where Ra and 15 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(O)ORa, where Ra is an alkyl group. 20 An "alkylsulfonyl group" is intended to mean the radical --SO 2 Ra, where Ra is an alkyl group. An "alkylaminocarbonyl group" is intended to mean the radical -C(O)NHRa, where Ra is an alkyl group. 11 WO 01/14329 PCTIUSOO/23033 A "dialkylaminocarbonyl group" is intended to mean the radical -C(O)NRaRb, where Ra and Rb are each independently an alkyl group. A "mercapto group" is intended to mean the radical -SH. An "alkylthio group" is intended to mean the radical -SRa, where Ra is an alkyl 5 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 . An "aryloxy group" is intended to mean the radical -ORc, where Rc is an aryl group. 10 A "heteroaryloxy group" is intended to mean the radical -ORd, where Rd is a heteroaryl group. An "arylthio group" is intended to mean the radical -SRc, where Re is an aryl group. A "heteroarylthio group" is intended to mean the radical -SRd, where Rd is a 15 heteroaryl group. A "leaving group" (Lv) is intended to mean any suitable group that will be displaced by a substitution reaction. One of ordinary skill in the art will know that any conjugate base of a strong acid can act as a leaving group. Illustrative examples of suitable leaving groups include, but are not limited to, -F, -Cl, -Br, alkyl chlorides, 20 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 12 WO 01/14329 PCT/USOO/23033 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 5 intended to be within the scope of this invention. Table 1 Protecting Groups 10 Ada Adamantane acetyl Alloc Allyloxycarbonyl Allyl Allyl ester Boc tert-butyloxycarbonyl Bzl Benzyl 15 Cbz Benzyloxycarbonyl Fmoc Fluorenylmethyloxycarbonyl OBzl Benzyl ester OEt Ethyl ester OMe Methyl ester 20 Tos (Tosyl) p-Toluenesulfonyl Trt Triphenylmethyl Reagents and Solvents ACN Acetonitrile AcOH Acetic acid 25 Ac.sub.2 0 Acetic acid anhydride AdacOH Adamantane acetic acid AIBN 2,2-azobisisobutyronitrile Alloc-Cl Allyloxycarbonyl chloride BHT 2,6-di-tert-butyl-4-methylphenol 30 Boc.sub.2 0 Di-tert butyl dicarbonate CDI 1,1 '-carbonyldiimidazole DIEA Diisopropylethylamine DIPEA N,N-diisopropylethylamine DMA Dimethylacetamide 35 DMF N,N-dimethylformamide DMSO Dimethyl sulfoxide EDTA ethylenediaminetetraacetic acid Et.sub.3 N Triethylamine EtOAc Ethyl acetate 40 FDH formate dehydrogenase FmocOSu 9-fluorenylmethyloxy carbonyl 13 WO 01/14329 PCTIUSOO/23033 N-hydroxysuccinimide ester HATU N-[(dimethylamino)-1H-1, 2, 3-triazol [4, 5-b] pyridiylmethylene] N-methylmethanaminium hexafluorophosphate N-oxide HOBT 1 -Hydroxybenzotriazole 5 HF Hydrofluoric acid LDH lactate dehydrogenase LiHMDS Lithium bistrimethylsilylamide MeOH Methanol Mes (Mesyl) Methanesulfonyl 10 MTBE t-butyl methyl ether NAD Nicotinamide adenine dinucleotide NADH Hydrogen-peroxide oxidoreductase NaHMDS Sodium bistrimethylsilylamide NMP 1 -methyl-2-pyrrolidinone 15 nin. Ninhydrin i-PrOH Iso-propanol Pip Piperidine PPL Lipase pTSA p-toluensulfonic acid monohydrate 20 Pyr Pyridine TEA Triethylamine TET triethylenetetraamine TFA Trifluoroacetic acid THF Tetrahydrofuran 25 Triflate (Tf) Trifluoromethanesulfonyl 30 The term "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. Illustrative examples of suitable organic moieties include, but are not limited to, hydroxyl groups, alkyl groups, oxo groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl 35 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. 14 WO 01/14329 PCT/US00/23033 The term "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. Illustrative examples of suitable substituents include hydroxy groups, halogens, oxo groups, alkyl groups, acyl groups, sulfonyl groups, 5 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. The term "optionally substituted" is intended to expressly indicate that the 10 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. As defined above, various groups may be unsubstituted or substituted (i.e., they are optionally substituted) unless indicated otherwise herein (e.g., by indicating that the 15 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 20 pharmacologically active product produced through metabolism in the body of a specified compound. A "solvate" is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound. 15 WO 01/14329 PCT/USOO/23033 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 compound and that 5 is not biologically or otherwise undesirable. Examples of 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, 10 succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6 dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phylacetates, phenylpropionates, phylbutyrates, citrates, lactates, y-hydroxybutyrates, glycollates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, 15 naphthalene-2-sulfonates, and mandelates. 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. In such a fashion, the synthetic method can be only the synthetic 20 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. If the antipicornaviral agent of formula I formed from the process of the present invention is a base, a desired salt may be prepared by any suitable method 16 WO 01/14329 PCTIUSOO/23033 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; 5 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. If the antipicornaviral agent of formula I formed from the process of the 10 present invention is an 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. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; 15 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. In the case of compounds, salts, or solvates that are solids, it is understood by those skilled in the art that the compounds of formula I and the intermediates used in 20 the process of the present invention, salts, and solvates thereof, may exist in different crystal forms, all of which are intended to be within the scope of the present invention and specified formulas. The antipicornaviral agents of formula I, and the intermediates used in the process of the present invention, may exist as single stereoisomers, racemates, and/or 17 WO 01/14329 PCT/USOO/23033 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. Preferably, however, the intermediate compounds used in the process of the present invention are used in optically pure form. 5 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 yield a compound having the desired pharmacological activity. Preferably, "optically pure" is intended to mean a compound that comprises at least 10 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.) Preferably, the antipicornaviral agents of formula I formed from the process of the present invention are optically pure. The present invention relates to a process of preparing antipicornaviral agents 15 of formula I: 0 R2 Z N Z(I) H R3 R6 R1 wherein R 1 is H, F, an alkyl group, OH, SH, or an O-alkyl group;

R

2 and R 3 are each independently H; 18 WO 01/14329 PCT/USOO/23033 0

A

4 0 ; or C A (A3 )n NH2 (R 41

)(R

4 ) where n is an integer from 0 to 5, A, is CH or N, A 2 and each A 3 are independently selected from C(R 41

)(R

41 ), N(R 41 ), S, S(O), S(O) 2 , and 0, and A 4 is NH or NR41, where each R41 is independently H or lower alkyl, provided that no more than two 5 heteroatoms occur consecutively in the above-depicted ring formed by A 1 , A 2 , (A 3 ).,

A

4 and C=O, and at least one of R 2 and R 3 is 0

A

4 0 I_'A,",

(A

3 )n ;or C A 2

NH

2

(R

41

)(R

41 )

R

4 is 0 R9 ) N HORy 0 10 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; 19 WO 01/14329 PCT/USOO/23033

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 17 , -SR 17 , -NR 1 7 Ri 8 ,

-NR

1 9

NR

17 Ri 8 , or -NR 1 7 0RI 8 , where R 17 , R 18 , and R 1 9 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl 5 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 1 7 , -SR 17 , -NR 1 7 Ri 8 , -NR 1 9

NR

17 Ri 8 , or -NR 7 0Ris;

R

9 is a five-membered heterocycle having from one to three heteroatoms selected from 0, N, and S; and Z and Zi are each independently H, F, an alkyl group, a cycloalkyl group, a 10 heterocycloalkyl group, an aryl group, a heteroaryl group, -C(O)R 21 , -CO 2

R

21 , CN,

-C(O)NR

21

R

22 , -C(O)NR 21

OR

22 , -C(S)R 2 1 , -C(S)NR 2 1

R

22 , -NO 2 , -SOR 21 , -S0 2

R

2 1 ,

-SO

2

NR

2 1

R

22 , -SO(NR 21

)(OR

22 ), -SONR 21 , -S0 3

R

21 , -PO(OR 21

)

2 , -PO(R 2 1

)(R

22 ),

-PO(NR

2 1

R

22

)(OR

23 ), -PO(NR 2 1

R

22

)(NR

23

R

24 ), -C(O)NR 2 1

NR

22

R

23 , or

-C(S)NR

2 1

NR

22

R

23 , where R 21 , R 22 , R 23 , and R 24 are each independently H, an alkyl 15 group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or where any of two of R 21 , R 22 , R 23 , and R 24 , together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Zi are not both H; or Z 1 and R 1 , together with the atoms to which they are bonded, form a cycloalkyl or 20 heterocycloalkyl group, where Z 1 and Riare as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group; or Z and Z 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z 1 are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group. 20 WO 01/14329 PCT/USOO/23033 The present invention discloses that a compound of formula I may be prepared by subjecting a compound of formula II and a compound of formula III to a amide forming reaction: 0 R2 Z 0 R2 Z R4 1t OH + H2N Z1 R4 N Z, R3 H R

R

6 R 6 R 5 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. For example, 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 0 to yield desired compound of formula I. Any suitable purification method may be used to 10 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: (a) reacting the compound of formula II with a compound of formula IIIA in the presence of N-methylmorpholine to form a reaction mixture; and R2 Z

F

3 CCOOH . H 2 N Z1 (IIA) R3 15 (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. 21 WO 01/14329 PCT/USOO/23033 Preferably, the method for preparing the compound of formula I utilizing the more preferable amide-forming reaction utilizes some or all of the reagents and reaction conditions disclosed below. Thus, preferably, the compound of formula II and the compound of formula IIIA in DMF are combined in any suitable container. The 5 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-methylmorpholine is added to the reaction mixture. More preferably, the N-methylmorpholine is added via a syringe in one single portion and the reaction mixture cooled to about between -5 C and 50 C. More preferably, the 10 reaction mixture is cooled to about 0 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 a solution of the compound of formula Lv-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 so as to 15 maintain the reaction mixture at a constant temperature. For example, the solution of the compound of formula Lv-X may be added to the reaction mixture dropwise utilizing a syringe. Upon completion of 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 may be followed by monitoring the disappearance of the 20 compound of formula II by thin layer chromatography (hereinafter "TLC"). When the reaction is at least substantially complete, the compound of formula I may be precipitated out of solution to form a slurry by slowly adding water to the reaction mixture. The compound of formula I may then be removed from the slurry by any suitable means known to one of ordinary skill in the art. For example, the compound 22 WO 01/14329 PCT/USOO/23033 of formula I may be removed from the slurry by filtration. 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. 5 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 10 formula IV and its acid addition salts from a compound of formula V. 0 0 0 N N 0

R

4 1 R41 R, R41 NHX Z1 Z XN O (IV) (v) One of ordinary skill will recognize that the compounds of formula IV are a subgenus to those of formula III. The compound of formula V may be prepared from commercially available N 15 Boc L glutanic acid y- benzyl ester. Any suitable method may be used to prepare the 23 WO 01/14329 PCT/USOO/23033 compound of formula V. Preferably, the method disclosed in U.S. Patent Application No. 08/991,739 is used. U.S. Patent Application No. 08/991,739 is herein incorporated by reference in its entirety. The process of the present invention comprises the steps of: 5 (a) cyanomethylation of the compound of formula V using bis(trimethysily)amide and bromoacetonitrile to yield a compound of formula VI; 0 0 0 N R4 (VI) R1 CN XN /> 0 (b) the reduction, cyclization, and deprotection of the compound of formula VI in that respective order to yield a compound of formula VII; and 24 WO 01/14329 PCT/USOO/23033 0 N

R

4 1 (VII) NHX R1 OH (c) the oxidation and olefination of the compound of formula VII by reacting the compound with a S0 3 -pyridine complex to yield a reaction mixture and reacting the reaction mixture with a phosphorane of formula VIII. z PPh 3 < (VIII) z1 5 According to the present invention, and as disclosed above, the preparation of the compound of formula V from N-Boc glutanic acid y- benzyl ester may be carried out by any suitable method known in the art. Further, the cyanomethylation of the compound of formula V may be carried out using any suitable method, reagents and reaction conditions. Preferably, the 10 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 0 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 15 bis(trimethylsilyl)amide and bromoacetonitrile affords the compound of formula VI along with its epimer in a 5:1 ratio. However, the compound may be purified by any 25 WO 01/14329 PCT/USOO/23033 suitable method. Preferably, 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. 5 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 10 cobalt (II) chloride hexahydrate to a solution of the compound of formula VI in tetrahydrofiran 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, p-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. 15 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 crude product may be removed from solution by any suitable method. For example, the crude 20 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 crude compound of formula VII. More preferably, the product is dried over MgSO 4 The crude compound of formula VII may be further purified by 26 WO 01/14329 PCTIUSOO/23033 any suitable purification process. More preferably, the crude compound of formula VII is purified through a titration process using 1:1 ethyl acetate and hexanes. An overall yield of at least about 95% pure compound of formula VII is attainable if the preferred three step reduction, cyclization, and deprotection reaction 5 disclosed above is used. Any suitable method, reagents and reaction conditions may be used in the subsequent oxidation and olefination employing a S0 3 -pyridine complex and the phosphorane of formula VIII to yield the compound of formula IV. Preferably, the method disclosed below and all or some of the reagents and reaction conditions are 10 used. Accordingly, preferably, 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 50 C for at least about 15 minutes. After removing the source used to cool the solution to about 5 0 C, the reaction is stirred for at least about an additional 1 hour. 15 (Carboethoxymethylenetriphenyl)-phosphorane 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 20 preferably, the combined organic phases are washed with saturated brine and dried over MgSO 4 . 27 WO 01/14329 PCTIUSOO/23033 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. 5 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; NHX H3CO OCH3 O R41 R41 O NC NHX H3CO Y X OCH3 (X) 0 R41 R 4 1 0 10 (b) hydrogenation of the compound of formula X to yield an amine of formula XI; 28 WO 01/14329 PCT/USOO/23033 O OCH3 R41 R41 NH 2 . HOAc (XI) XHNg OCH3 0 (c) reacting the amine of formula XI with ET3N to yield a lactam ester of formula XII; N R41 R(XII) XHW N OCH 3 0 (d) the reduction of the lactam ester of formula XII through a suitable reduction 5 procedure to yield a compound of formula XIII; 0 N

R

4 1 R41NN (XIII) XHN OH 29 WO 01/14329 PCTIUSOO/23033 (e) the oxidation and olefination of the compound of formula XIII to yield a compound of formula XIV by reacting it with a compound of formula XV; and 0 N R1R41 (XIV) XHN Z11 Z Z PPh 3 (XV) Z1 5 (f) converting the compound of formula XIV to the compound of formula IV. Further, one of ordinary skill in the art will realize that the above disclosed method may be used to prepare the compound of formula XIV. Specifically, steps (a)-(e) disclose a process for preparing the compound of formula XIV. 10 The compound of formula IX may be prepared by any suitable method known in the art. For example, 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 30 WO 01/14329 PCTIUSOO/23033 Duralski et al, Tetrahedron Lett. 1998, 30, 3585. These references are herein incorporated by reference in their entirety. Preferably, the dianionic alkylation reaction is performed using the method and all or some of the reagents and reaction conditions disclosed below. Therefore, 5 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 10 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. 15 The compound of formula IX may be hydrogenated to the amine of formula XI by any suitable method known in the art. Preferably, 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. According to this preferred hydrogenation method, the 20 compound of formula IX is dissolved in HOAc and shaken with 5% 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. 31 WO 01/14329 PCT/USOO/23033 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 5 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 H NMR. After stripping off the solvent, methyl tert-butyl ether is added. The precipitate is then filtered. 0.5 M HCl is added to the filtrate diluted with H 2 0. After splitting the phases, the aqueous phase may be extracted with ethyl acetate. The 10 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 15 formula XII to the compound of formula XIII. Preferably, 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. Thus, more preferably, LiBH 4 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 20 mixture is stirred at 00 C for 10 minutes, before being allowed to warm to ambient temperature and stirred for an additional 2 hours. Then, the reaction is quenched. Even more preferably, 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 0. After splitting the phases, the aqueous phase may be extracted with ethyl acetate. The 32 WO 01/14329 PCT/USOO/23033 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. 5 Any suitable oxidation and olefination method may 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 reagents 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 10 of the compound of formula XIII in CH 2 CI2. 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 IH NMR. Saturated NaHCO 3 solution is added before the mixture is stirred for 30 15 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 crude 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 crude compound of formula XIV. More preferably, the crude compound of formula XIV is purified by flash 20 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. 33 WO 01/14329 PCT/USOO/23033 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. EXAMPLES: 5 The following illustrates an example of the amide-forming reaction between two compounds falling within the scope of formulae II and III to prepare a compound falling within the scope of formula I. Specifically, this example, as depicted in Scheme 1 below, illustrates the reaction of 1 with 2 to prepare the protease inhibitor AG7088. Scheme I 0 0 0 0 NH NH N OH TFA, CH2C1 2 0 O H 2 N BocHN

CO

2 Et

CO

2 Et 2 1A HATU, DIPEA

CH

3 CN, HO O H 0 0 N _ N H H 0 0

CO

2 Et AG7088 C F 10 34 WO 01/14329 PCT/USOO/23033 The following examples disclose the preparation of compound 1 falling within the scope of formula IV. The first example, as depicted in Scheme 2 below, illustrates the use of the cyanomethylation route disclosed above. The second example, depicted in Scheme 3 below, illustrates the second more preferable cost effective route for 5 preparing the same compound. Scheme 2 0 0 0 0 N 0 N: NaHMDS, THF, -78 0 C CN BocN Bromoacetonitrile 60% BocN 3, N-Acyloxazolidinone 1. NaBH 4 , CoCl 2 .6H 2 0 MeOH:THF, 0 0 C-rt. 47% over 3 steps 0.5M HCl, EtOAc 2. pTSA, MeOH, 18 h 3. EtOAc, aq, MeOH 4. Hexanea/EtOAc 0O NH NH 1. Et 3 N, S0 3 -Pyridine, DMSO 2. Ph 3

P=CHCO

2 Et 3. Brine, EtOAc then column chromatography BocHN 55-61% BocHN HO

CO

2 Et 1 5 35 WO 01/14329 PCT/USOO/23033 Scheme 3 NC HBoc NHBoc H 2 , 50 psi, Pd/C, 2 eq. LiHMDS, -78 0 C HOAc, rt., 3 days

H

3 CO

OCH

3 H 3 CO

OCH

3 58% 6 7 0 OCH 3 0 NH ET N, MeOH/THF, 45 C, 10 h LiBH 4 , THF,

NH

2 .HOAc 0 0 C, then rt., 2 h

OCH

3 60%

OCH

3 83% BocHN BocHN o 0 8 9 0 NH NH 1. Ph 3 CHCOOEt, PhCOOH, CH 2

CI

2 , DMSO 2. Dess-Martin periodineane BocHN 0 OH 5 OH rt.. 5h COOEt OAc 55% Preparation of 4 (Scheme 2) A solution of 3 (1.0 kg, 2.34 mol, 1.0 equiv.) in THF (8.0 L) was added dropwise to a stirring solution of NaHMDS in THF (IM in THF, 2.96 L, 1.28 equiv.) at -70"C in a nitrogen atmosphere over a period of 5 hours. The resulting solution was stirred at -70"C for 0.5 hours and freshly distilled bromoacetonitrile (320 mL, 2.0 equiv.) was then added dropwise over a period of 25 minutes. The reaction mixture was stirred at -70"C for additional 1 hour until the disappearance of the starting material 3. The reaction was quenched by addition of saturated ammonium chloride 36 WO 01/14329 PCT/USOO/23033 solution (7.0 L), and extracted with methyl tert-butyl ether (24 L). The organic phase was washed with brine (3X6.0 L). The solvent was removed under reduce pressure to afford a dark brown oil (1.5 kg). This crude product was dissolved in methylene chloride (8.0 L) and passed over a bed of silical gel (600 g) and activated carbon (250 5 g). After rinsing the cake with methylene chloride (4.0 L), the filtrate was concentrated on a rotary evaporator to afford a light brown oil (1,28 Kg), which was then dissolved in ethyl acetate (2.5 L). To the resulting solution, excess hexanes (14.5 L) were added under vigorous stirring and a white solid precipitated out in 30 minutes. The slurry was cooled with an ice-water bath and stirred for 4.5 hours, followed by 10 filtration to afford 4 as a light brown solid (662 g, 60%): 'H NMR (CDCl 3 ) 6 1.46 (s, 3 H), 1.49 (s, 9 H), 1.59 (s, 3 H), 1.75-1.95 (in, 1 H), 2.15-2.31 (m, 1 H), 2.55-3.15 (in, 3 H), 3.36 (d, J= 10.8 Hz, 1 H), 3.62-4.10 (in, 3 H), 4.13-4.32 (in, 3 H), 4.70 (in, 1 H), 7.15-7.42 (in, 5 H). Preparation of 6 (Scheme 3) 15 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) according to literature procedures. Preparation of 7 (Scheme 3) A solution of N-Boc L-(+)-glutamic acid dimethyl ester (6, 10 g, 36.3 mmol, 1 20 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 37 WO 01/14329 PCT/USOO/23033 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 0 (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 5 NaHCO 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). Flash chromatography over silica gel (3 : 1 hexanes/ethyl acetate) afforded a colorless oil (7, 6.67 g, 10.8 mmol, 58%): 1 H NMR (CDCl 3 ) 6 1.46 (s, 9 H), 2.12-2.24 (in, 2 H), 2.77 2.82 (in, 2 H), 2.85-2.91 (in, 1 H), 3.78 (s, 3 H), 3.79 (s, 3 H), 4.32-4.49 (in, 1 H), 5.13 10 (d, J= 6.0 Hz, 1 H); 13 C NMR (CDC13) 6 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 C 2

H

22

N

2 0 4 , 314.1486). Preparation of 8 (Scheme 3) Compound 7 (4.60 g, 14.6 mmol) was dissolved in HOAc (120 mL) and 15 shaken with 5% Pd on C (20 g) under H 2 gas (50 psi) for 3 days. The mixture was filtered over Celite. The filtrate was evaporated under reduced pressure and the residue was repeatedly evaporated from methyl tert-butyl ether to yield a light pink solid (8, 8.32 g), which was used directly in the next step. 1H NMR (CD 3 0D) 6 1.47 (s, 9 H), 1.85-2.10 (in, 4 H), 2.60-2.62 (in, 1 H), 2.92-2.96 (in, 2 H), 3.74 (s, 3 H), 3.77 20 (s, 3 H), 4.22-4.26 (in, 1 H); Note: Experiments have demonstrated that less 5% Pd on C can drive the reaction to completion, i.e., 1 g of 5% Pd on C was efficient for the reduction of 2 g of 7. Preparation of 9 (Scheme 3) 38 WO 01/14329 PCT/USOO/23033 Crude 8 was dissolved in 1:1 MeOH/THF (40 mL) and Et 3 N (7 mL) was added to the solution. The resulting mixture was stirred at 45'C for 10 hours until the disappearance of the starting material monitored by 'H NMR. After stripping off the solvent on a rotovapor, methyl tert-butyl ether (200 mL) was added and a white solid 5 precipitated out. The solid precipitate was removed by filtration. The filtrate was diluted with 200 mL of H 2 0 followed by addition of 0.5 M HCl (5 mL). The phases were split, 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 MgSO 4 , filtered and concentrated on a rotovapor to give a light brown oil. Flash 10 chromatography furnished a white solid (9, 2.5 g, 8.74 mmol, 60%): 'H NMR (CDCl 3 ) 6 1.37 (s, 9 H), 1.75-1.80 (in, 2 H), 2.04-2.09 (in, 1 H), 2.39-2.42 (in, 2 H), 3.25-3.29 (in, 2 H), 3.67 (s, 3 H), 4.23-4.26 (in, 1 H), 5.47 (d, J= 8.0 Hz, 1 H), 6.29 (s, 1 H); 13C NMR (CDCl3) 6 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 C 13

H

22

N

2 0 5 , 286.1587). 15 Preparation of 5 from 4 (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 20 reaction mixture was allowed to warm to ambient temperature and stirred for 20 hours while being monitored by TLC for the disappearance of the starting material (4). 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 39 WO 01/14329 PCT/USOO/23033 the organic phases were combined, washed with brine (1X3.0 L), concentrated on a rotary evaporator to afford a crude material (440 g), which was used directly in the following hydrolysis reaction. To a solution of the crude material (440 g, 1 equiv.) in methanol (800 mL) was added p-toluensulfonic acid monohydrate (4.0 g, 0.015 5 equiv.). The reaction was stirred at ambient 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 bicarbonate (2X100 mL). The combined aqueous phases were extracted with ethyl acetate (2X200 mL). All the organic phases were combined, concentrated on a rotary evaporator to afford 275 g of the crude product, 10 which was charged with a solution of 2.5% methanol (20 mL) in water (780 mL) and stirred at ambient temperature overnight. The granular solid (chiral auxiliary) was removed by filtration and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in ethyl acetate (1.5L), dried over MgSO 4 , filtered and concentrated to afford a viscous oil. The oil was further purified through a titration 15 process using 1: 1 ethyl acetate (1 L) and hexanes (1 L) to afford 5 as a white solid (104 g, 47% overall yield from 4). Preparation of 5 from 9 (Scheme 3) To a stirring solution of 9 (1.75 g, 6.10 mmol) in THF (40 mL) was added LiBH 4 (270 mg, 12.2 mmol, 2 equiv.) in several portions at 0C in an Argon 20 atmosphere. The reaction mixture was stirred at 0"C for 10 minutes, then allowed to warm to ambient temperature and stirred for additional 2 hours. The reaction was quenched by the dropwise addition of 0.5 M HCl (24 mL) with cooling in an ice bath (Note: formation of gases was observed). The solution was diluted with ethyl acetate (100 mL) and H 2 0 (50 mL). The phases were split, and the aqueous layer was 40 WO 01/14329 PCT/USOO/23033 extracted with ethyl acetate (6 x 150 mL). The combined organic phases were dried over MgSO 4 , filtered and concentrated on rotovapor to give a light brown oil. Flash chromatography afforded a white solid (5, 1.308 g, 5.06 mmol, 83%): 'H NMR (CDCl 3 ) 6 1.46 (s, 9 H), 1.61-1.67 (in, 1 H), 1.82-1.91 (in, 1 H), 1.94-2,00 (in, 1 H), 5 2.43-2.48 (in, 1 H), 2.49-2.55 (in, 1 H), 3.32-3.34 (in, 3 H), 3.58-3.66 (in, 2 H), 3.68 3.79 (in, 2 H), 5.47 (d, J= 7.0 Hz, 1 H), 6.24 (s, 1 H); 13 C NMR (CDCl 3 ) 6 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

C

13

H

22

N

2 0 5 , 258.1650). Preparation of 1 from 5 10 Procedure A (Scheme 2) To a solution of 5 (50.0 g, 0.184 mol, 1 equiv.) methylsulfoxide (500 mL) was added triethylamine (116 mL). The resulting solution was cooled to 5"C with an ice bath, followed by addition of sulfur trioxide-pyridine complex (132 g). The reaction was stirred at that temperature for 15 min. The cold bath was removed and the 15 reaction was stirred for additional 1 hour. (Carboethoxymethylenetriphenyl) phosphorane (112 g) was added in one lot and the reaction was stirred at ambient temperature for 3 hours. The reaction was quenched by 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 MgSO 4 , filtered and concentrated to 20 afford a dark red oil. The oil was purified through a chromatography, followed by a titration process using ethyl acetate (60 mL) and excess of hexanes (240 mL). 1 was obtained as a white solid (36.0 g, 60%). Procedure B (Scheme 3) 41 WO 01/14329 PCT/USOO/23033 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.), (carboethoxymethylenetriphenyl)phosphorane (5.39g, 15.5 mmol, 4 equiv.) and DMSO (4.8 mL). Dess-Martin periodinane (4.1 g, 9.17 mmol, 2.5 equiv.) was added 5 in several portions to the solution, and the reaction mixture was then stirred for 5 hours at ambient temperature until the disappearance of the starting material 5. Saturated NaHCO 3 solution was added, and the mixture was stirred for 30 minutes. A white solid precipitated out, which was then filtered off. The organic phase of the filtrate was separated, washed with brine (250 mL), and concentrated on rotovapor to give a 10 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). Excess hexanes (12 mL) was added gradually to the stirring solution and a white solid precipitated out. The solid was filtered and dried in vacuum oven overnight to afford 1 (0.69g, 2.11 mmol, 55%). Chiral HPLC: 97% pure, 98% de and 100% E isomer; 1H NMR (CDCl 3 ) 6 1.22 15 (t, J = 7.2 Hz, 3 H), 1.38 (s, 9 H), 1.53-1.58 (in, 1 H), 1.66-1.84 (in, 1H), 1.85-2.00 (in, 1 H), 2.30-2.50 (in, 2 H), 3.20-3.37 (in, 2H), 4.13 (q, J= 7.2 Hz, 2 H), 4.20-4.35 (in, 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 16

H

26

N

2 0 6 , 326.1840). Preparation of AG7088 from 1 and 2 (Scheme 1). 20 751 mg of compound 1 was dissolved in DCM (10 mL/g of 1) in a single neck round bottom flask and cover with a septum. The flask was then purged with nitrogen followed by the addition of 1.4 mL TFA via syringe while the solution was being stirred. The progress of the reaction was monitored by TLC using 5% MeOH in DCM until after about 4 hours the starting material disappeared. The solvent and excess 42 WO 01/14329 PCT/USOO/23033 TFA were removed under vacuum at pressure of <50 mTorr @ 45'C. The product, compound 1A, was used immediately in the step set forth below. Compounds 1A and 2 were dissolved in DMF (7 mL/g of 2) in a single neck flask covered with a septum and fitted with a temperature probe. The flask was purged 5 with nitrogen. The resulting solution was divided into two portions. In a first portion was added 1.6 mL n-methylmorpholine via syringe and cooled to 0 0 C ± 5'C. In a second portion of the solution 281 mg CDMT was dissolved. This CDMT solution was then added dropwise via syringe to the first portion of the solution, maintaining the reaction temperature of 0 0 C ± 5'C. The resulting reaction mixture was then 10 allowed to warm to room temperature. The reaction was monitored for about 1 hour by TLC (7:3:1 hexanes:EtOAc:IPA) until the compound 2 disappeared. Once the reaction was complete the product AG7088 was precipitated out of solution by the slow addition of water to reaction mixture. The resulting slurry was filtered to obtain a yield of >85% white granular crystals of compound AG7088 having a purity of 15 >97%. The product may then be recrystallized by dissolving it in hot MeOH:EtOAc 1:1 followed by slow addition of hexanes (2 vols.) It is to 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 artisan will recognize 20 apparent modifications and variations that may be made without departing from the spirit of the invention. Thus, the invention is intended to be defined not by the above description, but by the following claims and their equivalents. 43

Claims (25)

1. A process useful in synthesizing antipicomaviral compounds, comprising: (a) performing cyanomethylation of a compound of formula V using bis(trimethysily)amide and bromoacetonitrile to yield a compound of 5 formula VI; 0 0 0 N R41 XN 0 0 0 O N 11 CN(VI) NX > 0 (b) performing reduction, then cyclization, and then deprotection of the compound of formula VI to yield a compound of formula VII; and 0 NH R41 (VII) R, NHX OH 44 WO 01/14329 PCTIUSOO/23033 (c) performing oxidation and olefination of the compound of formula VII by reacting the compound of formula VII with a S0 3 -pyridine complex to yield a reaction mixture and reacting the reaction mixture with a compound for formula VIII to form a compound of formula IV: Z 0 PPh 3 (VIII) NH R41 (FV) R1 NHX Z1 Z 5 wherein R 1 is H, F, an alkyl group, OH, SH, or an O-alkyl group; where each R is independently H or lower alkyl; and X is any suitable protecting group for nitrogen.

2. The process of claim 1, wherein the compound of formula V is prepared from 10 N-Boc L glutanic acid y-benzyl ester.

3. The process of claim 1, wherein X is a Boc group.

4. The process of claim 1, wherein R 41 is H.

5. The process of claim 1, wherein Zi is H.

6. The process of claim 1, wherein Z is -COOEt. 15

7. A process useful in synthesizing antipicornaviral compounds according to claim 1, further comprising the steps of: (d) deprotecting the compound of formula IV to yield a compound of formula IVA: 20 45 WO 01/14329 PCT/USOO/23033 0 NH R4, R 4 1 (IVA) R1 H 2 N Z, z and (e) subjecting a compound of formula II and the compound of formula IVA to 5 an amide-forming reaction to yield a compound of formula IA: H O N 0 R 4 0 4 z OH (II) R O R6 N Z1 (IA) H R 6 R, wherein R 2 and R 3 are each independently H; OO A 4 ; or C A A (A3)n A 2 NH 2 (R 4 1 )(R 4 1 ) 10 where n is an integer from 0 to 5, A 1 is CH or N, A 2 and each A 3 are independently selected from C(R 41 )(R 4 1 ), N(R 4 1 ), S, S(O), S(O) 2 , and 0, and A 4 is NH or NR 4 1 , where each R41 is independently H or lower alkyl, provided that no more than two 46 WO 01/14329 PCT/USOO/23033 heteroatoms occur consecutively in the above-depicted ring formed by A 1 , A 2 , (A 3 )n, A 4 and C=O, and at least one of R 2 and R 3 is 0 A 4 0 ;or A,,,, A (A 3 )n or A2~ NH 2 (R 41 )(R 41 ) R 4 is 0 R 7 R9R 0 5 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 17 , -SR 1 7 , -NR 1 7 Ri 8 , 10 -NR 1 9 NR 1 7 RI 8 , or -NR 1 7 0RI 8 , where R 1 7 , R 18 , and R 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 R 7 and R 8 is an alkyl group, an aryl group, a heteroaryl group, -OR 17 , -SR 17 , -NR 1 7 R 18 , -NR 19 NR 17 R 1 8 , or -NR 1 7 0R 18 ; R 9 is a five-membered heterocycle having from one to three heteroatoms selected from 15 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(O)R 21 , -C0 2 R 21 , CN, -C(O)NR 2 1 R 22 , -C(O)NR 21 0R 22 , -C(S)R 21 , -C(S)NR 2 1 R 22 , -NO 2 , -SOR 21 , -S0 2 R 21 , -S0 2 NR 2 1 R 22 , -SO(NR 2 1)(OR 22 ), -SONR 21 , -S0 3 R 21 , -PO(OR 21 ) 2 , -PO(R 21 )(R 22 ), 47 WO 01/14329 PCTIUSOO/23033 -PO(NR 2 1 R 22 )(OR 2 3 ), -PO(NR 21 R 22 )(NR 23 R 2 4 ), -C(O)NR 21 NR 22 R 23 , or -C(S)NR 21 NR 22 R 23 , where R 21 , 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, an acyl group, or a thioacyl group, or where any of two of R21, R 22 , R 23 , and R 24 , 5 together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z 1 are not both H; or Z 1 and R 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where ZI and Riare as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group; 10 or Z and Z 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Zi are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group.

8. The process of claim 7, wherein X is a Boc group.

9. The process of claim 7, wherein compound IV is 0 NH BocHN CO 2 Et 15

10. The process of claim 7, wherein the compound of formula II is 48 WO 01/14329 PCT/USOO/23033 N N OH F

11. The process of claim 7, wherein the compound of formula IVA is G NH H2N CO2Et

12. The process according to claim 7, wherein the compound of formula IA is N o 0 N- N N H H 00 COOEt F 5

13. A process useful in synthesizing antipicornaviral compounds, comprising: (a) performing dianionic alkylation of a compound of formula IX using bromoacetonitrile to prepare a compound of formula X; NC NHXNH H 3 CO OCH 3 (IX) H 3 CO NHX OCH 0 01 01 R 41 0 (b) performing hydrogenation of the compound of formula X to yield an amine 10 of formula XI; 49 WO 01/14329 PCT/USOO/23033 0 OCH 3 R4, R41 NH 2 . HOAc (XI) OCH 3 XHN 0 (c) reacting the compound of formula XI with ET 3 N to yield a lactam ester of formula XII; 0 N R4, 41 (XII) OCH3 XHN 0 5 (d) performing reduction of the lactam ester of formula XII to yield a compound of formula XIII: 0 N R41 R41 (XIII) XHN ; and OH (e) performing oxidation and olefination of the compound of formula XIII to yield a compound of formula XIV by reacting it with a compound of formula 10 XV: z PPh 3 (XV) Z5 50 WO 01/14329 PCT/USOO/23033 0 N R 4 1 (XIV) XHN Z1 Z wherein each R41 is independently H or lower alkyl; Z and Z 1 are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -C(O)R 21 , -C0 2 R 2 1 , CN, 5 -C(O)NR 2 1 R 22 , -C(O)NR 2 1 0R 22 , -C(S)R 21 , -C(S)NR 21 R 2 2 , -NO 2 , -SOR 21 , -S0 2 R 21 , -S0 2 NR 2 1 R 22 , -SO(NR 21 )(OR 22 ), -SONR 21 , -S0 3 R 21 , -PO(OR 21 ) 2 , -PO(R 21 )(R 22 ), -PO(NR 2 1 R 22 )(OR 23 ), -PO(NR 21 R 22 )(NR 23 R 24 ), -C(O)NR 21 NR 22 R 23 , or -C(S)NR 2 1 NR 22 R 23 , where R 21 , R 22 , R 2 3 , and R 24 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, 10 an acyl group, or a thioacyl group, or where any of two of R 21 , R 22 , R 23 , and R 24 , together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z 1 are not both H; or Z and ZI, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z 1 are as defined above except for moieties that 15 cannot form the cycloalkyl or heterocycloalkyl group; and X is any suitable protecting group for nitrogen.

14. The process useful in synthesizing antipicornaviral compounds according to claim 13, further comprising: 51 WO 01/14329 PCT/USOO/23033 preparing a compound of formula IV by converting the compound of formula XIV to yield the compound of formula IV: 0 N R 41 (IV) R1 NHX Z1 Z wherein R 1 is H, F, an alkyl group, OH, SH, or an O-alkyl group.

15. The process useful in synthesizing antipicornaviral compounds according to claim 5 14, further comprising: Step A: deprotecting the compound of formula IV to yield a compound of formula IVA: 0 N R41 R41 (IVA) R1 H 2 N ; and Z1 Z Step B: subjecting a compound of formula II and the compound of formula 10 IVA to an amide-forming reaction to yield a compound of formula IA: O N 0 R OH R4 0) N Z 1 (A) H R6 R1 52 WO 01/14329 PCT/USOO/23033 wherein R 2 and R 3 are each independently H; 0 A 4 0 or A A (A 3 )n SNH 2 (R 41 )(R 41 ) where n is an integer from 0 to 5, A 1 is CH or N, A 2 and each A 3 are independently selected from C(R 41 )(R 4 1 ), N(R 4 1 ), S, S(O), S(O) 2 , and 0, and A 4 is NH or NR41, 5 where each R 4 1 is independently H or lower alkyl, provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A 1 , A 2 , (A 3 ), A 4 and C=O, and at least one of R 2 and R 3 is 0 A 4 0 A, (A 3 )n or A 2 NH 2 (R41)(R 41 ) R 4 is 0 R, R9) N R R 8 0 10 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 17 , -SR 17 , -NR 17 Ris, 15 -NR 19 NR 1 7 Ris, or -NR 7 0Ri 8 , where R 17 , Ris, and R 19 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl 53 WO 01/14329 PCT/USOO/23033 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 17 , -SR 17 , -NR 1 7 Ri 8 , -NR 1 9 NR 17 Ri 8 , or -NR1 70Ris; R 9 is a five-membered heterocycle having from one to three heteroatoms selected from 0, N, and S; 5 Z and Zi are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -C(O)R 21 , -C 2 R 2 1 , CN, -C(O)NR 21 R 22 , -C(O)NR 21 OR 22 , -C(S)R 21 , -C(S)NR 21 R 22 , -NO 2 , -SOR 21 , -S0 2 R 21 , -S0 2 NR 21 R 22 , -SO(NR 2 1 )(OR 22 ), -SONR 21 , -S0 3 R 21 , -PO(OR 21 )2, -PO(R 21 )(R 22 ), -PO(NR 21 R 22 )(OR 23 ), -PO(NR 21 R 22 )(NR 23 R 24 ), -C(O)NR 21 NR 22 R 23 , or 10 -C(S)NR 21 NR 22 R 23 , where R 21 , 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, an acyl group, or a thioacyl group, or where any of two of R 21 , R 22 , R 23 , and R 2 4 , together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z, are not both H; 15 or Z 1 and R 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z 1 and Riare as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group; or Z and Z 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Zi are as defined above except for moieties that 20 cannot form the cycloalkyl or heterocycloalkyl group.

16. The process of claim 13, wherein X is a Boc group.

17. The process of claim 13, wherein R 4 1 is H.

18. The process of claim 13, wherein Z 1 is H.

19. The process of claim 13, wherein Z is -COOEt. 54 WO 01/14329 PCT/USOO/23033

20. The process of claim 14, wherein R 1 is H.

21. A process useful for the synthesis of a compound of formula IA', and acid addition salts thereof: O H N 0 0 N N N H H COOEt F 5 comprising the steps of: Step A: preparing a compound of formula IV': 0 NH BocHN CO 2 Et comprising: (a) performing cyanomethylation of a compound of formula V' using bis(trimethysily)amide and bromoacetonitrile to yield a compound of formula 10 VI'; 0 0 0 N (v) BocN 0 55 WO 01/14329 PCT/USOO/23033 (b) performing reduction, then cyclization, and then deprotection of the compound of formula VI' to yield a compound of formula VII'; and 0 0 0 N 0 CN (Vl') NH BocN 0 (VI) BocHN OH 5 (c) performing oxidation and olefination of the compound of formula VII by reacting the compound with a S0 3 -pyridine complex before the resulting reaction mixture is reacted with Ph 3 P=CHCO 2 Et; 56 WO 01/14329 PCT/USOO/23033 Step B: deprotecting the compound of formula IV to yield a compound of formula IVA': 0 NH (VA') H 2 N CO 2 Et and Step C: subjecting a compound of formula II' and the compound of formula 5 formula IVA' to an amide-forming reaction; 0 0 N-OH ) F

22. The process of claim 21, wherein the compound of formula V is prepared from N Boc L glutanic acid Y-benzyl ester.

23. A process useful in synthesizing antipicornaviral compounds, comprising: 10 (a) performing dianionic alkylation of a compound of formula IX' using bromoacetonitrile to prepare a compound of formula X'; NHBoc H 3 CO OCH 3 (aI) 0 0 NC NHBoc H 3 CO OCH 3 (X) 0 0 57 WO 01/14329 PCT/USOO/23033 (b) performing hydrogenation of the compound of formula X' to yield an amine of formula Xl'; 0 OCH 3 NH 2 .HOAc(XI) OCH 3 BocHN 0 (c) reacting the compound of formula XI' with ET 3 N to yield a lactam ester of formula 5 XII'; 0 NH (XII') OCH 3 BocHN 0 (d) performing reduction of the lactam ester of formula XII' to yield a compound of formula XIII': 0 NH (XIII') BocHN and OH 10 (e) performing oxidation and olefination of the compound of formula XIII' to yield a compound of formula XIV' by reacting it with Ph 3 P=CHCO 2 Et; 58 WO 01/14329 PCTJUSOO/23033 0 NH BocHN CO 2 Et

24. The process useful in synthesizing antipicornaviral compounds acording to claim 23, further comprising: converting the compound of formula XIV' to the compound of formula IV'; 5 0 NH (IV') BocHN CO 2 Et

25. The process useful in synthesizing antipicornaviral compounds acording to claim 10 24, further comprising: Step A: deprotecting the compound of formula IV' to yield a compound of formula IVA': 0 NH (VA') H 2 N CO 2 Et 59 WO 01/14329 PCTUSOO/23033 ; and Step C: subjecting a compound of formula II' and the compound of formula IVA' to an amide-forming reaction; 0 0 N......OH (f1) 07~ 0 5 60