Indian Patents. 218848:PROCESS FOR PREPARING INTERMEDIATES

Title of Invention	PROCESS FOR PREPARING INTERMEDIATES
Abstract	"PROCESS FOR PREPARING INTERMEDIATES' The present invention relates to a process for preparing intermediates that are useful to prepate certain antibacterial N-formyf hydroxylamine compounds which are peptide deformylase inhibitors, The process makes use a p-lactam intermediate. Certain optically pure intermediates are also claimed.

Full Text	5 INTERMEDIATES This invention is directed to a process for preparing intermediates that are useful to prepare certain antibacterial A/-formyl hydroxylamine compounds. Peptide deformylase is a metallopeptidase found in prokaryotic organisms such as bacteria. Protein synthesis in prokaryotic organisms begins with W-formyl methionine (fMet). After initiation of protein synthesis, the formyl group is removed by the enzyme peptide deformylase (PDF); this activity is essential for maturation of proteins. It has been shown that PDF is required for bacterial growth (see Chang et al., J. Bacterid., Vol. 171, pp. 4071-4072 (1989); Meinnel et al., J. Bacterid., Vol. 176, No. 23, pp. 7387-7390 (1994); Mazel et al.,EMBOJ., Vol. 13, No. 4, pp. 914-923 (1994)). Since protein synthesis in eukaryotic organisms does not depend on fMet for initiation, agents that will inhibit PDF are attractive candidates for development of new anti-microbial and anti-bacterial drugs. Co-pending Application Serial No. 10/171,706, filed June 14, 2002 (incorporated herein by reference in its entirety) and WO02/102790, disclose novel A/-formyl hydroxylamine compounds that inhibit PDF and are therefore useful as antibacterial agents. The compounds disclosed therein are certain W-[1-oxo-2-alkyl-3-(N-hydroxyformamido)-propyl]-(carbonylamino-aryl or -heteroaryl)-azacyclo4-7alkanes or thiazacyclo4.7alkanes which are described in more detail hereinafter. An improved process has been discovered for preparing intermediates useful for preparing these N-[1-oxo-2-alkyl-3-(A/-hydroxyforrnamido)-propyl]-(carbonylamino-aryl or -heteroaryl)-azacyclo4.7alkanes or thiazacycl04.7alkanes which makes use of a particular p-lactam intermediate. The present invention is directed to a novel process for preparing certain intermediates which are useful to prepare certain N-formyl hydroxylamine compounds which are useful for inhibiting bacteria. More specifically, the present invention is directed to a process for preparing a compound of the formula (VIII) comprising Step A: contacting a compound of the formula (I) with a compound of the formula (II) (ID in the presence of a carboxy-activating agent, in a suitable solvent under conditions suitable to form a compound of the formula (III) followed by Step B: contacting compound (111) with a compound of the formula (XIII) (XIII) a suitable solvent, under conditions suitable to form a compound of the formula (IV) followed by Step C: contacting compound (IV) with a base in a suitable solvent under conditions suitable to form a compound of the formula (V) followed by Step D: contacting compound (V) with a compound of the formula (VI) in a suitable solvent optionally in the presence of an activator under conditions suitable to form a compound of the formula (Vll) followed by Step E: contacting compound (VII) with a formylating agent in a suitable solvent under conditions suitable to form compound (Vlll); wherein Y is a hydroxy protecting group; each of R2, R3, R4 and R5 is independently hydrogen or an aliphatic group, or (R2 and R3) and/or (R4 and R5) collectively form a C4-7cycloalkyl; X is -CH2-, -S-, -CH(OH)-, -CH(OR)-, -CH(SH)-, -CH(SR)-, -CF2-, -C=N(OR)- or -CH(F)-; wherein R is alkyl; G is -OH or -OeM®, wherein M is a metal or an ammonium moiety; Ri is aryl or heteroaryl; X' is halo; R' is alkyl or aryl; and n is 0 to 3, provided that when n is 0, X is -CH2-. When the desired product is an A/-oxide of an aromatic moiety having a nitrogen heteroatom, e.g., when R1, is formula (X), (Xla) or (Xb), typically a pyridine derivative, it is necessary to perform an additional step after Step E, i.e., to oxidize the N of the aromatic ring (Step F). Therefore, the present invention includes Step F which comprises contacting the compound of formula (Vlll), wherein R1 is heteroaryl having an N heteroatom, with an oxidizing agent to form the corresponding W-oxide derivative. In addition to the above process comprising Steps A through E or F, the present invention is directed to each of the steps individually, and to any two or more sequential steps. Detailed Description of the Invention In particular, the present invention provides a process for preparing intermediates useful in the preparation of a A/-[1-oxo-2-alkyl-3-(A/-hydroxyformamido)-propyl]- (carbonylamino-aryl or-heteroaryl)-azacyclo4-7aikane or thiazacyclo4-7alkane, e.g., a compound of formula (IX) wherein R1, R2, R3, R,,RS, X and n are as defined above. To convert the compound of formula (VIII) to the compound of formula (IX), the hydroxy protecting group is removed using conventional hydrogenolysis techniques known in the art, e.g., by contacting the compound of formula (VIII) with a palladium catalyst, such as Pd/BaS04. The R1-i moiety can be a heteroaryl, e.g., an azacyclo4-7alkane, a thiazacyclo4-7alkane or an imidazacyc^alkane. Specific examples of R, moieties in the compounds disclosed herein are heteroaryls of formula (X) wherein each of Re, R7, RB and R9, independently, is hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, acyl, acyloxy, SCN, halogen, cyano, nitro, thioalkoxy, phenyl, heteroalkylaryl, alkylsulfonyl or formyl. A more specific R1 moiety is a heteroaryl of formula (Xla) wnerein R6, R7, R8 and R9 are as defined above for formula (X), e.g., wherein a) R6 is nitro, alkyl, substituted alkyl, phenyl, hydroxy, formyl, heteroalkylaryl, alkoxy, acyl or acytoxy; preferably alkyl, especially C1-7alkyl; hydroxyl; or alkoxy, especially a C1-7alkoxy; and R7, RB and R9 are hydrogen; or b) R6, Re and R9 are hydrogen; and R7 is alkyl, substituted alkyl, phenyl, halogen, alkoxy or cyano, preferably alkyl, especially C1-7alkyl; substituted alkyl, especially substituted C1-7alkyl, such as -CF3; or alkoxy, especially C1-7alkoxy; or c) R8, R7 and R9 are hydrogen; and R8 is alkyl, substituted alkyl, halogen, nitro, cyano, thioalkoxy, acyloxy, phenyl, alkylsulfonyl or carboxyalkyl, preferably alkyl, especially C^alkyl; substituted alkyl, especially -CF3; halogen such as chloro, bromo or fluoro; or carboxyalkyl; or d) R6, Rz and Ra are hydrogen; and R9 is alkyl, halogen or hydroxy; or e) R7 and R9 are hydrogen'; and each of Rg and R8, independently, is halogen, alkyl, substituted alkyl, phenyl or cyano; or f) Each of R7 and R9 is aikyl or substituted alkyl; and R6 and R8 are hydrogen; or g) R6 and R9 are hydrogen; R7 is alkyl or substituted alkyl; and R8 is nitro; or h) R8 and R9 are hydrogen; RB is cyano; and R7 is alkoxy; or i) R7 and R8 are hydrogen; and R6 is alkyl, substituted alkyl, alkoxy or SCN; and R9 is alkyl or substituted alkyl; or j) R6 and R7 are hydrogen; R8 is nitro or halogen; and Rg is alkyl or substituted alkyl; or k) Re, R7, Rg and R9 are hydrogen; or I) R6 and R7 together with the carbon atoms to which they are attached form a phenyl group, preferably substituted with hydroxy; and RB and R9 are hydrogen; or m) R6 and R7 are hydrogen; and Re and R9 together with the carbon atoms to which they are attached form a phenyl group; or n) n is 0; or 0) n is 0; each of R6, R7, Ra and R9, independently, is hydrogen, alkyl or halogen; and more particularly, Rg, R7, R8 and R9 are hydrogen; or p) n is O; R6, R8 and R9 are hydrogen; and R7 is alkyl; or q) n is 0; RB, R7 and Rg are hydrogen; and RB is alkyl or halogen. In another embodiment, R, is of formula (Xb) wherein Re, R7, RB and R9 are as defined above for formula (X); in particular, R7 and R8 together with the carbon atoms to which they are attached form a phenyl group; and R6 and Rg are hydrogen. In yet another embodiment, the R1 is of formula (XI) wherein each of R6, R7, R8 and R9 independently is hydrogen, alkyl, substituted alkyl, phenyl, halogen, hydroxy or alkoxy, e.g., wherein a) Re and Raare hydrogen; Rg is hydrogen or alkyl; and R7 is alkyl, substituted alkyl or phenyl; or b) R8, R7 and R9 are hydrogen; and R8 is halogen, alkyl or substituted alkyl; or c) R7, Ra and R9 are hydrogen; and R6 is hydroxy. In a particularly useful embodiment the heteroaryl is of the formula (Xla) wherein Re, R7, Ra and R9 are as defined above for formula (XI), in particular where Rs, R7, and R9 are hydrogen and R8 is fluoro. In another embodiment, R1 is an unsubstituted phenyl or the phenyl is substituted with alkoxy, e.g., methoxy; or aryloxy, e.g., phenoxy. In another embodiment, the R, is of formula (XII) wherein each of R10 and R„, independently, is hydrogen or halogen. In particular, R10 and Rii are both either hydrogen or both halogen. In the compound of formula (I), M is a metal, typically a mono- or di-valent metal or an ammonium moiety. Typical metals include Mg, Ca, Na, K, Li and the like. The ammonium moiety is of the formula wherein R" is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl. The ammonium moiety can be racemic or chiral. An example of an ammonium moiety is R-ct-methylbenzylammonium. Examples of R" groups include hydrogen, methyl, ethyl, propyl, butyl, phenyl, benzyl, methylbenzyl and the like. Unless otherwise stated, the following terms as used in the specification have the following meaning. The term "cycloalkane" or "cycloalkyl" contains from 3- to 7-ring carbon atoms, and is, e.g., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "azacyclo4.7alkane" contains 1-ring heteroatom which is a nitrogen. It contains from 4-7, and especially 4- or 5-ring atoms including the heteroatom. The term "thiazacyclo4.7alkane" contains 2-ring heteroatoms, nitrogen and sulfur. It contains from 4-7, and especially 5-ring atoms including the heteroatoms. The term "imidazacyclo4.7alkane" contains 2-ring heteroatoms which are both nitrogen, it contains from 4-7, and especially 5-ring atoms including the heteroatoms. The term "aliphatic group" refers to saturated or unsaturated aliphatic groups, such as alkyl, alkenyl or alkynyl, cycloalkyl or substituted alkyl including straight-chain, branched-chain and cyclic groups having from 1-10 carbons atoms. Preferably "alkyl" or "alk", whenever it occurs, is a saturated aliphatic group or cycloalkyl, more preferably C1-7alkyl, particularly C1-4alkyl. Examples of "alkyl" or "alk" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, (-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, cyclopropyl and especially n-butyl. The term "substituted alkyl" refers to an alkyl group that is substituted with one or more substituents preferably 1-3 substituents including, but not limited to, substituents, such as halogen, lower alkoxy, hydroxy, mercapto, carboxy, cycloalkyl, aryl, heteroaryl and the like. Examples of substituted alkyl groups include, but are not limited to, -CF3, -CF2-CF3, hydroxymethyl, 1- or 2-hydroxyethyl, methoxymethyl, 1- or 2-ethoxyethyl, carboxymethyl, 1-or 2-carboxyethyl and the like. The term "aryl" or "Ar" refers to an aromatic carbocyclic group of 6-14 carbon atoms having a single ring including, but not limited to, groups, such as phenyl; or multiple condensed rings including, but not limited to, groups, such as naphthyl or anthryl; and is especially phenyl. The term "heteroaryl" or "HetAr" refers to a 4- to 7-membered, monocyclic aromatic heterocycle or a bicycle that is composed of a 4- to 7-membered, monocyclic aromatic heterocycle and a fused-on benzene ring. The heteroaryl has at least one hetero atom, preferably one or two heteroatoms including, but not limited to, heteroatoms, such as N, O and S, within the ring. A preferred heteroaryl group is pyridinyl, pyrimidinyl or benzdioxolanyl. The aryl or heteroaryl may be unsubstituted or substituted by one or more substituents including, but not limited to, C1-7 alkyl, particularly CMalkyl, such as methyl, hydroxy, alkoxy, acyl, acyloxy, SCN, halogen, cyano, nitro, thioalkoxy, phenyl, heteroalkylaryl, alkylsulfonyl and formyl. The term "carbonylamine", as used herein, refers to a -NHC(O)- group wherein the amino portion of the group is linked to the aryl/heteroaryl and the carbonyl portion of the group is linked to the azacyclo4-7alkane, thiazacyclo4-7kane or imidazacyclo4-7alkane. The term "heteroalkyl" refers to saturated or unsaturated C1-10alkyl as defined above, and especially C1-4 Heteroalkyl which contain one or more heteroatoms, as part of the main, branched or cyclic chains in the group. Heteroatoms may independently be selected from the group consisting of -NR-, where R is hydrogen or alkyl, -S-, -O- and -P-; preferably -NR-, where R is hydrogen or alkyl; and/or -0-. Heteroalkyl groups may be attached to the remainder of the molecule either at a heteroatom (if a valence is available) or at a carbon atom. Examples of heteroalkyl groups include, but are not limited to, groups, such as -O-CH3, -CH2-0-CH3, -CH2-CH2-0-CH3, -S-CH2-CH2-CH3, -CH2-CH(CH3)-S-CH3 and -CH2-CH2-NH-CH2-CH2-. The heteroalkyl group may be unsubstituted or substituted with one or more substituents, preferably 1-3 substituents including, but not limited to, alkyl, halogen, alkoxy, hydroxyl, mercapto, carboxy and especially phenyl. The heteroatom(s) as well as the carbon atoms of the group may be substituted. The heteroatom(s) may also be in oxidized form. The term "alkoxy", as used herein, refers to a d.ioalkyl linked to an oxygen atom, or preferably C1-4alkoxy, more preferably C1-4alkoxy. Examples of alkoxy groups include, but are not limited to, groups such as methoxy, ethoxy, n-butoxy, terf-butoxy and allyloxy. The term "acyl", as used herein, refers to the group -(O)CR, where R is alkyl, especially C1-C4alkyl, such as methyl. Examples of acyl groups include, but are not limited to, acetyl, propanoyl and butanoyl. The term "acyloxy", as used herein, refers to the group -OC(0)R, wherein R is hydrogen, alkyl, especially C1-C4alkyl, such as methyl or ethyl, or phenyl or substituted alkyl as defined above. The term "alkoxycarbonyl", as used herein, refers to the group -COOR, wherein R is alkyl, especially Chalky!, such as methyl or ethyl. The term "halogen" or "halo", as used herein, refers to chlorine, bromine, fluorine, iodine and is especially fluorine. The term "thioalkoxy", as used herein, means a group -SR, where R is an alkyl as defined above, e.g., methylthio, ethylthio, propylthio, butylthio and the like. The term "heteroalkylaryl", as used herein, means a heteroalkyl group, e.g., -O-CH2-substttuted with an aryi group, especially phenyl, The phenyl group itself may also be substituted with one or more substituents, such as halogen, especially fluoro and chloro; and alkoxy, such as methoxy. The term "alkylsulfonyl", as used herein, means a group -S02R, wherein R is aikyl, especially Chalky I, such as methyl sulfonyl. "Protecting group" refers to a chemical group that exhibits the following characteristics: 1) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; 2) is selectively removable from the protected substrate to yield the desired functionality; and 3) is removable in good yield by reagents compatible with the other functional group(s) present or generated in such projected reactions. Examples of suitable protecting groups may be found in Greene et a!., "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley & Sons, Inc., NY (1999). Preferred hydroxy protecting groups include benzyl, Fmoc, TBDMS, photolabile protecting groups, such as Nvom, Mom and Mem. Other preferred protecting groups include NPEOC and NPEOM. It will be appreciated that the compounds disclosed herein may exist in the form of optical isomers, racemates ordiastereoisomers. In particular, in the compounds disclosed herein where Ri and R5 are different, the carbon atom to which the R4 and R5 groups are bonded is a chiral center and such compounds can exist in the R, S or racemic forms. It is preferred that the process of the invention prepares the R optically pure form. By "optically pure" is meant that the enantiomeric purity is greater than 50%, preferably greater than 80%, more preferably greater than 90%, and most preferably greater than 95%. The optically pure R isomer of compound (I) can be used, in which case all subsequent compounds in the synthesis will remain in the R optically pure form, with respect to the same chiral carbon atom. If an optically pure compound is used as the starting material, purification from the undesired diastereomer can be avoided at later steps. Such R form of compound (I) is represented below: wherein R2, R3, R4 and R5 are as defined above. The optically pure form of compound (I) is novel provided that when either R, or R5 is hydrogen, the other substituent, i.e., R4 or R5, is not hydrogen or methyl. In a particular embodiment of the novel compound of formula (I), R5 is hydrogen andR4 is C2.10alkyl, in a more particular embodiment C2.7alkyl, and in a even more particular embodiment C4alkyl. In a further embodiment an optically pure compound of formula (I) t R2, R3, and R5 are hydrogen and R4 is alkyl; such a compound has the structure (la): Another embodiment in compound (I) is where R4 is n-butyl, where such compound has the structure (lb) Another embodiment is where R2, R3 and R5 are hydrogen and R4 is n-butyl; such compound has the structure (Ic): More particular examples of the optically pure compound of formula (I) are as follows: Alternatively, the racemate form of compound (I) can be used and then the R form can be resolved at a later step and the R form used for subsequent steps. For example, the compound formed after opening the p-lactam ring, i.e., compound (VII), the product of Step D, can be resolved into its RS and SS diastereomers and only the RS diastereomer used for subsequent steps. The RS diastereomer of compound (VII) is depicted below: wherein R2, R3, R4 R5 Y, X, R, and n are as defined above, provided that R* and R5 are different. The diastereoisomers are resolved using standard techniques known in the art, for example, using silica gel column chromatography and an ethyl acetate/hexane solvent system (see, e.g., the methods taught in Chapter 4 of "Advanced Organic Chemistry", 5th edition, J. March, John Wiley and Sons, NY (2001)). In the compounds disclosed herein, the following significances are specific embodiments individually or in any sub-combination: 1. R1 is a heteroaryl of formula (Ha), wherein R6, R7 and R9 are hydrogen and Ra is methyl or trifluoromethyl; or R6, R7 and Rs are hydrogen and R9 is fluoro; or R6, RB and Rg are hydrogen and R7 is ethyl or methoxy; or R7, Ra and R9 are hydrogen and R5 is hydroxy; or R7 and R8 are hydrogen, Re is methoxy and Rg is methyl; or R, is a heteroaryl of formula (Ilia), wherein R6, R7 and R9 are hydrogen and R8 is fluoro or trifluoromethyl; or RE, Ra and R9 are hydrogen and R7 is ethyl; preferably R, is a heteroaryl of formula (lla), wherein Re, Ra and R9 are hydrogen and R7 is ethyl or a heteroaryl of formula (Ilia), wherein R6, R7 and R9 are hydrogen and Ra is fluoro. 2. X is -CH2-, -CH(OH)-, -CH(OR)-, -CF2 or -CH(F)-, preferably X is -CH2-; 3. R., is alkyl, preferably Cv7alkyl, such as n-butyl; 4. n is 1. Temperature and pressure are not known to be critical for carrying out any of the steps of the invention, i.e.. Steps A through E. Generally, for any of the steps, a temperature of about -10°C to about 150°C, preferably about 0°C to about 80DC, is typically employed. Typically about atmospheric pressure is used for convenience; however, variations to atmospheric pressure are not known to be detrimental. Oxygen is not known to be detrimental to the process, therefore for convenience the various steps can be performed under ambient air, although an inert atmosphere, such as nitrogen or argon, can be used if desired. For convenience equimolar amounts of reactants are typically used; however molar ratios can vary from about 1 to 2 equivalents, relative to the other reactant. The pH for the various steps is typically about 2 to about 12. The solvent used for the various steps are typically organic solvents, although in some situations aqueous/organic solvents can be used. Examples of suitable solvents include dioxane; mtehylene chloride; dichloromethane; toluene, acetone; methyl ethyl ketone; THF; isopropyl acetate; DMF; alcohols, especially higher branched alcohols, such as f-butanol; and the like. For Step A, a typical temperature is about 0°C to about 50"C, preferably about 5°C to about 35°C; and a typical reaction time is about 1 hour to about 10 hours, preferably about 2 hours to about 5 hours. A pH of about 2 to about 7, preferably about 3 to about 5, more preferably about 4, is typically employed. The carboxy-activating agent can be for example, DCC, CDMT, EDCI and the like. The amount of carboxy-activating agent employed is typically about 0.5 to about 2 molar equivalents relative to compound (I). The solvent is water or a mixture of water and one or more organic solvents, such as THF, dioxane, alcohols, such as methanol, ethanol and the like. Specific examples of solvents include THF/water and water. In the event that an ammonium salt of compound (I) is used in the process, the salt will be dissolved in water containing at least a molar equivalent amount of base, such as alkaline metal hydroxide, such as NaOH and KOH; the base is added to liberate the free amine which is extracted into the organic phase, the aqueous phase is used for the coupling reaction. For Step B, a typical temperature is about -20°C to about 25°C, more typically about -5°C to about 5°C; and a typical reaction time is about 1 hour to about 2 hours, more typically about 2 hours to about 5 hours. For Step B, an alcoholic solvent should not be used. For reactant (XIII), X' is preferably chloro and R' is preferably lower alkyl or phenyl, with CH3SO2CI and tosyl chloride being most typical. The pH for Step B is basic and is typically about 9 to about 10. The base used for Step B can be any conventional base known in the art that will activate the hydroxy group of compound (III), and such base will be used in a hydroxyl-activating amount which is at least about 1 molar equivalent relative to compound (III). The base can also act as solvent in which case it will be present in a solvating amount which is in excess of the above amount. Examples of bases that can be employed include pyridine; DMAP; a trialkylamine, e.g., trimethylamine; resin-bound bases; Hunig bases; and the like. A particular solvent is pyridine, THF or EtOAc. For cyclization Step C, atypical temperature is about20°C to about 150°C, more typically about 40°C to about 80°C; and a typical reaction time is about 1 hour to about 20 hours, more typically about 2 hours to about 4 hours. The pH for Step C is basic, typically, about 8 to about 12. The base used in Step C can be any base known in the art that is capable of de-protonating the amide group of compound (IV). Examples of suitable bases include inorganic or organic bases, such as potassium carbonate; lithium carbonate; sodium carbonate; lithium bicarbonate; sodium bicarbonate; alkyl lithium, e.g., butyl lithium; and the like. The amount of base employed is a de-protonating amount which is typically in molar excess to the amount of compound (IV), e.g., about 1-5 equivalents relative to compound (IV). For certain solvents, such as THF, dioxane, dimethoxyethane and the like, it may be necessary to use a catalytic amount of a phase transfer catalyst, such as trialkylarylammonium salt or a tetraalkylammonium salt, e.g., tetrabutylammonium chloride or tetrabutylammonium bromide. The examples of solvents are ketones, such as acetone or methyfethylketone. For Step D, a typical temperature is about 30°C to about 150°C, more typically about 60°C to about 80°C; and a typical reaction time is about 3 hours to about 20 hours, more typically about 5 hours to about 10 hours. The pH for Step D is typically about 5 to about 11. The activator for Step D is a compound which protonates the p-lactam keto oxygen; such activators include, e.g., mild (weak) organic acids, such as branched or unbranched carboxylic acids, e.g., 2-ethylhexanoic acid, acetic acid, isobutryic acid and the like. If an aqueous alcoholic solvent is used an activator is not needed; examples ofd aqueous alcoholic solvents include MeOWHjO, EtOHH20 and the like. If an activator is used a typical solvent is THF, dioxane or dimethoxyethane. If an activator is used it is used in an protonating amount which is typically about 0.1 molar equivalents to about 2 molar equivalents relative to compound (V). For Step E, a typical temperature is about -30°C to about 50°C, more typically about 0°C to about 25°C; and a typical reaction time is about 10 minutes to about 5 hours, more typically about 20 minutes to about 1 hour. The pH for Step E is not critical and can vary considerably. For Step E the solvent should not be an alcoholic solvent. The formylating agent can be, for example, HC02H/Ac20, trifluoroethylformate, and the like, and is present in a formylating amount which is typically about 1 molar equivalent to about 2 molar equivalents relative to compound (VII). Atypical solvent is EtOAc, isopropylacetate, (-butylacetate or THF. For Step F, a typical temperature is about 10°C to about 35°C, more typically about 20°C to about 22"C; and a typical reaction time is about 60 minutes to about 18 hours, more typically about 4 hours to about 8 hours. The pH for Step F is typically about 4 to about 8. The solvent for Step F is typically an organic solvent, i.e., ethyl acetate, iso-propyl acetate, methylene chloride, and the like. The oxidizing agent can be a conventional agent known in the art, e.g., as disclosed in March, "Advanced Organic Chemistry", Chapter 19, 5m edition, Wiley Interscience, NY, incorporated herein by reference. Typical oxidizing agents include urea/hydrogen peroxide with phthalic anhydride; magnesium monoperoxyphthalate (MMPP); MCPBA, Oxone (available from Aldrich), and the like. Insofar as the production of starting materials is not particularly described, the compounds are known or may be prepared analogously to methods known in the art or as disclosed in the examples hereinafter. The following abbreviations are used: Ac = acetyl CDMT = chlorodimethoxy triazine DIEA = diisopropylethylamine DCC = dicyclohexylcarbodimide DMAP = dimethylaminopyridine DMF = dimethylformamide EDCI = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 2-EHA = 2-ethylhexanoic acid EtOAc = ethyl acetate EtOH = ethanol Fmoc = 9-fluorenylmethyl-oxycarbonyl HPLC = high performance liquid chromatography MeOH = methanol Mom = methoxy methyl ether Mem = methoxy ethoxy methyl ether NPEOC = 4-nitrophenethyloxycarbonyl NPEOM = 4-nitrophenethyloxy-methyloxycarbonyl Nvom = nitroveratryl oxymethyl ether TBDMS = f-butyldimethylsilyl, TMSCI = trimethylsilyl chloride RT = room temperature THF = tetrahydrofuran The following examples illustrate the process of the invention but should not be interpreted as a limitation thereon. Reaction Scheme I Product numbers in the following examples refer to reaction scheme I depicted immediately above. Product A3 A flask was charged with 2.80 g (19.2 mmol) of A1, 80 mL of THF, 20 mL of water, and 4.73 g (38.4 mmol) of A2. The resulting solution was stirred at RT and the pH of the solution was adjusted to 4.2-4.5 with 2N HCI acid solution. 5.52 g (28.8 mmol) of EDCI was added in three portions (2.12 g, 2.26 g, 1.14 g) within 15 minutes. The resulting solution was stirred at RTfor2 hours, and the pH of the solution was adjusted to 4.2-4.5 during the reaction. The progress of the reaction was monitored by HPLC. After the reaction was completed, THF was evaporated under reduced pressure, and the residue was extracted with 3 x 70 mL of ethyl acetate and the combined organic phase was washed sequentially with 2 x 50 mL of 10% citric acid solution, 50 mL of water, 2 x 50 mL of 5% sodium bicarbonate solution and 50 mL brine dried over MgSO4. The evaporation of organic solvent afforded 2.4 g of A3 (94% yield). Product A4 A flask was charged with 7.53 g (30 mmol) of A3 and 30 mL of pyridine. The resulting solution was cooled to 0 ± 2°C with ice-salt bath. Then, 2.78 mL (36 mmol) of methanesulfonyl chloride was slowly added and maintained the temperature at 0 ± 2°C for 1.5 hours. After the reaction monitored by HPLC was completed, the mixture was poured into cold 120 mL of 1N HCI acid, and extracted with 2 x 100 mL of ethyl acetate. The organic phase was washed sequentially with 2 x 70 mL of 1N HCI acid until the aqueous solution was acidic, 100 mL of saturated sodium bicarbonate solution, 100 mL of brine and dried over MgS04. The evaporation of organic solvent gave 9.87 g of A4 (~100% yield). Product A5 A flask was charged with 16.07 g (116 mmol) of potassium carbonate (powdered), 631 mL of acetone. The suspension was heated to reflux. Then, 12.49 g (38 mmol) of A4 in 91 mL of acetone was slowly added (30 minutes). The resulting mixture was stirred at reflux for 1 hour. After the reaction monitored by HPLC was completed, the suspension was filtered through celite, and washed with 200 mL of ethyl acetate. The organic solvent was concentrated and diluted with 400 mL of ethyl acetate and washed with 100 mL of 1N HCI acid, 100 mL of saturated sodium bicarbonate solution, 100 mL of brine and dried over MgS04. The concentration of organic solvent under reduced pressure afforded 7.96 g of A5 (liquid, 90% yield). When the A5 is racemic, attacking with chiral A6 results in two diastereomers A7 and A7' They can be separated by silica gel column using EtOAc and hexanes (1:1) as eluent system. A7 was the second fraction from column and it was identified by comparing with the authentic sample from the other approach. There are several methods to open the p-lactam ring in A5. The results for opening the lactam ring are summarized in Table 1. Product A7 and A7' A flask was charged with 1.165 g (5 mmol) of A5, 10mLofTHF, 1.24 g (6 mmol) of A6 and 0.2 mL (1.25 mmol) of 2-ethyl hexanoic acid. The resulting solution was heated to reflux Product A8 A small flask was charged with 0.35 g (3.43 mmol) of acetic anhydride, and cooled to A flask was charged with 0.62 g (1.40 mmol) of A7 and 5 mL of ethyl acetate. The solution was cooled to -3 to 0°C with ice-salt bath. Then, the solution prepared from above procedure was slowly added (30 minutes). After addition, the reaction was completed (monitored by HPLC). The solution was diluted with 100 mL of ethyl acetate, and washed sequentially with 25 mL of water, 2 x 25 mL of saturated sodium bicarbonate, 25 mL of brine and dried over MgSO4. The organic solvent was evaporated to give 0.61 g of A8. The lactam ring can also be opened by a base, such as lithium hydroxide. As depicted below, the opening ring product was obtained in 91.5% yield with high purity after work-up. A flask was charged with 1.165 g (5mmol) of A5, 15 mL of THF, 5 mL of methanol. The resulting solution was cooled to 0°C. Then, 0.25 g of lithium hydroxide monohydrate in 5 mL of water was added. The solution was stirred and allowed to warm to 22°C for 18 hours. After the reaction monitored by HPLC was completed, the pH of the mixture was adjusted to 2 with 2N HCI acid. The organic solvents were removed, and the residue was extracted with 2 x 50 mL of ethyl acetate, and washed with 2 x 30 mL of brine and dried over MgSCv The evaporation the organic solvent gave 1.15 g of desired product in 91.5% yield with high purity. A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer and nitrogen inlet-outlet, is charged with 102.39 g of (2R>2-(hydroxymethyl)hexanoic acid, 123.0 g of O-benzy I hydroxy I amine hydrochloride and 2.25 L of water. Adjust the pH by adding one equivalent of NaOH to a pH of 4-5. Stir the reaction mixture at 18°C ± 3°C (external temperature: 15-18°C)for 30 minutes to give a cloudy solution. Add 161.3 a of 1-f3-(dimethvlarnino)propyl1-3-ethvlcarbodiimide hydrochloride (EDCI) over a period of 60 minutes in 6 portions, while maintaining the internal temperature at 18°C ± 3°C (external temperature: 10°C ± 3°C). Wash the funnel once with 50 mL of water. Stir the thick suspension at 20°C ± 3°C for 2 hours. Filter the solids through a polypropylene filter cloth and a BOchner funnel then wash the flask and filter cake once with 0.5 L of water. Air-dry the cake at 20°C ± 3°C (house vacuum) for 2 hours, then dry the wet cake (-265 g weight) at 65°C ± 3°C (15 mbar) for 24 hours to give 162 g of (2R)-2-(hydroxymethyl)-/\/-(phenylmethoxy)hexanamide (C3) as a white solid in 95% yield, m.p. 100-102°C; [a]D"= +0.556 (c,1.0,MeOH). From sodium salt: A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer and nitrogen inlet-outlet, is charged with 117.8 g of (2R)-2-(hydroxymethyl)hexanoic acid sodium salt, 123.0 g of O-benzvlhydroxvlamine hydrochloride, and 2.25 L of water. Stir the reaction mixture at 18°C ± 3°C (external temperature: 15-18°C)for 30 minutes to give a cloudy solution. Add 161.3 q of 1-f3-(dimemvlamino)propyH-3-EDCI over a period of 60 minutes in 6 portions, while maintaining the internal temperature at 18°C ± 3°C (external temperature: 10X ± 3°C). Wash the funnel once with 50 mL of water. Stir the temperature for 2 hours. The solids were filtered and washed with water (30 ml_), dried in an oven at 50°C for 14 hours to give 9.86 g of C4 (-100% yield); [α]D25=+5.901(c,1.0,MeOH). A flask was charged with 3.86 g (27.8 mmol) of potassium carbonate, 50 mL of THF and 0.3 g of tetrabutylammonium bromide. The suspension was heated to 40°C and stirred at this temperature for 30 minutes. Then, 3.0 g (9.1 mmol) of C4 was added in one portion. The mixture was heated to 60°C and stirred at this temperature for 1 hour. After the reaction is completed as monitored by HPLC, the solid was filtered and washed with 20 mL of THF. The organic solvent was concentrated to 8.58 ml_/g (THF/C5) for the following step without further purification. The pure C5: [a]D25=+24.63(c,1.0,MeOH). Compound C6 A flask was charged with 2.12 g (9.1 mmol) of C5from previous experiment in 20 mL of THF, 2.26 g (10.9 mmol) of Y5a and 0.8 mL of 2-ethyl hexanoic acid. The resulting solution was heated to reflux (70°C) for 8 hours, and the reaction was monitored by HPLC. THF was evaporated and the residue was dissolved in 50 mL of ethyl acetate. The organic layer was washed sequentially with 20 mL of water 2 x 20 mL of 1 N HCI solution, 20 mL of saturated sodium bicarbonate and 20 mL of brine. The concentration of organic solvent gave 3.78 g of C6 (94% yield) in 21 mL of ethyl acetate which was used for the following step. The pure C6: [ct]D25=-74.43 (c, 1.0, MeOH). A flask was charged with 22.6 g (0.22 mole) of acetic anhydride, and cooled to Then, 32.3 g (0.674 mole) of formic acid (96%) was slowly added to the flask (25 minutes), and maintained the temperature between 5-10°C. After addition, the solution was warmed to RT and stirred at this temperature for 30 minutes. A flask was charged with 36 g (81.4 mmol) of C6 and 200 mL of ethyl acetate. The solution was cooled to -5°C to -10°C with methanol-ice bath. Then, the solution prepared from above procedure was slowly added (30 minutes). After the reaction was completed (monitored by HPLC). The solution was diluted with 100 mL of water and warmed to 10"C, and stirred for 20 minutes. The organic layer was washed sequentially with 3 x 100 mL of saturated sodium bicarbonate, 100 mL of brine. Added 374 mL of ethyf acetate, and distilled ethyl acetate under vacuum in house vacuum until the residue volume about 274 mL. Heated the solution >50°C, and added 822 mL of heptane while maintaining the temperature WE CLAIM: 1. A process for preparing a compound of the formula (Vill) comprising step A: contacting a compound of the formula (I) with a compound of the formula (It) 01) in the presence of a carboxy activating agent, in a suitable solvent under conditions suitable to form a compound of the formula (III) followed by step B. contacting compound (111) with a compound of the formula (XIII) (XIII) in the presence of a base in a suitable solvent, under conditions suitable to form a compound of the formula (IV) followed by Step C: contacting compound (IV) with s base in a suitable solvent under conditions suitable to form a compound of the formula (V) followed by Step D; contacting compound (V) with a compound of the formula (VI) in a suitable solvent optionally in the presence of an activator under conditions suitable to form a compound of the formula (VII) followed by Step E: contacting compound (Vil) with a formylating agent in a suitable solvent under conditions suitable to form compound (VIII); wherein V is a hydroxy protecting group; Each of R2, R3, R4 and R5, independently, is hydrogen or an aliphatic sjroup, or (R2 and R3) and/or (R* and R5) collectively form a C4-7cycloalky1; X is -CH2-, -S-, -CH(OH)-, -GH{OR)-, -CH(SH}-, -CH{SR)-. -CF3-, -C=N(OR)- or -CH(F)-, wherein R is alky!. G is -OH or -Os M. wherein M is a metal or an ammonium moiety, R, "is aryl or heteroaryl; X' is halo; R' is alkyl or aryl; and n is 0 to 3, provided that when n is 0, X is -CHr- 2. The process as claimed in claim 1, followed by additional Step F which comprises contacting the compound of formula (VIM), wherein Ri is heteroaryl having an N heteroatom, with an oxidizing agent to form the corresponding W-oxide derivative. 3. The process as claimed in claim 1, followed by additional step of removing the hydroxyl-protecting group by contacting compound (VIII) with a palladium catalyst to form the compound of formula (IX) wherein R), R2, R3, R4, R5, X and n are as defined above. 4. The process as claimed in claim 1, wherein each of R2, R3, and R5 is hydrogen; R4 is butyl; X is -CH2-; n is 1; Y is benzyl or t-butyldimethylsilyl; and R; is of the formula wherein R6 and R9 are hydrogen; R7 is hydrogen or C 1-7 alkyl; and Rg is hydrogen, halogen or C1-7 alkyl. 5. The process as claimed in claim 2, wherein R7 is hydrogen; and R8 is fluoro. 6. The process as claimed in claim 2, wherein R7 is C1-7 alkyl; and Rg is hydrogen. 7. The process as claimed in claim 1, wherein R1 is of the formula (XIa) wherein R6, R7 and R9 are hydrogen; and Rg is halogen or C1-7 alkyl. 8. The process as claimed in claim 7, wherein R8 is fluoro. 9. The process as claimed in claim 1, carried out at a temperature of 0°C to 80°C, a pH of 2 to 12, and in one or more solvents selected from the group consisting og dioxane, methylene chloride, dichloromethane, tdiuene, acetone, methyl ethyl ketone, THF, isopropyl acetate DMF and an alcohol. 10. The process as claimed in claim 1, wherein each of R2, R3, R4 and R5, independently, is hydrogen or alkyl, or (R2 and R3) and/or (R4 and R6) collectively form a C4-7 cycloalkyl; and Y is a hydroxy-protecting group. 11. The process as claimed in claim 10, wherein R2, R3 and R5 are hydrogen; R4 is n-butyl; and Y is benzyl or t-butyldimethylsilyl. 12. The process as claimed in claim 1, wherein step A is carried out at a temperature of 5°C to 35°C for 2 hours to 5 hours, at a pH of 3 to 5, wherein the carboxy-activating agent is DCC, CDMT or EDCI and the solvent is THF/water. 13. The process as claimed in claim 1, wherein each of R2, R3 and R5 are hydrogen; R4 is c1-7 alkyl; X is chloro; R is methyl or phenyl or totuyl; and Y is benzyl or t-butyldimethylsilyl. 14. The process as claimed in claim 13, wherein R4 is n-butyl; and R is methyl. 15. The process as claimed in claim 1, wherein step B is carried out at a temperature of-S°C to 5°C for 2 hours to 5 hours at a pH of 9 to 10, wherein the base is pyridine, DMAP, a trialkylamine, a resin-bound bases or a Hunig bases, and the solvent is pyridine, THF or EtOAc. 16. The process as claimed in claim 1, wherein each of R2, R3 and R5 are hydrogen; R4 is C1.7 alkyl; X is chloro; R is methyl or phenyl; and Y is benzyl or t- buty Idimethy Isi lyl. 17. The process as claimed in claim 16, wherein R, is n-butyl; and R is methyl. 18. The process as claimed in claim 1, wherein step C is carried out at a temperature of 40°C to 80°C for 2 hours to 4 hours at a pH of 8 to 12, wherein the base is potassium carbonate, lithium carbonate, sodium carbonate, lithium bicarbonate, sodium bicarbonate or an alkyl lithium, and the solvent is acetone or methylethylketone. 19. The process as claimed in claim 1, wherein each of R2, R3 and R5 are hydrogen; R4 is C1-7alkyl; X is -CH2; Y is benzyl or t-butyldimethylsilyl; and Ri is a moiety of the formula (XIa) wherein R& and R9 are hydrogen; R7 is hydrogen or C1-7 alkyl; and R8 is hydrogen, halogen or C1-7 alkyl. 20. The process as claimed in claim 19, wherein R4 is n-butyl; and Rt is a moiety of the formula 34 wherein R7 is hydrogen R8 is fluoro. 21. The process as claimed in claim 1, wherein step D is carried out at a temperature of 60°C to 80°C for 5 hours to 10 hours at a pH of 5 to 11, in which process an activator is present, and wherein the activator is 2-ethylhexanoic acid, acetic acid or isobutryic acid and the solvent is THF, dioxane or dimethoxyethane. 22. The process as claimed in claim 21, carried out in the absence of an activator and wherein the solvent is MeOH-H2O or EtOH-H2O. 23. The process as claimed in claim 19, wherein R4 is n-butyl; and R1 is a moiety of the formula wherein R7 is hydrogen; and R8 is fluoro 24. The process as claimed in claim 1, wherein step E is carried out at a temperature of 0"C to 25°C for 20 minutes to 1 hour, wherein the formylating agent is HC02H/Ac20 or trifluoroethyformate, and the solvent is EtOAc, isopropylacetate, t-butylacetate or THF. 25. A compound having the formula (VII) wherein each of R2, R3, R4, R5, independently, is hydrogen or alkyL, or (R2 and R3) can collectively form a C4.7 cycloalkyl; Y is a hydroxy-protecting group; X is -CH2-, -S-, -CH(OH)-, -CH(OR)-, CH(SH)-, -CH(SR)-, -CF2. .C=N(OR)-or - CH(F)-; wherein R is alkyl; R, is aryl or heteroaryl; and n is 0 to 3, provided that when n is 0, X is - CH2-, and that R4 and R5 are different. 26. The compound as claimed in claim 25, wherein each of R2, R3 and R5 are hydrogen; R4 is C1-7 alkyl; X is -CH2-; Y is benzyl or t-butyldimethylsilyl; and R1; is a moiety of the formula (XIa) wherein R$ and R9 are hydrogen; R7 is hydrogen or C]_7 alkyl; and Rg is hydrogen, halogen or Cl7 alkyl. 27. The compound as claimed in claim 26, wherein R4 is n-butyl; and R1 is a moiety of the formula wherein R7 is hydrogen; and R8 is fluoro.

Full Text

5 INTERMEDIATES
This invention is directed to a process for preparing intermediates that are useful to prepare certain antibacterial A/-formyl hydroxylamine compounds.
Peptide deformylase is a metallopeptidase found in prokaryotic organisms such as bacteria. Protein synthesis in prokaryotic organisms begins with W-formyl methionine (fMet). After initiation of protein synthesis, the formyl group is removed by the enzyme peptide deformylase (PDF); this activity is essential for maturation of proteins. It has been shown that PDF is required for bacterial growth (see Chang et al., J. Bacterid., Vol. 171, pp. 4071-4072 (1989); Meinnel et al., J. Bacterid., Vol. 176, No. 23, pp. 7387-7390 (1994); Mazel et al.,EMBOJ., Vol. 13, No. 4, pp. 914-923 (1994)). Since protein synthesis in eukaryotic organisms does not depend on fMet for initiation, agents that will inhibit PDF are attractive candidates for development of new anti-microbial and anti-bacterial drugs.
Co-pending Application Serial No. 10/171,706, filed June 14, 2002 (incorporated herein by reference in its entirety) and WO02/102790, disclose novel A/-formyl hydroxylamine compounds that inhibit PDF and are therefore useful as antibacterial agents. The compounds disclosed therein are certain W-[1-oxo-2-alkyl-3-(N-hydroxyformamido)-propyl]-(carbonylamino-aryl or -heteroaryl)-azacyclo4-7alkanes or thiazacyclo4.7alkanes which are described in more detail hereinafter. An improved process has been discovered for preparing intermediates useful for preparing these N-[1-oxo-2-alkyl-3-(A/-hydroxyforrnamido)-propyl]-(carbonylamino-aryl or -heteroaryl)-azacyclo4.7alkanes or thiazacycl04.7alkanes which makes use of a particular p-lactam intermediate.
The present invention is directed to a novel process for preparing certain intermediates which are useful to prepare certain N-formyl hydroxylamine compounds which are useful for inhibiting bacteria.
More specifically, the present invention is directed to a process for preparing a
compound of the formula (VIII)

comprising Step A:
contacting a compound of the formula (I)

with a compound of the formula (II)
(ID
in the presence of a carboxy-activating agent, in a suitable solvent under conditions suitable to form a compound of the formula (III)

followed by Step B:
contacting compound (111) with a compound of the formula (XIII)
(XIII)

a suitable solvent, under conditions suitable to form a compound of the formula (IV)

followed by Step C:
contacting compound (IV) with a base in a suitable solvent under conditions suitable to form a compound of the formula (V)

followed by Step D:
contacting compound (V) with a compound of the formula (VI)

in a suitable solvent optionally in the presence of an activator under conditions suitable to form a compound of the formula (Vll)

followed by Step E:
contacting compound (VII) with a formylating agent in a suitable solvent under conditions suitable to form compound (Vlll);
wherein
Y is a hydroxy protecting group;
each of R2, R3, R4 and R5 is independently hydrogen or an aliphatic group, or (R2 and R3)
and/or (R4 and R5) collectively form a C4-7cycloalkyl;
X is -CH2-, -S-, -CH(OH)-, -CH(OR)-, -CH(SH)-, -CH(SR)-, -CF2-, -C=N(OR)- or -CH(F)-;
wherein
R is alkyl;
G is -OH or -OeM®, wherein M is a metal or an ammonium moiety; Ri is aryl or heteroaryl;
X' is halo;
R' is alkyl or aryl; and
n is 0 to 3, provided that when n is 0, X is -CH2-.
When the desired product is an A/-oxide of an aromatic moiety having a nitrogen heteroatom, e.g., when R1, is formula (X), (Xla) or (Xb), typically a pyridine derivative, it is necessary to perform an additional step after Step E, i.e., to oxidize the N of the aromatic ring (Step F). Therefore, the present invention includes Step F which comprises contacting the compound of formula (Vlll), wherein R1 is heteroaryl having an N heteroatom, with an oxidizing agent to form the corresponding W-oxide derivative.
In addition to the above process comprising Steps A through E or F, the present invention is directed to each of the steps individually, and to any two or more sequential steps.
Detailed Description of the Invention
In particular, the present invention provides a process for preparing intermediates useful in the preparation of a A/-[1-oxo-2-alkyl-3-(A/-hydroxyformamido)-propyl]-

(carbonylamino-aryl or-heteroaryl)-azacyclo4-7aikane or thiazacyclo4-7alkane, e.g., a compound of formula (IX)

wherein R1, R2, R3, R,,RS, X and n are as defined above.
To convert the compound of formula (VIII) to the compound of formula (IX), the hydroxy protecting group is removed using conventional hydrogenolysis techniques known in the art, e.g., by contacting the compound of formula (VIII) with a palladium catalyst, such as Pd/BaS04.
The R1-i moiety can be a heteroaryl, e.g., an azacyclo4-7alkane, a thiazacyclo4-7alkane or an imidazacyc^alkane. Specific examples of R, moieties in the compounds disclosed herein are heteroaryls of formula (X)

wherein each of Re, R7, RB and R9, independently, is hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, acyl, acyloxy, SCN, halogen, cyano, nitro, thioalkoxy, phenyl, heteroalkylaryl, alkylsulfonyl or formyl.
A more specific R1 moiety is a heteroaryl of formula (Xla)

wnerein R6, R7, R8 and R9 are as defined above for formula (X), e.g.,
wherein
a) R6 is nitro, alkyl, substituted alkyl, phenyl, hydroxy, formyl, heteroalkylaryl, alkoxy,
acyl or acytoxy; preferably alkyl, especially C1-7alkyl; hydroxyl; or alkoxy, especially a C1-7alkoxy; and R7, RB and R9 are hydrogen; or
b) R6, Re and R9 are hydrogen; and
R7 is alkyl, substituted alkyl, phenyl, halogen, alkoxy or cyano, preferably alkyl, especially C1-7alkyl; substituted alkyl, especially substituted C1-7alkyl, such as -CF3; or alkoxy, especially C1-7alkoxy; or
c) R8, R7 and R9 are hydrogen; and
R8 is alkyl, substituted alkyl, halogen, nitro, cyano, thioalkoxy, acyloxy, phenyl, alkylsulfonyl or carboxyalkyl, preferably alkyl, especially C^alkyl; substituted alkyl, especially -CF3; halogen such as chloro, bromo or fluoro; or carboxyalkyl; or
d) R6, Rz and Ra are hydrogen; and R9 is alkyl, halogen or hydroxy; or
e) R7 and R9 are hydrogen'; and
each of Rg and R8, independently, is halogen, alkyl, substituted alkyl, phenyl or cyano; or
f) Each of R7 and R9 is aikyl or substituted alkyl; and R6 and R8 are hydrogen; or
g) R6 and R9 are hydrogen;
R7 is alkyl or substituted alkyl; and R8 is nitro; or
h) R8 and R9 are hydrogen; RB is cyano; and R7 is alkoxy; or
i) R7 and R8 are hydrogen; and
R6 is alkyl, substituted alkyl, alkoxy or SCN; and R9 is alkyl or substituted alkyl; or

j) R6 and R7 are hydrogen; R8 is nitro or halogen; and Rg is alkyl or substituted alkyl; or
k) Re, R7, Rg and R9 are hydrogen; or
I) R6 and R7 together with the carbon atoms to which they are attached form a phenyl group, preferably substituted with hydroxy; and RB and R9 are hydrogen; or
m) R6 and R7 are hydrogen; and
Re and R9 together with the carbon atoms to which they are attached form a phenyl group; or
n) n is 0; or
0) n is 0;
each of R6, R7, Ra and R9, independently, is hydrogen, alkyl or halogen; and more particularly, Rg, R7, R8 and R9 are hydrogen; or
p) n is O;
R6, R8 and R9 are hydrogen; and R7 is alkyl; or
q) n is 0;
RB, R7 and Rg are hydrogen; and RB is alkyl or halogen.
In another embodiment, R, is of formula (Xb)

wherein
Re, R7, RB and R9 are as defined above for formula (X); in particular, R7 and R8 together with the carbon atoms to which they are attached form a phenyl group; and

R6 and Rg are hydrogen.
In yet another embodiment, the R1 is of formula (XI)

wherein each of R6, R7, R8 and R9 independently is hydrogen, alkyl, substituted alkyl, phenyl, halogen, hydroxy or alkoxy, e.g.,
wherein
a) Re and Raare hydrogen;
Rg is hydrogen or alkyl; and
R7 is alkyl, substituted alkyl or phenyl; or
b) R8, R7 and R9 are hydrogen; and
R8 is halogen, alkyl or substituted alkyl; or
c) R7, Ra and R9 are hydrogen; and
R6 is hydroxy.
In a particularly useful embodiment the heteroaryl is of the formula (Xla)

wherein Re, R7, Ra and R9 are as defined above for formula (XI), in particular where Rs, R7, and R9 are hydrogen and R8 is fluoro.
In another embodiment, R1 is an unsubstituted phenyl or the phenyl is substituted with alkoxy, e.g., methoxy; or aryloxy, e.g., phenoxy.

In another embodiment, the R, is of formula (XII)

wherein each of R10 and R„, independently, is hydrogen or halogen. In particular, R10 and Rii are both either hydrogen or both halogen.
In the compound of formula (I), M is a metal, typically a mono- or di-valent metal or an ammonium moiety. Typical metals include Mg, Ca, Na, K, Li and the like. The ammonium moiety is of the formula

wherein R" is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl.
The ammonium moiety can be racemic or chiral. An example of an ammonium moiety is R-ct-methylbenzylammonium. Examples of R" groups include hydrogen, methyl, ethyl, propyl, butyl, phenyl, benzyl, methylbenzyl and the like.
Unless otherwise stated, the following terms as used in the specification have the following meaning.
The term "cycloalkane" or "cycloalkyl" contains from 3- to 7-ring carbon atoms, and is, e.g., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "azacyclo4.7alkane" contains 1-ring heteroatom which is a nitrogen. It contains from 4-7, and especially 4- or 5-ring atoms including the heteroatom.
The term "thiazacyclo4.7alkane" contains 2-ring heteroatoms, nitrogen and sulfur. It contains from 4-7, and especially 5-ring atoms including the heteroatoms.
The term "imidazacyclo4.7alkane" contains 2-ring heteroatoms which are both nitrogen, it contains from 4-7, and especially 5-ring atoms including the heteroatoms.

The term "aliphatic group" refers to saturated or unsaturated aliphatic groups, such as alkyl, alkenyl or alkynyl, cycloalkyl or substituted alkyl including straight-chain, branched-chain and cyclic groups having from 1-10 carbons atoms. Preferably "alkyl" or "alk", whenever it occurs, is a saturated aliphatic group or cycloalkyl, more preferably C1-7alkyl, particularly C1-4alkyl. Examples of "alkyl" or "alk" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, (-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, cyclopropyl and especially n-butyl.
The term "substituted alkyl" refers to an alkyl group that is substituted with one or more substituents preferably 1-3 substituents including, but not limited to, substituents, such as halogen, lower alkoxy, hydroxy, mercapto, carboxy, cycloalkyl, aryl, heteroaryl and the like. Examples of substituted alkyl groups include, but are not limited to, -CF3, -CF2-CF3, hydroxymethyl, 1- or 2-hydroxyethyl, methoxymethyl, 1- or 2-ethoxyethyl, carboxymethyl, 1-or 2-carboxyethyl and the like.
The term "aryl" or "Ar" refers to an aromatic carbocyclic group of 6-14 carbon atoms having a single ring including, but not limited to, groups, such as phenyl; or multiple condensed rings including, but not limited to, groups, such as naphthyl or anthryl; and is especially phenyl.
The term "heteroaryl" or "HetAr" refers to a 4- to 7-membered, monocyclic aromatic heterocycle or a bicycle that is composed of a 4- to 7-membered, monocyclic aromatic heterocycle and a fused-on benzene ring. The heteroaryl has at least one hetero atom, preferably one or two heteroatoms including, but not limited to, heteroatoms, such as N, O and S, within the ring. A preferred heteroaryl group is pyridinyl, pyrimidinyl or benzdioxolanyl.
The aryl or heteroaryl may be unsubstituted or substituted by one or more substituents including, but not limited to, C1-7 alkyl, particularly CMalkyl, such as methyl, hydroxy, alkoxy, acyl, acyloxy, SCN, halogen, cyano, nitro, thioalkoxy, phenyl, heteroalkylaryl, alkylsulfonyl and formyl.
The term "carbonylamine", as used herein, refers to a -NHC(O)- group wherein the amino portion of the group is linked to the aryl/heteroaryl and the carbonyl portion of the group is linked to the azacyclo4-7alkane, thiazacyclo4-7kane or imidazacyclo4-7alkane.

The term "heteroalkyl" refers to saturated or unsaturated C1-10alkyl as defined above, and especially C1-4 Heteroalkyl which contain one or more heteroatoms, as part of the main, branched or cyclic chains in the group. Heteroatoms may independently be selected from the group consisting of -NR-, where R is hydrogen or alkyl, -S-, -O- and -P-; preferably -NR-, where R is hydrogen or alkyl; and/or -0-. Heteroalkyl groups may be attached to the remainder of the molecule either at a heteroatom (if a valence is available) or at a carbon atom. Examples of heteroalkyl groups include, but are not limited to, groups, such as -O-CH3, -CH2-0-CH3, -CH2-CH2-0-CH3, -S-CH2-CH2-CH3, -CH2-CH(CH3)-S-CH3 and -CH2-CH2-NH-CH2-CH2-.
The heteroalkyl group may be unsubstituted or substituted with one or more substituents, preferably 1-3 substituents including, but not limited to, alkyl, halogen, alkoxy, hydroxyl, mercapto, carboxy and especially phenyl. The heteroatom(s) as well as the carbon atoms of the group may be substituted. The heteroatom(s) may also be in oxidized form.
The term "alkoxy", as used herein, refers to a d.ioalkyl linked to an oxygen atom, or preferably C1-4alkoxy, more preferably C1-4alkoxy. Examples of alkoxy groups include, but are not limited to, groups such as methoxy, ethoxy, n-butoxy, terf-butoxy and allyloxy.
The term "acyl", as used herein, refers to the group -(O)CR, where R is alkyl, especially C1-C4alkyl, such as methyl. Examples of acyl groups include, but are not limited to, acetyl, propanoyl and butanoyl.
The term "acyloxy", as used herein, refers to the group -OC(0)R, wherein R is hydrogen, alkyl, especially C1-C4alkyl, such as methyl or ethyl, or phenyl or substituted alkyl as defined above.
The term "alkoxycarbonyl", as used herein, refers to the group -COOR, wherein R is alkyl, especially Chalky!, such as methyl or ethyl.
The term "halogen" or "halo", as used herein, refers to chlorine, bromine, fluorine, iodine and is especially fluorine.
The term "thioalkoxy", as used herein, means a group -SR, where R is an alkyl as defined above, e.g., methylthio, ethylthio, propylthio, butylthio and the like.

The term "heteroalkylaryl", as used herein, means a heteroalkyl group, e.g., -O-CH2-substttuted with an aryi group, especially phenyl, The phenyl group itself may also be substituted with one or more substituents, such as halogen, especially fluoro and chloro; and alkoxy, such as methoxy.
The term "alkylsulfonyl", as used herein, means a group -S02R, wherein R is aikyl, especially Chalky I, such as methyl sulfonyl.
"Protecting group" refers to a chemical group that exhibits the following characteristics: 1) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; 2) is selectively removable from the protected substrate to yield the desired functionality; and 3) is removable in good yield by reagents compatible with the other functional group(s) present or generated in such projected reactions. Examples of suitable protecting groups may be found in Greene et a!., "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley & Sons, Inc., NY (1999). Preferred hydroxy protecting groups include benzyl, Fmoc, TBDMS, photolabile protecting groups, such as Nvom, Mom and Mem. Other preferred protecting groups include NPEOC and NPEOM.
It will be appreciated that the compounds disclosed herein may exist in the form of optical isomers, racemates ordiastereoisomers. In particular, in the compounds disclosed herein where Ri and R5 are different, the carbon atom to which the R4 and R5 groups are bonded is a chiral center and such compounds can exist in the R, S or racemic forms. It is preferred that the process of the invention prepares the R optically pure form. By "optically pure" is meant that the enantiomeric purity is greater than 50%, preferably greater than 80%, more preferably greater than 90%, and most preferably greater than 95%. The
optically pure R isomer of compound (I) can be used, in which case all subsequent
compounds in the synthesis will remain in the R optically pure form, with respect to the same chiral carbon atom. If an optically pure compound is used as the starting material, purification from the undesired diastereomer can be avoided at later steps. Such R form of
compound (I) is represented below:

wherein R2, R3, R4 and R5 are as defined above. The optically pure form of compound (I) is novel provided that when either R, or R5 is hydrogen, the other substituent, i.e., R4 or R5, is not hydrogen or methyl. In a particular embodiment of the novel compound of formula (I), R5 is hydrogen andR4 is C2.10alkyl, in a more particular embodiment C2.7alkyl, and in a even more particular embodiment C4alkyl.
In a further embodiment an optically pure compound of formula (I) t R2, R3, and R5 are hydrogen and R4 is alkyl; such a compound has the structure (la):

Another embodiment in compound (I) is where R4 is n-butyl, where such compound has the structure (lb)

Another embodiment is where R2, R3 and R5 are hydrogen and R4 is n-butyl; such compound has the structure (Ic):

More particular examples of the optically pure compound of formula (I) are as
follows:

Alternatively, the racemate form of compound (I) can be used and then the R form can be resolved at a later step and the R form used for subsequent steps. For example, the compound formed after opening the p-lactam ring, i.e., compound (VII), the product of Step D, can be resolved into its RS and SS diastereomers and only the RS diastereomer used for subsequent steps. The RS diastereomer of compound (VII) is depicted below:

wherein R2, R3, R4 R5 Y, X, R, and n are as defined above, provided that R* and R5
are different.
The diastereoisomers are resolved using standard techniques known in the art, for example, using silica gel column chromatography and an ethyl acetate/hexane solvent system (see, e.g., the methods taught in Chapter 4 of "Advanced Organic Chemistry", 5th edition, J. March, John Wiley and Sons, NY (2001)).

In the compounds disclosed herein, the following significances are specific embodiments individually or in any sub-combination:
1. R1 is a heteroaryl of formula (Ha), wherein R6, R7 and R9 are hydrogen and Ra is methyl or trifluoromethyl; or R6, R7 and Rs are hydrogen and R9 is fluoro; or R6, RB and Rg are hydrogen and R7 is ethyl or methoxy; or R7, Ra and R9 are hydrogen and R5 is hydroxy; or R7 and R8 are hydrogen, Re is methoxy and Rg is methyl; or R, is a heteroaryl of formula (Ilia), wherein R6, R7 and R9 are hydrogen and R8 is fluoro or trifluoromethyl; or RE, Ra and R9 are hydrogen and R7 is ethyl; preferably R, is a heteroaryl of formula (lla), wherein Re, Ra and R9 are hydrogen and R7 is ethyl or a heteroaryl of formula (Ilia), wherein R6, R7 and R9 are hydrogen and Ra is fluoro.
2. X is -CH2-, -CH(OH)-, -CH(OR)-, -CF2 or -CH(F)-, preferably X is -CH2-;
3. R., is alkyl, preferably Cv7alkyl, such as n-butyl;
4. n is 1.
Temperature and pressure are not known to be critical for carrying out any of the steps of the invention, i.e.. Steps A through E. Generally, for any of the steps, a temperature of about -10°C to about 150°C, preferably about 0°C to about 80DC, is typically employed. Typically about atmospheric pressure is used for convenience; however, variations to atmospheric pressure are not known to be detrimental. Oxygen is not known to be detrimental to the process, therefore for convenience the various steps can be performed under ambient air, although an inert atmosphere, such as nitrogen or argon, can be used if desired. For convenience equimolar amounts of reactants are typically used; however molar ratios can vary from about 1 to 2 equivalents, relative to the other reactant. The pH for the various steps is typically about 2 to about 12. The solvent used for the various steps are typically organic solvents, although in some situations aqueous/organic solvents can be used. Examples of suitable solvents include dioxane; mtehylene chloride; dichloromethane; toluene, acetone; methyl ethyl ketone; THF; isopropyl acetate; DMF; alcohols, especially higher branched alcohols, such as f-butanol; and the like.
For Step A, a typical temperature is about 0°C to about 50"C, preferably about 5°C to about 35°C; and a typical reaction time is about 1 hour to about 10 hours, preferably about 2 hours to about 5 hours. A pH of about 2 to about 7, preferably about 3 to about 5, more preferably about 4, is typically employed. The carboxy-activating agent can be for

example, DCC, CDMT, EDCI and the like. The amount of carboxy-activating agent employed is typically about 0.5 to about 2 molar equivalents relative to compound (I). The solvent is water or a mixture of water and one or more organic solvents, such as THF, dioxane, alcohols, such as methanol, ethanol and the like. Specific examples of solvents include THF/water and water. In the event that an ammonium salt of compound (I) is used in the process, the salt will be dissolved in water containing at least a molar equivalent amount of base, such as alkaline metal hydroxide, such as NaOH and KOH; the base is added to liberate the free amine which is extracted into the organic phase, the aqueous phase is used for the coupling reaction.
For Step B, a typical temperature is about -20°C to about 25°C, more typically about -5°C to about 5°C; and a typical reaction time is about 1 hour to about 2 hours, more typically about 2 hours to about 5 hours. For Step B, an alcoholic solvent should not be used. For reactant (XIII), X' is preferably chloro and R' is preferably lower alkyl or phenyl, with CH3SO2CI and tosyl chloride being most typical. The pH for Step B is basic and is typically about 9 to about 10. The base used for Step B can be any conventional base known in the art that will activate the hydroxy group of compound (III), and such base will be used in a hydroxyl-activating amount which is at least about 1 molar equivalent relative to compound (III). The base can also act as solvent in which case it will be present in a solvating amount which is in excess of the above amount. Examples of bases that can be employed include pyridine; DMAP; a trialkylamine, e.g., trimethylamine; resin-bound bases; Hunig bases; and the like. A particular solvent is pyridine, THF or EtOAc.
For cyclization Step C, atypical temperature is about20°C to about 150°C, more typically about 40°C to about 80°C; and a typical reaction time is about 1 hour to about 20 hours, more typically about 2 hours to about 4 hours. The pH for Step C is basic, typically, about 8 to about 12. The base used in Step C can be any base known in the art that is capable of de-protonating the amide group of compound (IV). Examples of suitable bases include inorganic or organic bases, such as potassium carbonate; lithium carbonate; sodium carbonate; lithium bicarbonate; sodium bicarbonate; alkyl lithium, e.g., butyl lithium; and the like. The amount of base employed is a de-protonating amount which is typically in molar excess to the amount of compound (IV), e.g., about 1-5 equivalents relative to compound (IV). For certain solvents, such as THF, dioxane, dimethoxyethane and the like, it may be necessary to use a catalytic amount of a phase transfer catalyst, such as trialkylarylammonium salt or a tetraalkylammonium salt, e.g., tetrabutylammonium chloride

or tetrabutylammonium bromide. The examples of solvents are ketones, such as acetone or methyfethylketone.
For Step D, a typical temperature is about 30°C to about 150°C, more typically about 60°C to about 80°C; and a typical reaction time is about 3 hours to about 20 hours, more typically about 5 hours to about 10 hours. The pH for Step D is typically about 5 to about 11. The activator for Step D is a compound which protonates the p-lactam keto oxygen; such activators include, e.g., mild (weak) organic acids, such as branched or unbranched carboxylic acids, e.g., 2-ethylhexanoic acid, acetic acid, isobutryic acid and the like. If an aqueous alcoholic solvent is used an activator is not needed; examples ofd aqueous alcoholic solvents include MeOWHjO, EtOHH20 and the like. If an activator is used a typical solvent is THF, dioxane or dimethoxyethane. If an activator is used it is used in an protonating amount which is typically about 0.1 molar equivalents to about 2 molar equivalents relative to compound (V).
For Step E, a typical temperature is about -30°C to about 50°C, more typically about 0°C to about 25°C; and a typical reaction time is about 10 minutes to about 5 hours, more typically about 20 minutes to about 1 hour. The pH for Step E is not critical and can vary considerably. For Step E the solvent should not be an alcoholic solvent. The formylating agent can be, for example, HC02H/Ac20, trifluoroethylformate, and the like, and is present in a formylating amount which is typically about 1 molar equivalent to about 2 molar equivalents relative to compound (VII). Atypical solvent is EtOAc, isopropylacetate, (-butylacetate or THF.
For Step F, a typical temperature is about 10°C to about 35°C, more typically about 20°C to about 22"C; and a typical reaction time is about 60 minutes to about 18 hours, more typically about 4 hours to about 8 hours. The pH for Step F is typically about 4 to about 8. The solvent for Step F is typically an organic solvent, i.e., ethyl acetate, iso-propyl acetate, methylene chloride, and the like. The oxidizing agent can be a conventional agent known in the art, e.g., as disclosed in March, "Advanced Organic Chemistry", Chapter 19, 5m edition, Wiley Interscience, NY, incorporated herein by reference. Typical oxidizing agents include urea/hydrogen peroxide with phthalic anhydride; magnesium monoperoxyphthalate (MMPP); MCPBA, Oxone (available from Aldrich), and the like.

Insofar as the production of starting materials is not particularly described, the compounds are known or may be prepared analogously to methods known in the art or as disclosed in the examples hereinafter.
The following abbreviations are used: Ac = acetyl
CDMT = chlorodimethoxy triazine DIEA = diisopropylethylamine DCC = dicyclohexylcarbodimide DMAP = dimethylaminopyridine DMF = dimethylformamide EDCI = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
2-EHA = 2-ethylhexanoic acid
EtOAc = ethyl acetate
EtOH = ethanol
Fmoc = 9-fluorenylmethyl-oxycarbonyl
HPLC = high performance liquid chromatography
MeOH = methanol
Mom = methoxy methyl ether
Mem = methoxy ethoxy methyl ether
NPEOC = 4-nitrophenethyloxycarbonyl
NPEOM = 4-nitrophenethyloxy-methyloxycarbonyl
Nvom = nitroveratryl oxymethyl ether
TBDMS = f-butyldimethylsilyl,
TMSCI = trimethylsilyl chloride
RT = room temperature
THF = tetrahydrofuran

The following examples illustrate the process of the invention but should not be
interpreted as a limitation thereon.
Reaction Scheme I

Product numbers in the following examples refer to reaction scheme I depicted immediately above.
Product A3
A flask was charged with 2.80 g (19.2 mmol) of A1, 80 mL of THF, 20 mL of water, and 4.73 g (38.4 mmol) of A2. The resulting solution was stirred at RT and the pH of the solution was adjusted to 4.2-4.5 with 2N HCI acid solution.
5.52 g (28.8 mmol) of EDCI was added in three portions (2.12 g, 2.26 g, 1.14 g) within 15 minutes. The resulting solution was stirred at RTfor2 hours, and the pH of the solution was adjusted to 4.2-4.5 during the reaction. The progress of the reaction was monitored by HPLC. After the reaction was completed, THF was evaporated under reduced pressure, and the residue was extracted with 3 x 70 mL of ethyl acetate and the combined organic phase was washed sequentially with 2 x 50 mL of 10% citric acid solution, 50 mL of

water, 2 x 50 mL of 5% sodium bicarbonate solution and 50 mL brine dried over MgSO4. The evaporation of organic solvent afforded 2.4 g of A3 (94% yield).
Product A4
A flask was charged with 7.53 g (30 mmol) of A3 and 30 mL of pyridine. The resulting solution was cooled to 0 ± 2°C with ice-salt bath. Then, 2.78 mL (36 mmol) of methanesulfonyl chloride was slowly added and maintained the temperature at 0 ± 2°C for 1.5 hours. After the reaction monitored by HPLC was completed, the mixture was poured into cold 120 mL of 1N HCI acid, and extracted with 2 x 100 mL of ethyl acetate. The organic phase was washed sequentially with 2 x 70 mL of 1N HCI acid until the aqueous solution was acidic, 100 mL of saturated sodium bicarbonate solution, 100 mL of brine and dried over MgS04. The evaporation of organic solvent gave 9.87 g of A4 (~100% yield).
Product A5
A flask was charged with 16.07 g (116 mmol) of potassium carbonate (powdered), 631 mL of acetone. The suspension was heated to reflux. Then, 12.49 g (38 mmol) of A4 in 91 mL of acetone was slowly added (30 minutes). The resulting mixture was stirred at reflux for 1 hour. After the reaction monitored by HPLC was completed, the suspension was filtered through celite, and washed with 200 mL of ethyl acetate. The organic solvent was concentrated and diluted with 400 mL of ethyl acetate and washed with 100 mL of 1N HCI acid, 100 mL of saturated sodium bicarbonate solution, 100 mL of brine and dried over MgS04. The concentration of organic solvent under reduced pressure afforded 7.96 g of A5 (liquid, 90% yield).

When the A5 is racemic, attacking with chiral A6 results in two diastereomers A7 and A7' They can be separated by silica gel column using EtOAc and hexanes (1:1) as eluent system. A7 was the second fraction from column and it was identified by comparing with the authentic sample from the other approach.

There are several methods to open the p-lactam ring in A5. The results for opening the lactam ring are summarized in Table 1.

Product A7 and A7'
A flask was charged with 1.165 g (5 mmol) of A5, 10mLofTHF, 1.24 g (6 mmol) of A6 and 0.2 mL (1.25 mmol) of 2-ethyl hexanoic acid. The resulting solution was heated to reflux Product A8

A small flask was charged with 0.35 g (3.43 mmol) of acetic anhydride, and cooled to A flask was charged with 0.62 g (1.40 mmol) of A7 and 5 mL of ethyl acetate. The solution was cooled to -3 to 0°C with ice-salt bath. Then, the solution prepared from above procedure was slowly added (30 minutes). After addition, the reaction was completed (monitored by HPLC). The solution was diluted with 100 mL of ethyl acetate, and washed sequentially with 25 mL of water, 2 x 25 mL of saturated sodium bicarbonate, 25 mL of brine and dried over MgSO4. The organic solvent was evaporated to give 0.61 g of A8.
The lactam ring can also be opened by a base, such as lithium hydroxide. As depicted below, the opening ring product was obtained in 91.5% yield with high purity after work-up.

A flask was charged with 1.165 g (5mmol) of A5, 15 mL of THF, 5 mL of methanol. The resulting solution was cooled to 0°C. Then, 0.25 g of lithium hydroxide monohydrate in 5 mL of water was added. The solution was stirred and allowed to warm to 22°C for 18 hours. After the reaction monitored by HPLC was completed, the pH of the mixture was adjusted to 2 with 2N HCI acid. The organic solvents were removed, and the residue was extracted with 2 x 50 mL of ethyl acetate, and washed with 2 x 30 mL of brine and dried over MgSCv The evaporation the organic solvent gave 1.15 g of desired product in 91.5% yield with high purity.

A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer and nitrogen inlet-outlet, is charged with 102.39 g of
(2R>2-(hydroxymethyl)hexanoic acid, 123.0 g of O-benzy I hydroxy I amine hydrochloride and 2.25 L of water. Adjust the pH by adding one equivalent of NaOH to a pH of 4-5. Stir the reaction mixture at 18°C ± 3°C (external temperature: 15-18°C)for 30 minutes to give a cloudy solution. Add 161.3 a of 1-f3-(dimethvlarnino)propyl1-3-ethvlcarbodiimide hydrochloride (EDCI) over a period of 60 minutes in 6 portions, while maintaining the internal temperature at 18°C ± 3°C (external temperature: 10°C ± 3°C). Wash the funnel once with 50 mL of water. Stir the thick suspension at 20°C ± 3°C for 2 hours. Filter the solids through a polypropylene filter cloth and a BOchner funnel then wash the flask and filter cake once with 0.5 L of water. Air-dry the cake at 20°C ± 3°C (house vacuum) for 2 hours, then dry the wet cake (-265 g weight) at 65°C ± 3°C (15 mbar) for 24 hours to give 162 g of (2R)-2-(hydroxymethyl)-/\/-(phenylmethoxy)hexanamide (C3) as a white solid in 95% yield, m.p. 100-102°C; [a]D"= +0.556 (c,1.0,MeOH).
From sodium salt:
A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer and nitrogen inlet-outlet, is charged with 117.8 g of (2R)-2-(hydroxymethyl)hexanoic acid sodium salt, 123.0 g of O-benzvlhydroxvlamine hydrochloride, and 2.25 L of water.
Stir the reaction mixture at 18°C ± 3°C (external temperature: 15-18°C)for 30 minutes to give a cloudy solution. Add 161.3 q of 1-f3-(dimemvlamino)propyH-3-EDCI over a period of 60 minutes in 6 portions, while maintaining the internal temperature at 18°C ± 3°C (external temperature: 10X ± 3°C). Wash the funnel once with 50 mL of water. Stir the

temperature for 2 hours. The solids were filtered and washed with water (30 ml_), dried in an oven at 50°C for 14 hours to give 9.86 g of C4 (-100% yield); [α]D25=+5.901(c,1.0,MeOH).

A flask was charged with 3.86 g (27.8 mmol) of potassium carbonate, 50 mL of THF and 0.3 g of tetrabutylammonium bromide. The suspension was heated to 40°C and stirred at this temperature for 30 minutes. Then, 3.0 g (9.1 mmol) of C4 was added in one portion. The mixture was heated to 60°C and stirred at this temperature for 1 hour. After the reaction is completed as monitored by HPLC, the solid was filtered and washed with 20 mL of THF. The organic solvent was concentrated to 8.58 ml_/g (THF/C5) for the following step without further purification. The pure C5: [a]D25=+24.63(c,1.0,MeOH).

Compound C6
A flask was charged with 2.12 g (9.1 mmol) of C5from previous experiment in 20 mL of THF, 2.26 g (10.9 mmol) of Y5a and 0.8 mL of 2-ethyl hexanoic acid. The resulting solution was heated to reflux (70°C) for 8 hours, and the reaction was monitored by HPLC. THF was evaporated and the residue was dissolved in 50 mL of ethyl acetate.
The organic layer was washed sequentially with 20 mL of water 2 x 20 mL of 1 N HCI solution, 20 mL of saturated sodium bicarbonate and 20 mL of brine. The concentration of organic solvent gave 3.78 g of C6 (94% yield) in 21 mL of ethyl acetate which was used for the following step. The pure C6: [ct]D25=-74.43 (c, 1.0, MeOH).

A flask was charged with 22.6 g (0.22 mole) of acetic anhydride, and cooled to Then, 32.3 g (0.674 mole) of formic acid (96%) was slowly added to the flask
(25 minutes), and maintained the temperature between 5-10°C. After addition, the solution was warmed to RT and stirred at this temperature for 30 minutes.
A flask was charged with 36 g (81.4 mmol) of C6 and 200 mL of ethyl acetate. The solution was cooled to -5°C to -10°C with methanol-ice bath. Then, the solution prepared from above procedure was slowly added (30 minutes). After the reaction was completed (monitored by HPLC). The solution was diluted with 100 mL of water and warmed to 10"C, and stirred for 20 minutes. The organic layer was washed sequentially with 3 x 100 mL of saturated sodium bicarbonate, 100 mL of brine. Added 374 mL of ethyf acetate, and distilled ethyl acetate under vacuum in house vacuum until the residue volume about 274 mL. Heated the solution >50°C, and added 822 mL of heptane while maintaining the temperature
WE CLAIM:
1. A process for preparing a compound of the formula (Vill)

comprising step A:
contacting a compound of the formula (I)

with a compound of the formula (It)
01)
in the presence of a carboxy activating agent, in a suitable solvent under conditions suitable to form a compound of the formula (III)

followed by step B.
contacting compound (111) with a compound of the formula (XIII)
(XIII)
in the presence of a base in a suitable solvent, under conditions suitable to form a compound of the formula (IV)

followed by Step C:
contacting compound (IV) with s base in a suitable solvent under conditions suitable to form a compound of the formula (V)

followed by Step D;
contacting compound (V) with a compound of the formula (VI)

in a suitable solvent optionally in the presence of an activator under conditions suitable to form a compound of the formula (VII)

followed by Step E:
contacting compound (Vil) with a formylating agent in a suitable solvent under conditions suitable to form compound (VIII);
wherein
V is a hydroxy protecting group;
Each of R2, R3, R4 and R5, independently, is hydrogen or an aliphatic sjroup, or (R2 and R3) and/or (R* and R5) collectively form a C4-7cycloalky1;
X is -CH2-, -S-, -CH(OH)-, -GH{OR)-, -CH(SH}-, -CH{SR)-. -CF3-, -C=N(OR)- or -CH(F)-,
wherein
R is alky!.
G is -OH or -Os M*. wherein M is a metal or an ammonium moiety, R, "is aryl or heteroaryl;
X' is halo;
R' is alkyl or aryl; and
n is 0 to 3, provided that when n is 0, X is -CHr-
2. The process as claimed in claim 1, followed by additional Step F which comprises contacting the compound of formula (VIM), wherein Ri is heteroaryl having an N heteroatom, with an oxidizing agent to form the corresponding W-oxide derivative.

3. The process as claimed in claim 1, followed by additional step of removing
the hydroxyl-protecting group by contacting compound (VIII) with a palladium catalyst
to form the compound of formula (IX)

wherein R), R2, R3, R4, R5, X and n are as defined above. *
4. The process as claimed in claim 1, wherein each of R2, R3, and R5 is
hydrogen; R4 is butyl; X is -CH2-; n is 1; Y is benzyl or t-butyldimethylsilyl; and R; is of
the formula

wherein
R6 and R9 are hydrogen;
R7 is hydrogen or C 1-7 alkyl; and
Rg is hydrogen, halogen or C1-7 alkyl.
5. The process as claimed in claim 2, wherein R7 is hydrogen; and R8 is fluoro.
6. The process as claimed in claim 2, wherein R7 is C1-7 alkyl; and Rg is
hydrogen.
7. The process as claimed in claim 1, wherein R1 is of the formula (XIa)

wherein
R6, R7 and R9 are hydrogen; and Rg is halogen or C1-7 alkyl.
8. The process as claimed in claim 7, wherein R8 is fluoro.
9. The process as claimed in claim 1, carried out at a temperature of 0°C to 80°C, a pH of 2 to 12, and in one or more solvents selected from the group consisting og dioxane, methylene chloride, dichloromethane, tdiuene, acetone, methyl ethyl ketone, THF, isopropyl acetate DMF and an alcohol.
10. The process as claimed in claim 1, wherein each of R2, R3, R4 and R5, independently, is hydrogen or alkyl, or (R2 and R3) and/or (R4 and R6) collectively form a C4-7 cycloalkyl; and Y is a hydroxy-protecting group.
11. The process as claimed in claim 10, wherein R2, R3 and R5 are hydrogen; R4 is n-butyl; and Y is benzyl or t-butyldimethylsilyl.
12. The process as claimed in claim 1, wherein step A is carried out at a temperature of 5°C to 35°C for 2 hours to 5 hours, at a pH of 3 to 5, wherein the carboxy-activating agent is DCC, CDMT or EDCI and the solvent is THF/water.
13. The process as claimed in claim 1, wherein each of R2, R3 and R5 are hydrogen; R4 is c1-7 alkyl; X is chloro; R is methyl or phenyl or totuyl; and Y is benzyl or t-butyldimethylsilyl.
14. The process as claimed in claim 13, wherein R4 is n-butyl; and R is methyl.
15. The process as claimed in claim 1, wherein step B is carried out at a temperature of-S°C to 5°C for 2 hours to 5 hours at a pH of 9 to 10, wherein the

base is pyridine, DMAP, a trialkylamine, a resin-bound bases or a Hunig bases, and the solvent is pyridine, THF or EtOAc.
16. The process as claimed in claim 1, wherein each of R2, R3 and R5 are hydrogen; R4 is C1.7 alkyl; X is chloro; R is methyl or phenyl; and Y is benzyl or t- buty Idimethy Isi lyl.
17. The process as claimed in claim 16, wherein R, is n-butyl; and R is methyl.
18. The process as claimed in claim 1, wherein step C is carried out at a temperature of 40°C to 80°C for 2 hours to 4 hours at a pH of 8 to 12, wherein the base is potassium carbonate, lithium carbonate, sodium carbonate, lithium bicarbonate, sodium bicarbonate or an alkyl lithium, and the solvent is acetone or methylethylketone.
19. The process as claimed in claim 1, wherein each of R2, R3 and R5 are hydrogen; R4 is C1-7alkyl; X is -CH2; Y is benzyl or t-butyldimethylsilyl; and Ri is
a moiety of the formula (XIa)

wherein
R& and R9 are hydrogen;
R7 is hydrogen or C1-7 alkyl; and
R8 is hydrogen, halogen or C1-7 alkyl.
20. The process as claimed in claim 19, wherein R4 is n-butyl; and Rt is a
moiety of the formula
34

wherein
R7 is hydrogen
R8 is fluoro.
21. The process as claimed in claim 1, wherein step D is carried out at a temperature of 60°C to 80°C for 5 hours to 10 hours at a pH of 5 to 11, in which process an activator is present, and wherein the activator is 2-ethylhexanoic acid, acetic acid or isobutryic acid and the solvent is THF, dioxane or dimethoxyethane.
22. The process as claimed in claim 21, carried out in the absence of an activator and wherein the solvent is MeOH-H2O or EtOH-H2O.
23. The process as claimed in claim 19, wherein R4 is n-butyl; and R1 is a moiety of the formula
wherein
R7 is hydrogen; and
R8 is fluoro
24. The process as claimed in claim 1, wherein step E is carried out at a
temperature of 0"C to 25°C for 20 minutes to 1 hour, wherein the formylating
agent is HC02H/Ac20 or trifluoroethyformate, and the solvent is EtOAc,
isopropylacetate, t-butylacetate or THF.

25. A compound having the formula (VII)

wherein each of R2, R3, R4, R5, independently, is hydrogen or alkyL, or (R2 and
R3) can collectively form a C4.7 cycloalkyl;
Y is a hydroxy-protecting group;
X is -CH2-, -S-, -CH(OH)-, -CH(OR)-, CH(SH)-, -CH(SR)-, -CF2. .C=N(OR)-or -
CH(F)-;
wherein
R is alkyl;
R, is aryl or heteroaryl; and n is 0 to 3, provided that when n is 0, X is - CH2-, and
that R4 and R5 are different.
26. The compound as claimed in claim 25, wherein each of R2, R3 and R5 are
hydrogen; R4 is C1-7 alkyl; X is -CH2-; Y is benzyl or t-butyldimethylsilyl; and R1;
is a moiety of the formula (XIa)

wherein
R$ and R9 are hydrogen;
R7 is hydrogen or C]_7 alkyl; and
Rg is hydrogen, halogen or Cl7 alkyl.

27. The compound as claimed in claim 26, wherein R4 is n-butyl; and R1 is a moiety of the formula

wherein
R7 is hydrogen; and R8 is fluoro.

Documents:

346-chenp-2005 abstract-duplicate.pdf

346-chenp-2005 abstract.pdf

346-chenp-2005 claims-duplicate.pdf

346-chenp-2005 claims.pdf

346-chenp-2005 correspondence-others.pdf

346-chenp-2005 correspondence-po.pdf

346-chenp-2005 description (complete)-duplicate.pdf

346-chenp-2005 description (complete).pdf

346-chenp-2005 form-1.pdf

346-chenp-2005 form-18.pdf

346-chenp-2005 form-26.pdf

346-chenp-2005 form-3.pdf

346-chenp-2005 form-5.pdf

346-chenp-2005 others.pdf

346-chenp-2005 pct.pdf

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Patent Number

218848

Indian Patent Application Number

346/CHENP/2005

PG Journal Number

23/2008

Publication Date

06-Jun-2008

Grant Date

16-Apr-2008

Date of Filing

09-Mar-2005

Name of Patentee

NOVARTIS AG

Applicant Address

Inventors:

#	Inventor's Name	Inventor's Address
1	PRASHAD, Mahavir
2	JIANG, Xinglong
3	KAPA, Prasad, Koteswara
4	LOESER, Eric, M
5	SLADE, Joel
6	LEE, George, Tien-San

PCT International Classification Number

C07D207/16

PCT International Application Number

PCT/EP2003/010416

PCT International Filing date

2003-09-18

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/411,920	2002-09-19	U.S.A.
2	60/480,242	2003-06-20	U.S.A.