PROCESSES FOR PRODUCTION OF 4-BIPHENYLYLAZETIDIN-2-ONES

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. Provisional Application Serial No. 60/866,174, filed November 16, 2006, the entire contents of which is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to processes for the production of 4- biphenylylazetidinone derivatives .

BACKGROUND OF THE INVENTION

[0003] l,4-Diphenylazetidin-2-ones and their utility for treating disorders of lipid metabolism are described in US patent 6,498,156, USRE37721, and PCT application WO02/50027, the foregoing disclosures of which are incorporated herein by reference as they relate to utility. Perhaps the most well-known member of the class of 1,4- diphenylazetidin-2-one hypocholesterolemics is ezetimibe, which is sold as ZETIA™:

[0004] A series of 4-(biphenylyl)azetidin-2-ones, such as (15)-l,5-anhydro-l-(4'- {(25',3i?)-3-[(35)-3-(4-fiuoroρhenyl)-3-hydroxypropyl]-4-ox o-l-phenylazetidin-2-yl}-3 ¹ - hydroxybiphenyl-4-yl)-D-glucitol (ADG) have also been shown to be inhibitors of cholesterol absorption. (See copending US application 10/986,570, which is incorporated herein by reference.) These compounds are members of the family of azetidinone cholesterol absorption inhibitors, which also include numerous variations on the 1 ,4- diphenylazetidin-2-one theme. Their utility for treating disorders of lipid metabolism are described in US patent 6,498,156 and many others.

[0005] U.S. Patents Nos. 5,631,365; 6,093,812; 5,306,817; and 6,627,757, for example, disclose and claim processes for the preparation of azetidinone derivatives related to ezetimibe.

[0006] The present invention is directed toward a process for preparation of ADG and similar 4-biphenyl substituted azetidin-2-ones.

SUMMARY OF THE INVENTION

[0007] An aspect of the present invention relates to a process for preparing a 1- phenylazetidinone of formula

wherein R ¹ and R ² are chosen from H, halogen, OH, ProtA-O-, and methoxy; X is chosen from iodine, bromine, chlorine, toluenesulfonate, methanesulfonate, and

trifluoromethanesulfonate; ProtA-O- is a protecting group for a phenol chosen from an oxymethyl ether, allyl ether, a tertiary alkyl ether, a benzyl ether, and a silyl ether; said process comprising reacting a lactone of formula

with an imine of formula

[0008] A second aspect of the present invention relates to a process for preparing an imine of formula

comprising treating a compound of formula

with benzyl halide or sulfonate, and a base.

[0009] A third aspect of the present invention relates to a process for preparing a 4- biphenylylazetidinone of formula

wherein R ^la and R ^2a are chosen from H, halogen, OH, and methoxy; R ⁵ is chosen from sugar, protected sugar, phosphonate, sulfonate, phenolic hydroxy, and protected phenolic hydroxy; said process comprising: (a) reacting a chiral lactone of formula

with an imine of formula

wherein ProtA-O- is a protecting group for a phenol chosen from an oxymethyl ether, allyl ether, a tertiary alkyl ether, a benzyl ether, and a silyl ether; X is chosen from iodine, bromine, chlorine, toluenesulfonate, methanesulfonate, and trifluoromethanesulfonate; to provide a trans azetidinone of formula

(b) reacting said trans azetidinone with a phenyl boronate of formula

wherein R ¹⁰ and R ¹¹ are independently selected from H and (CrC ₆ )alkyl, or R ¹⁰ and R ¹¹ together form a 5-6 membered ring; and

(c) deprotecting.

[0010] A fourth aspect of the present invention relates to a process for preparing a 4- biphenylylazetidinone of formula

wherein R ¹ and R ² are chosen from H, halogen, OH, ProtA-O-, and methoxy; ProtA-O- is a protecting group for a phenol chosen from an oxymethyl ether, a tertiary alkyl ether, a benzyl ether, and a silyl ether; and R ⁵ is chosen from sugar, protected sugar, phosphonate, sulfonate, phenolic hydroxy, and protected phenolic hydroxy; said process comprising reacting an amine of formula

with a lactone of formula

[0011] A fifth aspect of the present invention relates to a process for preparing a 4- biphenylylazetidinone of formula

wherein R ^la and R ^2a are chosen from H, halogen, OH, and methoxy; and R ⁵ is chosen from sugar, protected sugar, phosphonate, sulfonate, phenolic hydroxy, and protected phenolic hydroxy; said process comprising: (a) reacting a chiral lactone of formula

with an imine of formula

wherein ProtA-O- is a protecting group for a phenol chosen from an oxymethyl ether, allyl ether, a tertiary alkyl ether, a benzyl ether, and a silyl ether; to provide a trans azetidinone of formula

[0012] A sixth aspect of the present invention relates to a process for preparing a 4- biphenylylazetidinone of formula

wherein R ¹ and R ² are chosen from H, halogen, OH, ProtA-O-, and methoxy; ProtA-O- is a protecting group for a phenol chosen from an oxymethyl ether, a tertiary alkyl ether, a benzyl ether, and a silyl ether; and R ⁵ is chosen from sugar, protected sugar, phosphonate, sulfonate, phenolic hydroxy, and protected phenolic hydroxy; said process comprising: (a) reacting an imine of formula

with a lactone of formula

to provide an azetidinone of formula:

(b) cleaving the phenol from the 1 -position to provide a 3,4-disubstituted azetidin-2-one:

(c) arylating said 3,4-disubstituted azetidin-2-one with an R ¹ -substituted phenyl iodide and copper iodide.

[0013] A seventh aspect of the present invention relates to a process for preparing a 4- biphenylylazetidinone of formula

wherein R ^a and R ^2a are chosen from H, halogen, OH, and methoxy; and R ⁵ is chosen from sugar, protected sugar, phosphonate, sulfonate, phenolic hydroxy, and protected phenolic hydroxy; said process comprising: (a) reacting a chiral lactone of formula

with an imine of formula

wherein ProtA-O- is a protecting group for a phenol chosen from an oxymethyl ether, allyl ether, a tertiary alkyl ether, a benzyl ether, and a silyl ether; to provide a trans azetidinone of formula

(b) cleaving the phenol from the 1 -position to provide a 3,4-disubstituted azetidin-2-one:

(c) arylating said 3,4-disubstituted azetidin-2-one with an R ^la -substituted phenyl iodide and copper iodide; and

(d) deprotecting.

[0014] An eighth aspect of the present invention relates to a process for preparing a compound of formula

comprising reacting a carbaldehyde of formula

with aniline.

DETAILED DESCRIPTION OF THE INVENTION

[0015] Throughout this application, various references are cited. The disclosures of each of these publications in their entireties are hereby incorporated by reference as if written herein.

Definitions

[0016] In this specification the terms are defined when introduced and retain their definitions throughout; the substituents are defined when introduced and retain their definitions throughout.

[0017] Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. When not otherwise restricted, the term refers to alkyl of 20 or fewer carbons. Lower alkyl refers to alkyl groups of 1, 2, 3, 4, 5, and 6 carbon atoms.

Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t- butyl, and the like. Preferred alkyl and alkylene groups are those of C ₂₀ or below (e.g. Cj, C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C9, Cjo, Ci i, C ₁₂ , C ₁₃ , Cj ₄ , Ci ₅ , Ci ₆ , Cj ₇ , Cj ₈ , C19, C ₂ o). Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of 3, 4, 5, 6, 7, and 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl, and the like.

[0018] C, to C ₂₀ hydrocarbon (e.g. Ci, C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , Ci ₀ , C _n , C, ₂ , Ci ₃ , Ci ₄ , Cj ₅ , Ci ₆ , Cn, Ci ₈ , C ₁₉ , C ₂₀ ) includes alkyl, cycloalkyl, alkenyl, alkynyl, aryl, and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl, and naphthylethyl. The term "phenylene" refers to ortho, meta, or para residues of the formulae:

[0019] Alkoxy or alkoxyl refers to groups of 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms of a straight, branched, cyclic configuration, and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. Lower-alkoxy refers to groups containing one to six carbons.

[0020] Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyl, and the like. The term oxaalkyl is intended as it is understood in the art [see Naming and Indexing; of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, f 196, but without the restriction

of 1127(a)], i.e., it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds). Similarly, thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons have been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.

[0021] Polyol refers to a compound or residue having a plurality of -OH groups. Polyols may be thought of as alkyls in which a plurality of C-H bonds have been replaced by C-OH bonds. Common polyol compounds include for example glycerol, erythritol, sorbitol, xylitol, mannitol, and inositol. Linear polyol residues will generally be of the empirical formula -C _y H _2y+ iOy, and cyclic polyol residues will generally be of the formula -C _y H _2y-1 Oy. Those in which y is 3, 4, 5, and 6 are preferred. Cyclic polyols also include reduced sugars, such as glucitol.

[0022] Acyl refers to groups of 1, 2, 3, 4, 5, 6, 7, and 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic, and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include formyl, acetyl, propionyl, isobutyryl, t-butoxycarbonyl, benzoyl, benzyloxycarbonyl, and the like. Lower-acyl refers to groups containing one to six carbons.

[0023] Aryl and heteroaryl refer to aromatic or heteroaromatic rings, respectively, as substituents. Heteroaryl contains one, two, or three heteroatoms selected from O, N, or S. Both refer to monocyclic 5- or 6-membered aromatic or heteroaromatic rings, bicyclic 9- or 10-membered aromatic or heteroaromatic rings, and tricyclic 13- or 14-membered aromatic or heteroaromatic rings. Aromatic 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5, 6, 7, 8, 9, and 10-membered aromatic heterocyclic rings include, e.g., imidazole,

pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole, and pyrazole.

[0024] Arylalkyl means an alkyl residue attached to an aryl ring. Examples are benzyl, phenethyl, and the like.

[0025] Substituted alkyl, aryl, cycloalkyl, heterocyclyl, etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with halogen, haloalkyl, hydroxy, loweralkoxy, carboxy, carboalkoxy (also referred to as alkoxycarbonyl), carboxamido (also referred to as alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.

[0026] The term "halogen" means fluorine, chlorine, bromine, or iodine.

[0027] The term "sugar" is used in its normal sense, as defined in Hawley's Condensed Chemical Dictionary, 12 ^th Edition, Richard J. Lewis, Sr.; Van Nostrand Reinhold Co. New York. It encompasses any carbohydrate comprised of one or two saccharose groups. The monosaccharide sugars (often called simple sugars) are composed of chains of 2-7 carbon atoms. One of the carbons carries aldehydic or ketonic oxygen, which may be combined in acetal or ketal forms. The remaining carbons usually have hydrogen atoms and hydroxyl groups (or protecting groups for hydroxyl, such as acetate). Among monosaccharides which would be considered within the term "sugars" as intended in this application, are arabinose, ribose, xylose, ribulose, xylulose, deoxyribose, galactose, glucose, mannose, fructose, sorbose, tagatose, fucose, quinovose, rhamnose, manno- heptulose, and sedoheptulose. Among the disaccharides are sucrose, lactose, maltose, and cellobiose. Unless specifically modified, the general term "sugar" refers to both D- sugars and L-sugars. The sugar may also be protected. The sugar may be attached through oxygen (as in US patent 5,756,470) or through carbon (making a desoxy sugar,

as in PCT WO 2002066464), the disclosures of both of which are incorporated herein by reference.

[0028] Reduced C-attached sugars or C-glycosyl compounds are also encompassed by the invention. The reduced sugars (e.g. glucitol), which could be classed either as polyols or as sugars, are also known as alditols. Alditols are polyols having the general formula HOCH ₂ [CH(OH)J _n CH ₂ OH (formally derivable from an aldose by reduction of the carbonyl group).

[0029] Terminology related to "protecting", "deprotecting" and "protected" functionalities occurs throughout this application. Such terminology is well understood by persons of skill in the art and is used in the context of processes which involve sequential treatment with a series of reagents. In that context, a protecting group refers to a group that is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection" occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified, as it is in the processes of the invention, the person of ordinary skill can readily envision those groups that would be suitable as "protecting groups". Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry [See e.g. Protective Groups in Organic Synthesis by T. W. Greene and P.G.M.Wuts, 2nd Edition; John Wiley & Sons, New York (1991)].

[0030] In processes of the invention, one may contemplate, for example, for the protection of the hydroxyls on the sugar, acetic anhydride, acetyl chloride, or pentafluorophenyl acetate in the presence of a base and acetylimidazole in the presence of a platinum catalyst. The acetyl may be cleaved at the appropriate stage with base (e.g. potassium carbonate in aqueous methanol, guanidine in ethanol, lithium hydroxide in

aqueous methanol, triethylamine in methanol, methanolic ammonia), with potassium cyanide in ethanol or with a source of fluoride ion (e.g. potassium fluoride or cesium fluoride) in methanol. For protection of the non-sugar alcohols, (e.g. ProtA) one may contemplate, for example, benzyl ethers. The benzyl may be unsubstituted or substituted (e.g. p-methoxybenzyl, dimethoxybenzyl, trimethoxybenzyl, nitrobenzyl, halobenzyl, and the like). The term "benzyl ether" as used herein to refer to a protecting group, is intended to encompass any arylmethylene ether, including naphthyl methyl ethers.

[0031] The abbreviations Me, Et, Ph, Tf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, toluensulfonyl, and methanesulfonyl respectively. A comprehensive list of abbreviations utilized by organic chemists (i.e. persons of ordinary skill in the art) appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled "Standard List of Abbreviations" is incorporated herein by reference. Additional abbreviations used within the present application include Bn and OAc. Bn represents a benzyl substituent and OAc represents an -O-acetate substituent.

[0032] As used herein, and as would be understood by the person of skill in the art, the recitation of "a compound" is intended to include salts, solvates, and inclusion complexes of that compound as well as any stereoisomeric form, or a mixture of any such forms of that compound in any ratio. Accordingly, when a substituent is referred to as a carboxylic acid, a carboxylate, a phosphonic acid, a phosphonate, a sulfonic acid, a sulfonate, and the like, the term is intended to include salts.

[0033] The graphic representations of racemic, ambiscalemic and scalemic, or enantiomerically pure compounds used herein are taken from Maehr L Chem. Ed. 62, 114-120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines and single thin lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken

bold lines are geometric descriptors indicating the relative configuration shown but denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration. Thus, the formula XI is intended to encompass both of the pure enantiomers of that pair:

XI

means either pure 3R,4S:

or pure 3S,4R:

whereas

refers to a mixture of R ₅ S and S,R, i.e., having a trans relative configuration on the beta lactam ring.

[0034] The term "enantiomeric excess" is well known in the art and is defined for a resolution of ab into a + b as

cone, of a - cone, of b ee _a 100 cone, of a + cone, of b

The term "enantiomeric excess" is related to the older term "optical purity" in that both are measures of the same phenomenon. The value of ee will be a number from 0 to 100, zero being racemic and 100 being pure, single enantiomer. A compound which in the past might have been called 98% optically pure is now more precisely described as 96% ee; in other words, a 90% ee reflects the presence of 95% of one enantiomer and 5% of the other in the material in question.

[0035] 1-Phenylazetidinone compounds of the formula

are prepared by reacting a lactone of formula

with an imine of formula

[0036] 1-Phenylazetidinone compounds of the formula

are prepared by reacting a lactone of formula

with an imine of formula

[0037] In these processes and compounds, R ¹ and R ² are chosen from H, halogen, OH, ProtA-O, and methoxy. The substituent X is chosen from iodine, bromine, chlorine, toluenesulfonate, methanesulfonate, and trifluoromethanesulfonate. ProtA-O- is a protecting group for a phenol chosen from an oxymethyl ether, allyl ether, a tertiary alkyl ether, a benzyl ether, and a silyl ether. In certain embodiments R is hydrogen and R is fluorine. The process for 1-phenylazetidinone is an example of such an embodiment.

[0038] ProtA-O- is a protecting group for a phenol chosen from protecting groups in Greene and Wuts, Chapter 3, that do not require removal with strong acid. Examples of such groups include oxymethyl ethers [e.g. MOM and 2-(trimethylsilyl)ethoxymethyl (SEM)], allyl ethers [e.g. allyl ether and 2-methylallyl ether], tertiary alkyl ethers [e.g. t- butyl ether], benzyl ethers [e.g. benzyl ether and various benzyl ether derivatives having substitution on the phenyl ring], and silyl ethers [e.g. trimethylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl].

[0039] Palladium catalysts that may be used in the processes and reactions of the present invention include palladium acetate, palladium chloride, palladium bromide, palladium acetylacetonate, bis(tri-o-tolyl)phosphine palladium dichloride, bis(triphenylphosphine)palladiurn dichloride, tetrakis(triphenylphosphine)palladium [(Ph ₃ P) ₄ Pd], tris(dibenzylidene-acetone)palladium [(dba) ₃ Pd ₂ ]and bis(dibenzylideneacetone) palladium [(dba) ₂ Pd]. Ligands for the reaction with the diboron species may be l,r-bis(di-o-tolylphosphino)ferrocene (DTPF); 1,1 '- bis(diphenylphosphino)ferrocene (DPPF); 1 -di-t-butylphosphino-2-methylaminoethyl ferrocene; [2'-(diphenylphosphino)[l,l '-binaphthalen]-2-yl]diphenylphosphine oxide (BINAP) and 2,2'-bis(di-p-tolylphosρhino)-l,l'-binaphthyl (tol-BINAP) and trialkyl or triarylphosphines, such as tri-t-butylphosphine, tricyclohexyl phosphine, triphenylphosphine, and (tri-o-tolyl)phosphine.

[0040] In certain embodiments, R ¹ and R ² are chosen from H, halogen, and methoxy; ProtA-O- is chosen from methoxymethyl ether, t-butyl ether, and benzyl ether; and X is chosen from iodine, bromine, chlorine, toluenesulfonate, methanesulfonate, and trifluoromethanesulfonate. The reaction is brought about by treatment with lithium diisopropylamide. In another embodiment, R ¹ is hydrogen; R ² is fluorine; ProtA-O- is benzyl ether; and X is bromine. Further, in another embodiment the lactone is chiral.

[0041] Thus, for example, one may prepare a 1 -phenylazetidinone of formula

by reacting a lactone of formula

with an imine of formula

The reaction of the lactone with the imine is accomplished in the presence of a base chosen from alkyl lithium, metal hydride, metal alkoxide, and metal amide. The reaction is commonly carried out in a fluid medium comprising one or more solvents, which may be chosen from hydrocarbons, ethers, dipolar aprotic solvents, and mixtures thereof. The fluid medium may additionally comprise a cosolvent, such as hexamethylphosphoramide (HMPA), hexamethylphosphorous triamide (HMPT), N,N-dimethylimidazolidinone

(DMI), or l,3-dimethyl-3,4,5,6-tetrahydro-2-(lH)-pyrimidone (DMPU). It will commonly be found that the cyclization produces a mixture of trans isomers

, which may be separated by chromatography or crystallization.

[0042] 4-Biphenylylazetidinones of the formula

may be prepared by reacting a lactone of formula

with an imine of formula

as described above, followed by reacting the azetidinone with a phenyl borate of formula

When the ultimately desired compounds are of the formula

they may be obtained by deprotecting the protected azetidinone.

[0043] 4-Biphenylylazetidinone compounds of the formula

may also be prepared by reacting an imine of formula

with a lactone of formula

[0044] In these processes and compounds, R ¹ and R ² are chosen from H, halogen, ProtA- O-, and methoxy. ProtA-O- is as described supra. R ⁵ is a sugar, protected sugar, phosphonate, and phenolic hydroxy or protected phenolic hydroxy. In certain embodiments R ¹ is hydrogen and R ² are fluorine. The process for ADG is an example of such an embodiment.

[0045] In certain embodiments, R ¹ and R ² are chosen from H, halogen, and methoxy. ProtA-O- is chosen from methoxymethyl ether, t-butyl ether, and benzyl ether. R ⁵ is chosen from 1,5-anhydro-D-glucitol; 2,3,4,6-tetra-O-acetyl-l,5-anhydro-D-glucitol; phosphonic acid; dimethyl phosphonate; OH; O-benzyl; O-t-butyldimethylsilyl; and O- acetyl. In another embodiment, R ¹ is hydrogen; R ² is fluorine; and ProtA-O- is benzyl ether. Further, in another embodiment the lactone is chiral.

[0046] In another embodiment of the present invention, isomers of an ADG-related compound, as described supra, are synthesized. The isomers can be separated by crystallization or by chromatographic means to provide pure compounds of the aforementioned.

[0047] After a 4-biphenylylazetidinone, as described supra, is synthesized, the protecting groups are cleaved under appropriate conditions to produce the corresponding compounds having a free phenol, free alcohol, and/or free sugar/polyol. When the protecting group is, for example, benzyl, hydrogenolysis may be employed for deprotection; when the protecting group is, for example, t-butyldimethylsilyl, tetrabutylammonium fluoride may be employed for deprotection; when the protecting group is, for example, acetate, hydrolysis with aqueous base or methanolysis in the presence of fluoride anion may be employed for deprotection.

[0048] Thus, for example, one may prepare a 4-biphenylylazetidinone of formula

by reacting a chiral lactone of formula

with an inline of formula

to provide a trans azetidinone of formula

The trans azetidinone is then reacted with a phenyl borate of formula

and deprotected.

[0049] In this example, R ¹ and R ² are chosen from H, halogen, OH, and methoxy. R ⁵ is chosen from 1,5-anhydro-D-glucitol; 2,3,4,6-tetra-O-acetyl-l,5-anhydro-D-glucitol; 1,5- anhydro-D-glucitol in the para position; phosphonic acid; dimethyl phosphonate; phosphonic acid in the para position; OH; O-benzyl; O-t-butyldimethylsilyl; O-acetyl; OH in the meta position; and sulfonate. ProtA-O- is a protecting group for a phenol chosen from an oxymethyl ether, allyl ether, a tertiary alkyl ether, a benzyl ether, and a silyl ether. X is chosen from iodine, bromine, chlorine, toluenesulfonate, methanesulfonate, and trifluoromethanesulfonate.

[0050] In an additional example, one may prepare a 4-biphenylylazetidinone of formula

by reacting chiral lactone of formula

with an imine of formula

to provide a trans azetidinone of formula

The trans azetidinone is then deprotected.

[0051] In this example, R ^la and R ^2a are chosen from H, halogen, OH, and methoxy. R ⁵ is chosen from 1,5-anhydro-D-glucitol; 2,3,4, 6-tetra-O-acetyl-l,5-anhydro-D-glucitol; 1,5-anhydro-D-glucitol in the para position; phosphonic acid; dimethyl phosphonate; phosphonic acid in the para position; OH; O-benzyl; O-t-butyldimethylsilyl; O-acetyl; OH in the meta position; and a sulfonate. ProtA-O- is a protecting group for a phenol chosen from an oxymethyl ether, allyl ether, a tertiary alkyl ether, a benzyl ether, and a silyl ether. X is chosen from iodine, bromine, chlorine, toluenesulfonate, methanesulfonate, and trifiuoromethanesulfonate.

[0052] 4-Biphenylylazetidinones may also be synthesized by a third route. In this third route, one may prepare a 4-biphenylylazetidinone of formula

by reacting an imine of formula

with a lactone of formula

to provide an azetidinone of formula

The phenol at the 1 -position then is cleaved off to provide a 3,4-disubstituted azetidin-2- none of formula

[0053] Cleavage is accomplished by treatment with an oxidant (for example, a cerium salt) and base. The 3,4-disubstituted azetidin-2-none is then arylated. R ¹ -substituted phenyl arylating agents are commonly of the formula:

wherein X ^a is a halogen, e.g., iodine, or a sulfonate, e.g., triflate. In one embodiment, the arylation is carried out with an R ¹ -substituted phenyl iodide and copper iodide.

[0054] In this example, R ¹ and R ² are chosen from H, halogen, OH, ProtA-O-, and methoxy. ProtA-O- is a protecting group for a phenol chosen from an oxymethyl ether, a tertiary alkyl ether, a benzyl ether, and a silyl ether. R ⁵ is chosen from 1,5-anhydro-D- glucitol; 2,3,4,6-tetra-O-acetyl-l,5-anhydro-D-glucitol; phosphonic acid; dimethyl phosphonate; OH; O-benzyl; O-t-butyldimethylsilyl; and O-acetyl.

[0055] In a further example, one may prepare a single isomer of a 4- biphenylylazetidinone of formula

by reacting a chiral lactone of formula

with an imine of formula

to provide a trans azetidinone of formula

It will commonly be found that the cyclization produces a mixture of trans isomers

which may be separated by chromatography or crystallization. The phenol at the 1 - position then is cleaved off to provide a 3,4-disubstituted azetidin-2-none of formula

The 3,4-disubstituted azetidin-2-none is then arylated with an R ¹ -substituted phenyl iodide and copper iodide, and deprotected.

[0056] In the foregoing examples, R ^la and R ^2a are chosen from H, halogen, OH, and methoxy. R ⁵ is chosen from 1,5-anhydro-D-glucitol; 2,3,4,6-tetra-O-acetyl-l,5-anhydro- D-glucitol; 1,5-anhydro-D-glucitol in the para position; phosphonic acid; dimethyl phosphonate; phosphonic acid in the para position; OH; O-benzyl; O-t- butyldimethylsilyl; O-acetyl; OH in the meta position; and sulfonate ProtA-O- is a protecting group for a phenol chosen from an oxymethyl ether, allyl ether, a tertiary alkyl ether, a benzyl ether, and a silyl ether.

[0057] In the above examples for preparing 4-biphenylylazetidinones, the reaction of the lactone with the imine is accomplished in the presence of a base chosen from alkyl lithium, metal hydride, metal alkoxide, and metal amide. The reaction is carried out in a fluid medium comprising one or more solvents chosen from hydrocarbons, ethers, dipolar aprotic solvents, and mixtures thereof. The fluid medium may additionally comprise a cosolvent chosen from hexamethylphosphoramide (HMPA), hexamethylphosphorous triamide (HMPT), N,N-dimethylimidazolidinone (DMI), and l,3-dimethyl-3,4,5,6- tetrahydro-2-(lH)-pyrimidone (DMPU).

[0058] A process for preparing an imine of formula

is presented in accordance with the present invention. The process comprises treating a compound of formula

with benzyl halide or sulfonate, and a base.

[0059] A process for preparing a compound of formula

is also presented in accordance with the present invention. The process comprises reacting a carbaldehyde of formula

with aniline.

[0060] The compounds of formula

may be prepared according to the method shown in Scheme 9, in which R ¹⁰ and R ¹¹ form a dioxaborole. The scheme and supporting experimental description are noteworthy in that borate esters are not commonly made from aryl chlorides. In the present instance, a high yield is obtained. It appears to result from a combination of phosphine ligand and palladium catalyst, and the use of high temperatures (>100°C). The reaction of silylated lactone with Grignard goes in good yield, whereas the corresponding lithium reagent provides no quantifiable product.

[0061] Exemplary processes that fall within the scope of the invention are illustrated in the schemes below. These schemes also illustrate the interrelatedness of the processes and intermediates.

Scheme 2

Equation 1

Equation 2

Equation 3

Scheme 4

Scheme 5

Scheme 6

Scheme 6 (cont.)

Scheme 7

Scheme 7 (cont.)

p-hydroxyaniline

Scheme 8 (cont.)

Scheme 9

Methanesulfonic acid Methanol

[0062] Preparation of (3i?,45)-4-[2-(benzyloxy)-4-bromophenyl]-3-[(35)-3-(4- fluorophenyl)-3-hydroxypropyl]-l-phenylazetidin-2-one and (35',4i?)-4-[2-(benzyloxy)-4- bromophenyl]-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-l-p henylazetidin-2-one

[0063] Referring to Scheme 1, 5-(4-fluorophenyl)-5-oxopentanoic acid 100 was dissolved in dichloromethane and cooled to - 4 °C in an ice/brine bath, stirred for 40 min, and then treated with 1.0 M (i?)-l-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[l,2- c][l,3,2]oxazaborole in toluene. After 10 min, a borane-methyl sulfide complex was added drop- wise. The reaction was quenched by slow addition of methanol, 6% aqueous hydrogen peroxide, and 1.0 M aqueous sulfuric acid. The reaction was stirred at room temperature for 60 min. and poured into a separatory funnel. The organic layer then was separated and the aqueous layer extracted with dichloromethane. The dichloromethane extract was dried and concentrated to give (65)-6-(4-fluorophenyl)tetrahydro-2H-pyran- 2-one 101.

[0064] A 2, 2-hydroxy-4-bromobenzaldehyde 14 was prepared by reaction of 3- bromophenol with paraformaldehyde in the presence of magnesium chloride and excess triethylamine in acetonitrile. Treatment of 14 with aniline resulted in the formation of the corresponding imine, 5-bromo-2-[(E)-(phenylimino)methyl]phenol, 102 in good yield. The imine 102 was converted to the corresponding benzyl ether, iV-{(l£)-[2-(benzyloxy)- 4-bromophenyl]methylene} aniline 103 upon treatment with benzyl bromide and potassium carbonate in λζiV-dimethylformamide (DMF).

[0065] The enolate of 101 was generated by treatment with lithium diisopropylamide and then condensed with the imine 103 giving a mixture of trans-beta-lactams (3R,4S)-4- [2-(benzy loxy)-4-bromophenyl] -3 - [(3 S)-3 -(4-fluoropheny l)-3 -hydroxypropyl] - 1 - phenylazetidin-2-one 104 and (35',4i?)-4-[2-(benzyloxy)-4-bromophenyl]-3-[(35)-3-(4- fluorophenyl)-3-hydroxypropyl]-l-phenylazetidin-2-one 105. The isomers were separated by crystallization or by chromatographic means to provide pure 104 or 105.

[0066] Preparation of (4'-{(25',3i?)-3-[(35)-3-(4-fluorophenyl)-3-hydroxypropyl]-4 -oxo- 1 -phenylazetidin-2-yl } -3 '-hydroxybiphenyl-4-yl)phosphonic acid.

[0067] Referring to Scheme 2, Eq. 1, compound 104 was Suzuki cross coupled with [4- (dimethoxyphosphoryl)phenyl]boronic acid 106 and then deprotected by treatment with bromotrimethylsilane. Deprotection was followed by treatment with hydrogen over palladium on carbon providing the (4'-{(25',3i?)-3-[(35)-3-(4-fluorophenyl)-3- hydroxypropyl]-4-oxo-l-phenylazetidin-2-yl}-3'-hydroxybiphen yl-4-yl)phosphonic acid 21. The corresponding isomer of 21, (4'-{(2i?,35)-3-[(35)-3-(4-fluorophenyl)-3- hydroxypropyl]-4-oxo- 1 -phenylazetidin-2-yl } -3 '-hydroxybiphenyl-4-yl)phosphonic acid 108, can be prepared from the compound 107, described infra, using the aforementioned reaction methodology.

[0068] Preparation of (15)-l,5-anhydro-l-(4'-{(2^,3i?)-3-[(35)-3-(4-fluorophenyl)- 3- hydroxypropyl]-4-oxo-l-phenylazetidin-2-yl}-3'-hydroxybiphen yl-4-yl)-D-glucitol.

[0069] Referring to Scheme 2, Eq. 2, compound 104 was Suzuki cross coupled with 2,3,4,6-tetra-O-acetyl-l,5-anhydro-l-[4-(dihydroxyboryl)phen yl]hexitol 27 and then deprotected by treatment with KF in methanol. Deprotection was followed by treatment with hydrogen over palladium on carbon providing the (l _I S)-l,5-anhydro-l-(4'-{(2iS',3i?)- 3 - [(3«S)-3 -(4-fluorophenyl)-3 -hydroxypropyl] -4-oxo- 1 -phenylazetidin-2-yl } -3'- hydroxybiphenyl-4-yl)-D-glucitol 12. The corresponding isomer of 12, (15)-1,5- anhydro-l-(4'-{(25',3i?)-3-[(35)-3-(4-fluorophenyl)-3-hydrox ypropyl]-4-oxo-l- phenylazetidin-2-yl}-3'-hydroxybiphenyl-4-yl)-D-glucitol 116, can be prepared from the compound 115, described infra, using the aforementioned reaction methodology.

[0070] Preparation of (3i?,45)-4-(3,3 ^l -dihydroxybiphenyl-4-yl)-3-[(3 ₁ S)-3-(4- fluorophenyl)-3 -hydroxypropyl] - 1 -phenylazetidin-2-one.

[0071] Referring to Scheme 2, Eq. 3, compound 104 was Suzuki cross coupled with (3- hydroxyphenyl)boronic acid 22 and then deprotected by treatment with hydrogen over palladium on carbon can providing the (3i?,4iS)-4-(3,3'-dihydroxybiphenyl-4-yl)-3-[(3S)- 3-(4-fluorophenyl)-3-hydroxypropyl]-l-phenylazetidin-2-one 13. The corresponding isomer of 13, (35 ^f ,4i?)-4-(3,3'-dihydroxybiphenyl-4-yl)-3-[(3>S)-3-(4-fluor ophenyl)-3- hydroxypropyl]-l-phenylazetidin-2-one 25, can be prepared from the compound 113, described infra, using the aforementioned reaction methodology.

[0072] Alternate preparation of (4'-{(25,3λ)-3-[(35)-3-(4-fluorophenyl)-3- hydroxypropyl]-4-oxo-l-phenylazetidin-2-yl}-3'-hydroxybiphen yl-4-yl)phosphonic acid and (4'-{(2i?,35)-3-[(35)-3-(4-fluorophenyl)-3-hydroxypropyl]-4- oxo-l-phenylazetidin-2- yl } -3 '-hydroxybiphenyl-4-yl)phosphonic acid.

[0073] Referring to Scheme 3, a solution of 2-hydroxy-4-bromobenzaldehyde 14 in DMF was treated with benzyl bromide and potassium carbonate to give 2-(benzyloxy)-4- bromobenzaldehyde 1. The aldehyde 1 was Suzuki cross-coupled with [4 (dimethoxyphosphoryl)phenyl] boronic acid 106 to provide dimethyl [3'-(benzyloxy)-4'- formylbiphenyl-4-yl]phosphonate 17. The phosphonate 17 was reacted with aniline giving dimethyl {3'-(benzyloxy)-4'-[(E)-(phenylimino)methyl]biphenyl-4- yl} phosphonate 18.

[0074] The enolate of 101 was generated by treatment with lithium diisopropylamide and then condensed with imine 18 giving a mixture of trans-beta-lactams dimethyl (3 ¹ - (benzyloxy)-4'-{(25 ^r ,3i?)-3-[(35)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-l- phenylazetidin-2-yl}biphenyl-4-yl)phosphonate 20 and dimethyl (3'-(benzyloxy)-4'- {(2i?,3S)-3-[(3 ₁ S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-l-phenylazetidi n-2- yl}biphenyl-4-yl)phosphonate 107. The isomers were separated by crystallization means and can be separated by chromatographic means to provide pure 20 or 107. Compound 20 or 107 was deprotected by treatment with bromotrimethylsilane. Deprotection was

followed by hydrogenation over palladium on carbon to provide (4'-{(2S ^l ,3i?)-3-[(3S)-3- (4-fluorophenyl)-3-hydroxypropyl] -4-oxo- 1 -phenylazetidin-2-yl } -3 '-hydroxybiphenyl-4- yl)phosphonic acid 21, and its isomer 108, (4'-{(2i?,35)-3-[(35)-3-(4-fluorophenyl)-3- hydroxypropyl]-4-oxo-l-phenylazetidin-2-yl}-3'-hydroxybiphen yl-4-yl)phosphonic acid.

[0075] Alternate preparation of (3i?,45)-4-(3,3'-dihydroxybiphenyl-4-yl)-3-[(35)-3-(4- fluorophenyl)-3 -hydroxypropyl]- 1 -phenylazetidin-2-one and (35',4i?)-4-(3 ,3 '- dihydroxybiphenyl-4-yl)-3-[(3iS)-3-(4-fluorophenyl)-3-hydrox ypropyl]-l-phenylazetidin- 2-one.

[0076] Referring to Scheme 4, the aldehyde 1 was Suzuki cross-coupled with (3- benzyloxyphenyl)boronic acid 109 to provide 3,3'-bis(benzyloxy)biphenyl-4- carbaldehyde 110. The aldehyde 110 was reacted with aniline to give {(1E)-[3,3 ^T - bis(benzyloxy)biphenyl-4-yl]methylene}phenylamine 111. The enolate of 101 was generated by treatment with lithium diisopropylamide. It was then condesnsed with the imine 111 to give a mixture of trans-beta-lactams (3i?,45)-4-[3,3'- bis(benzyloxy)biphenyl-4-yl]-3-[(3 ₁ S)-3-(4-fluorophenyl)-3-hydroxypropyl]-l- phenylazetidin-2-one 112 and (35',4i?)-4-[3,3'-bis(benzyloxy)biphenyl-4-yl]-3-[(35)-3-(4- fluorophenyl)-3 -hydroxypropyl] -1 -phenylazetidin-2-one 113. The isomers were separated by crystallization or by chromatographic means to provide pure 112 or 113. The isomer 112 or 113 was deprotected by hydrogenation over palladium on carbon to give (3i?,45)-4-(3,3'-dihydroxybiphenyl-4-yl)-3-[(35)-3-(4-fluoro phenyl)-3- hydroxypropyl]-l -phenylazetidin-2-one 13, and its isomer, (35,47J)^-(S ₅ S'- dihydroxybiphenyl-4-yl)-3-[(3>S)-3-(4-fluorophenyl)-3-hyd roxypropyl]-l-phenylazetidin- 2-one 25.

[0077] Alternate preparation of (l>S)-l,5-anhydro-l-(4'-{(25',3i?)-3-[(35)-3-(4- fluorophenyl)-3 -hydroxypropyl] -4-oxo- 1 -phenylazetidin-2-yl } -3 '-hydroxybiphenyl-4-yl)-

D-glucitol and (15)-l,5-anhydro-l-(4'-{(2i?,35)-3-[(35)-3-(4-fluorophenyl)- 3- hydroxypropyl]-4-oxo- 1 -phenylazetidin-2-yl} -3 '-hydroxybiphenyl-4-yl)-D-glucitol.

[0078] Referring to Scheme 5, the aldehyde 1 was Suzuki cross-coupled with 2,3,4,6- tetra-O-acetyl-l,5-anhydro-l-[4-(dihydroxyboryl) phenyl]hexitol 27 to provide 2,3,4,6- tetra-O-acetyl-l,5-anhydro-l-[3'-(benzyloxy)-4'-formylbiphen yl-4-yl]hexitol 28. The aldehyde 28 was reacted with aniline to give 2,3,4,6-tetra-(9-acetyl-l,5-anhydro-l-{3'- (benzyloxy)-4'-[(E)-(phenylimino)methyl]biphenyl-4-yl}hexito l 114. The enolate of 101 was generated by treatment with lithium diisopropylamide. It was then condensed with the imine 114 to give a mixture of trans-beta-lactams (15)-2,3,4,6-tetra-(9-acetyl-l,5- anhydro- 1 -(3 '-(benzyloxy)-4'- { (2S,3R)-3 - [(3S)-3 -(4-fluorophenyl)-3-hydroxypropyl] -4- oxo-l-phenylazetidin-2-yl}biphenyl-4-yl)-D-glucitol 11 and (15)-2,3,4,6-tetra-O-acetyl- l,5-anhydro-l-(3'-(benzyloxy)-4 ^l -{(2i?,35)-3-[(35)-3-(4-fluorophenyl)-3-hydroxypropyl]- 4-oxo- 1 -phenylazetidin-2-yl }biphenyl-4-yl)-D-glucitol 115.

[0079] The isomers 11 and 115 were separated by crystallization or by chromatographic means to provide pure 11 or 115. The isomers were deprotected by treatment with KF in methanol and then followed by hydrogenation over palladium on carbon to provide (15)-l,5-anhydro-l-(4'-{(25,3i?)-3-[(35)-3-(4-fluorophenyl)- 3- hydroxypropyl]-4-oxo-l-phenylazetidin-2-yl}-3'-hydroxybiphen yl-4-yl)-D-glucitol 12, and its isomer (l>S)-l,5-anhydro-l-(4 ^l -{(2i?,35)-3-[(35)-3-(4-fluorophenyl)-3- hydroxypropyl]-4-oxo-l -phenylazetidin-2-yl} -3 '-hydroxybiphenyl-4-yl)-D-glucitol 116.

[0080] Alternate preparation of (4'-{(25,3i?)-3-[(35)-3-(4-fluorophenyl)-3- hydroxypropyl]-4-oxo-l-phenylazetidin-2-yl}-3'-hydroxybiphen yl-4-yl)phosphonic acid and (4'-{(2i?,35)-3-[(35)-3-(4-fluorophenyl)-3-hydroxypropyl]-4- oxo-l-phenylazetidin-2- yl } -3 '-hydroxybiphenyl-4-yl)phosphonic acid.

[0081] Referring to Scheme 6, a solution of 2-hydroxy-4-bromobenzaldehyde 14 in DMF is treated with benzyl bromide and potassium carbonate to give 2-(benzyloxy)-4- bromobenzaldehyde 1. The aldehyde 1 then is Suzuki cross-coupled with [4 (dimethoxyphosphoryl)phenyl] boronic acid 106 to provide dimethyl [3'-(benzyloxy)-4'- formylbiphenyl-4-yl]phosphonate 17. The phosphonate 17 is reacted with/?- hydroxyaniline giving dimethyl {3'-(benzyloxy)-4'-[(E)-(4-hydroxy- phenylimino)methyl]biphenyl-4-yl}phosphonate 117.

[0082] The enolate of 101 is generated by treatment with lithium diisopropylamide and then is condensed with the imine 117 giving a mixture of trans-beta-lactams dimethyl (3'- (benzyloxy)-4'-{(25',3i?)-3-[(35)-3-(4-fluorophenyl)-3-hydro xypropyl]-4-oxo-l-(4- hydroxy-phenyl)azetidin-2-yl}biphenyl-4-yl)phosphonate 118 and dimethyl (3'- (benzyloxy)-4'-{(2 _J R,35)-3-[(35)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-l-(4 - hydroxy-phenyl)azetidin-2-yl}biphenyl-4-yl)phosphonate 119. The isomers are separated by crystallization or by chromatographic means to provide pure 118 or 119.

[0083] A solution of 118 in aqueous acetonitrile is treated with 1 equivalent of 1.0 N NaOH solution and, then cooled to 5 ⁰ C and treated with 3 equivalents of aqueous cerium (IV) ammonium nitrate for 15 min. The solution is diluted with 1 :1 hexanes:ethyl acetate. The organic phase is washed with water and brine, dried over anhydrous Na ₂ SO ₄ , and filtered and concentrated in vacuo to afford the crude beta-lactam. The crude beta-lactam is purified by flash chromatography over silica gel to give (3 ¹ - (benzyloxy)-4'- { (2S,3R)-3 -[(35)-3 -(4-fluorophenyl)-3 -hydroxypropyl] -4-oxo-azetidin-2- yl}biphenyl-4-yl)phosphonate 120.

[0084] A 1-dram vial is charged with 120, copper (I) iodide (0.056 mmol), and potassium phosphate, tribasic (0.225 mmol). The vial is equipped with a magnetic stir bar and septa, and is vacuum/nitrogen gas purged (10 times) to remove oxygen. 1,4- Dioxane (0.46 mL), iodobenzene (0.116 mmol) and (+)-trøm'-l,2-diaminocyclohexane

(0.117 mmol) is added to the vial via syringe. The vial is capped and sealed with a Teflon-lined screw-cap while under a heavy stream of nitrogen gas, and then placed into a pre-heated oil bath at 110 ⁰ C. The reaction is heated for 1 h, cooled to room temperature, and loaded directly onto a silica gel column for purification by chromatography (silica gel, equilibrated with 30% ethyl acetate-hexanes, eluted with 30% ethyl acetate-hexanes, 40% ethyl acetate-hexanes, 50% ethyl acetate-hexanes, and 60% ethyl acetate-hexanes. The collected fractions are combined and concentrated in vacuo to afford dimethyl (3 ¹ -(benzyloxy)-4'-{(25,3i?)-3-[(35)-3-(4-fluorophenyl)-3- hydroxypropyl]-4-oxo- 1 -phenylazetidin-2-yl}biphenyl-4-yl)phosphonate 20.

[0085] Compound 20 is deprotected by treatment with bromotrimethylsilane. Deprotection is followed by hydrogenation over palladium on carbon to provide (4'- { (25,3i?)-3 - [(35)-3 -(4-fluorophenyl)-3 -hydroxypropyl] -4-oxo- 1 -phenylazetidin-2-yl } -3 '- hydroxybiphenyl-4-yl)phosphonic acid 21. Its isomer 108, (4 ¹ -{(2i?,35)-3-[(3,S)-3-(4- fluorophenyl)-3 -hydroxypropyl]-4-oxo- 1 -phenylazetidin-2-yl } -3 '-hydroxybiphenyl-4- yl)phosphonic acid is prepared from compound 119 using the aforementioned reaction methodology.

[0086] Alternate preparation of (3i?,45)-4-(3,3'-dihydroxybiphenyl-4-yl)-3-[(35)-3-(4- fluorophenyl)-3-hydroxypropyl]-l-phenylazetidin-2-one and (35',4i?)-4-(3,3'- dihydroxybiphenyl-4-yl)-3-[(35)-3-(4-fluorophenyl)-3-hydroxy propyl]-l-phenylazetidin- 2-one.

[0087] Referring to Scheme 7, the aldehyde 1 is Suzuki cross-coupled with (3- benzyloxyphenyl)boronic acid 109 to provide 3,3'-bis(benzyloxy)biphenyl-4- carbaldehyde 110. The aldehyde 110 is reacted with/?-hydroxyaniline to give {(I E)- [3,3'-bis(benzyloxy)biphenyl-4-yl]methylene}phenylamine 121. The enolate of 101 is generated by treatment with lithium diisopropylamide. It is then condensed with the imine 121 to give a mixture of trans-beta-lactams (3R,4S)-4-[3,3'-

bis(benzyloxy)biphenyl-4-yl]-3-[(35')-3-(4-fluorophenyl)-3-h ydroxypropyl]-l-(4- hydroxy-phenyl)azetidin-2-one 122 and (35',4i?)-4-[3,3 ^l -bis(benzyloxy)biphenyl-4-yl]-3- [(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-l-(4-hydroxy-pheny l)azetidin-2-one 123. The isomers are separated by crystallization or by chromatographic means to provide pure 122 or 123.

[0088] A solution of 122 in aqueous acetonitrile is treated with 1 equivalent of 1.0 N NaOH solution and, then cooled to 5 ⁰ C and treated with 3 equivalents of aqueous cerium (IV) ammonium nitrate for 15 min. The solution is diluted with 1 :1 hexanes:ethyl acetate. The organic phase is washed with water and brine, dried over anhydrous Na ₂ SO ₄ , and filtered and concentrated in vacuo to afford the crude beta-lactam. The crude beta-lactam is purified by flash chromatography over silica gel to give (3i?,45)-4- [3 ,3 '-bis(benzyloxy)biphenyl-4-yl] -3 - [(3<S)-3 -(4-fluorophenyl)-3-hydroxypropyl]- azetidin-2-one 124.

[0089] A 1-dram vial is charged with 124, copper (I) iodide (0.056 mmol), and potassium phosphate, tribasic (0.225 mmol). The vial is equipped with a magnetic stir bar and septa, and is vacuum/nitrogen gas purged (10 times) to remove oxygen. 1,4- Dioxane (0.46 mL), iodobenzene (0.116 mmol) and (+)-trα«5-l,2-diaminocyclohexane (0.117 mmol) is added to the vial via syringe. The vial is capped and sealed with a Teflon-lined screw-cap while under a heavy stream of nitrogen gas, and then placed into a pre-heated oil bath at 110 °C. The reaction is heated for 1 h, cooled to room temperature, and loaded directly onto a silica gel column for purification by chromatography (silica gel, equilibrated with 30% ethyl acetate-hexanes, eluted with 30% ethyl acetate-hexanes, 40% ethyl acetate-hexanes, 50% ethyl acetate-hexanes, 60% ethyl acetate-hexanes). The collected fractions were combined and concentrated in vacuo to afford dimethyl (3i?,45)-4-[3,3 ^l -bis(benzyloxy)biphenyl-4-yl]-3-[(3 ₁ S)-3-(4-fluorophenyl)- 3 -hydroxypropyl] - 1 -phenylazetidin-2-one 112.

[0090] Compound 112 is deprotected by treatment with bromotrimethylsilane. Deprotection is followed by hydrogenation over palladium on carbon to provide (3i?,45)- 4-[3,3'-bis(benzyloxy)biphenyl-4-yl]-3-[(3iS)-3-(4-fluorophe nyl)-3-hydroxypropyl]-l- phenylazetidin-2-one 13. Its isomer (35 ^l ,4i?)-4-(3,3'-dihydroxybiphenyl-4-yl)-3-[(3,S)-3- (4-fluorophenyl)-3-hydroxypropyl]-l-phenylazetidin-2-one 25 is prepared from compound 113 using the aforementioned reaction methodology.

[0091] Alternate preparation of (lS)-l,5-aiώydro-l-(4'-{(2S,3i?)-3-[(35)-3-(4- fluorophenyl)-3-hydroxypropyl]-4-oxo-l-phenylazetidin-2-yl}- 3'-hydroxybiphenyl-4-yl)- D-glucitol and (15)-l,5-anhydro-l-(4'-{(2λ,35)-3-[(35)-3-(4-fluorophenyl)- 3- hydroxypropyl]-4-oxo-l-phenylazetidin-2-yl}-3'-hydroxybiphen yl-4-yl)-D-glucitol.

[0092] Referring to Scheme 8, the aldehyde 1 is Suzuki cross-coupled with 2,3,4,6- tetra-(9-acetyl-l,5-anhydro-l-[4-(dihydroxyboryl) phenyl]hexitol 27 to provide 2,3,4,6- tetra-O-acetyl-l,5-anhydro-l-[3'-(benzyloxy)-4'-formylbiphen yl-4-yl]hexitol 28. The aldehyde 28 is reacted with/>-hydroxyaniline to give 2,3,4,6-tetra-O-acetyl-l,5-anhydro- l-{3'-(benzyloxy)-4'-[(£)-((4-hydroxy-phenyl)imino)methyl]b iphenyl-4-yl}hexitol 125. The enolate of 101 is generated by treatment with lithium diisopropylamide. It is then condensed with the imine 125 to give a mixture of trans-beta-lactams (15)-2,3,4,6-tetra- O-acetyl-1 ,5-anhydro- 1 -(3'-(benzyloxy)-4'-{(25,3i?)-3-[(35)-3-(4-fluorophenyl)-3- hydroxypropyl]-4-oxo- 1 -(4-hydroxy-phenyl)azetidin-2-yl}biphenyl-4-yl)-D-glucitol 126 and (15)-2,3 ₃ 4,6-tetra-(9-acetyl-l,5-anhydro-l-(3 ¹ -(benzyloxy)-4 ^T -{(2i?,3 ₍ S)-3-[(35)-3-(4- fluorophenyl)-3 -hydroxypropyl] -4-oxo- 1 -(4-hydroxy-phenyl)azetidin-2-yl } biphenyl-4- yl)-D-glucitol 115. The isomers 126 and 1115 were separated by crystallization or by chromatographic means to provide pure 126 or 115.

[0093] A solution of 126 in aqueous acetonitrile is treated with 1 equivalent of 1.0 N NaOH solution and, then cooled to 5 °C and treated with 3 equivalents of aqueous cerium (IV) ammonium nitrate for 15 min. The solution is diluted with 1:1 hexanes:ethyl

acetate. The organic phase is washed with water and brine, dried over anhydrous Na ₂ SO ₄ , and filtered and concentrated in vacuo to afford the crude beta-lactam. The crude beta-lactam is purified by flash chromatography over silica gel to give (l<S)-2,3,4,6- tetra-O-acetyl- 1 ,5-anhydro- 1 -(3 '-(benzyloxy)-4 ^T - { (25,3i?)-3-[(35)-3-(4-fluorophenyl)-3- hydroxypropyl]-4-oxo-azetidin-2-yl}biphenyl-4-yl)-D-glucitol 9.

[0094] A 1-dram vial is charged with 9, copper (I) iodide (0.056 mmol), and potassium phosphate, tribasic (0.225 mmol). The vial is equipped with a magnetic stir bar and septa, and is vacuum/nitrogen gas purged to remove oxygen. 1,4-Dioxane (0.46 mL), iodobenzene (0.116 mmol) and (+)-tr<ms-l,2-diaminocyclohexane (0.117 mmol) is added to the vial via syringe. The vial is capped and sealed with a Teflon-lined screw-cap while under a heavy stream of nitrogen gas, and then placed into a pre-heated oil bath at 110 ⁰ C. The reaction is heated for 1 h, cooled to room temperature, and loaded directly onto a silica gel column for purification by chromatography (silica gel, equilibrated with 30% ethyl acetate-hexanes, eluted with 30% ethyl acetate-hexanes, 40% ethyl acetate-hexanes, 50% ethyl acetate-hexanes, 60% ethyl acetate-hexanes). The collected fractions were combined and concentrated in vacuo to afford dimethyl (15)-2,3,4,6-tetra-O-acetyl-l,5- anhydro- 1 -(3 '-(benzyloxy)-4'- { (2S,3R)-3-[(3S)-3 -(4-fluorophenyl)-3 -hydroxypropyl] -4- oxo- 1 -phenylazetidin-2-yl } biphenyl-4-yl)-D-glucitol 11.

[0095] Compound 11 is deprotected by treatment with bromotrimethylsilane. Deprotection is followed by hydrogenation over palladium on carbon to provide ( 15)- 1,5- anhydro-l-(4'-{(25,3i?)-3-[(35)-3-(4-fluorophenyl)-3-hydroxy propyl]-4-oxo-l- phenylazetidin-2-yl}-3'-hydroxybiphenyl-4-yl)-D-glucitol 12. Its isomer (15)-1,5- anhydro-l-(4'-{(2i?,35')-3-[(35)-3-(4-fluorophenyl)-3-hydrox ypropyl]-4-oxo-l- phenylazetidin-2-yl}-3'-hydroxybiphenyl-4-yl)-D-glucitol 116 is prepared from compound 115 using the aforementioned reaction methodology.