FILED OF THE INVENTION : This invention relates to a process for manufacturing R- (R*, R*)]-2- (4-fluorophenyl)-B, D-dihydroxv-5- (I-methylethyl)-3- phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt, atorvastatin and the novel intermediates produced during the course of manufacture. The said compound is useful as inhibitors of the enzyme HMG-CoA reductase and are thus useful as hxpolipidemic and hypocholesterolemic agents.

BACKGROUND OF THE INVENTION US Patent. No. 4, 681, 893, discloses a route using resolution of the racemic product using R (+) a-methyl benzyl amine. US patent No. 5, 003, 080 discloses a synthetic route for the preparation of the chiral form of atorvastatin. The patent discloses a process for the preparation of the lactone or its salts by coupling an ester of (4R)-6- (2-aminoethyl)-2, 2-dialkyl-1, 3-dioxane-3-acetate with 4-fluoro-a- [2- methyl-1-oxopropyl] y-oxo-N-xZiphenylbenzenebutaneamide followed by deprotection and hydrolysis to give the product. The product suffers from the fact ozonolysis is required as one of the steps for the synthesis of the amino ketal intermediate, which is hazardous for large scale preparation. The patent describes an alternate <BR> <BR> <BR> <BR> <BR> procedure wherein 4-fluoro-α-[2-methyl-1-oxopropyl]γ-oxo-N-ß- diphenvlbenzenebutaneamide is reacted with 3-amino propinaldehyde acetal followed by conventional procedures to give atorvastatin

US patent No. 5,216,174, No. 5,097,045, No. 5,103,024, No.

5. 124, 482, No. 5. 149. 837, No. 5. 155. 251, No. 5,216,174, No.

5, 245, 047, No. 5, 273, 995, No. 5. 248. 793, and No. 5, 397, 792 describes various minor modifications in the procedure for the preparation of atorvastatin calcium salt.

Synthesis of esters of (4R)-6-(2-aminoethyl)-2,2-dialkyl-1, 3- dioxane-3-acetate is an important part of the preparation of atorvastatin calcium. US patent 5. 155, 251 also discloses a synthetic route for the synthesis of (3R) 4-cano-3-hvdrox butsric acid esters from (S)-3-hydroxa butyrolactone. which in turn is sythesized trom a suitable carbohydrate substrate.

Other patents like 5,292, 939, 5, 319, 110 and 5, 374, 773 discloses iscloses the preparation of 3,4-dihydroxybutyric acid. However, isolation of this highly water soluble compound or its lactone is not attempted.

Another multi step procedure starting from (S)-malic acid (J. org. Chem, 1981, 46, 4319) is reported. Esters of (S)-malic acid have also been used (Chem. Lett., 1984, 1389) for the synthesis of the hydroxy lactone involving BA : S-NaBH4 reduction. followed by lactonization. While a six step procedure from D-isoascorbic acid is also reported (Syn., 1987, 570) but this process requires a silica gel chromatographic separation of the diasteromic mixtures.

Optical resolution of the racemic hydroxvlactones using lipase . is disclosed in US patent 5, 084. 392 but this mcthod suûers from poor enatiomeric excess and loss of the other active isomer Thus. these prior art procedures involves cumbersome reaction conditions or expensive starting materials, reagents which are difficult to handle or hazardous for scale up. coupled with a multi step procedure which results in poor overall yield.

The object of the present invention is to disclose an inexpensive, simple and salable route for the synthesis of atonastatin.

To achieve the said objective, this invention provides a process involves the synthesis of compound R- (R*, R*)]-2- (4-fluorophenvl)- B, D-dihydroxnt-5-(1-methylethyl)-3-phenyl4-[(phenylamino) carbonyll-lH-pyrrole-l-heptanoic acid hemi calcium salt (formula XXII) comprising : a) reacting of compound of formula XVII with a compound of structure XIV in a non-polar solvent to give an intermediate of structure XXI, b) deprotection, followed bv hydrolysis of the compound of structure XXI followed by cyciization inethyl acetate to give the lactone, c) treating the lactone with NH3 to give the ammonium salt, and d) reacting the ammonium salt with CaC12 gives the corresponding calcium salt of formula XXII.

The non-polar solvent in step (a) is selected from xylene or acetonitrile.

The de-protecting agent in step (b) is selected from moist silica or PTSA.

The ammonium salt in step (c) is prepared by treating with aqueous NH3 or metahanolic NH3 or by passing NH3 gas to the compound taken in EtOAc, MeOH. isopropyl alcohol. diisopropvl ether or cyclohexane The compound of formula XVII is prepared bv :

a) reacting meldrum acid with isobutyryl chloride in the presence of base in CH2CI2 to give an intermediate of formula XVIII, b) reacting the intermediate of formula XVIII with base in CH2Cl2 to give an intermediate of formula XIX, c) reacting the intermediate of formula XIX with benzaldehyde in the presence of base and toluene to give a compound of formula XX, and d) reacting of compound of formula XX with 4- fluorobenzaldehyde with a metal cyanide and polar solvent in the presence of a base to give the compound of formula XVII.

In step (b) the base is selected from aniline, pyrindine, triethylamine, dimethylaniline, diethylisopropylamine.

In step (c) the base is selected from piperidine, pyrrolidine or diiospropylethlamine.

In the metal cyanide in step (d) is selected from NaCN, CuCN, KCN, AgCN or tetraalkyl ammonium cyanide The polar solvent in step (d) is selected from DMSO. DMF, CH3CN.

The base in step (d) is selected from diisopropylethyl amine, 1- methylimidazole, pyridine The compound of (4R)-methyl 6- (2-aminoethyl)-2, 2-dimethyl- 1. 3-dioxane-3-acetate (Formula XIV) used in step (a) is prepared by : a) reacting a compound ofibrmuia II with meldrum's acid followed by hydrolysis to give a compound of formula 111, b) reacting a compound of formula III with thionvl chloride to give an acid chloride which is then reacted with a meldrum's acid followed by alcoholosis to give a compound of formula IV,

c) reducing a compound of formula IV to give a compound of formula V, d) reducing a compound of formula V to give a dihvdros, ester of formula VI. e) converting a compound of formula VI to give a compound of formula VII, tu ammonclvsis of a compound of formula VII to give a compound of formula VIII, g) alternatively reacting thé compound of formula VII with phthalimide salt to give a compound of formula XVI, h) reacting) a compound of formula XVI with hydrazine hydrate to give the compound of formula VIII. and :) whcrc Rs = ter-butyl in formula VIII, formula XIV is obtained Rs in step (a) is chosen from. OMs, OTs. Br, Cl or I.

The alcohol in step (b) is chosen from methanol. ethanol. isopropanol, benzyl alcohol.

The reducing agent in step (c) is baker's yeast or a reagent of formula R*2Bcl where R*2 is chosen from (-) a spinelle or (+)-a-pinene.

The reducing agent in step (d) is chosen from dimethoxyethylboron or triethoxboron and sodium borohydride.

The protecting group for conversion in step (e) is chosen from acetone. benzophenone, acetophenone or benzaldehyde.

The reagent for ammonolysis in step (f) is chosen from aqueous NH. methanolic NHR or gaseous NHR in a solvent chosen from EtOAc. cyclohexane. methanol. isopropanol or diisopropyl ether Thé phthalimide salt in step (g) is chosen from potassium. sodium or lithium.

The compound of (4R)-methyl 6- (2-aminoethyl)-2, 2-dimethyl- 1, 3-dioxane-3-acetate (Formula XIV) used in step (a) is prepared by : a) reacting a compound of formula II with meldrum's acid followed by hydrolysis to give a compound of formula IX, b) reacting a compound of formula IX with tert-butyl acetate with a base at-30 to-80°C to give a compound of formula X, c) reducing a compound of formula X to give a compound of formula XI, d) reducing a compound of formula XI to give a dihydroxy ester of formula XII, e) Converting a compound of formula XII to give a compound of formula XIII, ammonoiysis of a compound ot tormula XIII to give a compound of formula XIV, g) altemativcly reacting the compound of formula XIII with phthalimide salt to give a compound of formula XV and h) reacting a compound of formula XV with hydrazine hydrate to give the compound of formula VIII R4 in step (a) is chosen from, OMs, OTs, Br, Cl or I.

The reducing agent in step (c) is baker's yeast or a reagent of formula R*2BCI where R*2 is chosen form (-) a pinene or (+)-a- pinène.

The reducing agent in step (d) is chosen from dimethoxyethylboron or triethoxyboron and sodium borohydride.

The protccting group for conversion in step (e) is chosen from acetone, benzophenone. acetophenone or benzaldehyde.

The reagent for ammonolysis in step (t) is chosen from aqueous NH3, methanolic NH3 or gaseous NH3 in a solvent chosen from EtOAc, cyclohexane, methanol, isopropanol or diisopropyi ether The phthalimide salt in step (g) is chosen from potassium, sodium or lithium.

The intermediate compounds of formula XVIII, XIV, XV. VII & whenever prepared by the above process.

The intermediate of formula VM. whcrein Rs is chosen from Cl-Cs alkyl, benzvl, isopropyl, cycloheyl or tert-butll.

The intermediate of formula IX, wherein R4 is chosen from CH2Br, CH2Cl, CH2I, CH2OMs or Cli, Ots.

DETAILED DESCRIPTION OF THE INVENTION The process of the present invention in its first aspect is new, improved, economical, and commercially feasible method for preparing HMG CoA reductase inhibitors of Formula XXII which are useful as inhibitors of the enzyme HMG CoA reductase and are thus useful as hypolipidemic or hypocholesterolemic agents is outlined in Scheme 5.

Structure XXII The synthetic scheme for the synthesis of the amino ester of formula VIII is outlined in scheme I Scheme-1 Thus, a halo acetic acid of formula I, where X = Cl, Br or I is treated with sodium or potassium salt of tritluoromethane sulfonic acid or p-toluenesulfonic acid in the presence of base chosen from Et3N, pyridine, N. N-dimethylaniline. N. N-diisopropyethyl amine. etc.. in a solvent like, CH2Cl2, CH3CN, DMF etc., to give an intermediate which is then converted to an acid chloride by choosing a reagent from thionyl chloride, oxalyl chloride, PCl5 etc in the

presence of a base chosen from EtRN, pyridine, N, N-dimethylaniline, N, N-diisopropylethyl amine. etc., in a solvent like, CH2Cl2, CH3CN, DMF etc., to give a compound of formula II, which is subsequently treated with meldrum's acid in presence of pyridine and CH2CI2 to give an acyl meldrum acid which is hydrolyzed to give a compound of formula III.

A p-keto acid of formula III is then converted to its acid chloride by reacting with a reagent chosen from PCl5, oxalyl chloride, thionyl chloride etc., in the presence of a base chosen from pyridine, Et3N. diisopropylethyl amine, N, N-dimethvlaniline etc., in a solvent chosen from CH2Cl2, CH3CN. DMF etc. to give an acid chloride which is then reacted with meldrum acid as described earlier to give an acyl meldrum acid which on subséquent reaction with an alcohol R50H Where Rs = Ci-Ce alkyl, C3 to C6-cvcloalkyl, benzyl etc., to give an intermediate of formula IV.

The diketo ester compound of formula IV is then reduced either with baker's yeast or with a reagent of formula R*2BCl Where R*2 is chosen from (-a-pinene. (+)-α-pinene, etc., to give a hydroxy keto ester of formula V. A hydroxy ketone ester of Formula V is treated with a borane reagent of formula R210BOCH3 wherein Rl° is a alkyl group of Cl to 3, for example, methoydiethylborane in the absence of air and subsequent treatment with a metal hydride, such as. for example. sodium borohvdride in a solvent such as. for example. methanol, tetrahydrofuran, mixtures thereof and the like at about 0°C. to about -110°C. for about 5 hours followed by subsequent treatment with an acid. such as, for example, glacial acetic acid, and the like to attord a compound of Formula Vf

Preferably, the reaction is carried out with methoxydiethylborane under a nitrogen atmosphere and subsequent treatment with sodium borohydride in a mixture of methanol and tetrahydrofuran at about- 20°C. to about-78°C. for about 5 hours followed by the addition of glacial acetic acid.

A 3, 5-dihydroxy ester of Formula VI is treated with a ketal- forming reagent of R'COR- wherein R1 or R2' is independently from C1 to C3 alkvl, phenvi. benzvl, substituted phenvl etc, for example. a ketal-forming reagent selected from acetone, 2. 2-dimethoxypropane. 2-methoxvpropene. cyclopentanone. cyclohexanone. 1,1-dimethoxycyclopentane, 1,1- dimethoxycyclohexane, and the like or optionally an acetai forming reagent, for example, benzaldehyde, and the like in the presence of an acid, such as, for example, methanesulfonic acid, camphorsulfonic acid, paratoluenesulfonic acid, and the like. in the presence of excess reagent or in an inert solvent, such as, for example, dichloromethane, and the like at about 0°C. to about the reflux temperature of the reagent or solvent to afford a compound of Formula VI wherein R' and R-are as defined above. Preferably, the reaction is carried out with a ketone forming reagent of Formula VII, for example, 2, 2- dimethoxypropane and acetone in the presence of methanesulfonic acid at room temperature.

A compound of formula VII. which is then taken up in a solvent like, methanol, EtOAc, hexane or a mixture of these solvents and is converted to a compound of formula VIII bs treating with gaseous NH ?. or by treating with aqueous Nl14OH solution or methanolic ammonia to give a compound of formula VIII

Optionally a compound of formula XIV can be prepared as described in scheme 2 Sdleme-2 Thus a compound of formula II where. R = CH2Br, CH2Cl, CH2I, CH2OMs, CH2OTs, etc., with meldrum acid in the presence of a base chosen from pyridine, Et3N, N,N-dimethylaniline. N. N- diisopropyicthylaminc etc in CH2Cl2 to given an acyl meldrum acid of fort-nul IX.

The acvl meldrum acid is taken in a solvent selected from hexane. THF. ether. or a mixture of hexane, THF or ether and was cooled to-30 to-800C. A solution of tertiars buhl acetate and a base chosen from n-BuLi. LDA. Lithium pyrrolidide, etc., is added at a temperature between-30 to--80°C to afford the diketo ester compound of formula X.

The diketo ester compound of formula X is then reduced either with baker's veast or with a reagent of formula R*, BCI Where R* is chosen from (-)-a-pinene, (+)- (x-pinene. etc.. to give a hydroxy kcto ester of formula XI. A hydroxy ketone ester of Formula XI is treated with a borane reagent of formula R2l°BOCHR wherein R" is a alkyl group of Cl to 3. for example, methoxvdiethylborane in the absence of air and subsequent treatment with a metal hydride, such as, for example. sodium borohydride in a solvent. such as. for example, methanol, tetrahydroluran. mixtures thereof and the like at about 0°C to about -110°C. for about 5 hours followed by subsequent treatment with an acid, like glacial acetic acid. and the like to afford a compound of Formula XII. Preferably. the reaction is carried out with methoxydiethylborane under a

nitrogen atmosphere and subsequent treatment with sodium borohydride in a mixture of methanol and tetrahydrofuran at about 20'C. to about-78°C. for about 5 hours followed by the addition of glacial acetic acid.

A 3, 5-dihndroxy ester of Formula XII is treated with a ketal- forming reagent of RtCOR2 wherein R1 or R2 is independently from C1 to C3 alkyl, phenyl, benzyl. substituted phenyl etc., for example. a ketal-forming reagent selected from the group consisting of acetone, 2. 2-dimethoxypropane. <BR> <BR> <BR> <BR> <P>2-methoxypropene. cvclopentanone. cyclohexanone. l. I- dimethoxycyclopentane, 1,1-dimethoxyclyclohexane, and the like or optionally an acetal forming reagent, for examle, benzaldehyde, and the like in the presence of an acid, such as methanesulfonic acid. camphorsulfonic acid, paratoluenesulfonic acid. and the like, in the presence of excess reagent or in an inert solvent. such as, for example. dichloromethane. and the like at about 0°C. to about the reflux temperature of the reagent or solvent to attord a compound of Formula XIII wherein R1 and R2 are as defined above. Preferably, the reaction is carried out with a ketone forming reagent, for example.

2, 2-dimethoxypropane and acetone in the presence of methanesulfonic acid at about room temperature.

A compound of formula XIII, which is then taken up in a solvent like. methanol, EtOAc, hexane or a mixture of these solvents and is converted to a compound of Formula XIV by treating with gaseous NH3. or by treating with aqueous NH4OH solution or methanohc ammonia.

Alternativelv. the intermediate of tbrmula VII or XIII can be converted to VIII and XIV respectively as shown in scheme 3

Scheme-3 where R6 is chosen from L. i. K, Na, quaternary ammonium etc., to give the substituted phthalimide of formula XV or XVI which on treatment with hydrazine hydrate gives the desired amino compound.

A amino ester of Formula VIII or XIV is reacted with a diketon of Formula XVII wherein the process for the preparation of the compound of formula XVII is described in scheme 4 Sclienie-4 A compound of formula XVII is prepared as described in scheme 6. which comprises of reacting isobutyryl ch l chloride and meldrum's acid in the presence of a base chosen from pyridine. triethylamine. diisopropylethyl amine, dimethylaniline etc in CH2Cl2 at 0-5°C for about 18h to give an intermediate of formula XVIII.

Preferably the reaction is done in pyridine and CH2Cl2 at 0°C. The acyl meldrum acid so obtained is then reacted with aniline in a soldent chosen from CH2Cl2, acetonitril,e toluene etc., at the reflux temperature of the solvent for about 12h to atlòrd the amide of formula XIX. Preferably the reaction is carried out in CH2Cl2 by stirring at room temperature.

The keto amide is then reacted with benzaldehyde in the presence of a base chosen from aqueous NaOH in acetic acid, sodium acetate and acetic acid, pxTrolidine and acetic acid, piperdine and toluène. pyrrolidine and toluene etc., at the retlux temperature and by removal of water for about 26h to give the methylenephenyl intermediate of formula XX The compound of formula XX is treated with 4- lluorobenzaldehvde in the presence ofa catalyst chosen from metallic cyanide where the metal is Ag. K. Na. Cu, tetraalkylammonium etc.,

or trimethylsilyl cyanide in a polar solvent chosen from DMSO, DMF, acetonitrile etc., at the reflux temperature of the solvent to give a compound of formula XVII. Preferably the reaction is carried out by reacting 4-fluorobenzaldehyde and sodium cyanide in DMSO at reflux temperature.

The diketon of formula XVII is reacted with the amino ester of formula VIII or XIV as described in Scheme 5 in the presence of a catalyst of Formula Rl, CO2H wherein Ri, is chosen from trifluoromethane sulfonic acid. methane sulfonic acid, p-toleue sulfonic acid and a solvent or mixtures thereof such as, for example. acetonitrile, xylene, diisopropyl ether and the like for about 24 to about 48 hours from 5 to 10°C to about the reflux temperature of the solvent with the removal of water to afford a compound of Formula VII. Preferably, the reaction is carried out in the presence of methanesulfonic acid and a mixture of xylene-hexane at reflux for about 48 hours with the removal of water.

Scheme-5 The compound of formula XXI is converted to atorvastatin calcium as shown in scheme 6 Scheme-6 Which involves the deprotection of the ketal followed by hydrolysis of the ester to give the free acid which is converted to its ammonium salt by reacting with either NH4OH, methanolic NH3 or by bubbling gaseous NH3 to the solution of carboxylic acid in a solvent chosen from a mixture of EtOAc, hexane, diisopropyl ether isopropanol, cyclohexane and methanol Preferably the intermediate of formula XXI is de-protected using moist silica in CH, CIß at room

temperature over a period of 24h and is then hydrolyzed using methanolic sodium hydroxide and acidified using dil HCI to give the free acid which is converted to its ammonium salt by passing gaseous NH3 in EtOAc. The ammonium salt is then treated with calcium acetate to give atorvastatin calcium.

The invention will now be described with reference to the following example.

Example 1 1. 1 Preparation of 4-methyl-3-oxo-N-phenylpetanamide (Formula XIX).

To a suspension of malonic acid (104g) in acetic anhydride (120mL) at room temperature ? Conc H2SO4 (3mL) was added. The mixture was cooled to 20°C followed by the addition of acetone (80mL) drop wise. The contents were stirred at room temperature (15min) and kept at 0-5°C overnight and filtered. The solid was washed with cold water and cold acetone and dried. The crude material was recrvstallized from acetone-hexane mixture.

Meldrum's acid (59g) was dissolved in CH2CI2 (200 mL) and cooled to 0°C Pyridine (73mL) was added drop wise over a period of 30 min and the mixture was stirred for an additional 10 min.

Isobutyryl chloride (44g) was added drop wise over a period of 30 min. and the mixture was stirred at 0°C for 1 h followed by stirring at room temperature over night. The mixture was poured into 1. 5N HCI containing crushed ice. The layers were separated and the aqueous laver was extracted with CH2C (2xlOOmL) The combined extracts were washed with 1. 5N HCI (2xlOOmL) followed by saturated NH4CI solution (2x100mL) and dried over Nua,, and concentrated under reduced pressure to afford the crude acyl meldrum's acid which was used for the next step.

The crude acyl meldrum's acid (84g) was taken in benzene (300mL) and aniline (111mL) was added. The mixture was retluxed for 4h. Cool the reaction mixture to room temperature and wash with 2N HCI (SxIOOmL) and benzene was removed under reduced pressure to get formula XIX.

1. 2 Preparation of 4-methyl-3-oxo-N-phenyl-2- (phenylmethylene) pentanamide (Formula XX).

The crude amide was taken in acetic acid and piperdine. To this mixture at room temperature benzaldehyde was added. The contents were allowed to stir under retlux for 2h. Pour the contents into water and extract with CH2Cl2. The organic extracts were washed with bicarbonate. bisulfite solution. dried and concentrated under reduced pressure to afford the crude compound of formula XX 1. 3 Preparation of 4-fluoro-a-f2-methyl-l-oxopropyll-y-oxo-N- ß3iphenylbenzenebutaneamide (Formula XVII).

To 4-fluorobenzaidehvde in anhydrous DMF. sodium cyanide was added and the contents were retluxed for 4h. To this the intermediate from example 3 was added and the contents were stirred for an additional 18h. Usual work up affords the crude diketo compound of formula XVII.

1. 4 Preparation of 4-trifluoromethanesulfonyl-3-oxo-butyric acid (Formula III).

To a solution of chloroacetic acid in pyridine at O"C and CH2Cl2, trifluoromethane sulfonyl chloride was added slowly After the reaction was complete, oxalvl chloride was added and the contents

were reiluxed for 3h and the solvent was removed-under reduced pressure to give the crude acid chloride.

Meldrum's acid (59g) was dissolved in CH2CI2 (200 mL) and cooled to 0°C. Pyridine (73mL) was added drop wise over a period of 30 min and the mixture was stirred for an additional 10 min.

Trifluromethanesulfonyl acetylchloride (44g) was added drop wise over a period of 30 min. and the mixture was stirred at 0°C for Ih followed by stirring at room temperature over night. The mixture was poured into 1. 5N HCI containing crushed ice. The layers were separated and me aqueous layer was extracted with Cl ICIo (2xlOOmL) The combined extracts were washed with I. 5N HCI (2x100mL) followed by saturated NH4CI solution (2xlOOmL) and dried over Na2804 and concentrated under reduced oressure to atbrcl the crude acyl meldrum's acid was hydrolyzed to give the title compound of formula III.

1. 5 Preparation of methyl 6-trifluoromethane sulfonyl-5, 3- dioxo-butryate (Formula IV).

The crude compound from example 5 was taken in CH2CI2 and pyridine and was cooled to 0-5°C. OXalyl chloride was slowly introduced and the contents were refluxed for 6h. The solvent was removed under reduced pressure to afford the crude acid chloride.

Meldrum's acid (59g) was dissolved in CH2Cl2 (200 mL) and cooled to 0°C. Pvridine (73mL) was added drop wise over a period of 30 min and the mixture was stirred for an additional 10 min. The acid chloride (44g) was added drop wise over a period of 30 min. and the mixture was stirred at 0°C for 1 h followed by stirring at room temperature over night. The mixture was poured into 1. 5N HCI containing crushed ice. The layers were separated and the aqueous

layer was extracted with CH2Cl2 (2x100mL). The combined extracts were washed with 1. 5N HCI (2xl00mL) followed bv saturated NH4CI solution (2xlOOmL) and dried over Na2SO, and concentrated under reduced pressure to atïbrd the crude acyl meldrum's acid was refluxed in methanol to give the title compound of formula IV 1. 6 reparation of methyl 6-trifluoromethane sulfoyl-5-oxo-3- hydroxybutryate (Formula V).

To a mixture of drv bakers'yeast and glucose in boiled water was stirred at ambient temperature. The crude diketo ester from example 5 was then added and the reaction mixture was stirred for an additional period 8-13h at ambient temperature. Celite was added to the reaction mixture and filtered The celite bed was washed thoroughly with ethyl acetate and the combined ethyl acetate extracts was dried and concentrated under reduced pressure to afford the title product which was used for the next step without further purification 1. 7 Preparation of (4methyl 6-trifluoromethyl sulfonyl methyl-2, 2-dimethyl-1, 3-dioxane4-acetate (Formula VII).

The crude product from example 6 was taken up in dry THF and isopropanol under nitrogen atmosphere. The solution was cooled to-78°C and a solution of diethvlmethoxvborane was added. The reaction mixture was cooled to-80°C and sodium borohydride was added in portion over a period of 4h. The temperature was maintained between-70 to-85oC and was allowed to warm to room temperature and stand for 18h T he reaction was quenched bv addition of acetic acid and concentrated under reduced pressure to afford an oily residue.

The crude oil was taken up in acetone and 2,2- dimethoxypropane was added tollowed bs catals tic amount of trifluoromethanesulfonic acid. The contents were stirred at room temperature for 4h and after the completion of the reaction was washed with bicarbonate solution. The organic extracts was washed with water and was concentrated to give an oil which was crystallized from hexane.

1. 8 Preparation of (4R)-methyl 6- (2-aminoethyl)-2, 2-dimethyl- 1, 3-dioxane-3-acetate (Formula VIII) The crude messlate from example 8 was taken up in methanol and NH3 gas wasw bubbled. The contents were then stirred for 6-luth at room temperature. After the reaction was coinpieie, solvent was removed under reduced pressure to afford the crude title compound of formula VIII.

1. 9 Preparation of tR- (R*, R*) j-2- (4-fIuorophenyt)-p, o- dihydroxy-5-(1-methylethyl)-3-phenyl-4-[phenylaminocarbonyl] - 1 H-pvrrole-1-heptanoic acid, hemi calcium salt (Formula XXII) A solution of (4R)-methyl 6-(2-aminoethyl)-2,2-dimethyl-1, 3- dioxane-3-acetate (of formula XIV) and 4-fluoro-a- [2-methyl-l- oxopropyl]γ-oxo-N-ß-diphenylbenzenebutaneamide (formual XVII) and acetic acid in xvlene were heated to reflux to 4Ah The solution was diluted with diisopropyl ether and methanol and was washed with dilute methanolic sodium hydroxide solution dilute HO and the solvent was then removed under vacuum. Thé crude oii was stirred with moist silica in CH2Cl2 and was stirred at room temperature tor I gli. A solution of aqueous NaOH was then added at room temperature and was stirred tor h I lle reaction mixture was diluted

with water and was washed with diisopropyl ether. The aqueous laver was acidified with HCI and was taken up in diisopropyl ether. The crude acid intermediate was then taken up in EtOAc and NH3 gas was bubbled. The contents were stirred for completion of the reaction and solvent was removed upon which the product crystallized. The crude ammonium salt is then taken up in diisopropyl ether-isopropanol mixture and a solution of calcium acetate was added at room temperature upon which the calcium salt precipitated tiom the solution. The product was filtered and dried under vacuum to get formula XXII of acceptable pharmaceutical purity The invention has been described bs reference to specific embodiments, this was for the purpose of illustration onln :. Numerous alternative embodiments will be apparent to those skilled in the art and are considered within the scope of these claims

Scheme-1 OH ci OH '0'Meldrurn Acid// p p RSOH Base OR- If, I II oR ; O O O 000 'R*2BCI IV O OH OH O OH R50%' 1 R, R) Rz\/R RzR NH3 OO VIR vil CRS VIII VII

Scheme-2 HO /Cl OtBu 101 M /O A R4 Acid, O O Base II Base O O O H Base- 000 IX X IX X R*2BC1 Y ' ButO ButO Bu R'CORz I-, Rz\/Ri On0 R1 <1oCO2tBu H2N v C02tBu OO NH3 x' xm Scheme-3

Scheme-4 Scheme-5

Scheme-6