TITLE OF THE INVENTION

PROCESS FOR PREPARING AN ANTI-HYPERCHOLESTEROLEMIC COMPOUND

BACKGROUND OF THE INVENTION The instant invention relates to a process for preparing anti-hypercholesterolemic compounds. It has been clear for several decades that elevated blood cholesterol is a major risk factor for coronary heart disease (CHD), and many studies have shown that the risk of CHD events can be reduced by lipid-lowering therapy. Prior to 1987, the lipid-lowering armamentarium was limited essentially to a low saturated fat and cholesterol diet, the bile acid sequestrants (cholestyramine and colestipol), nicotinic acid (niacin), the fibrates and probucol. Unfortunately, all of these treatments have limited efficacy or tolerability, or both. With the introduction of lovastatin, the first inhibitor of HMG-CoA reductase to become available for prescription in 1987, for the first time physicians were able to obtain large reductions in plasma cholesterol with very few adverse effects. A more recent class of anti-hyperlipidemic agents that has emerged includes inhibitors of cholesterol absorption. Ezetimibe, the first compound to receive regulatory approval in this class, is currently marketed in the U.S. under the tradename ZETIA ^® is described in U.S. Patent No.'s Re. 37721 and 5,846,966. The process for synthesizing ZETIA ^® is also described in U.S. Patent Nos. RE37721 and 5,846,966. Novel azetidinones, which are cholesterol absorption inhibitors, have been described and disclosed in US2007/0078098.

The present invention relates to a process for preparing inhibitors of cholesterol absorption using a metal-catalyzed dynamic kinetic resolution (DKR) asymmetric transfer hydrogenation (ATH) reaction, followed by a synthesis involving two consecutive cross-coupling reactions. The metal-catalyzed DKR reaction occurs via an asymmetric transfer hydrogenation of a racemic acyclic β-ketoamide bearing an aliphatic sidechain to give the resulting syn β- hydroxyamide in a very high enantio- and diastereoselectivity. Subsequent cyclization of the DKR-ATH product provides beta-lactam intermediates which can be utilized in a process for preparing novel azetidinones comprising two consecutive cross-coupling reactions. The use of two consecutive cross-coupling reactions is a more convergent route and produces higher yields than other processes.

In the ongoing effort to discover novel treatments for hyperlipidemia and atherosclerotic process, the instant invention provides a novel process for preparing cholesterol absorption inhibitors.

SUMMARY OF THE INVENTION

The present invention relates to a process for preparing inhibitors of cholesterol absorption of Formula II:

II

and the pharmaceutically acceptable salts and esters thereof, employing a metal-catalyzed dynamic kinetic resolution (DKR) asymmetric transfer hydrogenation (ATH) reaction of racemic acyclic β-ketoamide bearing α-substituted aliphatic side chain (Intermediate A) and subsequent cyclization of the resulting b-hydroxyamide product (Intermediate B), followed by a synthesis involving two consecutive cross-coupling reactions.

An example of an cholesterol absorption inhibitor of Formula II that can be prepared using the instant invention is N-[3-(4-{(2.S,3/?)-2-{4-[3,4-dihydroxy-3- (hydroxymethyl)butyl]phenyl} -3-[(35)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin- 1 - yl}phenyl)propyl] methanesulfonamide, which has the following chemical structural formula:

Compound A

For brevity, this compound may also be referred to herein as "Compound A." Additional objects will be evident from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

In the present invention, a chemically unprecedented, novel dynamic kinetic resolution (DKR) transfer hydrogenation of a racemic beta-keto amide is used to prepare a beta-

hydroxy amide intermediate having the desired specific stereochemistry. The beta-hydroxy amide intermediate can then be further cyclized to produce the beta-lactam anti- hypercholesterolemic compounds useful for the treatment of hypercholesterolemia and for preventing, halting, or slowing the progress of atherosclerosis and related conditions and disease events.

The stereoselective transformation of compounds of Intermediate A to the corresponding compounds of Intermediate B is accomplished by a dynamic kinetic resolution (DKR) of the racemic beta-keto amide of Intermediate A, in which the ketone is converted to an alcohol via asymmetric transfer hydrogenation (ATH) in the presence of 1) a suitable catalyst system, 2) a reductant system and 3) a solvent system, affording the beta-hydroxy amide of

Intermediate B.

(Intermediate A) (Intermediate B)

The reductant system is comprised of a suitable reducing agent and a base. Suitable DKR-ATH process catalysts are optically active catalyst systems prepared by combining a transition metal precursor and an optically chiral ligand. An example of such chiral ligands is an optically active 1 ,2-diamine.

In an embodiment, the instant invention is related to a process for preparing a compound of Intermediate B:

(Intermediate B) wherein

Ra is selected from -H or a protecting group; Rb is selected from halo, amino, OH, OCj-Cg alkyl, dialkylamine, Cj-Cgalkyl, , C2-Cg alkenyl, C2-C6 alkynyl, aryl, or heteoaryl, said alkyl, alkenyl, alkynyl, aryl or heteroaryl are optionally substituted with one to three groups selected from AJI , or heteroaryl;

Re and Rd are independently selected from Cj-Cgalkyl, C2-C6 alkenyl, C2-Cg alkynyl, aryl, or heteoaryl, said alkyl, alkenyl, alkynyl, aryl or heteroaryl are optionally substituted with one to three groups selected from halo, amino, OH, OC]-Cg alkyl, dialkylamine, Cj-Cgalkyl, C2-C6 alkenyl, 02-Cg alkynyl, aryl, or heteoaryl;

ArI is aryl, optionally substituted with one to five groups selected from R4;

R4 is independently selected from the group consisting of: -OR5, -O(CO)R5, -O(CO)OR8, -OCi-salkyl-ORS, -O(CO)NR5R6, -NR5R6, -NR5(CO)R6, -NR5(CO)OR8, -NR5(CO)NR6R7, -NR5SO2R ⁸ , -COOR5, -CONR5R6, -COR5, -SO2NR5R6, -S(O) _t R8, -O-Ci-ioalkyl-COORS, -O-Ci-ioalkyl-CONRSR ^β and halo; R5, R6 and R7 are independently selected from the group consisting of -H, -Ci-6alkyl, aryl and aryl-substituted -Ci-6alkyl;

R8 is independently selected from the group consisting of -Ci-βalkyl, aryl and aryl-substituted -Ci-βalkyl; t is an integer selected from 0, 1 and 2;

comprising the steps of: a) mixing a DKR-ATH process catalyst system, a DKR reductant system and a DKR solvent system with a compound of Intermediate A

(Intermediate A), wherein all substituents are as defined above; and b) isolating Intermediate B.

In another embodiment, the instant invention is related to a process for preparing a compound of Intermediate B*:

(Intermediate B*) wherein,

Ra is selected from -H or a protecting group; Rb is selected from Cj-Cgalkyl, C2-C6 alkenyl, C2-Cg alkynyl,, aryl, or heteoaryl, said alkyl, alkenyl, alkynyl, aryl or heteroaryl are optionally substituted with one to three groups selected from Ar^, _or heteroaryl;

ArI is aryl, optionally substituted with one to five groups selected from R4;

Ai-3 is \-

Cgalkyl, dialkylamino, -Ci-I5alkyl mono- or poly-substituted with -OH, -CH=CH-Ci -I3alkyl mono- or poly-substituted with -OH, -C≡C-Ci-i3alkyl mono- or poly-substituted with -OH, and CH ₂

Il

^" ' ² ' ^{y~ '} ^ ^H2υ ; v is an integer selected from O and 1; and Rl 3 is selected from the group consisting of -H and -OH;

Ar^ is phenyl substituted with R9, where R9 is selected from the group consisting of halo, OH, OC!-C ₆ alkyl, dialkylamino, -C≡C-(CH2) _y -NRlθRl 1, -C=C-(CH2) _y -NRlθRl 1 and -(CH2V

NRlORl I;

R4 is independently selected from the group consisting of: -0R5, -O(CO)R5, -O(CO)OR8, -O- Cl -5alkyl-OR5, -O(CO)NR5R6, -NR5R6, -NR5(CO)R6, -NR5(CO)OR8, -NR5(CO)NR6R7, -

NR5SO2R ⁸ , -COOR5, -CONR5R6, -COR5, -SO2NR5R6, -S(0) _t R8, -0-Ci-ioalkyl-COOR5, -

0-Ci-ioalkyl-CONR5R6 and halo;

R5, R6 and R? are independently selected from the group consisting of -H, -Ci-6alkyl, aryl and aryl-substituted -Ci-όalkyl; R8 is independently selected from the group consisting of -Ci-6alkyl, aryl and aryl-substituted

-Ci-6alkyl;

RlO is independently selected from the group consisting of -H and -Ci-3alkyl;

Rl 1 is independently selected from the group consisting of -H, - Ci-3alkyl, -C(O)-Ci .3 alkyl,

-C(O)-NRlORlO ₅ -SO2-Ci-3alkyl, and -Sθ2-phenyl; t is an integer selected from O, 1 and 2; w is an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8; and y is an integer selected from 1, 2, 3, 4, 5 and 6;

comprising the steps of: a) mixing a DKR-ATH process catalyst system, a DKR reductant system and a DKR solvent system with a compound of Intermediate A*

(Intermediate A*), wherein all substituents are as defined above; and b) isolating Intermediate B*.

In a further embodiment, the DKR-ATH process catalyst is an optically active catalyst system (OACS) represented by the formula:

(OACS Formula Ia) wherein:

M is selected from the group of metals consisting of iron, cobalt, nickel, ruthenium, rhodium, iridium, osmium, palladium and platinum;

Y is selected from hydrogen, halogen atom, carboxyl group, hydroxy group and alkoxyl group;

L is selected from benzene and cyclopentadienyl, optionally substituted with one to three

-C i-i oalkyl groups; a is 0 or 1 ; and

RS, Rm, Rn ₅ Rp _; and Rq are independently selected from hydrogen, -Ci-ioalkyl, -C3- lOcycloalkyl, aryl, and heteroaryl, each of which may be optionally substituted with -Ci_6alkyl or halogen, and are the same or different such that the carbon bonded with these substituent groups occupies a chiral center; and any one of R ^m and R ⁿ and any one of RP and RQ are optionally bonded together to form a ring.

The instant invention is further related to a process for preparing a compound of Formula I

wherein

AJI is aryl, optionally substituted with one to five groups selected from R4;

Ar ³ is , where Rl 2 i _s selected from the group consisting of halo, OH, OCi-

C6alkyl, dialkylamino, -Ci-isalkyl mono- or poly-substituted with -OH, -CH=CH-Ci-13 alkyl mono- or poly-substituted with -OH, -C≡C-Ci-i3alkyl mono- or poly-substituted with -OH, and CH ₂

- ⁽ 2VC-CH ₂ OH . _v j _{s an} integer selected from O and 1; and R ¹ 3 is selected from the group consisting of -H and -OH;

Ar^ is phenyl substituted with R9, where R9 is selected from the group consisting of halo, OH, OCi-C ₆ alkyl, dialkylamino, -C≡C-(CH2)y-NRlθRl 1, -C=C-(CH2)y-NRlθRl 1 and -(CH2) _W -

NRlORl I ;

R is selected from the group consisting of -0R6, -0(C0)R6, -0(CO)O R8, -O(CO)NR6R7, _a sugar residue, a disugar residue, a trisugar residue and a tetrasugar residue;.

Rl is selected from the group consisting of -H, -Ci-6alkyl and aryl, or R and Rl together are oxo;

R4 is independently selected from the group consisting of: -0R5, -0(C0)R5, -0(C0)0R8, -O- Ci-5alkyl-OR5, -O(CO)NR5R6, -NR5R6, -NR5(CO)R6, -NR5(CO)OR8, - NR5(CO)NR6R7,

-NR5SO2R ⁸ , -COOR5, -CONR5R6, -C0R5, -SO2NR5R6, -S(0) _t R8, -0-Ci_ioalkyl-COOR5,

-0-Cl-loalkyl-CONR5R6 and halo;

R5, R6 and R7 are independently selected from the group consisting of -H, -Ci-6alkyl, aryl and aryl -substituted -Ci-6alkyl; R8 is independently selected from the group consisting of -Ci_6alkyl, aryl and aryl-substituted

-Ci-6alkyl;

RlO is independently selected from the group consisting of -H and -Ci-3alkyl;

Rl 1 is independently selected from the group consisting of -H, - Ci-3alkyl, -C(O)-C i-3alkyl, -

C(O)-NRlORlO, -Sθ2-Ci-3alkyl, and -Sθ2-phenyl; p is an integer selected from 1, 2 or 3; t is an integer selected from O, 1 and 2; w is an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8; and y is an integer selected from 1, 2, 3, 4, 5 and 6; and

comprising the steps of: a) adding hydroxy-group activator to Intermediate B*, as described above, in the presence of base in an organic solvent; b) adding a phase transfer catalyst and optionally adding a second base; and

c) isolating a compound of Formula I.

In a further embodiment, the invention relates to a process of preparing a compound of Formula I, as described above, comprising the steps of: a) adding a hydroxy-group activator to Intermediate B*, as described above, in an organic solvent, followed by a base, wherein the hydroxy-group activator is selected from the group consisting of phosphoryl halides, sulfonyl halides, carboxylic acid chlorides, carboxylic acid anhydrides or sulfonic acid anhydrides; b) adding a phase transfer catalyst, which is a quarternary ammonium salt and a second base; and c) isolating a compound of Formula I.

In a further embodiment, the second base is an aqueous inorganic base solution. In a further embodiment, the process for preparing a compound of Formula I, as described above, comprises the steps of: a) adding methanesulfonyl chloride to Intermediate B* in toluene, followed by triethylamine; b) adding an aqueous solution of KOH, followed by BnEt ₃ N ⁺ Cl ^' c) separating the organic phase and washing the organic phase with diluted H ₂ SO ₄ ; d) isolating a compound of Formula I.

In a further embodiment, in step d), a compound of Formula I is isolated by crystallization. The instant invention is further related to a process for preparing a compound of

Formula II

II

and the pharmaceutically acceptable salts and esters thereof, wherein

ArI is ary^ optionally substituted with one to five groups selected from R4;

R is selected from the group consisting of -OR6, -O(CO)R6, -0(CO)O Re, -O(CO)NR6R7, _a sugar residue, a disugar residue, a trisugar residue and a tetrasugar residue;

Rl is selected from the group consisting of -H, -Ci_6alkyl and aryl, or R and Rl together are oxo;

R4 is independently selected from the group consisting of: -0R5, -O(CO)R5, -0(CO)ORS, -O-

Ci_5alkyl-OR5, -O(CO)NR5R6, -NR5R6, -NR5(CO)R6, -NR5(CO)OR8, -NR5(CO)NR6R7,

-NR5SO2R ⁸ , -COOR5, -CONR5R6, -COR5, -SO2NR5R6, -S(O) _t R8, -O-Ci-ioalkyl-COORS,

-0-Ci-ioalkyl-CONR5R6 and fluoro; R5, R6 and R7 are independently selected from the group consisting of -H, -Ci_6alkyl, aryl and aryl-substituted -Ci-6alkyl;

R8 is independently selected from the group consisting of -Ci-6alkyl, aryl and aryl-substituted

-Ci- ₆ alkyl;

R9 is selected from the group consisting of halo, OH, OCj-Cgalkyl, dialkylamino,-C≡C- (CH2)y-NRl ORl 1 , -C=C-(CH2)y-NRl ORI 1 and -(CH2) _w -NRl ORI 1 ;

RlO is independently selected from the group consisting of -H and -Ci-3alkyl;

Rl 1 is independently selected from the group consisting of -H, - Ci-3alkyl, -C(O)-C i-3alkyl, -

C(O)-NRlORlO ₅ -SO2-Ci-3alkyl, and -Sθ2-phenyl;

Rl 2 is selected from the group consisting of halo, OH, OCj-Cgalkyl, dialkylamino, -Ci_i5alkyl mono- or poly-substituted with -OH, -CH=CH-C 1.13alkyl mono- or poly- substituted with -OH,

CH ₂

Il

-C≡C-Ci-πalkyl mono- or poly-substituted with -OH, and -( ^CH 2)v-C-CH ₂ OH . Rl 3 is selected from the group consisting of -H and —OH. t is an integer selected from O, 1 and 2; v is an integer selected from 0 and 1 ; w is an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8; and y is an integer selected from 1, 2, 3, 4, 5 and 6;

comprising the steps of: a) mixing a first organic nucleophile and a beta-lactam of Formula Ia

Ia wherein

ArI is ary^ optionally substituted with one to five groups selected from R.4; Ar^ and Ar^ is selected from a phenyl substituted with one to three electrophiles; R is selected from the group consisting of -OR6, -O(CO)R6, -0(CO)O R8, -O(CO)NR6R7, _a sugar residue, a disugar residue, a trisugar residue and a tetrasugar residue; and all other definitions are as defined above;

in a first cross-coupling reaction; b) adding a second organic nucleophile in a second cross-coupling reaction; and c) isolating the compound.

In an embodiment of the instant invention, the process for preparing a compound of Formula II, as described above, comprises the steps of: a) mixing a first organic nucleophile, a beta-lactam of Formula Ia, as described above, a base, and a solvent in a cross-coupling reaction, wherein said first organic nucleophile is selected from an organoborane or an aliphatic hydrocarbon compound; b) adding a second organic nucleophile in a second cross coupling reaction, wherein said second organic nucleophile is selected from an organoborane or an aliphatic hydrocarbon compound; and c) isolating the compound.

In a further embodiment, the instant invention is directed to the process for preparing a compound of Formula II, as described above, comprises the steps of: a) mixing a first organoborane, a beta-lactam of Formula Ia, as described above, a base, a Pd precursor and a ligand in a cross coupling reaction; b) adding a second organoborane in a second cross coupling reaction; and c) isolating the compound.

In a further embodiment, the instant invention is directed to the process for preparing a compound of Formula II, as described above, comprises the steps of: a) mixing a first aliphatic hydrocarbon compound, a beta-lactam of Formula Ia, as described above, a base, a Pd precursor and a ligand in a cross coupling reaction; b) adding a second aliphatic hydrocarbon compound in a second cross coupling reaction; and c) isolating the compound.

In a further embodiment of the invention, wherein the first aliphatic hydrocarbon compound or the second aliphatic hydrocarbon compound is selected from an alkenyl or alkynyl, the process comprises a step of reducing said alkenyl or alkynyl to an alkyl by adding a reducing agent prior to isolating the compound.

In a further embodiment of the instant invention, the process for preparing a compound of Formula II, as described above, comprises the steps of: a) mixing a hydroborating agent, an aliphatic hydrocarbon compound and a solvent to form an adduct solution; b) adding a beta-lactam of Formula Ia, as described above, a base, a Pd precursor and a ligand to the adduct solution in a cross coupling reaction; c) adding an organoborane, and optionally base, in a second cross coupling reaction; and d) isolating the compound.

In a further embodiment of the invention, after step (c), a de-protecting agent is added, prior to isolating the compound.

In a further embodiment, the process for preparing a compound of Formula II comprises the steps of: a) mixing a hydroborating agent, an aliphatic hydrocarbon compound and a first solvent to form an adduct solution; b) mixing a beta-lactam of Formula Ia, as described above, and a base in second solvent and water to create a first biphasic mixture; c) dissolving a first Pd precursor and a first ligand in an organic solvent to prepare a catalyst solution; d) adding the catalyst solution to the first biphasic mixture to form a resulting mixture; e) adding the adduct solution to the resulting mixture; f) adding an organoborane, a base, a second Pd precursor, water, and optionally, a ligand, in the second cross coupling reaction; g) adding a de-protecting agent; and h) isolating the compound.

In a further embodiment, the instant invention is a process for preparing Compound A

comprising the steps of: a) mixing 9-BBN, THF and N-allyl methyl sulfonamide to form an adduct solution; b) mixing 4-(4-Bromo-phenyl)-3-[3-(tert-butyl-dimethyl-silanyloxy)-3-( 4- fluoro-phenyl)-propyl]-l-(4-iodo-phenyl)-azetidin-2-one, K2CO3, THF and water to create a biphasic mixture; c) dissolving allylpalladium(II) chloride dimer, triphenyl phosphine in PI1CH3 to prepare a catalyst solution; d) adding the catalyst solution to the first biphasic mixture to form a resulting mixture; e) adding the adduct solution to the resulting mixture in a first cross-coupling reaction; f) performing solvent switch to toluene; g) adding potassium trifluoroborate salt, K2CO3, PdCl2 (dtbpf) and water in a second cross-coupling reaction to create a second biphasic mixture; h) adding H2SO4; and i) isolating Compound A.

In a further embodiment, the instant invention is a process for preparing

Compound A comprising the steps of: a) mixing 9-BBN, THF and N-allyl methylsulfonamide to form an adduct solution; b) mixing the 4-(4-Bromo-phenyl)-3-[3-(tert-butyl-dimethyl-silanyloxy)-3- (4-fiuoro-phenyl)-propyl]-l-(4-iodo-phenyl)-azetidin-2-one, K2CO3, THF and water to create a biphasic mixture; c) dissolving allylpalladium(II) chloride dimer, triphenyl phosphine in PhCH3 to prepare a catalyst solution; d) adding the catalyst solution to the first biphasic mixture to form a resulting mixture;

e) adding the adduct solution to the resulting mixture in a first cross-coupling reaction; f) adding a solution of triol boronic acid and K ₂ CO ₃ in water in a second cross-coupling reaction to create a second biphasic mixture which comprises an organic layer and an aqueous layer; g) isolating a product from the organic layer of the second biphasic mixture; h) adding an organic solvent and H2SO4; and i) isolating Compound A.

As used herein, the term "DKR-ATH process catalyst system" refers to an optically active catalyst system (OACS), which combines a transition metal precursor and an optically active diamine derivative (OADD). As used herein, the terms "optically active catalyst systems" or "OACS" is represented by the formula:

(OACS Formula Ia)

In an embodiment, M is selected from ruthenium, rhodium, and iridium. In a preferred embodiment, M is ruthenium. In another embodiment, Y is selected from hydrogen and halogen. In an embodiment, Y is -Cl. In a further embodiment, L is an optionally- substituted phenyl group, including p-cymene. In another embodiment, one of Rm and Rn is aryl or heteroaryl, preferably phenyl, and the other is -H. In another embodiment, one of RP and Rq is aryl or heteroaryl, preferably phenyl and the other is -H. In a preferred embodiment, one of both R ^m or Rn and RP or RQ are phenyl, while the others are -H. In an additional embodiment, RS is an optionally substituted benzene, preferably substituted with one to give groups independently selected from methyl or fluoro.

In a further embodiment, the OACS is selected from:

and

In one embodiment of the optically active catalyst system (OACS) preparation, the transition metal catalyst and OADD are present in a 1 : 1 metal :ligand (1 :2 dimeπligand) ratio, or less preferably, with ligand in excess of this ratio. In another embodiment of the OACS preparation, the catalyst system is pre-prepared and added to the DKR reaction mixture as an isolated solid. In a further embodiment, the OACS is prepared in situ by the separate or concurrent addition of the transition metal catalyst and OADD and used directly in the DKR reaction. The concentration of the OACS present in the reaction is preferably about 0.25 to about 2% on a metal-complex basis (about 0.125 to about 1% on a transition metal dimer basis) and more preferably about 0.5 to about 1% on a metal-complex basis, which may yield a higher conversion percentage, shorter reaction time, and improved selectivity.

As used herein, a "transition metal precursor" is illlustrated as

MX _m L _n , wherein: M is selected from the group of metals consisting of iron, cobalt, nickel, ruthenium, rhodium, iridium, osmium, palladium and platinum; X is a halogen atom;

L is selected from benzene and cyclopentadienyl, optionally substituted with one to three substituents selected from -Ci-ioalkyl; m is an integer selected from 0, 1, 2, 3, and 4; and n is an integer selected from 1 and 2.

In one embodiment, M is selected from ruthenium, rhodium, and iridium. In another embodiment, M is ruthenium. In another embodiment, X is selected from -F, -Br or -Cl.

In another embodiment, X is -Cl. In another embodiment, m is selected from 1, 2, and 3. In further embodiment, the transition metal precursor is illustrated by the formula: [RuCl2(P- cymene)]2

As used herein, an optically active diamine derivative (OAAD) for the preparation of the OACS is represented by the following formula:

(OAAD Formula I) wherein:

R ^s is selected from -Ci-ioalkyl and aryl, each of which may be optionally substituted with halogen or -Cl-6alkyl;

Rm, Rn, Rp, and Rq are independently selected from H, -Ci-K)alkyl, -Cs-iocycloalkyl, aryl, and heteroaryl, each of which may be optionally substituted with -Ci-6alkyl or halogen, and are the same or different such that one or both carbons bonded with these substituent groups comprises an asymmetric center and any one of R ^m and R ⁿ and any one of RP and RQ are optionally bonded together to form a ring. In an embodiment of the OADD, Rs is selected from, -CF3, - (CF2)3CF3> and aryl, said aryl being optionally substituted. In another embodiment, Rs is

selected from -CF3, -(CF2)3CF3, and wherein X is -CH3, -F or -CF3. In an embodiment of the OADD, Rm, Rn, Rp _; and RQ are independently selected from H, -Ci-ioalkyl, and aryl, said alkyl and aryl may be optionally substituted with -Ci-6alkyl or halogen; and any one of R ^m and R ⁿ and any one of RP and RQ are optionally bonded together to form a ring. In another embodiment, R ^m , R ⁿ , RP, and RQ are selected from hydrogen, -Ci_ lOalkyl and phenyl. In a further embodiment, R ^m and Rq are hydrogen, Rn and RP are independently selected from -C 1.1 (jalkyl and Rn and RP are bonded together to form a ring. I _n a

As used herein, the "DKR reductant system" comprises a reducing agent and a base. Such a system can be selected from a broad range of hydrogen donor/base systems known

to those skilled in the art. In one embodiment, the DKR reductant system comprises an alcohol and a strong base, or more preferably, a secondary alcohol such as 2-propanol and a metal alkoxide or metal hydroxide base such as KOH or potassium t-butoxide. In another embodiment, the DKR reductant system is a formate salt. In a further embodiment, the DKR reductant system comprises a hydrogen donor and a secondary or tertiary amine. In a preferred embodiment, the hydrogen donor is formic acid and the amine is triethyl amine, yielding CO ₂ as one reaction product of the DKR asymmetric hydrogenation. This limits the reverse reaction and epimerization, which increases the yield of the syn product of Intermediate B. The hydrogen donor should be added slowly to the reaction mixture to achieve optimal selectivity, limit epimerization, and increase catalyst life. The rate of addition of the hydrogen donor is preferably about 2 to about 24 hours. In another embodiment, the rate of addition is about 8 to about 12 hours.

The "DKR solvent system" can be selected from a broad range of organic solvents known to those skilled in the art. In one embodiment, the solvent system is selected from the group consisting of 1) alcohols, 2) amides, 3) aromatic solvents, and 4) halogenated alkanes. Examples of each of these solvent systems include, but not limited to, 1) 2-propanol, 2-butanol, methanol, ethanol, isobutanol, tert-butanol; 2) N,N'-dimethylformamide, N ₅ N'- dimethylacetamide, N-methylpyrrolidine, dimethylpropylene urea; 3) toluene, benzene, xylene, chlorobenzene, dichlorobenzenes, trifluorotoluene; 4) dichloromethane, dichloroethane. In a preferred embodiment, the DKR solvent system is toluene or dichloromethane.

The reaction temperature for the process for preparing a compound of

Intermediate B or Intermediate B* is selected from a range of about -10 to about 60° C. Outside of this range, selectivity and/or reactivity may be lost, and catalyst efficiency may be reduced. In an embodiment, the reaction temperature is about 20 to about 40° C. In a further embodiment, the reaction temperature is about 30° C. In another embodiment of the invention, the reaction is run under an atmosphere containing a quantity of O ₂ . In a further embodiment, the reaction is run under an inert atmosphere that improves selectivity and catalyst activity, or more preferably under a nitrogen atmosphere.

As used herein, a "phase transfer catalyst" is a catalyst which facilitates the migration of a reactant in a heterogeneous system from one phase into another phase where the reaction can take place. Examples of phase transfer catalysts include, but are not limited to, quaternary ammonium salts or phosphonium salts known to the arts. [See Charles M. Stark, Charles L. Liotta, Marc Halpern, In Phase Transfer Catalysis: Fundamentals, Applications, and Industrial Perspectives, Chapman & Hall, New York, 1994, and Eckehard V. Demlov, In Phase Transfer Catalysis, Weinheim, New York, 1993.] Quaternary ammonium salt is defined as tetra- substituted nitrogen salts, in which the substituents on the nitrogen include, but not limited to, various linear or branched alkyl groups and/or substituted or non-substituted aryl groups and

where the counteranion of the salts include, but not limited to, halides, sulfates, bisulfates, hydroxides. In an embodiment, the phase transfer catalyst is a tetra alkyl ammonium salt, such as BnEtβNCl or BnMe ₃ NCl. In an embodiment, the preferred phase transfer catalyst is benzyltriethylammonium chloride (BnEt ₃ N ⁺ Cl ^" ). As used herein, a "hydroxy-group activator" is a chemical agent, widely used and known to the arts, that would react with the hydroxy functionality to afford a new, more labile functional group that is more prone to be displaced during a (nucleophilic) substitution reaction. Examples of an hydroxy-group activator include, but are not limited to, phosphoryl halides, sulfonyl halides, carboxylic acid chlorides, and carboxylic or sulfonic acid anhydrides . Further examples of hydroxy-group activators include, but are not limited to, diethylphosphorylchloride, diphenylphosphoryl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, pivaloyl chloride, benzoyl chloride, acetyl chloride, acetic anhydride, pivaloic anhydride, benzoic anhydride, triflouromethanesulfonic anhydride, methanesulfonic anhydride and the like. In a preferred embodiment, the hydroxy-group activator is methanesulfonyl chloride or methanesulfonic anhydride.

Organic solvent is defined as an appropriate reaction media that is inert toward the hydroxy-group activator, but effective in promoting the activation and the subsequent cyclization (b-lactam formation). Examples of such solvents include, but not limited to, toluene, benzene, xylene, chlorobenzene, dichlorobenzenes, trifluorotoluene, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), tert-butyl methyl ether (MTBE), p-dioxane, dimethoxyethane (DME), ethyl acetate, isopropyl acetate, N,N'-dimethylformamide (DMF), N,N'-dimethylacetamide (DMAc), acetonitrile. In the instant embodiment, the preferred solvent is toluene.

In the instant invention, unless otherwise defined, the terms "first" and "second" are utilized to demonstrate that an element of the process may be added more than once during the process. The first and second element (e.g. "first organic nucleophile" and "second organic nucleophile") may be different or the same. The terms are used to indicate that the element is being added a second time during the described step of the instant invention.

As used herein, the phrase "organic nucleophile" refers to carbon-containing electron donors having sp, sp2, or sp3 configuration. Examples of organic nucleophiles include, but are not limited to, aliphatic hydrocarbon compounds, alkyl-, alkynyl-, alkenyl-substituted organometallic reagents including organoboranes, organozincs, organotins, organoindiums, organomagnesium (such as Grignard reagents), and the like. Iri an embodiment of the instant invention, the "first organic nucleophile" and "the second organic nucleophile" are independently selected from the group consisting of an aliphatic hydrocarbon compound or an organoborane.

As used herein, the term "organoborane" refers to organic derivatives Of BH _3. As used herein, examples of an organoborane include, but are not limited to, trialkyl boranes,

alkyltrifluoroborates, alkyldialkoxyborates, dialkylalkoxyborates, alkyltrihydroxyborates and the like. In an embodiment of the instant invention, the organoborane is selected from potassium trifluoroborate salt or alkyldialkoxyborates, 2-(2-dihydroxyboranyl-ethyl)-propane-l,2,3-triol.

As used herein, the phrase "hydroborating agent" refers to compounds capable of performing concurrent addition of a hydrogen and boron across an unsaturated bond such as alkenes or alkynes. Examples of a hydroborating agent include, but are not limited to, borane, diborane, 9-Borabicyclo[3.3.1]nonane (9-BBN), dioxane-monochloroborane, dioxane- dichloroborane, pinacolborane, and the like. In an embodiment of the instant invention, the hydroborating agent is 9-BBN. As used herein, the phrase "aliphatic hydrocarbon compound" refers to an alkyl, alkenyl, or an alkynyl, wherein such alkyl, alkenyl or alkynyl may be unsubstituted or substituted.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, Ci-Cio _> as in "CI -CJ O alkyl" is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons in a linear or branched arrangement. For example, "CI -C J O alkyl" specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on. In an embodiment, examples of "alkyl" include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl and i-butyl. If no number of carbon atoms is specified, the term "alkenyl" or "alkene" refers to a non-aromatic hydrocarbon radical, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present. Thus, "C2-C6 alkenyl" means an alkenyl radical having from 2 to 6 carbon atoms. Alkenyl groups include ethenyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated. The term "alkynyl" or "alkynes" refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present. Thus, "C2-C6 alkynyl" means an alkynyl radical having from 2 to 6 carbon atoms. Alkynyl groups include ethynyl, propynyl, butynyl, 3-methylbutynyl and so on. The straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.

If substituted, the aliphatic hydrocarbon compound may be substituted with one to three substituents selected from -(CH2)y-NRlθRl 1, -(CH2)y-NRlθRl 1 and -NRl ORI 1, -OH,

-CH=CH-C 1-I3alkyl mono- or poly- substituted with -OH, -C≡C-Ci- 13 alkyl mono- or poly-

CH ₂

Il substituted with -OH, and -( ^CH 2)v-C-CH ₂ OH

In an embodiment of the instant invention, the aliphatic hydrocarbon compound is selected from N-Prop-2-ynyl-methanesulfonamide, N-Allyl-methanesulfonamide, 5-Ethynyl-2,2- dimethyl-l,3-dioxinan-5-ol, 2,2-Dimethyl-5-vinyl-l,3-dioxinan-5-ol, Acetic acid 2- acetoxymethyl-2-hydroxy-but-3-ynyl ester, Acetic acid 2-acetoxymethyl-2-hydroxy-but-3-enyl ester.

As used herein, the term "reducing" refers to the addition of hydrogen atoms across unsaturated compounds, such as alkenyl or alkynyl groups. In the case of alkenyl groups, addition of two hydrogen atoms is required to produce the corresponding alkyl groups, while in the case of alkynyl groups, four hydrogen atoms are needed to arrive at the same corresponding alkyl groups. The transformation can be effected with or without metal catlysts. Examples of "reducing agents" include, but are not limited to, molecular hydrogen (H2), formic acid, 2- propanol, diisobutylaluminium hydride (DIBAL), diazadicarboxylate (diimide dicarboxylate) or its precursors, sodium bis-(2-methoxyethoxy)aluminium hydride (RedAl). Examples of metal catalysts include, but not limited to, palladium black, palladium on carbon, rhodium on carbon, rhodium on alumina, rhodium on silica gel, palladium (II) hydroxide on carbon (Pearlman's catalyst), palladium-platinum mixture, platinum on carbon. In an embodiment of the instant invention, the reducing agent is selected from molecular hydrogen and palladium on carbon.

As used herein, the phrase "adduct solution" refers to a solution which contains an organoborane. In an embodiment of the instant invention, a hydroborating agent, an aliphatic hydrocarbon compound and a solvent are mixed together and the resulting solution, referred to as an adduct solution, contains an organoborane.

As used herein, the phrase "de-protecting agent" refers to either an acid labile protecting group or a basic labile protecting group, as appropriate. The term "acid labile protecting group" herein refers to appropriate alcohol or 1,2- and 1,3-diol protecting groups that would survive all of the prior chemical transformations that lead to the point of its removal under acidic conditions (pH <7). Examples of such a group include, but are not limited to, all silyl ethers (TMS, TBS, TBDPS, TES, ane the like), alkyl ethers (including acyclic acetals/ketals such as methoxymethyl, tetrahydropyranyl, ethoxyethyl, or acyclic ethers such as benzyl, allyl, methyl, and the like), cyclic acetals/ketals (including 5-, 6- or higher member ring size acetonide, benzylidene,and the like), or cyclic ortho esters. The term "basic labile protecting group" herein refers to appropriate alcohol or 1,2- and 1 ,3-diol protecting groups that would survive all prior chemical steps leading to the point of its removal under basic conditions (pH >7). Examples of such a group include, but are not limited to all alkyl or aryl esters, carbonates or phosphates.

As used herein, the term "solvent" refers to non-polar, polar aprotic or polar protic solvents. Examples of a solvent include, but are not limited to, THF, alcohols, acetic acid, MeCN, DMF, DMSO, DCM, Toluene, ethyl acetate, acetone, water, and the like. In an

embodiment of this invention, the first solvent is THF or toluene. In an embodiment of this invention, the second solvent is selected from THF or toluene.

As used herein, the term "a beta-lactam of Formula Ia" refers to an electrophile- substituted, aromatic containing beta-lactam, which is a cyclic amide ring with a heteroatomic ring structure, consisting of three carbon atoms and one nitrogen atom and is further substituted with an aromatic ring. In the instant invention, the beta-lactam is represented by Formula Ia below:

Ia wherein

ArI is selected from the group consisting of aryl and R4-substituted aryl; AJ2 and Ar^ are selected from a phenyl substituted with one to three electrophiles; and R is selected from the group consisting of -OR.6, -O(CO)R6, -0(CO)O R8, -O(CO)NR6R7, _a sugar residue, a disugar residue, a trisugar residue and a tetrasugar residue. As used herein, the term "electrophile" refers to a heteroatom-containing functional group, directly bound to the aromatic ring in the compound of interest. Examples of this electrophile include, but are not limited to, halides (fluoride, chlorides, bromides, iodides), aliphatic or aromatic thiol derivatives, alkyl/aryl sulfonate/sulfates derivatives (trifluoromethanesulfonate, p-toluenesulfonate, methanesulfonate or other longer chain sulfonate esters), phosphonates (dialkyl phosphonates), or trialkylammonium derivatives. In an embodiment, the electrophile is a halide.

As used herein, the phrase "Pd precursor" refers to molecules that can be used as a source of Pd. Examples of a Pd precursor include, but are not limited to, [allyl-PdCl]2, PdCl ₂ (dtbpf), Pd(OAc) ₂ , Pd ₂ (dba) ₃ , Pd(ACN) ₂ Cl ₂ , PdCl ₂ , PdBr ₂ , Pd(benzonitrile) ₂ Cl ₂ , Pdtfa ₂ . In an embodiment of the instant invention, the Pd precursor is selected from [allyl- PdCl] ₂ . In an embodiment of the instant invention, the second Pd precursor is selected from

PdCl ₂ (dtbpf).

As used herein, the term "ligand" herein refers to any atom or molecules capable of forming a bond with appropriate metal. Examples are, but not limited to, triphenylphosphine, tri-ortho-tolylphosphine, diphenylphosphinoferrocene, tricylohexylphosphine, tri- tertbutylphosphine, diphenylphosphinemethane, diphenylphosphinoethane, diphenylphosphinepropane, diphenylphosphinobutane, dibenzylideneacetone, carbon monoxide, bis-oxazoline derivatives, acetonitriles, benzonitriles, cyclooctadiene, norbonadienes.

As used herein, the phrase "first ligand" or "second ligand" refers to organic molecules that have nucleophilic atoms such as phosphorus, oxygen, sulfur, nitrogen or carbon that form complexes with palladium. Examples of a first ligand include, but are not limited to, triphenyl phosphine and other monodentate triaryl phosphines or mixed alkyl/ aryl monodentate phosphines, tri-tertbutyl phosphine or other monodentate trialkyl phosphines, dppf or other bidentate diphosphine ligands, triphenylphosphite or other monodentate triaryl phosphites or mixed alkyl/ aryl monodentate phosphites and the like. In an embodiment of the instant invention, the first ligand is triphenyl phosphine.

Examples of a second ligand include, but are not limited to, triphenylphosphine or triorthotolylphosphine and other monodentate triaryl phosphines or mixed alkyl/ aryl monodentate phosphines, tri-tertbutyl phosphine or other monodentate trialkyl phosphines, dppf or other bidentate diphosphine ligands, triphenylphosphite or other monodentate triaryl phosphites or mixed alkyl/ aryl monodentate phosphites. In an embodiment of the instant invention, the second ligand is selected from dtbpf, tri-orthotolylphosphine, or SPHOS water soluble catalyst.

As used herein, the term "base" refers to an organic base, an inorganic base, and the like. Examples of a base include, but are not limited to, K2CO3, CS2CO3, Li2CO3,

Na2CC>3, KOH, LiOH, NaOH, CsOH, K3PO4, KF, Et3N and other tertiary amines, diisopropylamine and other secondary amines, and butylamine and other primary amines. In an embodiment of the instant invention, the base is K2CO3.

As used herein, the phrase "hydroxide solution" refers to a solution of water and NaOH.

As used herein, the term "acid" refers to organic or inorganic acids. Examples of an organic acid include, but are not limited to, carboxylic acids such as stearic acid, acetic acid, formic acid, propionic acid, butyric acid, and the like. Examples of inorganic acid include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, and the like. In an embodiment of the instant invention, the acid is selected from trithiocyanuric acid and H ₂ SO ₄ .

As used herein, the term "cross-coupling reaction" herein refers to a metal- catalyzed chemical transformation resulting in the formation of a new carbon-carbon bond. The presence of an appropriate metal is essential to affect the desired transformation. The metal is further defined as (1) elemental metals, (2) metal salts, (3) metal or metal salts impregnated on a solid support, (4) metals or metal salts coordinated with ligands. Respective examples of each of these species include, but not limited to: (1) palladium black, nickel, raney nickel, platinum, copper, iridium, rhodium, ruthenium; (2) palladium acetate, palladium (II) chloride, nickel (II) chloride, nickel (II) acetylacetonato, nickel (II) bromide, palladium allyl chloride dimer (II), palladium (II) hydroxide, palladium (II) bromide, palladium (II) trifluoroacetate, iron (III)

trichloride, iron (III) tribromide, rhodium (I) acetate, rhodium (III) trichloride, iridium (III) trichloride, platinum (II) chloride, platinum (II) bromide, ruthenium (II) chloride, copper (I) iodide, copper (I) acetate, cobalt (II) acetate, cyclooctadiene iridium (I) chloride dimer; (3) palladium on carbon, platinum on carbon, palladium (II) hydroxide on carbon, rhodium on alumina, rhodium on silica gel, rhodium on carbon; (4) ligand-bound palladium (II) chloride, ligand-bound palladium (0), ligand-bound nickel (II) chloride, ligand-bound nickel (0), ligand- bound rhodium (I) chloride, ligand-bound iridium (I) chloride.

As used herein, the phrase "solvent switch" refers to an activity involving switching from one solvent to another by either removing the first solvent by distillation prior to adding the second solvent or by azetropically removing the first solvent in the presence of a second solvent.

As used herein, the phrase "ruthenium-complex catalyst" refers to ruthenium complexes bearing a chiral ligand group, capable of affecting the desired transfer hydrogenation of the ketone functionality efficiently in high/good selectivity. As used herein, the phrase "chiral ligand" refers to chiral molecules capable of forming at least one bond with the metal used in the transfer hydrogenation step. Examples of a chiral ligand include, but not limited to, TsDPEN (N-tosyl diphenylethylenediamine), FsDPEN (N-pentafluorobenzene diphenylethylenediamine), N-trifluoromethylbenzene diphenylethylenediamine, N-tosyl (l,2)-cyclohexyldiamine, N-pentafluorobenzene (1,2)- cyclohexyldiamine, and N-trifluoromethylbenzene 1 ,2-cyclohexyldiamine.

As used herein, the phrase "isolating the compound" refers to techniques known in the art by which one may obtain the final compound. Examples of such techniques inlcude, but are not limited to, crystallization, filtration, distillation and the like. In one embodiment of the instant invention, the compound is isolated via crystallization. The term "patient" includes mammals, especially humans, who use the instant active agent for the prevention or treatment of a medical condition. Administering of the drug to the patient includes both self-administration and administration to the patient by another person. The patient may be in need of treatment for an existing disease or medical condition, or may desire prophylactic treatment to prevent or reduce the risk for diseases and medical conditions affected by inhibition of cholesterol absorption.

The term "therapeutically effective amount" is intended to mean that amount of a pharmaceutical drug that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. The term "prophylactically effective amount" is intended to mean that amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician. Particularly, the dosage a patient

receives can be selected so as to achieve the amount of LDL cholesterol lowering desired; the dosage a patient receives may also be titrated over time in order to reach a target LDL level. The dosage regimen utilizing the compound of the instant invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; and the renal and hepatic function of the patient. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition. The compound of the instant invention is a cholesterol absorption inhibitor and is useful for reducing plasma cholesterol levels, particularly reducing plasma LDL cholesterol levels, when used either alone or in combination with another active agent, such as an anti- atherosclerotic agent, and more particularly a cholesterol biosynthesis inhibitor, for example an HMG-CoA reductase inhibitor. Atherosclerosis encompasses vascular diseases and conditions that are recognized and understood by physicians practicing in the relevant fields of medicine. Atherosclerotic cardiovascular disease including restenosis following revascularization procedures, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease including multi-infarct dementia, and peripheral vessel disease including erectile dysfunction are all clinical manifestations of atherosclerosis and are therefore encompassed by the terms "atherosclerosis" and "atherosclerotic disease."

Compound A may be administered to prevent or reduce the risk of occurrence, or recurrence where the potential exists, of a coronary heart disease event, a cerebrovascular event, and/or intermittent claudication. Coronary heart disease events are intended to include CHD death, myocardial infarction (i.e., a heart attack), and coronary revascularization procedures. Cerebrovascular events are intended to include ischemic or hemorrhagic stroke (also known as cerebrovascular accidents) and transient ischemic attacks. Intermittent claudication is a clinical manifestation of peripheral vessel disease. The term "atherosclerotic disease event" as used herein is intended to encompass coronary heart disease events, cerebrovascular events, and intermittent claudication. It is intended that persons who have previously experienced one or more non-fatal atherosclerotic disease events are those for whom the potential for recurrence of such an event exists.

N-[3-(4-{(2 ₁ S,3/?)-2-{4-[3,4-dihydroxy-3-(hydroxymethyl)butyl]phenyl}-3- [(35)- 3 -(4-fluorophenyl)-3 -hydroxypropyl] -4-oxoazetidin- 1 -yl } phenyl)propyl] methanesulfonamide was determined to inhibit cholesterol absorption employing the Cholesterol Absorption Assay in Mice, below. This assay involves comparing a test compound to ezetimibe with respect to their ability to inhibit cholesterol absorption in mice. Both ezetimibe and the tested compound

inhibited cholesterol absorption by >90% at the highest dose tested. The tested compound had an ID 50 < lmg/kg.

Cholesterol Absorption Assay in Mice: C57BL/6 male mice (n = 6/group), aged 10 - 14 weeks, were dosed orally with 0.2 ml 0.25 % methyl cellulose solution with or without test compound or ezetimibe (0.12-10 mg/kg). Thirty minutes later all of the mice were dosed orally with 0.2 ml INTRALIPID™ containing 2 μCi [ ³ H] -cholesterol per mouse. Five hours later, the animals were euthanized, and liver and blood were collected. Cholesterol counts in liver and plasma were determined, and percent inhibition of cholesterol absorption was calculated. A variety of chromatographic techniques may be employed in the preparation of

Form I. These techniques include, but are not limited to: High Performance Liquid Chromatography (HPLC) including normal- reversed- and chiral-phase; Medium Pressure Liquid Chromatography (MPLC), Super Critical Fluid Chromatography; preparative Thin Layer Chromatography (prep TLC); Gas Chromatography (GC); flash chromatography with silica gel or reversed-phase silica gel; ion-exchange chromatography; and radial chromatography. All temperatures are degrees Celsius unless otherwise noted. Degrees Celsius may be noted in the examples as "C" without the degree symbol (e.g. 50C) or "°C" with a degree symbol (e.g. 5O ⁰ C). Some abbreviations used herein include:

Ac Acyl (CH ₃ C(O)-)

ACN Acetonitrile

Aq. Aqueous

BBN 9-Borabicyclo[3.3.1]nonane

Bn Benzyl

C. Celsius calc. Calculated

DCM dichloromethane

DIEA λζiV-diisopropylethylamine

DMAP 4-dimethylaminopyridine

DMF N,N-dimethylformamide

DMSO Dimethyl Sulfoxide

Dtbpf 1 , 1 -bis(di-tørrt>utylphosphino)ferrocene equiv. Equivalent(s)

ES-MS Electron Spray Ion-Mass Spectroscopy

EtOAc Ethyl acetate h Hour(s)

HPLC High performance liquid chromatography

IPA Isopropyl Alcohol

IPAC Isopropyl Acetate

MeCN Acetonitrile

Min Minute(s)

MMC rex Media mill crystallization mp Melting point

ML mother liquors

MS Mass spectrum

OAB Oxazaborolidine

OTBS Tert-butyldimethylsiloxy

Pd ₂ (dba) 3 Tris(dibenzylideneacetone)dipalladium (0)

PdCl2(dtbpf) Dichloro[l,l,-bis(di-ter/butylphosphino)ferrocene] palladium (II)

Pd(OAc) ₂

Pdtfa ₂ Palladium (II) acetate

Ph Palladium (II) trifluoroacetate

Phenyl

Prep. Preparative r.t. (or rt or RT) Room temperature

Sat. Saturated

SPHOS 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl

TBAI tetrabutylammonium iodide

TBS Tert-butyl dimethylsilyl

TBSCl Tert-butyl dimethylsilyl chloride

TEA Triethyl amine

TES Triethyl silyl

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin layer chromatography

TMS Trimethyl silyl

TMSOK Potassium trimethylsilanolate wrt with regard to

General Schemes

SCHEME 1

O O Catalyst A (0.5-1 mo 1%) OH O

U I Et ₃ N, HCO ₂ H

K I M INln IPK ^ri R ^c ^V^NHR ^d ' _b PhCH ₃ or CH ₂ CI ₂ R ^b

30-40 ⁰ C

Intermediate A Intermediate B

Entry R ^c R ^D R ^α %Yield

P-FPhCH-(S)-

1 P-BrPh p-IPh 90 OTBS-Et-

2 Ph Et Ph 88

3 Ph Et P-OMePh 85

4 Ph Bn Ph 68

5 Ph AIIyI Ph 74

6 Ph Cinnamyl Ph 77

7 P-BrPh Cinnamyl p-IPh 87

P-FPhCH-(S)-

8 P-AIIyIOPh p-FPh 85 OTBS-Et-

9 c-Hex Cinnamyl Ph 80

10 Ph Ph-Pr- Bn 75

SCHEME 2

1 DMAP ₁ ACN ₁ O ⁰ CtORT

2 4-iodoanιlιne, TFA, 40 - 70 ⁰ C

I)NaCI, Acetone reflux TBSCI, imidazole 2) OAB reduction DMF, 40°C

KOtBu NMP

85%

SCHEME 2 (CONTD)

A 30-33 ⁰ C

For Scheme 3: Sequential cross-couplings of intermediate 1 could be carried out to generate intermediate 3. One of the approaches involves a direct production of 3 via two sp ² - sp coupling reactions, using either Suzuki or Molander reactions. Alternatively, sequential sp ² - sp couplings or sp ² -sp couplings would generate the corresponding unsaturated intermediates 13 and 7 respectively, which upon reduction with H ₂ gas arrives at the same intermediate 3. In addition to these approaches, any combinations of the sequential coupling reactions (i.e, sp ² -sp followed by sp ² -sp ³ ; 6 other possible combinations), followed by the appropriate hydrogenation conditions, would also afford the common intermediate 3.

SCHEME 3

SCHEME 4

1. organoborane

(aliphatic + hydroborating agent)

2. aliphatic or organoboranes

Route a2

SCHEME 4- ROUTE Al

OH

OR OR

Pd, Ligand, base ii (R= CMe ₂ ) viii (R= Ac) xiii (R= TBS)

Route a1 R= H

1. Metal, H ₂

2. Deprotection _

Compound A

SCHEME 4- ROUTE A2

Route a2

Compound A

SCHEME 4- ROUTE A3

OH

Route a3 OR OR

1. Metal, H ₂

2. Deprotection

Compound A

SCHEME 5

.NHSO ₂ Me (a)

R: Acid labile group

Compound A

SCHEME 5A

EaIIyI-PdCI] ₂ . PPh ₃ K ₂ CO ₃ , PhCH ₃ , H ₂ O

Compound A

SCHEME 5b

IaIIyI-PdCI] ₂ , PPh ₃ K ₂ CO ₃ , PhCH ₃ , H ₂ O

Compound A

SCHEME 6

1. aliphatic (alkeny I)

2. aliphatic or organoboranes

Route b2

SCHEME 6 - ROUTE Bl

Route b1

OH

OR OR

Pd, Ligand, base ii (R= CMe ₂ ) viii (R= Ac) xiii (R= TBS) R= H

Compound A

SCHEME 6 - ROUTE B2

Compound A

SCHEME 6 - ROUTE B3

1. Metal, H ₂

2. Deprotection

Compound A

1. aliphatic (alky ny I)

2. aliphatic or organoboranes

Route c1

Route c2

SCHEME 7 - ROUTE Cl

OH

OR OR

Pd, Ligand, base ii (R= CMe ₂ ) viii (R= Ac)

Route c1 xiii (R= TBS)

R= H

1. Metal, H ₂

2. Deprotection

Compound A

SCHEME 7 - ROUTE C2

Route c2

Compound A

SCHEME 7 - ROUTE C3

OH

OR OR

Compound A

SCHEME 8

Pd, Ligand, Base

Compound A

R: acid or base labile protecting group can be the same or different groups

SCHEME 8A

Compound A

EXPERIMENTAL DETAILS SECTION

The compounds of the present invention were prepared by the general methods outlined in the synthetic schemes above.

PREPARATION OF INTERMEDIATES Preparation of Acetonide-Trifluoroborate Salt (iv)

I. Vinyl alcohol (ii)

A RB flask was charged with solid, anhydrous ZnCl ₂ (0.10 mol equiv), followed by dry MTBE (8 mL/g wrt substrate) to give a slurry, which was aged at RT for 15 min and cooled to -5-O ⁰ C. A 1.6 M solution of vinyl-MgCl (1.4 mol equiv) in THF was then added over 15 min to give a light tan suspension, which was then aged for 45 min at O ⁰ C-RT and then treated with a solution of the ketone (i) (available commercially from TCI) (1 mol equiv) in

MTBE (1 mL/g) over 2 hours, while maintaining the temperature between -5 ⁰ C - 10 ⁰ C. At the end of addition, the suspension was aged for additional 30 min and then slowly quenched with a 3M solution of AcOH (1.5 mol equiv) at -5°C and aged at RT for 0.5 hour to give a clear biphasic layer. Solid NaCl (6% wrt amount of H ₂ O) was added, the mixture was stirred and the organic layer was cut. The water layer was re-extracted with MTBE (2x2mL/g) and combined with the first organic layer.

The combined organic layer was successively washed with 2mL/g each of 20% aqueous NaCl, 20% aqueous Na ₂ CO ₃ , brine and then dried over Na ₂ SO ₄ , and solvent switched to CH ₂ Cl ₂ to give a final concentration of 3-4 mL/g wrt to product assay. The crude solution could be used directly in the next step or purified by distillation under reduced pressure (9 torr, 80- 85 ⁰ C). Typical assay yield: 85-87%, typical recovery yield post distillation: 85-90%.

II. Hydroxy Pinacolate ester (iii)

Method A: A flask was charged with[IrCODCl] ₂ (0.25mol%), DPPM (0.5 mol%) and dry CH ₂ Cl ₂ (1 vol wrt vinyl-OH) and the resulting mixture was aged at RT for 10 min. To this solution was added simultaneously, a solution of vinyl alcohol (iv) (1 mol equiv, 4 vol) and pinacol borane (1.1 mol equiv) dropwise over 1.5-2 hours, while maintaining the temperature <30°C. The solution was stirred for additional 3-4 hours at RT, at which -3% of starting material remained as judged by GC. At this point, additional pinacol borane (0.1-0.2 mol equiv) was added and the reaction mixture was aged for additional 2-3 hours to give a full conversion. The solution was then solvent switched to MeCN to bring the final concentration to a 20 volume (wrt starting material).

Method B: A mixture of (COD)IrCl(I) dimer (0.25 mol%) and bis(diphenylphosphino) methane (0.5mol%) in dry CH ₂ Cl ₂ (1 vol wrt vinyl-OH) was aged for 15 minutes at RT. To this catalyst solution was then added neat pinacol borane (1.2-1.25 mol equiv) over 15 minutes with careful monitoring of the temperature. (20-25 ⁰ C, moderate hydrogen off-gassing will be observed). The catalyst/pinacol borane mixture was then aged for 15 minutes. In a separate vessel, a solution of the vinyl alcohol solution in dry CH ₂ Cl ₂ (4 vol) was prepared and kept at 30°C. To this solution was then charged 20-25% of the catalyst/pinacol borane mixture (ambient temperature) over approx. 10 min, followed by addition of the remaining catalyst/pinacol borane mixture over 30-60 min, using the rate of addition to control the temperature between 35 °C and reflux. At the end of addition, age for 10 min at 40 °C, sample and analyse by ¹ H NMR. Once the reaction is assayed to be complete, the solution was then solvent switched to MeCN to bring the final concentration to a 20 volume (wrt starting material).

III. Trifluoroborate salt iv To a solution of crude (v) in MeCN (20 vol wrt vinyl-OH) was added KHF ₂ (3 mol equiv), followed by H ₂ O dropwise (4 vol) over 0.5-1 h. The resulting biphasic mixture was then stirred vigorously for additional 1 h. The aqueous layer was discarded and the organic layer was diluted with MeCN (20 vol) and then concentrated to about a quarter of its volume and diluted with another MeCN (20 vol). The mixture was azeotropically distilled to remove H ₂ O by concentrating to 10 vol at room temperature. This process was repeated one more time by charging additional MeCN and distilling until the final desired volume of 10 L/kg and a KF value of 0.5%~1.5% was obtained. The resulting slurry was treated dropwise with MTBE (106 mL) at RT and the resulting suspension was aged at RT for 1 h. The solid was collected, the flask was rinsed with a 1 :2 mixture of MeCN:MTBE (10 vol) once and the wetcake was washed with MTBE (10 vol) and dried under N ₂ at 40-50°C for 10 h. Typical yield for both steps: 80-85%.

Side Chain Synthesis via Dihydroxyacetone Dimer - OAc Protecting Group

Ac ₂ O (4.1 βquiv) ZnCI ₂ (1.0 equiv)

X Pyridine (S e^V _{1 % AcO} ^^ _QAc ^ ^" Mg gBBrr ((22 eeqquuiivv,, 11M/THF) HO ^n ^-OH CH ₂ CI ₂ xtractions PhCH ₃ , -5 ⁰ C vi VIl

HBPin (1.3 equiv) CH ₂ CI ₂ or Heptane KHF ₂ (3 eςro/Vj [(COD)IrCI] ₂ (0.005-0.01 equiv) MeCNiH ₂ O viii dppm (0.01-0.02 equiv)

Xl

Acetate Protection of DHAD (vi)

To a thin slurry of dihydroxyacetone dimer vi in pyridine (5 equiv) was slowly added acetic anhydride (4.1 equiv) at RT. The resulting solution was aged overnight, diluted with CH ₂ Cl ₂ (10 vol) and quenched by adding cold 6N HCl (5-6 equiv). The aqueous layer was separated and back extracted with CH ₂ Cl ₂ (2x 3 vol). The combined organic layer was neutralized with 15% aqueous K ₂ CO ₃ to bring the pH to 7, washed with brine, dried with MgSO ₄ , filtered and concentrated. The crude product was crystallized from toluene: heptane to afford the desired product in 80% isolated yield as white solid.

Vinylation of ketone

A round bottom flask was charged with dry ZnCl ₂ (1 equiv) and dry toluene (8 vol) and the resulting slurry was cooled to -5 ⁰ C and treated with 1 M of vinyl-MgBr in THF (2 equiv). After aging at O ⁰ C for Ih and at 10-15 ⁰ C for 2h, the resulting mixture was cooled to - 1O ⁰ C and treated with a solution of bis- Acetate vii in a 1 :1 mixture of PhCH ₃ :THF over 15 min. The reaction mixture was then aged at 0°C-20°C over 2 hours and then quenched with a 3 M aqueous solution of AcOH (2-3 equiv). After partially saturating the aqueous layer with NaCl (8% total wrt the amount of H ₂ O), the organic layer was separated. The aqueous layer was re- extracted twice with MTBE and the combined organic layer was washed with 20% aqueous NaCl, 20% aqueous KHCO ₃ , brine, dried over MgSO ₄ , filtered and concentrated to give the product as yellow oil in 75% assay yield and used directly in the next step.

Hydroboration of alkene

Alkene solution: The alkene was added to a three neck flask equipped with a reflux condenser and a magnetic stir bar. DCM was added and the solution was degassed for -20 minutes by bubbling N ₂ through the solution at rt. The yellow solution was heated to 3O ⁰ C.

Catalyst/HBpin soln: [Ir(COD)Cl] ₂ and diphenylphosphinomethane were charged to a round bottom flask equipped with a magnetic stir bar. The flask was purged with N ₂ for ~5 minutes and the DCM was added. The yellow solution was stirred at rt for 15 minutes then the pinacolborane was charged in one portion. The solution turned faint yellow immediately and the solution was aged for an additional 15 minutes.

60 mL of the catalyst/HBpin solution was added to the alkene solution in 5 minutes during which the temperature rose to 35.6 ⁰ C. Light bubbling could also be observed during the initial stages of the catalyst/HBpin solution addition. In the next 5 minutes, 7 mL of catalyst/HBpin solution was added. Temperature rose to 41.6°C. The reaction was aged for 10 minutes during which the temperature rose to 44.4 °C. The remainder of the catalyst/HBpin solution was added in the next 10 minutes. Total addition time = 30 minutes. Final temperature = 42.3°C. The temperature controller was set to 40 °C and the reaction was aged for an additional 30 minutes, at which >99% conversion was typically achieved.

BF ₃ Formation

To a solution of bis-acetoxy-pinacolato-ester in THF/DCM was added KHF ₂ followed by slow addition Of H ₂ O. After aging for Ih, the organic layer was separated, solvent switched to EtOAc, azeotropically dried and crystallized from EtOAc:heptane to give the BF ₃ salt xi in 85%.

To a solution of BF ₃ salt x in MeOH was added 10% K ₂ CO ₃ and the suspension was aged at RT overnight. After solvent switching to PhCH ₃ , more K ₂ CO ₃ and H ₂ O were added and the resulting biphasic layer was aged for 3h and the water layer, containing the triol-boronic acid xi in 90% yield.

Side Chain Synthesis via Dihydroxyacetone Dimer - TBS Protecting Group

HBPin (1.3 equiv) CH ₂ CI ₂ or Heptane

[(COD)IrCI] ₂ (0.0025-0.005 equiv)

XlIl dppm (0.005-0.01 equiv) xiv

xv xi

TBS Protection of DHAD (vi)

To a suspension of dihydroxyacetone dimer vi and TBSCl (4.1 equiv) in dry CH ₂ Cl ₂ (10 vol) was added dry triethylamine (4.3 equiv) slowly at RT. The resulting mixture was aged for 12 hours, washed with cold IN HCl, 10% aqueous KHCO ₃ , brine, dried over MgSO ₄ , filtered and concentrated to give the product as a yellow oil (99% yield).

Vinylation of ketone

ZnCl ₂ solid was charged to a 4-neck 3 L flask equipped with a mechanical stirrer. MTBE was added in one portion and the suspension of ZnCl ₂ was stirred for 20 minutes at it. The light white slurry was cooled to -7°C and the solution of vinyl MgCl was added dropwise via an addition funnel over 40 minutes. The temperature of the opaque white slurry was maintained between -10 and -5°C. The cooling bath was removed and the slurry was stirred at rt for an additional 30 minutes. The slurry was cooled to -6 ⁰ C , and the solution of ketone xii in 140 mL (0.5 vols) MTBE was added dropwise over 2 hours. The temperature of the reaction was maintained between -10 to +1 ⁰ C. After the ketone addition is complete, the addition funnel that contained the ketone solution was washed with ~10 mL MTBE. The creamy white slurry was then aged at -5°C for 1 h upon which the reaction was judged to be complete by capillary GC analysis. The reaction was quenched by the addition of 3 M aq. HOAc solution over 30 minutes while maintaining the temperature less than +3 ⁰ C. The cooling bath was removed and 22 g of NaCl was added. The mixture was aged at rt for an additional 30 minutes. The layers were

separated and the aqueous layer (pH ~ 5) was washed with 2x220 mL MTBE (0.8 vols wrt to ketone xii). The combined organic layers were washed successively with 220 mL 20% NaCl, 220 mL of 20% Na ₂ CO ₃ , and 220 mL of saturated NaCl. The organic layers were dried over Na ₂ SO ₄ and concentrated under vacuum (~30 torr) to a yellow oil. The oil was judged to be 91.65 wt% alcohol xiii (92% yield) by NMR analysis with DMAC as the internal standard. Alcohol xiii contains 2-4 mol% of an olefin impurity which is yet to be determined. The residual THF and MTBE was removed by azeotropic distillation with 2x270 mL heptane. The final solution of xiii in heptane was 78.135 wt% (KF of soln = 36.7 ppm).

Hydroboration of alkene

Alkene solution: The alkene was added to a three neck flask equipped with a reflux condenser and a magnetic stir bar. DCM was added and the solution was degassed for ~20 minutes by bubbling N ₂ through the solution at it. The yellow solution was heated to 30°C.

Catalyst/HBpin soln: [Ir(COD)Cl] ₂ and diphenylphosphinomethane were charged to a round bottom flask equipped with a magnetic stir bar. The flask was purged with N ₂ for ~5 minutes and the DCM was added. The yellow solution was stirred at rt for 15 minutes then the pinacolborane was charged in one portion. The solution turned faint yellow immediately and the solution was aged for an additional 15 minutes.

60 mL of the catalyst/HBpin solution was added to the alkene solution in 5 minutes during which the temperature rose to 35.6°C. Light bubbling could also be observed during the initial stages of the catalyst/HBpin solution addition. In the next 5 minutes, 7 mL of catalyst/HBpin solution was added. Temperature rose to 41.6 ⁰ C. The reaction was aged for 10 minutes during which the temperature rose to 44.4°C. The remainder of the catalyst/HBpin solution was added in the next 10 minutes. Total addition time = 30 minutes. Final temperature = 42.3°C. The temperature controller was set to 40°C and the reaction was aged for an additional 30 minutes. An aliquot of the reaction was withdrawn and diluted with CDCl ₃ and 1 drop of D ₂ O.

BF ₃ salt formation To the crude solution of xiv in DCM (from rxn above) was added THF (equal volume) and KHF ₂ as a solid, followed by dropwise addition Of H ₂ O over Ih. The resulting biphasic layer was aged for 0.5h and allowed to settle. The organic layer was then separated and filtered through a medium-fritted funnel. The organic layer was concentrated, solvent switch to EtOAc and azeotropically dried. Crystallization from EtOAc/MeCN afforded the corresponding product as white solid in 92% yield.

Hydrolysis of BF ₃ salt

BF3 salt xv was charged to a flask equipped with a magnetic stir bar. THF and H ₂ O were added successively. The mixture was stirred at rt until a homogenous solution was obtained (~5 minutes). While stirring, the K ₂ CO ₃ was added in one portion. The flask was capped with a rubber septa, but vented with a 16 gauge needle. Bubbling could be observed during the course of the reaction. After stirring for 30 minutes, analysis of the THF layer showed complete conversion of the BF ₃ salt xv. The aqueous layer also contained some white solids. The reaction mixture was transferred to a separatory funnel and the flask was washed with ~2 mL THF. The layers were separated and the slightly cloudy THF layer was washed with 17.6 mL of 20% NaCl. The THF layer was transferred to a round bottom flask and used directly in the TBS deprotection step.

TBS deprotection of boronic acid

Dilute the THF solution of boronic acid xv with 17.6 mL acetonitrile (2:1 THF/acetonitrile). While stirring, the HBr solution was added at rt. The slight cloudiness of the THF/acetonitrile solution cleared during the addition of the sulfuric acid solution. The homogenous solution was stirred at rt for 14 h. The reaction was quenched by the addition of 31.2 mL of 0.15 M K ₂ CO ₃ solution (1.2 equiv relative to sulfuric acid). The reaction was aged for 5 minutes at rt and transferred to a separatory funnel. The flask was rinsed with ~1 mL of H ₂ O and 30 ml of toluene. The layers were separated and the aqueous layer was washed with an additional 30 mL toluene. A slight emulsion formed this time. The emulsion was allowed to dissipate by standing at rt for ~2 h. The layers were separated and the aqueous layer was analyzed by NMR in D ₂ O with DMAC as an internal standard. The combined organic layers were washed with 30 mL H ₂ O. The aqueous layer contained 5.53% of triol boronic acid. TBSOH was recovered in 98.7% yield in the combined organic layers. The aqueous layer of triol boronic acid xi was taken to the subsequent Suzuki coupling.

EXAMPLE 1

Process for preparing beta-lactam compound 1 Finkelstein reaction

In a flask, 3-chloro-4'-fluoropropriophenone, sodium iodide and acetone were charged. The solution was heated to reflux and aged for 2 to 3 hours. After the reaction is

complete, the batch is cooled to room temperature. Water (12 vol) is added slowly to quench reaction and to crystallize the product. The batch is aged two hours then filtered. The cake is washed with water (3 vol) and dried under vacuum at 45 ⁰ C to a final target of less than 0.2 wt % water.

OAB reduction

In a 5OL flask were combined the borane and OAB at room temperature. To this solution was added the keto-iodo as a solution in THF over 2 to 3 hours. The reaction was aged 30 minutes or until no starting material remained. The reaction is quenched into a flask containing IN HCl at 10°C so as to keep temperature below 18 ⁰ C. The batch is aged 1 to 2 hours or until the gas evolution is finished. MTBE is added and the aqueous layer is cut away. The MTBE layer is then washed with water.

After assaying the batch, the solution is concentrated to ~ 200 g product/L and then solvent switched to n-heptane. The final batch volume target is ~5 L/kg. The solids are cooled to 0°C over ca. 3hrs. The batch is filtered and the solids are washed with cold (0 to 5°C) heptane (1 to 3 vol) then dried under vacuum at 45°C.

TBS protection

In a flask were combined TBSCl, NaI, Hunig's base and acetonitrile in that order. After aging this solution for at least 15 minutes, the iodo alcohol solids are added. The heterogeneous mixture was heated to 60 ⁰ C and aged until the reaction is complete. After the reaction is complete, the batch is cooled to 20 to 25°C. Water (3 vol) and the n-heptane are added. The aqueous layer is cut away and the organic layer is then washed successively with

10% sodium bisulfite and water (6vol). The organic (heptane) layer is concentrated under vacuum at less than 4O ⁰ C to afford the product as a 95 wt % oil.

Amide formation

Acylation of Meldrum's acid:

A 50 L, 3 neck round bottom flask, equipped with a mechanical stirrer, a reflux condenser, a nitrogen inlet, an addition funnel, and a thermocouple probe, was charged with

Meldrum's acid (1.08 kg) and dry DMF (11.0 L, KF = 100 ppm). The resulting solution was cooled to 2°C and DMAP (1.75 kg) was added. The resulting suspension was stirred at 0°C for

40 minutes until most of the solids dissolved.

A solution of 4-bromobenzoyl chloride (1.37 kg) in dry DMF (1.8 L + 0.3 L rinse) was added over one hour while maintaining the batch temperature between -3°C and +2°C

(exothermic). The resulting yellow slurry was aged at O ⁰ C for 30 minutes before allowed to warm to 20°C and aged for one hour (may be aged overnight). The complete consumption of the acid chloride was confirmed by HPLC.

Amidation:

4-Iodoaniline (1.50 kg) was added in one portion, followed by the addition of trifluoroacetic acid (TFA, 925 mL) over 10 min (exothermic). The resulting slurry was gradually (over 30 to 60 minutes) heated to 60 ⁰ C during which a mild gas evolution was observed. The slurry was aged at 6O ⁰ C for 3.5 h to give a homogeneous solution.

After the reaction is complete, water (4.8 L) was added over 20 min while maintaining the batch temperature between 57 and 60 ⁰ C. A second water charge (1.7 L) was performed over 1 hour while maintaining the batch temperature between 57-60 ⁰ C.

The resulting slurry was aged at 57 to 60 ⁰ C for 1 hour, then cooled to 20 ⁰ C over 3 hours. After aging for one hour, the product was collected by filtration. The wet cake was

sequentially washed with 2: 1 DMF/H ₂ O (1.5 vol; displacement) and water (3 vol split between two equal displacement washes and 3 vol as single slurry wash). The cake was then dried under vacuum at 50°C.

Alkylation

In a flask was dissolved the ketoamide in NMP (4 vol). The flask was placed in a water bath. To the solution was added potassium-tert-butoxide (exothermic). Aged 15 to 30 minutes at ca. 20°C then added over one hour to a solution of O-TBS iodo and NMP (1 vol) at 5O ⁰ C. The reaction was aged for 8 to 15 hours.

After the reaction is complete, the batch is cooled to room temperature and quenched with a 5% NaCl solution (5 vol). The product is extracted with MTBE. The organic layer is then washed 3x with a 5% NaCl solution (5 vol each) in order to completely remove NMP. A Darco treatment (10 to 30 wt% activated carbon) is performed and the waste cake is washed with MTBE. The organic layer is concentrated down to ca. 1.1 volumes relative to final product. Heptane (0.5 vol) is then added. Crystals start to form and a nice seed bed is obtained. Then , triethylamine (5mol % relative to product) is added to drive the equilibrium to undesired diastereomer.

The remaining heptane (4 vol) is then added over 2 to 4 hours. The crystallization is aged for 8 hours (may be held overnight), then cooled to 0°C and aged (typically 3 hours or longer) to achieve the desired supernatant concentration (loss of 5% or less). The solids are filtered and washed with a cold (0 to 5°C) 10%MTBE/heptane solution (2 vol of solution). The solid is dried under vacuum at 35 to 45°C.

Process Description

Catalyst formation: A round bottom flask was charged with Ru-dimer and the ligand and purged with N2 several times. Toluene (112 mL) was then added, followed by neat Et3N. The resulting mixture was heated to 40°C for 1 hour, cooled to 33°C and treated with a premade solution of the starting material in PhCH3 (1 12mL). After stirring for -15 min, neat formic acid was added over 10-12 hours at 33°C, followed by additional aging for 10-12 hours at this temperature. Once the reaction was judged complete, the reaction mixture was solvent switched to iPA to bring the final volume to ~7mL/g wrt product assay, seeded with authentic sample, aged for 10-12 hours at RT and treated with H2O (3 mL/g) as the anti solvent over 1 hour. After additional aging at 0°C for 2 hours, the resulting slurry was then filtered and the wet cake was washed with cold 1 : 1 iPA:H2O (3-4 mL/g). Typical yield: 86-89%.

1. Pre-formed catalyst procedure

Et ₃ N, HCO ₂ H, PhCH ₃ , 30-33 ⁰ C

To a solution of the keto amide in dry toluene, purged of oxygen via nitrogen pressure purges, is added the ruthenium catalyst all at once as a solid at 20 to 25°C. The mixture is again purged using nitrogen pressure. Triethylamine (KF= <500 ppm) is added and the batch is warmed to 30 to 33 ⁰ C. Neat formic acid (KF= <1.7wt %) is then charged at a uniform rate over 8 hours. The reaction mixture is aged at 30 to 33 ⁰ C for an additional 15 hours.

Once the reaction is judged complete, the mixture is concentrated and solvent switched to isopropyl alcohol, while keeping the batch temperature below 3O ⁰ C (typically 25-

28°C). The final batch concentration target is ~6 L/kg product (ca. 160 g/L) and the final amount of toluene should be <0.1 wt% wrt iPA or <2 mol% wrt product.

The batch is warmed to 36 to 4O ⁰ C briefly (45 min) in order to dissolve any product solids, then cooled to 25°C and seeded (2.2 gms; 0.1 wt %). The batch is aged for 10 hours at 20 to 25 ⁰ C and water (3 volumes) is added over one hour. After cooling to 0 to 5°C, the batch is aged two hours and filtered. The cake is washed with four volumes of a cold (<5°C) 1 : 1 isopropyl alcohol: water mixture. The wet cake is dried with a stream of N ₂ under reduced pressure at RT for 2 hours, followed by heating with a maximum jacket temperature of 60 ⁰ C. The hydroxy amide product is typically afforded at 86 to 89% yield.

B-lactam cyclization procedure

Process Description The hydroxy amide (1.995 physical kg; 1.915 assay kgs total hydroxy amide) is dissolved in toluene and concentrated to remove residual iPA and H2O. The solution is brought to a total volume of 8mL/g (16 L) with respect to the total amount of hydroxy amide. The solution is then cooled to -15 ⁰ C. Mesyl chloride (230 mL, 1.1 eq) is added in one shot. Triethyl amine (415 mL, 1.1 eq) is then added, while maintaining the temperature below -5 ⁰ C. The mixture is aged for 1 hour, and then checked by NMR and HPLC to ensure complete formation of the mesylate.

The aqueous KOH solution (2 L, 1 vol) is then added, maintaining the temperature below O ⁰ C. The biphasic mixture is then brought to O ⁰ C. The phase transfer catalyst (6.25 g) is added in one shot as a solution in water (10 mL total volume / g PTC, 63 mL). The biphasic mixture is aged at O ⁰ C for one to four hours until complete conversion of the mesylate is obtained.

Once complete conversion of the mesylate is obtained, the reaction is diluted with 1 vol (2L) of water. The phases are then cut. The organics are then washed with 2 vol (4L) IM

H ₂ SO ₄ , twice with 2 vol H ₂ O, and 2 vol brine. The product solution is then assayed. After assay, the product solution is concentrated to 5 ml/g product, solvent switched to isopropyl alcohol, then diluted with iPA to a total volume of lOmL/g product (18 L). The slurry is then heated to 6O ⁰ C to obtain a solution. The yellow solution is then cooled to 5O ⁰ C and seeded with 1% bromo-iodo 2-azetidinone. This slurry is aged for 2 hours at 5O ⁰ C, and then cooled to 47 ⁰ C over 1 hr, and then cooled to 44 ⁰ C over 30 min. The slurry can then be cooled quickly to RT. Water (1 vol, 1.8 L) is then added over 2 hours. The slurry is then cooled and held at O ⁰ C for 2 hours. The slurry is then filtered and washed with 3 vol (5.4 L) cold (< 5°C) 10:1 iPA/H ₂ O. The cake is then dried under vacuum with a maximum jacket temperature of 35 ⁰ C. Overall isolated yield is expected at about 93 to 95%.

EXAMPLE 2

Step A: The 9-BBN solution, which is commercially available, (0.45M, 24OmL) was cooled to O ⁰ C at which time a slurry formed. N-allyl methylsulfonamide (11.95g) (which is commercially available) was added neat all at once and a 6mL (0.5mL/g) THF wash was used as a rinse. The mixture was then warmed to RT and the reaction was typically completed by NMR after 1 hour, but has been shown to be stable up to 14 hours. The resulting solution was quenched with water (24mL) over 30 min and the quenched solution was then degassed with bubbling N ₂ for 1 hour before using this adduct solution in the subsequent Suzuki reaction.

Step B: Solid I-Br-β lactam (1) (25.74g) and K ₂ CO ₃ (10.14g) were charged to a 3 neck 1-

L flask equipped with an addition funnel and overhead stirrer. The solids were then dissolved in PhCH ₃ (13OmL) and H ₂ O (39mL) and the reaction vessel was degassed 3x with N ₂ /vac. In a separate vessel, the catalyst solution was prepared by dissolving allylpalladium(II) chloride dimer (6.71mg) and triphenyl phosphine (28.87mg) in PhCH ₃ (6.7mL, lmL/mg Pd dimer) under an N ₂ atmosphere. This catalyst solution was the charged to the biphasic lactam mixture in one shot. The addition syringe was then washed with 1.ImL (O.lmL/g Pd dimer) PhCH ₃ and the resulting mixture was then warmed to 55 ⁰ C. Step C: The adduct solution (15OmL) was then added over 30 min, maintaining the temperature above 45 ⁰ C. The reaction was then heated at 55 ⁰ C for 3-4 hours, at which a complete conversion was typically observed. Upon completion of reaction, the reaction mixture was rapidly cooled to 2O ⁰ C.

Step D: The phases were separated, and the organic layer was subsequently washed with

0.5M NaOH (2x73mL) and with water (73mL). The resulting organic layer was then concentrated to 100 mL of total volume and solvent switched to PhCH ₃ . The entire aqueous work up must be performed under air-free conditions. The reaction gives 86-88% assay yield.

Preparation of Compound (3). To the toluene solution of aryl bromide (2) (70.3 g, 100.0 mmol, 730 mL total) was added the potassium trifluoroborate salt (4) (31.9 g, 120 mmol), K ₂ CO ₃ (27.6 g, 200 mmol), PdCl ₂ (dtbpf) (260 mg, 0.4 mmol) and H ₂ O (140 mL) under N ₂ atmosphere. The resulting biphasic mixture was rigorously purged with N ₂ (3x). The mixture was heated to 7O ⁰ C and aged for 7 h. After confirming that all of the material was consumed by HPLC, the mixture was then cooled to room temperature and the aqueous layer was discarded. The organic layer was subsequently washed with a 7% solution OfNaHCO ₃ and 15% solution of NaCl. The layers were cut and the organic portion was used.

Deprotection step via compound 3. A crude solution of compound 3 (10.0 g assay) was concentrated and solvent switched to MeCN (6 vol). Ecosorb C947 (3.0 g, 30 wt%), trithiocyanuric acid (0.50 g, 5 wt%) and 0.6 M H ₂ SO ₄ (7.0 mL, 0.7 vol) were added, and the resulting mixture was stirred at RT for 40 min. The mixture was then distilled (130-140 Torr, 35°C) at the constant volume using 15 wt% H ₂ O/MeCN (70 mL, 7 vol) to remove acetone. The reaction was stirred at 35 ⁰ C for 2-4 h until 99% of the TBS-ether was cleaved. The reaction was filtered, and the filtered cake was rinsed with 15 wt% H ₂ O/MeCN (40 mL, 4 vol). The combined filtrate was diluted with 5 mL toluene and washed with 5% Na ₂ CO ₃ aq (50 mL) and 15% NaCl aq (50 mL).

Compound A. Crude solution of Compound A was solvent switched to MeCN and azeotropically dried with MeCN [Karl Fischer titration Of H ₂ O < 250 ppm (30 wt%)]. The solution was filtered to remove precipitated inorganic salt. The volume of filtrate was adjusted to 3 vol of MeCN and the solution was heated to 60°C. The clear solution was cooled to 45°C. Upon reaching 45°C, the solution was seeded with Compound A (0.5 wt%). Toluene (10 Vol) was charged over 4h at 45°C. The slurry was cooled down to -10 °C at 15 °C/hour. After aging at -10 ⁰ C for 3 h, the slurry solution was filtered and the wet-cake was washed with 5v of

MeCN/Tol. (3:10, displacement). Slurry washed with 5v MeCN/Tol. (3: 10) followed by 5v of toluene slurry wash. Solids were dried under vacuum and nitrogen atmosphere at 45°C over 16h to give the final product in 95-97% yield.

EXAMPLE 2A (ALTERNATE METHOD)

Step A: The 9-BBN solution, which is commercially available, (0.45M, 24OmL) was cooled to O ⁰ C at which time a slurry formed. N-allyl methylsulfonamide (1 1.95g) (which is commercially available) was added neat all at once and a 6mL (0.5mL/g) THF wash was used as a rinse. The mixture was then warmed to RT and the reaction was typically completed by NMR after 1 hour, but has been shown to be stable up to 14 hours. The resulting solution was quenched

with water (24mL) over 30 min and the quenched solution was then degassed with bubbling N ₂ for 1 hour before using this adduct solution in the subsequent Suzuki reaction.

Step B: Solid I-Br-β lactam (1) (25.74g) and K ₂ CO ₃ (10.14g) were charged to a 3 neck 1- L flask equipped with an addition funnel and overhead stirrer. The solids were then dissolved in PhCH ₃ (13OmL) and H ₂ O (39mL) and the reaction vessel was degassed 3x with N ₂ /vac. In a separate vessel, the catalyst solution was prepared by dissolving allylpalladium(II) chloride dimer (6.7 lmg) and triphenyl phosphine (28.87mg) in PhCH ₃ (6.7mL, lmL/mg Pd dimer) under an N ₂ atmosphere. This catalyst solution was the charged to the biphasic lactam mixture in one shot. The addition syringe was then washed with 1.ImL (O.lmL/g Pd dimer) PhCH ₃ and the resulting mixture was then warmed to 55 ⁰ C.

Step C: The adduct solution (15OmL) was then added over 30 min, maintaining the temperature above 45°C. The reaction was then heated at 55 ⁰ C for 3-4 hours, at which a complete conversion was typically observed. Upon completion of reaction, the reaction mixture was rapidly cooled to 2O ⁰ C.

Step D: The phases were separated, and the organic layer was subsequently washed with

0.5M NaOH (2x73mL) and with water (73mL). The resulting organic layer was then concentrated to 100 mL of total volume and solvent switched to PhCH ₃ . The entire aqueous work up must be performed under air-free conditions. The reaction gives 86-88% assay yield.

Preparation of Compound (11). To the crude toluene: THF solution of aryl bromide (2) (7.7 g, 10.95 mmol) was added a solution of allylpalladium (II) chloride dimer (2 mg) and triorthotolylphosphine (83 mg) at RT under N ₂ [NOTE: This additional catalyst may not be necessary if sufficient amount of Pd catalyst from the previous step is already present in the crude solution of aryl bromide (2)]. The resulting mixture was then aged for Ih and then treated with an aqueous solution of xvi (25.6g, 8.4wt%, 13.14 mmol), containing 1.5 mol equivalents of K ₂ CO ₃ (2.27g). The resulting biphasic mixture was then heated to 100 ⁰ C in a sealed vessel and aged for 4 hours at which a complete conversion of starting material was typically observed. Upon cooling to RT, 2-propanol (15.4 mL) and H ₂ O (7.7 mL) were added and the resulting mixture was agitated and allowed to settled for 1 h. The organic layer was then separated and assayed to contain 92% yield of the desired product. The organic layer was then solvent switched to iPA to bring the final concentration of 3 vol and then diluted with equal volume of heptane. The resulting mixture was then heated to 35 ⁰ C, treated with AcOH (0.2 vol) and seeded with authentic sample (1%). The remaining heptane antisolvent (7 vol) was then added over 6-12 hours and the resulting suspension was aged at RT for 4h and then at O ⁰ C for 6-10 hours. The

slurry was then filtered and the wetcake was washed with 3: 1 heptane:iPA and dried under N ₂ to give the desired compound in 6.9 g or 84.6 % isolated yield.

Deprotection step via compound 11. To a mixture of iPA (3 vol) and IM aqueous H ₂ SO ₄ (3 vol) was added compound (11) all at once as a solid. The resulting mixture was stirred at 27 ⁰ C for 7-8h, at which a complete cleavage of TBS-ether was typically observed. The reaction mixture was then diluted with 2-MeTHF (5 vol) and washed with 15 wt% aqueous NaCl, followed by 6wt% aqueous NaHCO ₃ solution and 15 wt% aqueous NaCl solution to afford the crude solution of Compound A in 94-95% assay yield.

Compound A. Crude solution of Compound A was solvent switched to MeCN and azeotropically dried with MeCN [Karl Fischer titration of H ₂ O < 250 ppm (30 wt%)]. The solution was filtered to remove precipitated inorganic salt. The volume of filtrate was adjusted to 3 vol of MeCN and the solution was heated to 60 ⁰ C. The clear solution was cooled to 45 °C. Upon reaching 45°C, the solution was seeded with Compound A (0.5 wt%). Toluene (10 Vol) was charged over 4h at 45°C. The slurry was cooled down to -10°C at 15°C/hour. After aging at -10°C for 3 h, the slurry solution was filtered and the wet-cake was washed with 5v of MeCN/Tol. (3:10, displacement). Slurry washed with 5v MeCN/Tol. (3:10) followed by 5v of toluene slurry wash. Solids were dried under vacuum and nitrogen atmosphere at 45°C over 16h to give the final product in 95-97% yield.

EXAMPLE 3

Preparation of Compound 6 using Iodo Sonogashira

Add lactam 1 (40 kg) and copper iodide (936 g) to the vessel via the manway. Re-inert vessel, charge DMF (264 kg), stir suspension and cool to 1O ⁰ C. Re-inert the vessel then charge triethylamine (13.65 kg) using a small diaphragm pump. Rinse the pump with DMF (2L). Re- inert with pressure purge cycle x three. Charge dichloro bis(triphenylphosphine)palladium (1.08 kg) to the vessel via the manway in one portion. Re-inert vessel. In a separate vessel, mix propargylsulfonamide (8.98 kg) and DMF (37 kg) at 20 ⁰ C. Re-inert with pressure purge cycle x

three. Using pressure, transfer the sulphonamide/DMF to the vessel over 1-2 hours, allowing the batch temperature to increase from 10 to 25°C. If complete by LC, charge water (200 kg) and MTBE (149 kg) and stir for at minimum 15-30 minutes. Stop the stirrer and allow the layers to settle. Transfer the aqueous layer to a tared plastic lined drum. Charge EDTA disodium salt aq solution (5%, 200 kg) to the vessel and stir the batch for a minimum of 5-10 minutes. Stop the stirrer and allowed the layers to settle. Transfer the aqueous layer to a tared plastic lined drum. Charge water (200 kg) to the vessel and stir the batch for 5 minutes. Stop the stirrer and allow the layers to settle. Transfer the aqueous layer to a tared plastic lined drum. Transfer the organic phase to a clean vessel via an in-line filter and distil the contents to 60 L. Charge acetonitrile (270 kg) and concentrate to 160 - 200 L. Transfer the batch to a tared steel drum and store in cold room. Assay yield: 38.3 kg, 95%

EXAMPLE 4

Preparation of Compound 8 using Bromo Sonogashira

To a clean, inerted vessel, add the Acetic acid 2-acetoxymethyl-2-hydroxy-but-3- ynyl ester (12.05 kg) via the manway. Reinert the vessel, charge acetonitrile (10 VoIs, 95 kg) and warm to 30 °C. Using residual vacuum, charge chlorotrimethylsilane (7.14 kg) to the vessel, followed by dimethylamino pyridine (200 g) via the manway. Reinert the vessel and using residual vacuum, charge diisopropylamine (16.6 kg) over 20 minutes keeping the internal temperature between 35 and 4O ⁰ C. At the end of addition age for 10 minutes, cooling to 25 ⁰ C,

Transfer the batch to an oyster filter fitted with a polypropylene cloth. Pump the liquors containing the OTMS-alkyne to a clean plastic lined drum. Charge an acetonitrile wash (20 kg) to the vessel and stir for 5 minutes. Transfer to the filter and combine the wash with the OTMS- alkyne solution. To a separate clean, inerted vessel, containing the starting bromide in acetonitrile (36 kg bromide, 105 kg MeCN solution), charge the OTMS-alkyne solution from the drum. Rinse lines with acetonitrile (5 L). Charge diisopropylamine (11 kg) then extensively degas the mixture (> 30 min) using vacuum and sub-surface nitrogen bubbling. Add the bis(tri-t- butylphosphine) palladium(O) (281 g) to the vessel via the manway. Extensively degas the mixture (> 30 min) using vacuum and sub-surface nitrogen bubbling. Warm the batch to 33°C and age the reaction for 16 hours. At the end of this age remove sample for analysis by HPLC. Charge water (200 kg), MTBE (215 kg) and IPAc (63 kg) via the solvent addition line then acetic acid (9.2 kg). Stir the batch for at minimum 15-30 minutes. Stop the stirrer and allow the layers to settle. Check pH of aqueous phase is acidic. Transfer the aqueous layer to a tared plastic lined drum. Charge a 2 wt% NaCl aq solution (100 kg) to the vessel and stir the batch for a minimum of 5-10 minutes. Stop the stirrer and allowed the layers to settle. Transfer the organic to a clean vessel via an in-line filter and distill the contents to a volume of approximately 100 L. (batch temperature < 25°C). Add ethanol (250 kg). Assay yield: 47.7 kg, 103%

EXAMPLE 5 TMS Removal

Using partial vacuum, charge bromosonogashira solution in ethanol (19.0 kg active) to 400 L vessel and cool to 1O ⁰ C. Charge 2N HCl (1.5 L) to the vessel RE-1 101, adjusting the pH to < 1. Stir the batch at ~ 10 °C until the deprotection in complete by HPLC. Using residual vacuum, charge aq 2N NaOH to the batch via the reagent addition line, adjusting the pH of the batch to pH 6-7. Cool to 0 ⁰ C and stir for at minimum 30 min., transfer to clean tare drum via a 10 μm in-line filter. The solution was then charged to a clean 180 L vessel and

passed through the CUNO carbon filtration system (3-5 mL/min), containing 7 kg of R55SP carbon in cartridge form. The filter was washed with 15 kg EtOH. HPLC result = 12.9 kg Reaction yield = 82%

Hydrogenation

Inert 180 L hydrogenation vessel with N ₂ using a single, manual purge and vent sequence. Evacuate vessel >900mBar of vacuum then refill with N ₂ using manual purge operation. Pause this operation at >3.9Bar. Charge diol solution in ethanol (14.4 kg in 1 10 L EtOH) to the vessel and reinsert with vacuum/purge sequence. Suspend palladium on carbon (type 91 (Pearlman's), 20wt% dry basis, 50% wet) (2.59 kg) in ethanol (4 L) and charge to the vessel. Reinert and degas the reaction mixture. Stop the stirrer and start the hydrogen feed operation with a set pressure of 40 psi (-2.75 Bar). Restart the stirrer and allow the batch to react at 40 psi for 6 h .

Stop the hydrogen feed operation and perform a process vapours vent operation, then inert vessel RlO with N ₂ . The mixture was then filtered through an oyster filter (containing 6.2 kg of celite) and an Osmonix 0.1 μm cartridge to a nitrogen-purged, plastic-lined, drum. An ethanol wash (30 L) was charged to the filter via the vessel and was combined with the product ethanol solution.

Compound A- Final MMC Crystallization

Charge the diacetate solution in ethanol (14.7 kg) to an inerted 160 L vessel using residual vacuum. Concentrate under reduced pressure to approx 60 L, maintaining batch temperature below 40 degrees. Charge Ethanol (79 kg) using residual vacuum and concentrate to approx 60 L. Transfer batch to a clean 400 L vessel through 1 μm in-line filter. Charge ethanol (10 kg) and methanol (25 kg) to the 160 L vessel used for distillation and transfer through the filter to the dry diacetate solution in the 200 L vessel.

Cool solution to 10-15 degrees and charge solid TMSOK (0.39 kg) as a single charge. Maintain batch at approx 10-15 degrees and monitor reaction by HPLC until complete. Charge additional TMOSK as deemed necessary. Slowly charge 2N HCl to adjust the pH to ~ 6 as determined by pH meter. Charge DCM (5 vols, 100 kg) and water (5 vols, 75 kg) to the mixture. Stir for 10 mins and allow to settle. Separate lower organic phase and assay upper aqueous by HPLC. Transfer organic phase to a clean 160 L vessel and charge TMT resin (0.97 kg). Stir suspension at low rpm and monitor liquors for Pd levels (expected <10 ppm in solution) for at least 5 hours.

Transfer the contents of vessel via an oyster filter (with polypropylene cloth) to a clean drum. Rinse the vessel with 25 kg ethanol and discharge wash to drum via oyster filter to wash resin cake. Set the condensers to cold for distillation. Transfer contents of drum via 1 μm inline filter to a clean 160 L vessel and concentrate organic extracts to 60 L. Charge acetonitrile (145 kg) via in-line filter cartridge, while continuing the distillation maintaining batch temperature 35- 45 degrees, to a final volume of 30 L.

Silica plug procedure Pack a large oyster filter with 40 kg of silica gel and wet with 100 L of acetonitrile. Allow solvent to drain to the top of the cake then apply concentrated batch in MeCN to top of silica plug. Elute with 4:1 MeCN:THF (350 L), collecting fractions (4 x 20 L, 1 x 200L, 5 x 20 L). Analyse fractions by LC and pool all those containing a significant quantity of

product. Transfer fractions to a clean vessel via 1 μm inline filter and distil to 42 L (T = 40 ⁰ C). Check Karl fisher titre (less than 0.3%) and proton nmr for THF levels. Repeat the distillation with acetonitrile as necessary. Heat the batch to 45°C and seed with approx. 1% w/w Compound A. Hold at 45 degrees for at least 1 hour and ensure seeds persist. Hold at 30-40 degrees until crystallisation is well initiated (typically up to 6 hours). Allow to cool and stir at 20-30 degrees at least 12 hours, monitor liquors for product concentration by HPLC assay. Cool batch to 8 ⁰ C and charge IPAc (18 kg) to vessel to give a ratio of 5:3 acetonitrile : IPAc v:v , over at least 30 mins. Cool slurry to 3 ⁰ C over 16 h and monitor liquor concentration by HPLC. Transfer batch to oyster filter (fitted with polypropylene cloth) and pump the mother liquors to a clean drum. Charge acetnonitrile (23.1 kg) and IPAc (15.2 kgs) to vessel as a wash, then transfer to filter and combine with liquors in drum. Connect the filter to the process vent and apply nitrogen sweep for 15 h. Transfer to oven and dry under vacuum at 45°C for 24 h. 8.31 kg of solid was obtained (64% yield).

While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for any of the indications for the active agent used in the instant invention as indicated above. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.