WO2008057948A2

WO2008057948A2 - Processes for production of diphenylylazetidin-2-ones and related compounds

Info

Publication number: WO2008057948A2
Application number: PCT/US2007/083347
Authority: WO
Inventors: John J. Talley; Eduardo J. Martinez
Original assignee: Microbia Inc; Ironwood Pharmaceuticals Inc
Current assignee: Microbia Inc; Ironwood Pharmaceuticals Inc
Priority date: 2006-11-01
Filing date: 2007-11-01
Publication date: 2008-05-15
Anticipated expiration: 2009-05-01
Also published as: WO2008057948A3

Abstract

Processes for preparing a 4-biphenylylazetidinone of formula are described. The processes generally proceed by either cyclizing a biphenylyl-ßaminoacyl compound or by arylating a 1-unsubstituted 4-biphenylylazetidinone with an R1-substituted phenyl arylating agent. Many of the processes may also be applied to the synthesis of 1,4-diphenylazetidinone deriviatives.

Description

Docket No. 2221.037AWO

PROCESSES FOR PRODUCTION OF DIPHENYL YLAZETIDIN-2-ONES AND RELATED COMPOUNDS

FIELD OF THE INVENTION

[0001] The present invention relates to processes for the production of 4- biphenylylazetidinone derivatives and related compounds.

BACKGROUND OF THE INVENTION

[0002] 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 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™:

Other azetidinones, such as (3R,4S>4-(3,3'-Dihydroxybiphenyl-4-yl)-3-[(3S>3-(4- fluorophenyl)-3 -hydro xypropyl]- 1 -phenylazetidin-2-one (DFPA) Docket No. 2221.037AWO

DFPA

(4'-{(25',3R)-3-[(35^r)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-l-phenylazetidin-2- yl}-3'-hydroxybiphenyl-4-yl)phosphonic acid (4-BPA)

4-BPA and its isomer, (4'-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-l- phenylazetidin-2-yl}-3'-hydroxybiphenyl-3-yl)phosphonic acid (3 -BPA)

3 -BPA and

(15^r)-l,5-Anhydro-l-(4'-{(25',3R)-3-[(35^r)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo- 1 -phenylazetidin-2-yl} -3 '-hydroxybiphenyl-4-yl)-D-glucitol (ADG) Docket No. 2221.037AWO

ADG have also been shown to be inhibitors of cholesterol absorption. (See copending US application 10/986,570, which is incorporated herein by reference.) The family of azetidinone cholesterol absorption inhibitors includes 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.

[0003] 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.

[0004] The present invention is directed toward a process for preparation of DFPA, BPA-3, BPA-4 and ADG and similar substituted azetidin-2-ones.

Docket No. 2221.037AWO

SUMMARY OF THE INVENTION

[0005] An aspect of the present invention relates to a process for preparing a 4- biphenylazetidinone of formula

wherein

R¹ and R² are chosen from H, halogen, ProtA-O-, and methoxy;

U is (C2-C6)-alkylene in which one or more individual -CH₂- may be replaced by a radical chosen from -S-, -S(O)-, -SO₂-, -O-, -C(=O)-, -CH=CH-, -CH(OProtB)-, -NH-,

CHF, CF₂, -CH(O-loweralkyl)-, -CH(O-loweracyl)-, -CH(OSO₃H)- and -

CH(OPO₃H₂)-;

ProtA-O- and ProtA'-O- are protecting groups for a phenol chosen from an oxymethyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether;

ProtB-O- is HO- or a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester; and

R⁵ is a sugar, protected sugar, phosphonate, phenolic hydroxy or protected phenolic hydroxy; said process comprising cyclizing a compound of formula Docket No. 2221.037AWO

wherein Q is a chiral auxiliary. The chiral auxiliary is chosen from single enantiomers of triphenyl glycol and cyclic and branched nitrogen-containing moieties possessing at least one chiral center.

[0006] A second aspect of the present invention relates to a process for preparing a 4-biphenylazetidinone of formula

wherein

R^la and R^2a are chosen from H, halogen, -OH, and methoxy; and

R^5a is a sugar, phosphonic acid or OH.

The process comprises: Docket No. 2221.037AWO

(a) cyclizing a compound of formula

wherein

R¹ and R² are chosen from H, halogen, ProtA-O-, and methoxy;

R⁵ is a sugar, protected sugar, phosphonate, phenolic hydroxy or protected phenolic hydroxy;

ProtA-O- and ProtA'-O- are protecting groups for a phenol chosen from an oxymethyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether; ProtB-O- is HO- or a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester; Q is a chiral auxiliary, said chiral auxiliary chosen from single enantiomers of triphenyl glycol and cyclic and branched nitrogen-containing moieties possessing at least one chiral center; and

(b) deprotecting.

[0007] A third aspect of the present invention relates to a process for preparing a 1,4-diphenylazetidinone of formula Docket No. 2221.037AWO

wherein

R¹, R² and R⁶ are chosen from H, halogen, -OH, ProtA-O-, and methoxy;

U is (C₂-C6)-alkylene in which one or more individual -CH₂- may be replaced by a radical chosen from -S-, -S(O)-, -SO₂-, -0-, -C(=0)-, -CH=CH-, -CH(OProtB)-, -NH-,

CHF, CF₂, -CH(O-loweralkyl)-, -CH(O-loweracyl)-, -CH(OSO₃H)- and -

CH(OPO₃H₂)-;

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;

ProtB-O- is HO- or a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester;

R⁵ is chosen from H, halogen, -OH, ProtA-O-, methoxy and phenyl, said phenyl optionally substituted with a sugar, protected sugar, phosphonate, phenolic hydroxy or protected phenolic hydroxy.

The process comprises arylating a 1 -unsubstituted 4-phenylazetidinone of formula:

with an R¹ -substituted phenyl arylating agent. Docket No. 2221.037AWO

[0008] A fourth aspect of the present invention relates to a process for preparing a A- biphenylazetidinone of formula

wherein

R¹ and R² are chosen from H, halogen, ProtA-O-, and methoxy;

R⁵ is a sugar, protected sugar, phosphonate, phenolic hydroxy or protected phenolic hydroxy.

[0009] The process comprises arylating a 1-unsubstituted azetidinone of formula:

with an R¹ -substituted phenyl arylating agent.

[0010] A fifth aspect of the present invention relates to a process for preparing a A- biphenylylazetidinone of formula Docket No. 2221.037AWO

wherein

R^la and R^2a are chosen from H, halogen, -OH, and methoxy; and

R^5a is a sugar, phosphonic acid or OH.

The process comprises:

(a) arylating a 1 -unsubstituted azetidinone of formula:

with an R¹ -substituted phenyl arylating agent wherein

R¹ and R² are chosen from H, halogen, ProtA-O-, and methoxy;

(b) deprotecting. Docket No. 2221.037AWO

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

wherein R is chosen from H, halogen, ProtA-O-, and methoxy; and

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; said process comprising treating a 1 -(4-hydroxyphenyl)azetidinone of formula

with an oxidant and a base.

Docket No. 2221.037AWO

[0012] A seventh aspect of the present invention relates to a process for preparing a l-(4-hydroxyphenyl)azetidinone of formula

wherein R is chosen from H, halogen, ProtA-O-, and methoxy; and

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; said process comprising cyclizing a δ-oxoamine of formula

Docket No. 2221.037AWO

[0013] An eighth aspect of the present invention relates to a process for preparing a δ-oxoamine of formula

wherein R is chosen from H, halogen, ProtA-O-, and methoxy; and

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; said process comprising reacting an N-acyloxazolidine of formula

Docket No. 2221.037AWO

with an imine of formula

[0014] A ninth aspect of the present invention relates to a process for preparing an imine of formula

comprising reacting para aminophenol with 2-benzyloxy-4-bromobenzaldehyde.

[0015] A tenth aspect of the present invention relates to a process for preparing a compound of formula

comprising reacting 2-benzyloxy-4-bromobenzaldehyde in the presence of a Docket No. 2221.037AWO

phosphine, a palladium salt and a base with a compound of formula

wherein R¹⁰ and R¹¹ are independently selected from H and (Ci-Cβ) alkyl, or R¹⁰ and R¹¹ together form a 5-6 membered ring.

[0016] An eleventh aspect of the present invention relates to a compound of formula

[0017] A twelfth aspect of the present invention relates to a process for the preparation of a compound of formula

phosphine, a palladium salt and a base with a compound of formula

[0018] A thirteenth aspect of the present invention relates to a compound of formula

[0019] A fourteenth aspect of the present invention relates to a process for the preparation of a compound of formula

phosphine, a palladium salt and a base with a compound of formula

1

wherein R and R are independently selected from H and (Ci-Cβ) alkyl, or R and

R together form a 5-6 membered ring.

[0020] A fifteenth aspect of the present invention relates to a compound of formula

[0021] A sixteenth aspect of the present invention relates to a process for preparing a diphenyl heterocycle of formula

wherein

R¹, R² and R⁶ are chosen from H, halogen, -OH, ProtA-O-, and methoxy;

W is chosen from -CH₂-, -NR⁷-, -0-, -S-, -CH₂CH₂-, -CH₂NR⁷-, -NR⁷CH₂-, -CONR⁷-

, -CH₂O-, -OCH₂-, -CH₂S-, -SCH₂-, -CH=CH-, -CH=N-, -N=CH-, -C(O)O-, Docket No. 2221.037AWO

-CC=O)CH₂-, -C(=O)NR⁷, -C(=S)O-, -C(=S)CH₂-, -C(=S)NR⁷, -C(O)S-, -C(=S)-,

-S(O) and -SO₂-;

U is (C₂-Ce)-alkylene in which one or more individual -CH₂- may be replaced by a radical chosen from -S-, -S(O)-, -SO₂-, -0-, -C(O)-, -CH=CH-, -CH(OProtB)-, -NH-,

CHF, CF₂, -CH(O-loweralkyl)-, -CH(O-loweracyl)-, -CH(OSO₃H)- and -

CH(OPO₃H₂)-;

R⁵ is chosen from H, halogen, -OH, ProtA-O-, methoxy and phenyl, said phenyl optionally substituted with a sugar, protected sugar, phosphonate, phenolic hydroxy or protected phenolic hydroxy;

R⁷ is chosen from H and (Ci-Ce)alkyl; the process comprises arylating a 1 -unsubstituted phenyl heterocycle of formula:

with an R -substituted phenyl arylating agent.

Docket No. 2221.037AWO

[0022] A seventeenth aspect of the present invention relates to a process for preparing a diphenyl azetidinone of formula

wherein

R^1A, R^2A, R^1B, R^2B, R^5A, and R^6A, independently of one another are chosen from: (a) (Ci-C₃o)-alkylene-(LAG)_qa, wherein at least one carbon atom of the alkylene radical is replaced by: aryl or heteroaryl radicals, which are unsubstituted or substituted one, two, or three times by R^7A or by (C3-Cio)-cycloalkyl or heterocycloalkyl radicals, which are unsubstituted or substituted one, two, three or four times by R^7A, or wherein one or more carbon atoms of the alkylene radical is optionally replaced by a radical chosen from: -S(0)π_m- (where ma=0-2), -O-, -(C=O)-, -(C=S)-, -CH=CH-, -OC-, -N[(Ci-C₆)-alkyl]-, -N(phenyl)-, -N[(Ci-C₆)-alkyl-Phenyl]-, -N(CO-(CH₂)_1-10-COOH)- and -NH-; or

(b) H, F, Cl, Br, I, CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)-alkyl CONH₂, CONH(Ci_C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂- C₆)-alkynyl, -OH, ProtA-O- or O-(Ci-C₆)-alkyl, wherein the alkyl radical is unsubstituted or at least one hydrogen in the alkyl radical is replaced by fluorine; or

(c) SO₂NH₂, SO₂NH(Ci-C₆)-alkyl, SO₂N[(Ci-C₆)-alkyl]₂, S-(Ci-C₆)-alkyl, S-(CH₂)_na-Phenyl, SO-(C₁-C₆)-alkyl, SO-(CH₂-)_naphenyl, SO₂-(C₁-C₆)-alkyl, or SO₂-(CH₂)_na-Phenyl; wherein na=0-6, and wherein the phenyl radical is unsubstituted or substituted one or two times, each substituent chosen Docket No. 2221.037AWO

independently from: F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O-(d-C₆)-alkyl, (Ci- C₆)-alkyl, and NH₂; or

(d) NH₂ NH-(Ci-C₆)-alkyl, N[(Ci-C₆)-alkyl]₂, NH(Ci-C₇)-acyl, phenyl, or O-(CH₂)_na-Phenyl, wherein na=0-6, and wherein the phenyl ring is unsubstituted or substituted one, two, or three times, each substitutent chosen independently from: F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O-(Ci-C₆)-alkyl, (Ci-C₆)-alkyl, NH₂, NH-(Ci-C₆)-alkyl, N[(C₁-C₆)-alkyl]₂, SO₂CH₃, COOH, COO-(Ci-C₆)-alkyl, and CONH₂; or R^5A may additionally be phenyl optionally substituted with a sugar, protected sugar, phosphonate, phenolic hydroxy or protected phenolic hydroxy; and wherein at least one of the radicals R^1A to R^6A must have the meaning:

(Ci-C₃₀)-alkylene-(LAG)_qa

R^7A represents

(a) F, Cl, Br, I, OH, CF₃, NO₂, N₃, CN, COOH, COO(d-C₆)-alkyl, CONH₂, CONH(Ci-C₆)-alkyl, CON[(Ci-C₆)-alkyl]₂, (Ci-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂- C₆)-alkynyl, or 0-(Ci-C₆)-alkyl, wherein the alkyl radical is unsubstituted or at least one hydrogen in the alkyl radical may be replaced by fluorine; or

(b) PO₃H₂, SO₃H, SO₂NH₂, SO₂NH(Ci-C₆)-alkyl, SO₂N[(Ci-C₆)-alkyl]₂, S-(Ci-C₆)-alkyl, S-(CH₂)_na-Phenyl, SO-(d-C₆)-alkyl, SO-(CH₂)_na-Phenyl, SO₂-(Ci-C₆)-alkyl, or SO₂-(CH₂)_na-Phenyl, wherein na=0-6, and wherein the phenyl radical is unsubstituted or substituted one or two times each substituent chosen independently from: F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, 0-(Ci-C₆)- alkyl, (Ci-C₆)-alkyl, and NH₂; or

(c) C(=NH)(NH₂), NH₂, NH-(C₁-C₆)-alkyl, N[(C₁-C₆)-alkyl]₂, NH(Ci-C₇)-acyl, phenyl, or O-(CH₂)_na-Phenyl, wherein na=0-6, and wherein the phenyl ring is unsubstituted or substituted one, two, or three times, each substituent chosen independently from: F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O-(C₁-C₆)alkyl, (Ci-C₆)-alkyl, NH₂, NH(Ci-C₆)-alkyl, N[(Ci-C₆)-alkyl]₂, SO₂CH₃, COOH, COO-(Ci-C₆)-alkyl, and CONH₂;

(LAG) is a sugar residue, disugar residue, trisugar residue, tetrasugar residue; a sugar acid, an amino sugar; or Docket No. 2221.037AWO

a polyol; or an amino acid residue, or an oligopeptide residue comprising 2 to 9 amino acids; or an acyclic, mono-, di- or tricyclic trialkylammonium radical, an acyclic mono-, di- or tricyclic trialkylammoniumalkyl radical, -0(SO₂)OH; -(CH₂)o-io-S0₃H, -(CH₂)_0-

_I0-P(O)(OH)₂, -(CH₂)O-_I0-O-P(O)(OH)₂, -(CH₂)₀-ioCOOH, -(CH₂)_O-io-C(=NH)(NH₂),

-(CH₂)O_-1O-CC=NH)(NHOH), or -NR^8A-C(=NR^9A)(NR^10AR^11A); wherein R^8A, R^9A, R^10A and R^11A, independently of one another, are chosen from: H, (Ci-C₆)-alkyl, phenyl,

(Ci-C₆)-alkylphenyl, and (C₃-C₈)-cycloalkyl; qa=l-5 and

U is (C₂-Ce)-alkylene in which one or more individual -CH₂- may be replaced by a radical chosen from -S-, -S(O)-, -SO₂-, -0-, -C(=0)-, -CH=CH-, -CH(OProtB)-, -NH-,

CHF, CF₂, -CH(O-loweralkyl)-, -CH(O-loweracyl)-, -CH(OSO₃H)- and -

CH(OPO₃H₂)-;

ProtB-O- is HO- or a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester; said process comprising arylating a 1-unsubstituted 4-phenylazetidinone of formula:

with an R¹ -substituted phenyl arylating agent. R¹ -substituted in this context refers to a phenyl optionally substituted with either or both of R^1A and R^1B. Docket No. 2221.037AWO

[0023] An eighteenth aspect of the present invention relates to a process for preparing a 1,4-diphenylazetidinone of

formula

wherein R^1C is chosen from H, halogen, -OH, ProtA-O-, methoxy, and

R² and R⁶ are chosen from H, halogen, -OH, ProtA-O-, and methoxy;

U is (C₂-C6)-alkylene in which one or more individual -CH₂- may be replaced by a radical chosen from -S-, -S(O)-, -SO₂-, -O-, -C(=O)-, -CH=CH-, -CH(OProtB)-, -NH-,

CHF, CF₂, -CH(O-loweralkyl)-, -CH(O-loweracyl)-, -CH(OSO₃H)- and -

CH(OPO₃H₂)-;

R^109A is chosen from hydrogen, carbocyclyl and heterocyclyl; wherein R^109A may be optionally substituted on carbon by one or more substituents selected from Docket No. 2221.037AWO

R^23A; and wherein if said heterocyclyl contains an -NH- group, that nitrogen may be optionally substituted by a group selected from R^24A; R^110A is hydrogen or C_1-4alkyl;

R^111A and R^112A are independently selected from hydrogen,

carbocyclyl or heterocyclyl; or R^111A and R^112A together form C₂-6alkylene; wherein R^111A R^112A and the combination of R^111A and R^112A taken together may be independently optionally substituted on carbon by one or more substituents selected from R^25A; and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen may be optionally substituted by one or more R^26A;

R^113A is hydrogen,

carbocyclyl or heterocyclyl; wherein R^113A may be optionally substituted on carbon by one or more substituents selected from R^27A; and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen may be optionally substituted by one or more R^28A;

R^114A is hydrogen, halo, nitro, cyano, hydroxyl, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl , Ci-ioalkyl, C₂-ioalkenyl, C₂-ioalkynyl, Ci-ioalkoxy, Ci_ioalkoxycarbonyl, Ci-ioalkanoyl, Ci-ioalkanoyloxy, N- (Ci-ioalkyl)amino, N,N-(Ci-ioalkyl)2amino, N,N,N-(Ci-ioalkyl)3ammonio, Ci_ioalkanoylamino, N-(Ci_ioalkyl)carbamoyl, N,N-(Ci_ioalkyl)₂carbamoyl, Ci_ioalkylS(0)aa wherein aa is 0 to 2, N-(Ci_ioalkyl)sulphamoyl, N,N-(Ci_ioalkyl)₂sulphamoyl, N-(Ci_ioalkyl)sulphamoylamino, N,N-(Ci_ioalkyl)₂sulphamoylamino, Ci-ioalkoxycarbonylamino, carbocyclyl, carbocyclylCi-ioalkyl, heterocyclyl, heterocyclylCi-ioalkyl, carbocyclyl-(Ci-ioalkylene)ea-R^29A-(Ci-ioalkylene)fa, heterocyclyl-(Ci-ioalkylene)ga-R^30A-(Ci_ioalkyl)ha-, carboxy, sulpho, sulphino, phosphono, -P(O)(OR^31A)(OR^32A), -P(O)(OH)(OR^31A), -P(O)(OH)(R^31A), or P(O)(OR^31A)(R^32A), wherein R^31A and R^32A are independently selected from d_₆alkyl; wherein R^14A may be optionally substituted on carbon by one or more substituents selected from R^33A; and wherein if said heterocyclyl contains an -NH- group, that nitrogen may be optionally substituted by a group selected from R^34A; or R^14A is a group of formula (IA_A): Docket No. 2221.037AWO

IAA wherein:

T_A is-N(R^35A)-, -N(R^35A)C(O)-, -O-, and -S(O)_aa-; wherein aa is 0-2 and R^35A is hydrogen or

; R^15A is hydrogen or Ci_₄alkyl ;

R^16A and R^17A are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, Ci-βalkoxy, Ci-βalkanoyl, Ci-βalkanoyloxy, N-(Ci-6alkyl)amino, N,N-(Ci-6alkyl)2amino, Ci-βalkanoylamino, N-(Ci_6alkyl) carbamoyl, N,N-(Ci_6alkyl)₂carbamoyl, Ci_6alkylS(O)aa wherein aa is 0 to 2, Ci-βalkoxycarbonyl, N-(Ci_6alkyl)sulphamoyl, N,N-(Ci_6alkyl)₂sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino, amidino, phosphono, -P(OXOR^36AXOR^37A),-P(OXOHXOR^36A), -P(O)(OH)(R^36A) or -P(O)(OR^36A)(R^37A), wherein R^36A and R^37A are independently selected from C_1-6alkyl; wherein R^16A and R^17A maybe independently optionally substituted on carbon by one or more substituents selected from R^38A; and wherein if said heterocyclyl contains an- NH- group, that nitrogen may be optionally substituted by a group selected from R^39A; R^18A is selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, Ci-ioalkyl, C₂-ioalkenyl, C₂-ioalkynyl, Ci-ioalkoxy, Ci-ioalkanoyl, Ci-ioalkanoyloxy, N-(Ci-ioalkyl)amino, N₅N-(Ci- i₀alkyl)₂amino, Ci-ioalkanoylamino, N-(Ci_ioalkyl)carbamoyl, Ci_ioalkoxycarbonyl, N,N-(Ci_i₀alkyl)₂carbamoyl, Ci_i₀alkylS(O)_aa wherein aa is 0 to 2, N-(Ci- i₀alkyl)sulphamoyl, N,N-(Ci_ioalkyl)₂sulphamoyl, N-(Ci_ioalkyl)sulphamoylamino, N,N-(Ci_ioalkyl)₂sulphamoylamino, carbocyclyl, carbocyclylCi-ioalkyl, heterocyclyl, heterocyclylCi-ioalkyl, carbocyclyl-(Ci_ioalkylene)ea-R^40A-(Ci-ioalkylene)_fa- or heterocyclyl-(Ci-ioalkylene)ga-R^41A-(Ci-ioalkylene)ha-, carboxy, sulpho, sulphino, phosphono, -P(OXOR^42AXOR^43A), -P(O)(OH)(OR^42A), -P(O)(OH)(R^42A) or -P(O)(OR^42A)(R^43A) Docket No. 2221.037AWO

wherein R^42A and R^43A are independently selected from Q-βalkyl; wherein R^18A may be optionally substituted on carbon by one or more substituents selected from R^44A; and wherein if said heterocyclyl contains an -NH- group, that nitrogen may be optionally substituted by a group selected from R^45A; or R^18A is a group of formula (IB_A):

wherein:

R^19A is selected from hydrogen or Ci_₄alkyl;

R^20A is selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, Q-βalkoxy, Ci-βalkanoyl, Q-βalkanoyloxy, N-(Ci_6alkyl)amino, N,N-(Ci_6alkyl)₂amino, Ci_6alkanoylamino, N-(Q_6alkyl)carbamoyl, N,N-(Ci_6alkyl)₂carbamoyl, Ci_6alkylS(O)aa wherein aa is 0 to 2, Q-βalkoxycarbonyl, N-(Ci_6alkyl)sulphamoyl, N,N-(Ci_6alkyl)₂sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino, amidino, phosphono, -P(O)(OR^46A)(OR^47A), -P(O)(OH)(OR^46A), -P(O)(OH)(R^46A) or -P(O)(OR^46A)(R^47A), wherein R^46A and R^47A are independently selected from Oβalkyl; where R^20A may be independently optionally substituted on carbon by one or more substituents selected from R^48A; and wherein if said heterocyclyl contains an -NH- group, that nitrogen may be optionally substituted by a group selected from R^49A; R^21A is selected from halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, Ci-ioalkyl, C₂-ioalkenyl, C₂-ioalkynyl, Ci- loalkoxy, Ci-ioalkoxycarbonyl, Ci-ioalkanoyl, Ci-ioalkanoyloxy, N-(Ci-ioalkyl)amino, N,N-(Ci_ioalkyl)₂amino, N,N,N-(Ci_ioalkyl)₃ammonio, Ci-ioalkanoylamino, N-(Ci_ioalkyl)carbamoyl, N,N-(Ci_ioalkyl)₂carbamoyl, Ci-ioalkylS(0)_aa wherein aa is 0 to 2, N-(Ci_ioalkyl)sulphamoyl, N,N-(Ci_i₀alkyl)₂sulphamoyl, N-(Ci- i₀alkyl)sulphamoylamino, N,N-(Ci_ioalkyl)₂sulphamoylamino, Ci- loalkoxycarbonylamino, carbocyclyl, carbocyclylCi-ioalkyl, heterocyclyl, heterocyclyl(Ci_io)alkyl, carbocyclyl-(Ci_ioalkene)ea-R^50A-(Ci-ioalkylene)f_a, Docket No. 2221.037AWO

heterocyclyl(Ci-ioalkylene)ga-R^51A-(Ci-ioalkene)ha-, carboxy, sulpho, sulphino, phosphono, -P(O)(OR^52A)(OR^53A), -P(O)(OH)(OR^52A), -P(O)(OH)(R^52A) or -P(O)(OR^53A)(R^53A) wherein R^52A and R^53A are independently selected from d_₆alkyl; wherein R^21A may be independently optionally substituted on carbon by one or more R^54A; and wherein if said heterocyclyl contains an -NH- group, that nitrogen may be optionally substituted by a group selected from R^55A; pa is 1-3; wherein the values of R^16A may be the same or different; qa is 0-1; ra is 0-3; wherein the values of R^17A may be the same or different; ma is 0-2; wherein the values of R^3A may be the same or different; na is 1-2; wherein the values of R^9A may be the same or different; za is 0-3; wherein the values of R^20A may be the same or different;

_R23A _R25A _R27A _R33A _R38A _R44A _R48A ^ _R54A ^ _{indeperidently se}l_eCted from halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, Ci-ioalkyl, C₂-ioalkenyl, C₂-ioalkynyl, Ci_ioalkoxy, Ci-ioalkanoyl, Ci_ioalkanoyloxy, Ci-ioalkoxycar-bonyl, N-(Ci_ioalkyl)amino, N₅N-(Ci- ioalkyl)2amino, N,N,N-(Ci-ioalkyl)3ammonio, Ci-ioalkanoyl-amino, N-(Ci- i₀alkyl)carbamoyl, N,N-(Ci_ioalkyl)₂carbamoyl, Ci-ioalkylS(0)_aa wherein aa is 0 to 2, N-(Ci_ioalkyl)sulphamoyl, N,N-(Ci_ioalkyl)₂sulphamoyl, N-(Ci_ioalkyl)sulphamoylamino, N,N-(Ci_ioalkyl)₂sulphamoylamino, Ci-ioalkoxycarbonylamino, carbocyclyl, carbocyclylCi-ioalkyl, heterocyclyl, heterocyclylCi-ioalkyl, carbocyclyl-(Ci-ioalkylene)_ea- R^56A-(Ci-ioalkylene )f_a-, heterocyclyl-(Ci-ioalkylene)_ga-R^57A -(Ci-ioalkylene)h_a-, carboxy, sulpho, sulphino, amidino, phosphono, -P(O)(OR^58A)(OR^59A), -P(O)(OH)(OR^58A), -P(O)(OH)(R^58A) or -P(O)(OR^59A)(R^59A), wherein R^58A and R^59A are independently selected from d_₆alkyl; wherein R^23A, R^25A, R^27A, R^33A, R^38A, R^44A, R^48A and R^54A may be independently optionally substituted on carbon by one or more R^60A; and wherein if said heterocyclyl contains an -NH- group, that nitrogen may be optionally substituted by a group selected from R^61A;

_R24A _R26A _R28A _R34A _R39A _R4_{5Aj R}49_{Aj R}55A _{and R}61A _{&χQ independently selected from}

Ci-βalkyl, Q-βalkanoyl,

sulphamoyl, N-(Ci_6alkyl) sulphamoyl, Docket No. 2221.037AWO

N₅N-(C_1- 6alkyl)₂sulphamoyl, Q-βalkoxycarbonyl, carbamoyl, N-(Ci_6alkyl) carbamoyl, N,N-(Ci_₆alkyl)₂carbamoyl, benzyl, phenethyl, benzoyl, phenylsulphonyl and phenyl;

_R29A _R30A _R40A _R41A _R50A _R51A _R56A _{and R}57A ^ _{independently selected from} .Q., .

NR^62A-, -S(O)_xa-, -NR^62AC(O)NR^63a-, -NR^62AC(S)NR^63A-, -OC(O)N=C-, -NR^62AC(O)- or -C(O)NR^62A-; wherein R^62A and R^63A are independently selected from hydrogen or d-βalkyl, and xa is 0-2;

R^60A is selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N- dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl and

N,N-dimethylsulphamoyl ; ea, fa, ga and ha are independently selected from 0-2; said process comprising arylating a 1 -unsubstituted 4-phenylazetidinone of formula:

with an R -substituted phenyl arylating agent.

DETAILED DESCRIPTION OF THE INVENTION

[0024] 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. Docket No. 2221.037AWO

Definitions

[0025] 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, except for claims 34-48

[0026] 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 C20 or below (e.g. Ci, C₂, C3, C₄, C5, Ce, C₇, Cs, C9, C10, Cn, Ci₂, C13, Ci₄, Ci5, Ci6, Ci₇, Ci8, Ci9, C20). 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.

[0027] Ci to C₂₀ Hydrocarbon (e.g. C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, Ci₀, Cn, Ci₂, Ci3, Ci₄, Ci5, Ci6, Ci₇, Ci8, Ci9, C₂o) 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:

[0028] 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. Docket No. 2221.037AWO

[0029] 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, |196, but without the restriction of |127(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.

[0030] 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_yH_2y+iO_y, and cyclic polyol residues will generally be of the formula -C_yH2_y-i0_y. Those in which y is 3, 4, 5 and 6 are preferred. Cyclic polyols also include reduced sugars, such as glucitol.

[0031] Acyl refers to formyl and 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 of acyl include formyl, acetyl, propionyl, isobutyryl, ϊ-butoxycarbonyl, benzoyl, benzyloxycarbonyl and the like. Lower-acyl refers to groups containing one to six carbons.

[0032] 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- Docket No. 2221.037AWO

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.

[0033] Arylalkyl means an alkyl residue attached to an aryl ring. Examples are benzyl, phenethyl and the like.

[0034] 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.

[0035] The term "halogen" means fluorine, chlorine, bromine or iodine.

[0036] 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 Docket No. 2221.037AWO

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.

[0037] 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 HOCH₂ [CH(OH)]_nCH₂OH (formally derivable from an aldose by reduction of the carbonyl group).

[0038] 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)].

[0039] 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), Docket No. 2221.037AWO

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 and ProtB) 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).

[0040] 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.

[0041] 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 Docket No. 2221.037AWO

Means either pure 3R,4S:

or pure 3S,4R:

whereas

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

[0042] 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 x 100 cone, of a + cone, of b Docket No. 2221.037AWO

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.

[0043] DFPA, BPA-3, BPA-4 and ADG and similar substituted azetidin-2-ones of the formula

are prepared by cyclizing a compound of formula

[0044] In these processes and compounds, R¹ and R² are chosen from H, halogen, ProtA-O-, and methoxy. U is (C₂-C6)-alkylene in which one or more individual -CH₂- may be replaced by a radical chosen from -S-, -S(O)-, -SO₂-, -O-, -C(=O)-, - CH(OProtB)-, -NH-, CHF, CF₂, -CH(O-loweralkyl)-, -CH(O-loweracyl)-, - CH(OSO₃H)- and -CH(OPO₃H₂)-. R⁵ is a sugar, protected sugar, phosphonate, Docket No. 2221.037AWO

phenolic hydroxy or protected phenolic hydroxy; and Q is a chiral auxiliary chosen from single enantiomers of triphenyl glycol and cyclic and branched nitrogen- containing moieties possessing at least one chiral center. In certain embodiments R¹ is hydrogen and R² is fluorine. The process for ADG is an example of such an embodiment.

[0045] ProtA-O- and ProtA'-O- are 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].

[0046] ProtB-O- is HO- or a protecting group for a benzylic alcohol. For many reactions, including some illustrated below, it is unnecessary to protect the hydroxyl and in these cases, ProtB-O- is HO-. When a protecting group is desired, it is chosen from protecting groups in Greene and Wuts, Chapter 1, pages 17-86, the removal of which does not require strong acid. Examples include an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester [e.g. acetyl or benzoyl].

[0047] When R⁵ is a sugar or a protected sugar, as discussed above, it encompasses any carbohydrate comprised of one or two saccharose groups as well as reduced sugars (alditols) such as glycitol. The protecting groups may be chosen from any of those well known in the carbohydrate art. Examples include benzyl ethers, silyl ethers [e.g. trimethylsilyl] and acyl esters [e.g. acetyl].

[0048] 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)palladium dichloride, tetrakis(triphenylphosphine)palladium Docket No. 2221.037AWO

[(Ph₃P)₄Pd], tris(dibenzylidene-acetone)palladium [(dba)₃Pd₂]and bis(dibenzylideneacetone) palladium [(dba)₂Pd]. Ligands for the reaction with the diboron species may be l,l '-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-tolylphosphino)-l,l'-binaphthyl (tol-BINAP) and trialkyl or triarylphosphines, such as tri-t-butylphosphine, tricyclohexyl phosphine, triphenylphosphine and (tri-o-tolyl)phosphine.

[0049] In certain embodiments, R¹ and R² are chosen from H, halogen, ProtA-O-, and methoxy; ProtA-O- is chosen from methoxymethyl ether, ?-butyl ether and benzyl ether; and U is chosen from a (C2-C6)-alkylene in which one -CH₂- radical is - CH(OProtB). The cyclization reaction is brought about by treatment with N,O- bistrimethylsilyacetamide (BSA) and a catalytic amount of tetrabutylammonium fluoride hydrate (TBAF). In another embodiment, R¹ is hydrogen; R² is fluorine; ProtA-O- is benzyl ether; and ProtB-O- is HO-.

[0050] After an azetidine derivative, 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.

Docket No. 2221.037AWO

[0051] Thus, for example, one may prepare a 4-biphenylazetidinone of formula

wherein R^la and R^2a are chosen from H, halogen, -OH, and methoxy; and R^5a is a sugar, phosphonic acid or OH by cyclizing a compound of formula

and then deprotecting. The cyclization is accomplished by treatment with BSA and a source of a fluoride ion.

[0052] In this example, R and R are chosen from hydrogen, halogen, ProtA-O-, and methoxy. R⁵ is a sugar, protected sugar, phosphonate, and phenolic hydroxy or protected phenolic hydroxy. ProtA-O- and ProtA'-O- are a protecting group for a phenol chosen from an oxymethylether, a tertiary alkyl ether, a benzyl ether, or a silyl ether and ProtB-O- is a protecting group for a benzylic alcohol chosen from an Docket No. 2221.037AWO

oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexylether, a methoxybenzyl ether, a silyl ether, or an ester. Q is a chiral auxiliary chosen from single enantiomers of triphenyl glycol and cyclic and branched nitrogen-containing moieties possessing at least one chiral center.

[0053] Examples of such chiral auxiliaries include:

[0054] In these compounds, R , 10 is phenyl, benzyl, isopropyl, isobutyl or t-butyl; R 11 is hydrogen, methyl or ethyl; or R¹⁰ and R¹¹ together can form a cycle; R¹² is hydrogen, methyl or ethyl; R¹³ is hydrogen or methyl; R¹⁴ is methyl, benzyl, isopropyl, isobutyl or t-butyl; ProtC is methoxyoxymethyl (MOM), 2- Docket No. 2221.037AWO

(trimethylsilyl)ethoxymethyl (SEM), allyl or silyl [e.g. trimethylsilyl, t- butyldimethylsilyl, phenyldimethylsilyl]; and the wavy line indicates the bond by which the auxiliary is attached to the carbonyl of the parent.

[0055] In another particular embodiment, one may cyclize a δ-oxoamine of formula

and deprotect to afford a 4-biphenylazetidinone of formula

Docket No. 2221.037AWO

Deprotection of the benzyl ether is accomplished by catalytic hydrogenolysis and deprotection of the acetates with base. The cyclization is accomplished by treatment with BSA and a source of a fluoride ion.

[0056] The δ-oxoamine is obtained by reacting an N-acyloxazolidinone of formula

with an imine of formula

[0057] Compounds of the formula

Docket No. 2221.037AWO

are prepared by arylating a 1 -unsubstituted 4-phenylazetidinone of formula

with an R¹ -substituted phenyl arylating agent. R¹ -substituted phenyl arylating agents are commonly of the formula:

wherein X^a is a halogen, e.g. iodine, or a sulfonate, e.g. triflate.

[0058] In these processes and compounds, R¹, R² and R⁶ are chosen from H, halogen, -OH, ProtA-O-, and methoxy. U is (C₂-C6)-alkylene in which one or more individual -CH₂- may be replaced by a radical chosen from -S-, -S(O)-, -SO₂-, -0-, - C(=0)-, -CH=CH-, -CH(OProtB)-, -NH-, CHF, CF₂, -CH(O-loweralkyl)-, -CH(O- loweracyl)-, -CH(OSO₃H)-, and -CH(OPO₃H₂)-. 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. ProtB-O- is HO- or a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester. R⁵ is chosen from H, halogen, -OH, ProtA-O-, methoxy and phenyl. The phenyl is optionally substituted with a sugar, protected sugar, phosphonate, and phenolic hydroxy or protected phenolic hydroxy.

[0059] In certain embodiments, R¹ is hydrogen and R² is fluorine. In other embodiments, U is (C₂-Ce)-alkylene in which one -CH₂- is replaced by -CH(OProtB).

[0060] The arylation reaction is accomplished using a copper (I) iodide reagent under conditions that facilitate arylation. Docket No. 2221.037AWO

[0061] In a particular example, the compound in which R¹ and R² are F and R⁵ is OH (i.e. ezetimibe) may be prepared as shown below:

[0062] 4-Biphenylylazetidonones, such as DFPA, BPA-3, BPA-4 and ADG, of the formula

Docket No. 2221.037AWO

are prepared by arylating a 1 -unsubstituted azetidinone of formula

with an R -substituted phenyl arylating agent.

[0063] In these processes and compounds, R¹ and R² are chosen from H, halogen, ProtA-O-, and methoxy. ProtA-O- and ProtA'-O- are protecting groups for a phenol chosen from an oxymethyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether. ProtB-O- is HO- or a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester. R⁵ is a sugar, protected sugar, phosphonate, and phenolic hydroxy or protected phenolic hydroxy. In certain embodiments, R¹ is hydrogen, R² is fluorine, ProtB-O- is HO-, and ProtA'-O- is a benzyl ether.

[0064] After the compound described supra is synthesized, the protecting groups are cleaved under the conditions described earlier to produce the corresponding compounds having a free phenol, free alcohol and/or free sugar/polyol. Thus for example, one may prepare a 4-biphenylazetidinone of formula

Docket No. 2221.037AWO

by arylating a 1 -unsubstituted azetidinone of formula:

with an R -substituted phenyl arylating agent and then deprotecting.

[0065] In this example, R^la and R > 2^za^a are chosen from H, halogen, -OH, and methoxy; and R^5a is a sugar, phosphonic acid or OH. R¹ and R² are chosen from H, halogen, ProtA-O-, and methoxy. R⁵ is a sugar, protected sugar, phosphonate, phenolic hydroxy or protected phenolic hydroxy. ProtA-O- and ProtA'-O- are protecting groups for a phenol chosen from an oxymethyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether. ProtB-O- is HO- or a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester. Deprotection of acetates and methyl esters is accomplished with a base, deprotection of the benzyl ether is accomplished by cleaving the benzyl ether by catalytic Docket No. 2221.037AWO

hydrogeno lysis and deprotection of dimethylphosphonates may be accomplished with bromotrimethylsilane.

[0066] In particular embodiments, one may arylate 1 -unsubstituted azetidinones of formulae

Docket No. 2221.037AWO

with an R¹ -substituted phenyl iodide and copper iodide to afford compounds of formulae

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[0067] The 1-unsubstituted azetidinone is obtained by reacting a 4- bromophenylazetidinone of formula

with a compound of formula

R¹⁰ and R¹¹ are independently selected from H and (Ci-C₆) alkyl, or R¹⁰ and R¹¹ together may form a 5-6 membered ring. The 4-bromophenylazetidinone may be prepared by treating a l-(4-hydroxyphenyl)azetidinone of formula

with an oxidant and a base. R is chosen from H, halogen, ProtA-O-, and methoxy; and 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. Docket No. 2221.037AWO

[0068] The l-(4-hydroxyphenyl)azetidinone may be prepared by

by cyclizing a δ-oxoamine of formula

. R is chosen from H, halogen, ProtA-O-, and methoxy; and 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.

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[0069] The δ-oxoamine described supra is obtained by reacting an N- acyloxazolidine of formula

with an imine of formula

. R is chosen from H, halogen, ProtA- O-, and methoxy; and 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. The imine may be prepared by reacting para aminophenol with 2-benzyloxy-4-bromobenzaldehyde.

[0070] Also within the scope of the invention are three compounds useful as intermediates in the processes described herein and the processes for their synthesis. A compound of formula

Docket No. 2221.037AWO

is presented in accordance with the present invention and is synthesized by reacting 2- benzyloxy-4-bromobenzaldehyde in the presence of a phosphine, a palladium salt and a base with a compound of formula

R¹⁰ and R¹¹ are independently selected from H and (Ci-C₆) alkyl, or R¹⁰ and R¹¹ together may form a 5-6 membered ring. [0071] A compound of formula

R¹⁰ and R¹¹ are independently selected from H and (Ci-C₆) alkyl, or R¹⁰ and R¹¹ together may form a 5-6 membered ring. Docket No. 2221.037AWO

[0072] A compound of formula

is presented in accordance with the present invention and is synthesized by reacting 2- benzyloxy-4-bromobenzaldehyde in the presence of a phosphine, a palladium salt and

1

a base with a compound of formula

w dhieerein R¹⁰ and R¹¹ are independently selected from H and (Ci-Cβ) alkyl, or R¹⁰ and R¹¹ together may form a 5-6 membered ring.

[0073] A process for preparing diphenyl heterocycle of formula

is presented in accordance with the present invention. The process comprises arylating a 1-unsubstituted phenyl heterocycle of formula: Docket No. 2221.037AWO

with an R -substituted phenyl arylating agent.

[0074] The substituents R¹, R² and R⁶ are chosen from H, halogen, -OH, ProtA-O-, and methoxy. W is chosen from -CH₂-, -NR⁷-, -O-, -S-, -CH₂CH₂-, -CH₂NR⁷-, - NR⁷CH₂-, -CONR⁷-, -CH₂O-, -OCH₂-, -CH₂S-, -SCH₂-, -CH=CH-, -CH=N-, -N=CH- , -C(O)O-, -C(O)CH₂-, -C(=O)NR⁷, -C(=S)O-, -C(=S)CH₂-, -C(=S)NR⁷, -C(O)S-, -C(=S)-, -S(O) and -SO₂-. U is (C₂-Ce)-alkylene in which one or more individual - CH₂- may be replaced by a radical chosen from -S-, -S(O)-, -SO₂-, -0-, -C(O)-, - CH=CH-, -CH(OProtB)-, -NH-, CHF, CF₂, -CH(O-loweralkyl)-, -CH(O-loweracyl)-, - CH(OSO₃H)- and -CH(OPO₃H₂)-. 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. ProtB- O- is HO- or a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester. R⁵ is chosen from H, halogen, -OH, ProtA-O-, methoxy and phenyl. The phenyl substituent may be optionally substituted with a sugar, protected sugar, phosphonate, and a phenolic hydroxy or protected phenolic hydroxy.

[0075] In certain embodiments, R¹ is hydrogen and R² is fluorine. In another embodiment, R¹ is hydrogen, R² is fluorine, and U is a (C₂-Ce)-alkylene in which one - CH₂- may be replaced by ProtB-O-. In another embodiment, W is -C(O)O-. Examples of compounds in which W is -C(O)O- include: Docket No. 2221.037AWO

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[0076] In another embodiment, W is -C(=O)NH-. Examples of compounds in which W is -C(O)NH- include:

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, and

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[0077] In another embodiment, W is -C(=O)NCH3-. Examples of compounds in which W is -C(O)NH- include:

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[0078] In another embodiment, W is -C(=O)S-. Examples of compounds in which W is -C(O)S- include:

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[0079] In another embodiment, W is -C(=S)CH₂-. Examples of compounds in which W is -C(=S)CH₂- include:

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[0080] In another embodiment, W is -C(=S)O-. Examples of compounds in which W is -C(=S)O- include:

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[0081] In another embodiment, W is -C(=S)NH-. Examples of compounds in which W is -C(=S)NH- include:

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[0082] In another embodiment, W is -C(=S)NCH₃-. Examples of compounds in which W is -C(=S)NCH₃- include:

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[0083] In another embodiment, W is -SO₂-. Examples of compounds in which W is -SO₂- include:

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[0084] In another embodiment, W is -C(=S)-. Examples of compounds in which W is -C(=S)- include:

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[0085] The processes for preparing the above compounds are disclosed in application WO2006/102674 which is herein incorporated by reference in its entirety.

[0086] A process for preparing a diphenyl azetidinone of formula

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is presented in accordance with the present invention. The process comprises arylating a 1-unsubstituted 4-phenylazetidinone of formula:

with an R¹ -substituted phenyl arylating agent. The substituents R^1A, R^2A, R^1B, R^2B, R^5A, and R^6A, independently of one another are chosen from: (a) (Ci-C₃₀)-alkylene-(LAG)_qa, wherein at least one carbon atom of the alkylene radical is replaced by: aryl or heteroaryl radicals, which are unsubstituted or substituted one, two, or three times by R^7A or by (C₃-Cio)-cycloalkyl or heterocycloalkyl radicals, which are unsubstituted or substituted one, two, three or four times by R^7A, or wherein one or more individual carbon atoms of the alkylene radical is optionally replaced by a radical chosen from: -S(0)πm- (where ma=0-2), -0-, -(C=O)-, -(C=S)-, -CH=CH-, -C=C-, -N[(Ci-C₆)-alkyl]-, - N(phenyl)-, -N[(Ci-C₆)-alkyl-Phenyl]-, -N(CO-(CH₂)i-i₀-COOH)- and - NH-; or

(b) H, F, Cl, Br, I, CF₃, NO₂, N₃, CN, COOH, COO(Ci-C₆)-alkyl, CONH₂, CONH(Ci_C₆)-alkyl, CON[(Ci-C₆)-alkyl]₂, (Ci-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂- C₆)-alkynyl, -OH, ProtA-O- or O-(Ci-C₆)-alkyl, wherein the alkyl radical is unsubstituted or at least one hydrogen in the alkyl radical is replaced by fluorine; or

(c) SO₂NH₂, SO₂NH(Ci-C₆)-alkyl, SO₂N[(Ci-C₆)-alkyl]₂, S-(d-C₆)-alkyl, S-(CH₂)_na-Phenyl, SO-(d-C₆)-alkyl, SO-(CH₂-)_naphenyl, SO₂-(Ci-C₆)-alkyl, or SO₂-(CH₂)_na-Phenyl; wherein na=0-6, and wherein the phenyl radical is unsubstituted or substituted one or two times, each substituent chosen independently from: F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O-(d-C₆)-alkyl, (C₁- C₆)-alkyl, and NH₂; or Docket No. 2221.037AWO

(d) NH₂ NH-(Ci-C₆)-alkyl, N[(Ci-C₆)-alkyl]₂, NH(Ci-C₇)-acyl, phenyl, or O-(CH₂)_na-Phenyl, wherein na=0-6, and wherein the phenyl ring is unsubstituted or substituted one, two, or three times, each substitutent chosen independently from: F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O-(d-C₆)-alkyl, (Ci-C₆)-alkyl, NH₂, NH-(Ci-C₆)-alkyl, N[(Ci-C₆)-alkyl]₂, SO₂CH₃, COOH, COO-(Ci-C₆)-alkyl, and CONH₂.

R^5A may additionally be phenyl optionally substituted with a sugar, protected sugar, phosphonate, and phenolic hydroxy or protected phenolic hydroxy.

[0087] One of the radicals R^1A to R^6A must have the meaning:

(Ci-C₃₀)-alkylene-(LAG)_qa

R^7A represents

(c) C(=NH)(NH₂), NH₂, NH-(Ci-C₆)-alkyl, N[(C₁-C₆)-alkyl]₂, NH(Ci-C₇)-acyl, phenyl, or O-(CH₂)_na-Phenyl, wherein na=0-6, and wherein the phenyl ring is unsubstituted or substituted one, two, or three times, each substituent chosen independently from: F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O-(Ci-C₆)alkyl, (Ci-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N[(C₁-C₆)-alkyl]₂, SO₂CH₃, COOH, COO-(Ci-C₆)-alkyl, and CONH₂.

(LAG) is a sugar residue, disugar residue, trisugar residue, tetrasugar residue; a sugar acid, an amino sugar; a polyol; an amino acid residue, or an oligopeptide residue comprising 2 to 9 amino acids; or an acyclic, mono-, di- or tricyclic trialkylammonium radical, an acyclic mono-, di- or tricyclic trialkylammoniumalkyl radical, -0(SO₂)OH; Docket No. 2221.037AWO

-(CH₂)O-_I0-SO₃H, -(CH₂)O-_IO-P(O)(OH)₂, -(CH₂)O_-10-O-P(O)(OH)₂, -(CH₂)₀-i₀COOH, -(CH₂)o-io-C(=NH)(NH₂), -(CH₂)₀-i₀-C(=NH)(NHOH), or -NR^8A- C(=NR^9A)(NR^10AR^11A); wherein R^8A, R^9A, R^10A and R^11A, independently of one another, are chosen from: H, (Ci-C₆)-alkyl, phenyl, (Ci-C₆)-alkylphenyl, and (C₃-Cg)- cycloalkyl; qa=l-5.

[0088] U is (C₂-C6)-alkylene in which one or more individual -CH₂- may be replaced by a radical chosen from -S-, -S(O)-, -SO₂-, -O-, -C(=O)-, -CH=CH-, -CH(OProtB)-, - NH-, CHF, CF₂, -CH(O-loweralkyl)-, -CH(O-loweracyl)-, -CH(OSO₃H)- and - CH(OPO₃H₂)-. 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. ProtB-O- is HO- or a protecting group for a benzylic alcohol chosen from an oxymethyl ether, a tetrahydropyranyl or tetrahydrofuranyl ether, methoxycyclohexyl ether, a methoxybenzyl ether, a silyl ether and an ester.

[0089] The above process and resulting compounds are disclosed in application WO2006/086562, which is hereby incorporated by reference in its entirety.

[0090] The compounds of formula

may be prepared according to the method shown in Scheme 10, in which R¹⁰ and R¹¹ 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.

[0091] Exemplary processes that fall within the scope of the invention are illustrated Docket No. 2221.037AWO

in the schemes below. These schemes also illustrate the interrelatedness of the processes and intermediates. In the schemes that follow, solid arrows indicate reactions that are described in the examples; dashed arrows indicate reactions that are not exemplified.

Scheme 1

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Scheme 1 (cont.)

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Scheme 2

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Scheme 3

23 aniline isopropyl alcohol

I)BSA /TBAF 2) aq work up

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Scheme 4

29

I)BSA /TBAF 2) aq work up

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Scheme 5

condensation

Ph triphosgene HO. triethylamine

34

NaCNBH Wittig reagent

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Scheme 5 (cont.)

Ce(IV)NH₄NO₃ CH₃CN

(1 01 eq )

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Scheme 6

Ph

,Me triphosgene ?^ι triethylamine ^HY_°i Me

34

48

NaCNBH Wittig reagent

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Scheme 6 (cont.)

Ce(IV)NH₄NO₃ CH₃CN

ne (1 01 eq )

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Scheme 7

triphosgene tπethylamine

34

NaCNBH Wittig reagent

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Scheme 7 (cont.)

eq ) cyclohexane (1 01 eq ) 94 eq ) (O 25M) C

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Scheme 8

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Scheme 8 (cont.)

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Scheme 9

74 75

76

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Scheme 9 (cont.)

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Scheme 10

Methanesulfonic acid Methanol

[0092] Preparation of (15^r)-l,5-anhydro-l-(4'-{(25,3R)-3-[(35)-3-(4-fluorophenyl)-3- hydroxypropyl]-4-oxo-l-phenylazetidin-2-yl}-3'-hydroxybiphenyl-4-yl)-D-glucitol. Docket No. 2221.037AWO

[0093] Step 1. Referring to Scheme 1, a mixture of 2-(benzyloxy)-4- bromobenzaldehyde 1 and 4-aminophenol 2 were dissolved in isopropyl alcohol and warmed to 75 ⁰C Ih. The solution was allowed to cool to room temperature where upon crystals formed. The crystal were isolated by filtration and dried in vacuo to provide of 4-({(l£)-[2-(benzyloxy)-4-bromophenyl]methylene}amino)phenol 3 in 96% yield.

[0094] Step 2. (4R)-4-Benzyl-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-l,3- oxazolidin-2-one 4 and N,N-diisopropylethylamine were dissolved in dichloromethane, cooled to 5 ⁰C, and treated with chlorotrimethylsilane. In a separate reaction vessel, the imine 3 and an additional equivalent of N,N-diisopropylethylamine were suspended in dichloromethane and treated with chlorotrimethylsilane. After maintaining the two reaction mixtures at 5 ⁰C for Ih the two solutions were cooled to -30 ⁰C, and combined and treated with titanium tetrachloride. After an additional 12 h at -20 ⁰C, the combined solution was treated with acetic acid followed by aqueous tartaric acid. The reaction mixture then was extracted with a 1 : 1 mixture of hexanes and ethyl acetate. After concentration of the solution, the reaction product was purified by chromatography to afford (4R)-4-benzyl-3 -[(2R,5S)-2- {(S)-[2-(benzyloxy)-4- bromophenyl][(4-hydroxyphenyl)amino]methyl}-5-(4-fluorophenyl)-5- hydroxypentanoyl]-l,3-oxazolidin-2-one 5 in a 66% yield.

[0095] Step 3. A solution of 5 in methyl- tert-butylether (MTBE) was treated with three equivalents of N,O-bis-(trimethylsilyl)acetamide (BSA) at 55 ⁰C for 13 h. The solution was cooled to room temperature, and then treated with an additional two equivalents of N,O-bis-(trimethylsilyl)acetamide (BSA) and a catalytic amount of tetra-M-butylammonium fluoride (TBAF) for 5 h at room temperature. The reaction mixture further was treated with acetic acid and aqueous tartaric acid. The MTBE solution was diluted with 1: 1 hexanes: ethyl acetate and washed with water and brine, and dried over anhydrous Νa2SO/t, filtered and concentrated in vacuo to afford the crude beta-lactam. It was purified by flash chromatography to give pure (35^r,4i?)-4-[2- (benzyloxy)-4-bromophenyl]-3-[(35)-3-(4-fluorophenyl)-3-hydroxypropyl]-l-(4- hydroxyphenyl)azetidin-2-one 6 in a 55% yield. Docket No. 2221.037AWO

[0096] Step 4. A solution of 6 in aqueous acetonitrile was treated with 1 equivalent of 1.0 N NaOH solution and, then cooled to 5 ⁰C and treated with 3 equivalents of aqueous cerium (IV) ammonium nitrate for 15 min. The solution was diluted with 1 : 1 hexanes: ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous Na2S0/t, and filtered and concentrated in vacuo to afford the crude beta- lactam which was purified by flash chromatography over silica gel to give (3R,45')-4- [2-(benzyloxy)-4-bromophenyl]-3-[(35^r)-3-(4-fluorophenyl)-3 -hydro xypropyl]azetidin- 2-one 7 in a 34% yield.

[0097] Step 5. A solution of 7 and (lS)-2,3,4,6-tetra-O-acetyl-l,5-anhydro-l-[4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-D-glucitol 8 in degassed 1,4- dioxane was treated with degassed 2.0M potassium carbonate. Bis-triphenylphosphine palladium (II) chloride then was added and the reaction mixture warmed to 90 ⁰C for 1 h. The solution was cooled to room temperature and extracted with 1:2 hexanes :ethyl acetate. The extract was washed with water and brine, dried over anhydrous Na₂SO₄, and filtered and concentrated in vacuo to afford the crude beta-lactam. It was purified by flash chromatography over silica gel to give (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-oxoazetidin-2-yl}biphenyl-4-yl)-D-glucitol 9 in 63% yield with > 98.7% purity.

[0098] Step 6. A 1-dram vial was charged with 9 (101.2 mg, 0.125 mmol), copper (I) iodide (10.7 mg, 0.056 mmol), and potassium phosphate, tribasic (47.8 mg, 0.225 mmol). The vial was equipped with a magnetic stir bar and septa, and was vacuum/nitrogen gas purged (10 times) to remove oxygen. 1,4-Dioxane (0.46 mL), iodobenzene (13.0 μL, 23.7 mg, 0.116 mmol) and (+)-£raws-l,2-diaminocyclohexane (14.0 μL, 13.3 mg, 0.117 mmol) were added to the vial via syringe. The vial was 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 ⁰C. The reaction was heated for 1 h, cooled to room temperature, and loaded directly onto a silica gel column for purification by chromatography (25 mL silica gel, equilibrated with 30% ethyl acetate-hexanes, eluted with 30% ethyl acetate-hexanes (100 mL), 40% ethyl Docket No. 2221.037AWO

acetate-hexanes (50 mL), 50% ethyl acetate-hexanes (200 mL), 60% ethyl acetate- hexanes (100 mL)). Nine fractions were combined and concentrated in vacuo to afford (15^r)-2,3,4,6-tetra-O-acetyl-l,5-anhydro-l-(3'-(benzyloxy)-4'-{(25,3R)-3-[(35^r)-3-(4- fluorophenyl)-3 -hydro xypropyl]-4-oxo- 1 -phenylazetidin-2-yl} biphenyl-4-yl)-D- glucitol 10 (95.3 mg, 93% yield) as a white foam; R/ 0.25 (1 : 1 ethyl acetate-hexane); HPLC (Method A) R_τ 9.2 min; HPLC (Method A) purity 98.7 A%.

[0099] Step 7. A 25-mL one-necked flask was charged with 10 (95.3 mg, 0.107 mmol) and dissolved in methanol (1.0 mL). Anhydrous potassium fluoride (25.0 mg, 0.43 mmol) was added as a solid, the flask was capped, and the reaction stirred at 40 ⁰C for 39.5 h. The mixture was diluted with ethyl acetate (25 mL), transferred to a separatoy funnel, and washed with water (25 mL). The aqueos layer was re-extracted with ethyl acetate (2 x 25 mL), the combined organic layers were concentrated in vacuo, and then filtered to remove particulate material. The compound was purified by reverse-phase preparative HPLC (Polaris C18-A lOμ, 250 x 21.2 mm column, SN 9680087); flow rate: 20 mL/min; R_τ 24-30 min; 50% methanol-water, gradient to 0% methanol-water (15 min), hold 70% methanol-water (15 min), gradient to 100% methanol (5 min), hold 100% methanol (5 min). The fractions were combined and concentrated in vacuo to afford (15)-l,5-anhydro-l-(3'-(benzyloxy)-4'-{(25^r,3i?)-3- [(35^r)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-l-phenylazetidin-2-yl}biphenyl-4- yl)-D-glucitol 11 (74.7 mg, 97%) as an off-white foam; HPLC (Method A) R_r 6.3 min; HPLC (Method A) purity 99.7 A%; LRMS [M-OH]⁺ = 702.3.

[00100] Step 8. A 2-dram vial was charged with 11 (74.7 mg, 0.104 mmol) in 200- proof ethanol (2.0 mL) and 5% palladium on carbon (66.4 mg total weight, 1.66 mg Pd, 0.0103 mmol Pd) was added as a solid. The vial was placed inside a 500-mL hydrogenation pressure flask which was sealed, pressurized/released with hydrogen gas to purge the system, and placed under hydrogen (15 psi.). After 12 h of vigorous stirring at 23 ⁰C, the pressure was released and the mixture was filtered through Celite^® under a blanket of nitrogen gas, washed with methanol (75 mL), concentrated in vacuo, and then filtered to remove particulate material. The compound was purified by reverse-phase preparative HPLC (Polaris C18-A lOμ, 250 x 21.2 mm column, SN Docket No. 2221.037AWO

9680087); flow rate: 20 mL/min; R_τ 68-80 min; 49% methanol-water isocratic. The fractions were combined and concentrated in vacuo to afford (15')-l,5-anhydro-l-(4'- {(25^r,3R)-3-[(35')-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-l-phenylazetidin-2-yl}- 3'-hydroxybiphenyl-4-yl)-D-glucitol 12 (46.3 mg, 71% yield) as an off-white amorphous solid; R/ not useful due to excessive streaking; HPLC (Method A) R^ 4.8 min; HPLC (Method A) purity 99.4 A%; HPLC (Method B) R_τ 8.5 min; HPLC (Method B) purity 98.0 A%; LRMS [M-OH]⁺ = 612.3.

[00101] Preparation of (4'-{(25,3R)-3-[(35)-3-(4-fluorophenyl)-3-hydroxypropyl]-4- oxo-1 -phenylazetidin-2-yl}-3'-hydroxybiphenyl-4-yl)phosphonic acid.

[00102] Referring to Scheme 2, meta-bromophenol 13 was reacted with formaldehyde in the presence of magnesium chloride to provide 4-bromo-2 -hydro xybenzaldehyde 14. The 4-bromo-2-hydroxybenzaldehyde 14 then was reacted with benzyl bromide in the presence of potassium carbonate to afford 2-(benzyloxy)-4-bromobenzaldehyde 1. The benzaldehyde 1 was coupled with [4-(dimethoxyphosphoryl)phenyl]boronic acid

16 via Suzuki coupling to provide the biphenyl derivative 17. The biphenyl derivative

17 then was reacted with aniline in isopropyl alcohol producing a dimethyl {3'- (benzyloxy)-4'-[(£)-(phenylimino)methyl]biphenyl-4-yl}phosphonate 18.

[00103] The phosphonate 18 was condensed with (4S>4-benzyl-3-[(5S>5-(4- fluorophenyl)-5-hydroxypentanoyl]-l,3-oxazolidin-2-one 4. Added to the mixture was trimethylsilyl chloride and diisopropylethylamine, and then titanium tetrachloride. Aqueous workup produced dimethyl [4'-[(lS,2R,5S)-l -anilino-2-{[(4S>4-benzyl-2- OXO- 1 ,3 -oxazolidin-3 -yl]carbonyl } -5 -(4-fluorophenyl)-5 -hydroxyp entyl]-3 '- (benzyloxy)biphenyl-4-yl]phosphonate 19. The phosphonate 19 was treated with excess N,O-bistrimethylsilyl-acetamide and then reacted with a catalytic amount of tetrabutylammonium fluoride hydrate. The compound formed was dimethyl (3'- (benzyloxy)-4'-{(25',3R)-3-[(35)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-l- phenylazetidin-2-yl}biphenyl-4-yl)phosphonate 20. Docket No. 2221.037AWO

[00104] The phosphonate 20 was treated with trimethysilyl bromide and then hydrogenated over palladium on carbon to remove the protecting groups. The resulting product was (4'-{(25',3R)-3-[(35^r)-3-(4-fluorophenyl)-3-hydroxypropyl]-4- oxo-1 -phenylazetidin-2-yl}-3'-hydroxybiphenyl-4-yl)phosphonic acid 21.

[00105] Preparation of (3R,4S>4-(3,3'-dihydroxybiphenyl-4-yl)-3-[(3S>3-(4- fluorophenyl)-3 -hydro xypropyl]- 1 -phenylazetidin-2-one.

[00106] Referring to Scheme 3, 4-bromo-2-hydroxybenzaldehyde 1 was coupled with (3-hydroxyphenyl)boronic acid 22 via Suzuki coupling providing 3-(benzyloxy)-3'- hydroxybiphenyl-4-carbaldehyde 23. The compound 23 was condensed with aniline in isopropyl alcohol affording the imine 3'-(benzyloxy)-4'-[(£)-

(phenylimino)methyl]biphenyl-3-ol 24. The imine 24 then was condensed with (4S)- 4-benzyl-3-[(55^r)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-l,3-oxazolidin-2-one 4 resulting in the formation of (4S)-3-[(2R,5S>2-{(S)-anilino[3-(benzyloxy)-3'- hydroxybiphenyl-4-yl] methyl} -5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-benzyl- 1 ,3 - oxazolidin-2-one 25.

[00107] Ring closure of 25 was accomplished by treatment with excess N,O- bistrimethylsilyl-acetamide followed by reaction with a catalytic amount of tetrabutylammonium fluoride hydrate. Aqueous workup afforded the product (3R,4S)- 4-[3-(benzyloxy)-3'-hydroxybiphenyl-4-yl]-3-[(35)-3-(4-fluorophenyl)-3- hydroxypropyl]- 1 -phenylazetidin-2-one 26. Hydrogenation of 26 over palladium on carbon removed the benzyl group to provide (3i?,45')-4-(3,3'-dihydroxybiphenyl-4-yl)- 3-[(3,S)-3-(4-fluorophenyi)-3-hydroxypropyl]-l -phenylazetidin-2-one 27.

[00108] Preparation of (15^r)-l,5-anhydro-l-(4'-{(25,3R)-3-[(35)-3-(4-fluorophenyl)-3- hydroxypropyl]-4-oxo-l-phenylazetidin-2-yl}-3'-hydroxybiphenyl-4-yl)-D-glucitol.

[00109] Referring to Scheme 4, 4-bromo-2-hydroxybenzaldehyde 1 was coupled with 2,3,4,6-tetra-O-acetyl-l,5-anhydro-l-[4-(dihydroxyboryl)phenyl]hexitol 27 via Suzuki coupling. The resultant compound formed was 2,3,4,6-tetra-O-acetyl-l,5-anhydro-l- Docket No. 2221.037AWO

[3'-(benzyloxy)-4'-formylbiphenyl-4-yl]hexitol 28. Compound 28 was reacted with aniline in isopropyl alcohol affording 2,3,4,6-tetra-O-acetyl-l,5-anhydro-l-{3'- (benzyloxy)-4'-[(£)-(phenylimino)methyl]biphenyl-4-yl}hexitol 29 as the product. 29 was condensed with 2,3,4,6-tetra-O-acetyl-l,5-anhydro-l-{3'-(benzyloxy)-4'-[(£)- (phenylimino)methyl]biphenyl-4-yl}hexitol 4 yielding (15)-2,3,4,6-tetra-O-acetyl-l,5- anhydro-l-μ'-tClS'^R^^-l-anilino^-l^^^-benzyl^-oxo-l^-oxazolidin-S- yl]carbonyl}-5-(4-fluorophenyl)-5-hydroxypentyl]-3'-(benzyloxy)biphenyl-4-yl]-D- glucitol 30.

[00110] Ring closure of the D-glucitol 30 was accomplished by treatment with excess N,O-bistrimethylsilyl-acetamide followed by reaction with a catalytic amount of tetrabutylammonium fluoride hydrate. The resultant product was (15)-2,3,4,6-tetra-O- acetyl-l,5-anhydro-l-(3'-(benzyloxy)-4'-{(25,3R)-3-[(35)-3-(4-fluorophenyl)-3- hydroxypropyl]-4-oxo-l-phenylazetidin-2-yl}biphenyl-4-yl)-D-glucitol 10. Compound 10 then was treated with potassium fluoride in methanol followed by hydrogenation over palladium on carbon to remove the protecting groups. The final product formed was (15^r)-l,5-anhydro-l-(4'-{(25',3R)-3-[(35^r)-3-(4-fluorophenyl)-3- hydroxypropyl]-4-oxo-l-phenylazetidin-2-yl}-3'-hydroxybiphenyl-4-yl)-D-glucitol 12.

[00111] Preparation of (4R,5R)-5-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-(2- hydroxy-4-methoxyphenyl)-3-phenyloxazolidin-2-one analogs.

[00112] Referring to Scheme 5, (4R,5R)-5-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)- 4-(2-hydroxy-4-methoxyphenyl)-3-phenyloxazolidin-2-one 43 analogs were prepared by the condensation of commercially available 2-hydroxy-4-methoxybenzaldehyde 31 with para-anisidine 32 to produce the corresponding imine 33. Protection of the hydroxyl moiety of the imine 33a was accomplished by treatment with benzyl bromide and potassium carbonate in DMF to provide the imine 33b. Subsequent treatment with 2-((2S,5S,6R)-2,4,5-trimethyl-3-oxo-6-phenylmorpholin-2-yloxy)acetic acid 34, (prepared according to the method of B. A. Shinkre, V. G. Puranik, B, M. Bhawal, A. Deshmukh, Tetrahedron Asymmetry 2003, 14, 453, which is herein incorporated by reference in its entirety), with triphosgene [(CIsCO)₂CO] and triethylamine provided Docket No. 2221.037AWO

the beta-lactam (2R,5S,6R)-2-((2R,3S)-2-(2-(benzyloxy)-4-methoxyphenyl)-l -(4- methoxyphenyl)-4-oxoazetidin-3-yloxy)-2,4,5-trimethyl-6-phenylmorpholin-3-one 35. A solution of the beta-lactam 35 was dissolved in tetrahydrofuran and water with a catalytic amount ofpαrα-toluenesulfonic acid (TSA) to effect hydrolysis to the product (3 S,4R)-4-(2-(benzyloxy)-4-methoxyphenyl)-3 -hydroxy- 1 -(4-methoxyphenyl)azetidin- 2-one 36.

[00113] The azetidin-2-one 36 was then treated with sodium methoxide in methanol to effect conversion to the methyl ester with beta-lactam ring opening. Reaction of the resulting alcohol with triphosgene in the presence of diisopropylethylamine and N, N- dimethylaminopyridine (DMAP) gave (4R,5S)-methyl 4-(2-(benzyloxy)-4- methoxyphenyl)-3-(4-methoxyphenyl)-2-oxooxazolidine-5-carboxylate 37. The ester moiety of which was then converted into the corresponding hydroxymethyl substituent upon treatment with sodium cyanoborohydride. Swern oxidation converted the hydroxymethyl substituent into the corresponding aldehyde which was then reacted with Wittig reagent l-(4-fluorophenyl)-2-triphenyl-λ⁵-phosphanylidene)-ethanone to give the ketone (4R,5R)-4-(2-(benzyloxy)-4-methoxyphenyl)-5-((E)-3-(4- fluorophenyl)-3-oxoprop-l-enyl)-3-(4-methoxyphenyl)oxazolidin-2-one 38.

[00114] Treatment of 38 with copper hydride, according to the method of T. Tsuda, T. Fujii, K. Kawasaki, T. Saegusa J. Chem. Soc, Chem. Commuru, 1980, 1013 - 1014, which is herein incorporated by reference in its entirety, gave the ketone (4R,5R)-4-(2- (benzyloxy)-4-methoxyphenyl)-5 -(3 -(4-fluorophenyl)-3 -oxopropyl)-3 -(4- methoxyphenyl)oxazolidin-2-one 39. Compound 39 then was reduced with borane dimethylsulfide complex in the presence of a catalytic amount of tetrahydro-1-methyl- 3,3-diphenyl-lH,3H-pyrrolo[l,2-c][l,3,2]oxazaborole, (R-CBS), affording the compound (4R,5R)-4-(2 -(benzyloxy)-4-methoxyp henyl)-5-((S)-3-(4-fluorophenyl)-3 - hydroxypropyl)-3-(4-methoxyphenyl)oxazolidin-2-one 40.

[00115] Reaction of 40 with cerium (IV) ammonium nitrate in aqueous acetonitrile according to the method of Cainelli, G.; Giacomini, D.; Panunzio, M.; Martelli, G.; Spunta, G. Tetrahedron Letters 1987, 28, 3593-3596, which is herein incorporated by Docket No. 2221.037AWO

reference it its entirety, gave (4R,5R)-4-(2-(benzyloxy)-4-methoxyphenyl)-5-((S)-3-(4- fluorophenyl)-3-hydroxypropyl)oxazolidin-2-one 41. 41 then was coupled with a variety of iodobenzene or bromobenzene derivatives according to the method of Klapars, A.; Antilla, J.C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 1121-1129, which is herein incorporated by reference in its entirety, to afford the N- aryl (4R,5R)-4-(2-(benzyloxy)-4-methoxyphenyl)-5-((S)-3-(4-fluorophenyl)-3- hydroxypropyl)-3-phenyloxazolidin-2-one derivatives 42. Subsequent catalytic hydrogenation over palladium on carbon was employed to prepare the final (4R,5R)-5- ((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-(2-hydroxy-4-methoxyphenyl)-3- phenyloxazolidin-2-one analogues 43.

[00116] Preparation of (4R,5R)-5-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-(2,4- dihydroxyphenyl)-3 -phenyloxazolidin-2-one analogs.

[00117] Referring to Scheme 6, the dibenzyl ether 1 was prepared by treating the 2,4- dihydroxybenzaldehyde with benzyl bromide and potassium carbonate in methyl ethyl ketone. Subsequent treatment of 1 with para-anisidine 32 resulted in the formation of the corresponding imine, (E)-Ν-(2,4-bis(benzyloxy)benzylidene)-4- methoxybenzenamine 45. The imine 45 then was reacted with 2-((2S,5S,6R)-2,4,5- trimethyl-3-oxo-6-phenylmorpholin-2-yloxy)acetic acid 34 in the presence of triphosgene [(Cl₃CO)₂CO] and triethylamine affording the beta-lactam, (2R,5S,6R)-2- ((2R,3S)-2-(2,4-bis(benzyloxy)phenyl)-l-(4-methoxyphenyl)-4-oxoazetidin-3-yloxy)- 2,4,5 -trimethyl-6-phenylmorpholin-3 -one 46. A solution of the 46 was dissolved in tetrahydrofuran and water with a catalytic amount of pαrα-toluenesulfonic acid to effect hydrolysis to (3S,4R)-4-(2,4-bis(benzyloxy)phenyl)-3-hydroxy-l-(4- methoxyphenyl)azetidin-2-one 47.

[00118] The compound 47 is then treated with sodium methoxide in methanol to effect conversion to the methyl ester with beta-lactam ring opening. Subsequent reaction with triphosgene in the presence of diisopropylethylamine and NN- dimethylaminopyridine gives the oxazolidinone, (4R,5S)-methyl 4-(2,4- bis(benzyloxy)phenyl)-3-(4-methoxyphenyl)-2-oxooxazolidine-5-carboxylate 48. The Docket No. 2221.037AWO

ester moiety of the oxazolidinone 48 was then converted into the corresponding hydroxymethyl substituent upon treatment with sodium cyanoborohydride. Swern oxidation converted the hydroxymethyl substituent into the corresponding aldehyde which was then reacted with Wittig reagent l-(4-fluorophenyl)-2-triphenyl-λ⁵- phosphanylidene)-ethanone to give the ketone, (4R,5R)-4-(2,4-bis(benzyloxy)phenyl)- 5-((E)-3-(4-fluorophenyl)-3-oxoprop-l-enyl)-3-(4-methoxyphenyl)oxazolidin-2-one 49.

[00119] Subsequent treatment of 49 with copper hydride, described above, gave the ketone, (4R,5R)-4-(2,4-bis(benzyloxy)phenyl)-5-(3-(4-fluorophenyl)-3-oxopropyl)-3- (4-methoxyphenyl)oxazolidin-2-one 50. This was reduced with borane dimethylsulfide complex in the presence of a catalytic amount of tetrahydro-1-methyl- 3,3-diphenyl-lH,3H-pyrrolo[l,2-c][l,3,2]oxazaborole, (R-CBS), affording the compound (4R,5R)-4-(2,4-bis(benzyloxy)phenyl)-5-((S)-3-(4-fluorophenyl)-3- hydroxypropyl)-3-(4-methoxyphenyl)oxazolidin-2-one 51. Reaction of 51 with cerium (IV) ammonium nitrate in aqueous acetonitrile, as described above, resulted in the formation of (4R,5R)-4-(2,4-bis(benzyloxy)phenyl)-5-((S)-3-(4-fluorophenyl)-3- hydroxypropyl)oxazolidin-2-one 52. It then was coupled with a variety of iodobenzene or bromobenzene derivatives, as described above, to afford the N-aryl (4R,5R)-4-(2,4-bis(benzyloxy)phenyl)-5-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-3- phenyloxazolidin-2-one 53 derivatives. Subsequent catalytic hydrogenation of 53 over palladium on carbon was employed to prepare the (4R,5R)-5-((S)-3-(4-fluorophenyl)- 3-hydroxypropyl)-4-(2,4-dihydroxyphenyl)-3-phenyloxazolidin-2-one 43 analogs.

[00120] Preparation of (4R,5R)-5-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-(3R,4S)- 4-(3,3'-dihydroxybihphenyl-4-yl)-3-phenyloxazolidin-2-one analogs.

[00121] Referring to Scheme 7, 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. The benzaldehyde 14 was treated with para-anisidine 32 resulting in the formation of the corresponding imine, which is converted to the corresponding benzyl ether, (E)-Ν-(2-(benzyloxy)-4- Docket No. 2221.037AWO

bromobenzylidene)-4-methoxybenzenamine 54. The methoxybenzenamine 54 was treated with benzyl bromide and potassium carbonate in N.N-dimethylformamide (DMF). Treatment of 34 with triphosgene [(CIsCO^CO] and triethylamine in the presence of 54 provided the beta-lactam 55. A solution of 55 was dissolved in tetrahydrofuran and water with a catalytic amount of pαrα-toluenesulfonic acid to effect hydrolysis to the alcohol 56. The alcohol 56 was then treated with sodium methoxide in methanol to effect conversion to the methyl ester with beta-lactam ring opening. Reaction of the resulting alcohol with triphosgene in the presence of diisopropylethylamine and N,N-dimethylaminopyridine gave the oxazolidinone 57. The ester moiety of 57 was then converted into the corresponding hydroxymethyl substituent upon treatment with sodium cyanoborohydride. Swern oxidation converted the hydroxymethyl substituent into the corresponding aldehyde which was then reacted with Wittig reagent l-(4-fluorophenyl)-2-triphenyl-λ⁵-phosphanylidene)-ethanone to give the ketone 58. Suzuki coupling of 58 with 3-hydroxyphenylboronic acid gave the desired biphenyl derivative 59. Treatment of 59 with copper hydride, according to the method of T. Tsuda, T. Fujii, K. Kawasaki, T. Saegusa J. Chem. Soc, as described above, resulted in the formation of the ketone 60 which was reduced with borane dimethylsulfide complex in the presence of a catalytic amount of tetrahydro-1-methyl- 3,3-diphenyl-lH,3H-pyrrolo[l,2-c][l,3,2]oxazaborole, (R-CBS), which gave the compound 61. Reaction of 61 chlorotrimethylsilane in the presence of imidazole transiently protected the two hydroxyl moieties. Oxidation with cerium (IV) ammonium nitrate in aqueous acetonitrile, as described above, gave 62 after aqueous work-up. Coupling of 62 with a variety of iodobenzene or bromobenzene derivatives, as described above, provided the N-aryl derivatives 63. Catalytic hydrogenation of 63 over palladium on carbon was employed to prepare the (4R,5R)-5-((S)-3-(4- fluorophenyl)-3 -hydroxypropyl)-(3R,4S)-4-(3,3 '-dihydroxybihphenyl-4-yl)-3 - phenyloxazolidin-2-one analogues 64.

[00122] Preparation of (4R,5R)-5-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-(3R,4S)-

4-(3-benzyloxy-3 '-dimethylphosphonatebiphenyl-4-yl)-3-phenyloxazolidin-2-one analogs. Docket No. 2221.037AWO

[00123] Referring to Scheme 8, the reaction scheme begins with the conversion of commercially available 4-bromophenylboronic acid 65 to the corresponding pinacol ester 66 upon stirring with pinacol in toluene. Treatment of 66 with a mixture of trimethylphosphite, AIBN, and tris(trimethylsilyl)silane produced the dimethylphosphonate derivative 67. Suzuki coupling of 58 with 67 gave the biphenyl derivative 68. Treatment of 68 with copper, as described above, gave ketone 69 which was reduced with borane dimethylsulfide complex in the presence of a catalytic amount of tetrahydro- 1 -methyl-3,3 -diphenyl- lH,3H-pyrrolo[ l,2-c][l ,3,2]oxazaborole, (R-CBS), which resulted in the formation of compound 70. Reaction of 70 with cerium (IV) ammonium nitrate in aqueous acetonitrile, as described above, gave 71. Coupling of 71 with a variety of iodobenzene or bromobenzene derivatives, as described above, afforded the N-aryl derivatives 72. Catalytic hydrogenation of 72 over palladium on carbon, followed by treatment with bromotrimethylsilane and an aqueous work-up gave the final (4R,5R)-5-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)- (3R,4S)-4-(3 -benzyloxy-3 ' -dimethylphosphonatebiphenyl-4-yl)-3 -phenyloxazolidin-2- one analogues 73.

[00124] Preparation of (4R,5R)-5-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-(3R,4S)- 4-(3 -D-glucitol-3 '-benzyloxybiphenyl-4-yl)-3 -phenyloxazolidin-2-one analogs.

[00125] Referring to Scheme 9, the reaction scheme begins with the reaction of peracetyl D-glucose with 33% HBr in acetic acid which produced the anomeric bromide 74. Treatment of 74 with excess Grignard reagent 75, generated from 1,4- dibromobenzene and magnesium, followed by treatment of the crude product with acetic anhydride in pyridine provided the desired bromophenyl derivative 76. Conversion of 76 to the corresponding pinacol boronate ester 8 was accomplished by reaction with Zrø(pinicolato)diboron 77 under the influence of palladium catalysis. Suzuki coupling of 8 with 58 gave the expected biphenyl derivative 77. Treatment of 77 with copper hydride, as described above, gave ketone 78 which was reduced with borane dimethylsulfide complex in the presence of a catalytic amount of tetrahydro- 1- methyl-3,3 -diphenyl- lH,3H-pyrrolo[l,2-c][l,3,2]oxazaborole, (R-CBS), gave compound 79. Reaction of 79 with cerium (IV) ammonium nitrate in aqueous, as Docket No. 2221.037AWO

described above, afforded compound 80. Coupling of 80 with a variety of iodobenzene or bromobenzene, as described above, gave the N-aryl derivatives 81. Catalytic hydrogenation of 81 over palladium on carbon, followed by treatment with KF in methanol resulted in the formation of the (4R,5R)-5-((S)-3-(4-fluorophenyl)-3- hydroxypropyl)-(3R,4S)-4-(3-D-glucitol-3 '-benzyloxybiphenyl-4-yl)-3- phenyloxazolidin-2-one analogs 82.

Claims

Docket No. 2221.037AWOCLAIMSWe claim:

1. A process for preparing a 4-biphenylylazetidinone of formula

wherein

R¹ and R² are chosen from H, halogen, ProtA-O-, and methoxy;

CHF, CF₂, -CH(O-loweralkyl)-, -CH(O-loweracyl)-, -CH(OSO₃H)- and -

CH(OPO₃H₂)-;

wherein Q is a chiral auxiliary, said chiral auxiliary chosen from single enantiomers of triphenyl glycol and cyclic and branched nitrogen-containing moieties possessing at least one chiral center.

2. A process according to claim 1 for preparing a 4-biphenylazetidinone of formula

wherein

R¹ and R² are chosen from H, halogen, ProtA-O-, and methoxy;

ProtA-O- and ProtA'-O- are protecting groups for a phenol chosen from an oxymethyl ether, a tertiary alkyl ether, a benzyl ether and a silyl ether; Docket No. 2221.037AWO

R⁵ is a sugar, protected sugar, phosphonate, phenolic hydroxy or protected phenolic hydroxy; said process comprising cyclizing a compound of formula

3. A process for preparing a 4-biphenylazetidinone of formula

Docket No. 2221.037AWO

wherein

R^la and R^2a are chosen from H, halogen, -OH, and methoxy; and

R^5a is a sugar, phosphonic acid or OH; said process comprising

(a) cyclizing a compound of formula

wherein

R¹ and R² are chosen from H, halogen, ProtA-O-, and methoxy;

Q is a chiral auxiliary, said chiral auxiliary chosen from single enantiomers of triphenyl glycol and cyclic and branched nitrogen-containing moieties possessing at least one chiral center; and

(b) deprotecting. Docket No. 2221.037AWO

4. A process according to claim 1, 2 or 3 wherein cyclization is accomplished by treatment with N,O-bistrimethylsilylacetamide and a source of fluoride ion.

5. A process according to claim 2 or 3 wherein a compound of formula

is prepared by cyclizing a δ-oxoamine of formula

6. A process according to claim 5, wherein the δ-oxoamine is obtained by reacting an N-acyloxazolidinone of formula Docket No. 2221.037AWO

with an imine of formula

7. A process according to claim 2 or 3 wherein a compound of formula

Docket No. 2221.037AWO

is prepared by cyclizing a δ-oxoamine of formula

8. A process according to claim 7, wherein the δ-oxoamine is obtained by reacting an N-acyloxazolidinone of formula

with an imine of formula

Docket No. 2221.037AWO

9. A process according to claim 2 or 3 wherein a compound of formula

is prepared by cyclizing a δ-oxoamine of formula

Docket No. 2221.037AWO

10. A process according to claim 9, wherein the δ-oxoamine is obtained by reacting an N-acyloxazolidinone of formula

with an imine of formula

11. A process for preparing a 1,4-diphenylazetidinone of formula

wherein

R¹, R² and R⁶ are chosen from H, halogen, -OH, ProtA-O-, and methoxy;

CHF, CF₂, -CH(O-loweralkyl)-, -CH(O-loweracyl)-, -CH(OSO₃H)- and -

CH(OPO₃H₂)-; Docket No. 2221.037AWO

R⁵ is chosen from H, halogen, -OH, ProtA-O-, methoxy and phenyl, said phenyl optionally substituted with a sugar, protected sugar, phosphonate, phenolic hydroxy or protected phenolic hydroxy; said process comprising arylating a 1-unsubstituted 4-phenylazetidinone of formula:

with an R¹ -substituted phenyl arylating agent.

12. A process according to claim 11 for preparing a 1,4-diphenylazetidinone of formula

wherein

R¹, R² and R⁶ 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; Docket No. 2221.037AWO

with an R¹ -substituted phenyl arylating agent.

13. A process according to claim 12 wherein R*and R² are F; R⁶ is H; ProtB-O- is HO-; and R⁵ is chosen from HO- and Bn-O- wherein said arylating is accomplished in the presence of copper iodide and said phenyl arylating agent is an R⁵-substituted phenyl iodide.

14. A process for preparing a 4-biphenylylylazetidinone of formula

Docket No. 2221.037AWO

R¹ and R² are chosen from H, halogen, ProtA-O-, and methoxy;

R⁵ is a sugar, protected sugar, phosphonate, phenolic hydroxy or protected phenolic hydroxy; said process comprising arylating a 1-unsubstituted azetidinone of formula:

with an R¹ -substituted phenyl arylating agent.

15. A process for preparing a 4-biphenylazetidinone of formula

wherein

R^la and R^2a are chosen from H, halogen, -OH, and methoxy; and

R > 5a^a is a sugar, phosphonic acid or OH; Docket No. 2221.037AWO

said process comprising

(a) arylating a 1 -unsubstituted azetidinone of formula:

with an R¹ -substituted phenyl arylating agent wherein

R¹ and R² are chosen from H, halogen, ProtA-O-, and methoxy;

(b) deprotecting.

Docket No. 2221.037AWO

16. A process according to claim 11, 12 or 14 wherein a compound of formula

is prepared by arylating a 1 -unsubstituted azetidinone of formula:

with an R -substituted phenyl iodide and copper iodide.

Docket No. 2221.037AWO

17. A process according to claim 11, 12 or 14 wherein a compound of formula

is prepared by arylating a 1 -unsubstituted azetidinone of formula:

with an R¹ -substituted phenyl iodide and copper iodide.

Docket No. 2221.037AWO

18. A process according to claim 11, 12 or 14 wherein a compound of formula

is prepared by arylating a 1 -unsubstituted azetidinone of formula:

with an R¹ -substituted phenyl iodide and copper iodide. Docket No. 2221.037AWO

19. A process according to claim 3 or 15 for preparing a compound of formula

wherein said deprotecting is accomplished by cleaving acetates with base, cleaving methylphosphonates with bromotrimethylsilane and cleaving benzyl ethers by catalytic hydrogenolysis.

20. A process according to claim 15, wherein the 1 -unsubstituted azetidinone is obtained by reacting a 4-bromophenylazetidinone of formula

with a compound of formula 1

Docket No. 2221.037AWO

wherein R¹⁰ and R¹¹ are independently selected from H and (Ci-Cβ) alkyl, or R¹⁰ and

R together form a 5-6 membered ring.

21. A process for preparing a 4-bromophenylazetidinone of formula

wherein R is chosen from H, halogen, ProtA-O-, and methoxy; and

with an oxidant and a base. Docket No. 2221.037AWO

22. A process for preparing a 1 -(4-hydroxyphenyl)azetidinone of formula

wherein R is chosen from H, halogen, ProtA-O-, and methoxy; and

Docket No. 2221.037AWO

23. A process for preparing a δ-oxoamine of formula

wherein R² is chosen from H, halogen, ProtA-O-, and methoxy; and

with an imine of formula

Docket No. 2221.037AWO

24. A process for preparing an imine of formula

comprising reacting />αrα aminophenol with 2-benzyloxy-4-bromobenzaldehyde.

25. A process for preparing a compound of formula

comprising reacting 2-benzyloxy-4-bromobenzaldehyde in the presence of a phosphine, a palladium salt and a base with a compound of formula

wherein R , 10 and R are independently selected from H and (Ci-Cβ) alkyl, or R¹⁰ and R¹¹ together form a 5-6 membered ring. Docket No. 2221.037AWO

26. A compound of formula

wherein R ,70 is OH or benzyloxy.

A compound according to claim 26 wherein R 70 is -OH.

28. A compound according to claim 26 wherein R 70 is -OBn

29. A process for the preparation of a compound of formula

wherein R and R are independently selected from H and (Ci-Cβ) alkyl, or R and

R together form a 5-6 membered ring. Docket No. 2221.037AWO

30. A compound of formula

wherein R is OH or benzyloxy.

31. A compound according to claim 30 wherein R 70 is -OH.

32. A compound according to claim 30 wherein R is -OBn

33. A process for the preparation of a compound of formula

Docket No. 2221.037AWO

R together form a 5-6 membered ring.

34. A compound of formula

wherein R >70 is OH or benzyloxy.

35. A compound according to claim 34 wherein R 70 is -OH.

36. A compound according to claim 34 wherein R 70 is -OBn

37. A process for preparing a diphenyl heterocycle of formula

wherein

R¹, R² and R⁶ are chosen from H, halogen, -OH, ProtA-O-, and methoxy;

, -CH₂O-, -OCH₂-, -CH₂S-, -SCH₂-, -CH=CH-, -CH=N-, -N=CH-, -C(O)O-,

-C(O)CH₂-, -C(=O)NR⁷, -C(=S)O-, -C(=S)CH₂-, -C(=S)NR⁷, -C(O)S-, -C(=S)-,

-S(O) and -SO₂-; Docket No. 2221.037AWO

CHF, CF₂, -CH(O-loweralkyl)-, -CH(O-loweracyl)-, -CH(OSO₃H)- and -

CH(OPO₃H₂)-;

R⁷ is chosen from H and (Ci-Ce)alkyl; said process comprising arylating a 1-unsubstituted phenyl heterocycle of formula:

with an R¹ -substituted phenyl arylating agent.

38. A process according to claim 37 wherein W is -C(=0)0-.

39. A process for preparing a diphenyl azetidinone of formula Docket No. 2221.037AWO

wherein

_R ^IA _R ^2A _R ^IB^ _R ^2B _{^ R} ^5A _{^ and R} ^6A _^ independently of one another are chosen from: (a) (Ci-C₃o)-alkylene-(LAG)_qa, wherein at least one carbon atom of the alkylene radical is replaced by: aryl or heteroaryl radicals, which are unsubstituted or substituted one, two, or three times by R^7A or by (C₃-Cio)-cycloalkyl or heterocycloalkyl radicals, which are unsubstituted or substituted one, two, three or four times by R^7A, or wherein one or more individual carbon atoms of the alkylene radical is optionally replaced by a radical chosen from: -S(0)π_m- (where ma=0-2), -O-, -(C=O)-, -(C=S)-, -CH=CH-, -C=C-, -N[(Ci-C₆)-alkyl]-, - N(phenyl)-, -N[(Ci-C₆)-alkyl-Phenyl]-, -N(CO-(CH₂)i-i₀-COOH)- and - NH-; or

(c) SO₂NH₂, SO₂NH(Ci-C₆)-alkyl, SO₂N[(Ci-C₆)-alkyl]₂, S-(Ci-C₆)-alkyl, S-(CH₂)_na-Phenyl, SO-(Ci-C₆)-alkyl, SO-(CH₂-)_naphenyl, SO₂-(Ci-C₆)-alkyl, or SO₂-(CH₂)_na-Phenyl; wherein na=0-6, and wherein the phenyl radical is unsubstituted or substituted one or two times, each substituent chosen independently from: F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O-(d-C₆)-alkyl, (C₁- C₆)-alkyl, and NH₂; or Docket No. 2221.037AWO

(d) NH₂ NH-(Ci-C₆)-alkyl, N[(Ci-C₆)-alkyl]₂, NH(Ci-C₇)-acyl, phenyl, or O-(CH₂)_na-phenyl, wherein na=0-6, and wherein the phenyl ring is unsubstituted or substituted one, two, or three times, each substitutent chosen independently from: F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O-(d-C₆)-alkyl, (Ci-C₆)-alkyl, NH₂, NH-(Ci-C₆)-alkyl, N[(Ci-C₆)-alkyl]₂, SO₂CH₃, COOH, COO-(Ci-C₆)-alkyl, and CONH₂; or R^5A may additionally be phenyl optionally substituted with a sugar, protected sugar, phosphonate, phenolic hydroxy or protected phenolic hydroxy; and wherein at least one of the radicals R^1A to R^6A must have the meaning:

(Ci-C₃₀)-alkylene-(LAG)_qa

R^7A represents

(a) F, Cl, Br, I, OH, CF₃, NO₂, N₃, CN, COOH, COO(Ci-C₆)-alkyl, CONH₂, CONH(Ci-C₆)-alkyl, CON[(Ci-C₆)-alkyl]₂, (Ci-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂- C₆)-alkynyl, or 0-(Ci-C₆)-alkyl, wherein the alkyl radical is unsubstituted or at least one hydrogen in the alkyl radical may be replaced by fluorine; or

(b) PO₃H₂, SO₃H, SO₂NH₂, SO₂NH(Ci-C₆)-alkyl, SO₂N[(Ci-C₆)-alkyl]₂, S-(Ci-C₆)-alkyl, S-(CH₂)_na-Phenyl, SO-(Ci-C₆)-alkyl, SO-(CH₂)_na-Phenyl, SO₂-(Ci-C₆)-alkyl, or SO₂-(CH₂)_na-Phenyl, wherein na=0-6, and wherein the phenyl radical is unsubstituted or substituted one or two times each substituent chosen independently from: F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, 0-(Ci-C₆)- alkyl, (Ci-C₆)-alkyl, and NH₂; or

(c) C(=NH)(NH₂), NH₂, NH-(Ci-C₆)-alkyl, N[(C₁-C₆)-alkyl]₂, NH(Ci-C₇)-acyl, phenyl, or O-(CH₂)_na-Phenyl, wherein na=0-6, and wherein the phenyl ring is unsubstituted or substituted one, two, or three times, each substituent chosen independently from: F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O-(Ci-C₆)alkyl, (Ci-C₆)-alkyl, NH₂, NH(Ci-C₆)-alkyl, N[(C₁-C₆)-alkyl]₂, SO₂CH₃, COOH, COO-(Ci-C₆)-alkyl, and CONH₂;

(LAG) is a sugar residue, disugar residue, trisugar residue, tetrasugar residue; a sugar acid, an amino sugar; or a polyol; or an amino acid residue, or an oligopeptide residue comprising 2 to 9 amino acids; or Docket No. 2221.037AWO

an acyclic, mono-, di- or tricyclic trialkylammonium radical, an acyclic mono-, di- or tricyclic trialkylammoniumalkyl radical, -0(SO₂)OH; -(CH₂)o-io-S0₃H, -(CH₂)_0- ₁₀-P(O)(OH)₂, -(CH₂)_O-_IO-O-P(O)(OH)₂, -(CH₂)₀-i₀COOH, -(CH₂V io-C(=NH)(NH₂), -(CH₂)O_-1O-CC=NH)(NHOH), or -NR^8A-C(=NR^9A)(NR^10AR^11A); wherein R^8A, R^9A, R^10A and R^11A, independently of one another, are chosen from: H, (Ci-C₆)-alkyl, phenyl, (Ci-C₆)-alkylphenyl, and (C₃-C₈)-cycloalkyl; qa=l-5 and

CHF, CF₂, -CH(O-loweralkyl)-, -CH(O-loweracyl)-, -CH(OSO₃H)- and -

CH(OPO₃H₂)-;

with an R¹ -substituted phenyl arylating agent wherein R¹ is optionally either or both of R^1A and R^1B.

Docket No. 2221.037AWO

40. A process for preparing a 1,4-diphenylazetidinone of formula

wherein

R^1C is chosen from H, halogen, -OH, ProtA-O-, methoxy, and

R² and R⁶ are chosen from H, halogen, -OH, ProtA-O-, and methoxy;

CHF, CF₂, -CH(O-loweralkyl)-, -CH(O-loweracyl)-, -CH(OSO₃H)- and -

CH(OPO₃H₂)-;

R is chosen from hydrogen, Ci_₄alkyl, carbocyclyl and heterocyclyl; wherein R 109 A may be optionally substituted on carbon by one or more substituents selected from Docket No. 2221.037AWO

R^111A and R^112A are independently selected from hydrogen,

R^113A is hydrogen,

IAA wherein:

; R^15A is hydrogen or Ci_₄alkyl ;

R^16A and R^17A are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, Ci-βalkoxy, Ci-βalkanoyl, Ci-βalkanoyloxy, N-(Ci-6alkyl)amino, N,N-(Ci-6alkyl)2amino, Ci-βalkanoylamino, N-(Ci_6alkyl) carbamoyl, N,N-(Ci_6alkyl)₂carbamoyl, Ci_6alkylS(O)aa wherein aa is 0 to 2, Ci-βalkoxycarbonyl, N-(Ci_6alkyl)sulphamoyl, N,N-(Ci_6alkyl)₂sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino, amidino, phosphono, -P(OXOR^36AXOR^37A),-P(OXOHXOR^36A), -P(O)(OH)(R^36A) or -P(O)(OR^36A)(R^37A), wherein R^36A and R^37A are independently selected from C_1-6alkyl; wherein R^16A and R^17A maybe independently optionally substituted on carbon by one or more substituents selected from R^38A; and wherein if said heterocyclyl contains an- NH- group, that nitrogen may be optionally substituted by a group selected from R^39A; R^18A is selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, Ci-ioalkyl, C₂-ioalkenyl, C₂-ioalkynyl, Ci-ioalkoxy, Ci-ioalkanoyl, Ci-ioalkanoyloxy, N-(Ci-ioalkyl)amino, N₅N-(Ci- i₀alkyl)₂amino, Ci-ioalkanoylamino, N-(Ci_ioalkyl)carbamoyl, Ci_ioalkoxycarbonyl, N,N-(Ci_i₀alkyl)₂carbamoyl, Ci_i₀alkylS(O)_aa wherein aa is 0 to 2, N-(Ci- i₀alkyl)sulphamoyl, N,N-(Ci_ioalkyl)₂sulphamoyl, N-(Ci_ioalkyl)sulphamoylamino, N,N-(Ci_ioalkyl)₂sulphamoylamino, carbocyclyl, carbocyclylCi-ioalkyl, heterocyclyl, heterocyclylCi-ioalkyl, carbocyclyl-(Ci_ioalkylene)ea-R^40A-(Ci-ioalkylene)_fa- or heterocyclyl-(Ci-ioalkylene)ga-R^41A-(Ci-ioalkylene)ha-, carboxy, sulpho, sulphino, phosphono, -P(O)(OR^42A)(OR^43A), -P(O)(OH)(OR^42A), -P(O)(OH)(R^42A) or -P(O)(OR^42A)(R^43A) Docket No. 2221.037AWO

wherein:

R^19A is selected from hydrogen or Ci-₄alkyl;

heterocyclyl(Ci-ioalkylene)ga-R^51A-(Ci-ioalkene)ha-, carboxy, sulpho, sulphino, phosphono, -P(O)(OR^52A)(OR^53A), -P(O)(OH)(OR^52A), -P(O)(OH)(R^52A) or -P(O)(OR^53A)(R^53A) wherein R^52A and R^53A are independently selected from d_₆alkyl; wherein R^21A may be independently optionally substituted on carbon by one or more R^54A; and wherein if said heterocyclyl contains an -NH- group, that nitrogen may be optionally substituted by a group selected from R^55A' pa is 1-3; wherein the values of R^16A may be the same or different; qa is 0-1; ra is 0-3; wherein the values of R^17A may be the same or different; ma is 0-2; wherein the values of R^3A may be the same or different; na is 1-2; wherein the values of R^9A may be the same or different; za is 0-3; wherein the values of R^20A may be the same or different;

_R23A _R25A _R27A _R33A _R38A _R44A _R48A ^ _R54A ^ _{indeperidently se}l_eCted from halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, Ci-ioalkyl, C₂-ioalkenyl, C₂-ioalkynyl, Ci_ioalkoxy, Ci-ioalkanoyl, Ci_ioalkanoyloxy, Ci-ioalkoxycar-bonyl, N-(Ci_ioalkyl)amino, N₅N-(Ci- ioalkyl)2amino, N,N,N-(Ci-ioalkyl)3ammonio, Ci-ioalkanoyl-amino, N-(Ci- ioalkyl)carbamoyl, N₅N-(Ci-ioalkyl)₂carbamoyl, Ci_ioalkylS(0)_aa wherein aa is 0 to 2, N-(Ci_ioalkyl)sulphamoyl, N,N-(Ci_ioalkyl)₂sulphamoyl, N-(Ci_ioalkyl)sulphamoylamino, N,N-(Ci_ioalkyl)₂sulphamoylamino, Ci-ioalkoxycarbonylamino, carbocyclyl, carbocyclylCi-ioalkyl, heterocyclyl, heterocyclylCi-ioalkyl, carbocyclyl-(Ci-ioalkylene)_ea- R^56A-(Ci-ioalkylene )f_a-, heterocyclyl-(Ci-ioalkylene)_ga-R^57A -(Ci-ioalkylene)h_a-, carboxy, sulpho, sulphino, amidino, phosphono, -P(O)(OR^58A)(OR^59A), -P(O)(OH)(OR^58A), -P(O)(OH)(R^58A) or -P(O)(OR^59A)(R^59A), wherein R^58A and R^59A are independently selected from d_₆alkyl; wherein R^23A, R^25A, R^27A, R^33A, R^38A, R^44A, R^48A and R^54A may be independently optionally substituted on carbon by one or more R^60A; and wherein if said heterocyclyl contains an -NH- group, that nitrogen may be optionally substituted by a group selected from R^61A;

Ci-βalkyl, Q-βalkanoyl,

sulphamoyl, N-(Ci_6alkyl) sulphamoyl, Docket No. 2221.037AWO

R^60A is selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N- dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl ; ea, fa, ga and ha are independently selected from 0-2; said process comprising arylating a 1 -unsubstituted 4-phenylazetidinone of formula:

with an R -substituted phenyl arylating agent.

41. A process for preparing a 1,4-diphenylazetidinone of formula:

wherein

represents an aryl or heteroaryl residue said aryl or heteroaryl residue optionally substituted at a suitable position with an aryl or substituted aryl; R¹, R² and R⁴ are independently hydrogen or other than hydrogen; Docket No. 2221.037AWO

U is (C₂-Ce)-alkylene in which one or more individual -CH₂- may be replaced by a radical chosen from -S-, -S(O)-, -SO₂-, -0-, -C(=0)-, -CH=CH-, -CHOH-, -NH-, CHF, CF₂, -CH(O-loweralkyl)-, -CH(O-loweracyl)-, -CH(OSO₃H)-, -CH(OPO₃H₂)-, - CH(OB(OH)₂)-, or -NOH-; said process comprising arylating a 1-unsubstituted 4-phenylazetidinone of formula

with an R¹ -substituted phenyl arylating agent.

42. A process according to claim 41 wherein R⁴ is hydrogen.

43. A process according to claim 41 wherein R⁴ is other than hydrogen.

44. A process according to claim 41 wherein R⁴ is -OH.

45. A process according to claim 41 wherein R is hydrogen.

46. A process according to claim 41 wherein R² is other than hydrogen.

47. A process according to claim 41 wherein R a halogen.

48. A process according to claim 41 wherein R² is F.

49. A process according to claim 41 wherein R¹ is hydrogen.

50. A process according to claim 41 wherein R¹ is other than hydrogen.

51. A process according to claim 41 wherein U is -CH2CH2CH(OH)-

52. A process for preparing a 1,4-diphenylazetidinone of formula: Docket No. 2221.037AWO

wherein

represents an aryl or heteroaryl residue; which can optionally be further substituted at a substitutable position with Ar-R^5g; Ar represents an aryl residue; R¹ is hydrogen or a substituent other than hydrogen.

R is selected from the group consisting of H, halogen, -OH, loweralkyl, OCF₂H, OCF3, CF₂H, CH₂F, -O-loweralkyl, methylenedioxy, ethylenedioxy, hydroxyloweralkyl, -CN, CF₃, nitro, -SH, -S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, -PO3H2, -SO3H, -B(OH)2, a sugar, a polyol, a glucuronide and a sugar carbamate;

R⁴ is selected from the group consisting of H, halogen, -OH, loweralkyl, -O- loweralkyl, hydroxyloweralkyl, -CN, CF₃, nitro, -SH, -S-loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, -PO3H2, -SO3H, -B(OH)2, a sugar, a polyol, a glucuronide and a sugar carbamate;

R^5g is selected from the group consisting of halogen, -OH, loweralkyl, -O-loweralkyl, methylenedioxy, ethylenedioxy, hydroxyloweralkyl, -CN, CF3_; nitro, -SH, -S- loweralkyl, amino, alkylamino, dialkylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, acyl, carboxy, alkoxycarbonyl, carboxyalkyl, carboxamido, alkylsulfoxide, acylamino, amidino, -PO3H2, -SO3H, - B(OH)₂, a sugar, a polyol, a glucuronide and a sugar carbamate; U is (C₂-C6)-alkylene in which one or more individual -CH₂- may be replaced by a radical chosen from -S-, -S(O)-, -SO₂-, -0-, -C(=0)-, -CH=CH-, -CHOH-, -NH-, Docket No. 2221.037AWO

CHF, CF₂, -CH(O-loweralkyl)-, -CH(O-loweracyl)-, -CH(OSO₃H)-, -CH(OPO₃H₂)-, -

CH(OB(OH)₂)-, or -NOH-; said process comprising arylating a 1-unsubstituted 4-phenylazetidinone of formula

with an R¹ -substituted phenyl arylating agent.

53. A process according to claim 52 wherein R¹ is hydrogen.

54. A process according to claim 52 wherein R¹ is other than hydrogen.

55. A process according to claim 52 wherein U is -CH₂CH₂CH(OH)-.

56. A process according to claim 55 wherein R¹ is fluoro, R² is fluoro and R⁴ is OH.