Field of the Invention
The present invention relates to an improved process for the manufacture of (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3, 5-dihydroxy-heptanoic acid hemi calcium salt
Background of the Invention
Cardiovascular disease and its associated maladies, dysfunctions and complications are a principal cause of disability and the chief cause of death One specific factor significantly contributing to this pathophysiologic process is atherosclerosis, which has been generally recognized as the leading health care problem both with respect to mortality and health care costs
Atherosclerosis is characterized by the deposition of fatty substances, primarily cholesterol, resulting in plaque formation on the inner surface of the arterial wall and degenerative change to the arteries
It is now well established that cardiovascular disorders including myocardial infarction, coronary heart disease, hypertension and hypotension, cerebrovascular disorders including stroke, cerebral thrombosis and memory loss due to stroke, peripheral vascular disease and intestinal infarction are caused by blockage of arteries and arterioles by atherosclerotic plaque Atherosclerotic plaque formation is multifactorial in its production Hypercholesterolemia, especially elevated levels of low-density lipoprotein cholesterol (LDL), is an important risk factor for atherosclerosis and arteriosclerosis and associated diseases
The HMG-CoA reductase inhibitors (statins) have been used in reducing blood levels of LDL cholesterol Cholesterol is produced via the mevalonic acid pathway Reducing the formation of mevalonic acid, a precursor to cholesterol, leads to a corresponding decrease in hepatic cholesterol biosynthesis with a reduction in the cellular pool of cholesterol
PCT Publication No WO 2004/106299 discloses (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt, having the Formula I,
(Formula Removed)
as an effective HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitor and thus is useful as hypolipidemic and hypocholesterolemic agent
A procedure for the synthesis of (3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt is claimed in WO 2004/106299 The aforementioned procedure involved
o A synthetic route involving isolation and purification of intermediates at each step of
the process by column chromatography, o Total overall yield is low, o High cost of production and the process not amenable to large scale manufacture
Summary of the Invention
This invention provides an improved process for the manufacture of compound of Formula I, described above, at a commercial scale
The objective of the present invention is to provide an improved process, which avoids the use of column chromatography as a purification method, and is cost effective and easily amenable to large-scale production
The present invention relates to a process of making high purity compound of Formula I with increased overall yield by making changes in reaction conditions that include use of different solvents and solvent combinations, temperature conditions, time period and work-up procedures at each stage of the process Also, the present invention relates to isolation of intermediates of high purity with superior yields without resorting to purification by column chromatography at any stage of the process
The present invention further involves a one-pot process for the conversion of dihydroxy compound to the desired calcium salt of Formula I in the final step, thus making the process more economical
In order to achieve the above-mentioned objective and in accordance with the purpose of the invention as embodied and broadly described herein, there is provided a process for the preparation of compound of Formula I
(Formula Removed)
Detailed Description
The compound of Formula I, (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt can be prepared by the following reaction sequence as depicted in scheme I
(Scheme Removed)

Thus, amine of Formula-ll when reacted with methyl-4-methyl-3-oxopentanoate in refluxmg hydrocarbon solvent results in a [3-ketoamide of Formula IV (wherein R is aryl, alkyl or arylalkyi) The compound of Formula IV on reaction with benzaldehyde affords compound of Formula V, which is a mixture of E & Z isomers The compound of
Formula V on subjecting to acyhon condensation with 4-fluorobenzaldehyde affords a 1, 4 diketo compound of Formula VI The compound of Formula VI on condensation with chiral amine of Formula VII results in a compound of Formula VIM, which on subsequent deprotection gives a compound of Formula IX Selective reduction of carboxyl group in compound of Formula IX affords a compound of Formula X Acid catalyzed cleavage of the ketal group in compound of Formula X results in a dihydroxy compound of Formula XI which can be converted into calcium salt of the desired Formula I in two ways
i) By directly converting the compound of Formula XI into its hemi calcium salt of Formula I under phase transfer catalysis using Ca(OH)2 or
n) By converting the compound of Formula XI to its sodium salt, generated in situ, using sodium hydroxide and subsequent displacement of sodium with Ca using calcium acetate or calcium chloride to generate the hemi calcium salt of Formula I
The reaction of an amine of Formula II with 4-methyl-3-oxopentanoate can be carried out in one or more solvents, for example, hydrocarbon solvents (eg, hexane, heptane, xylene or toluene, in presence of an organic base, for example, triethylamine, pyridine or 1, 2-ethylenediamine in catalytic amount
The reaction of a compound of Formula IV with benzaldehyde can be carried out in one or more solvents, for example, hexane, heptane or toluene, in presence of an organic base, for example, pipendme, pyridine or p-alanine, and an organic acid, for example, glacial acetic acid or benzoic acid
The reaction of a compound of Formula V with 4-fluorobenzaldehyde can be carried out in presence of a catalyst (e g, sodium cyanide, 3-ethyl-5- (2-hydroxyethyl)-4-methyl thiazolium bromide or 3-benzyl-5- (2-hydroxyethyl)-4-methyl thiazohum chloride), in a solvent free condition or in a solvent, for example, polar solvent (eg, methanol, ethanol, propanol or isopropanol), ether solvent (eg, dioxane, diethyl ether or tetrahydrofuran) or mixture thereof, in presence of an organic base (e g, triethylamine or pyridine) Alternatively, the reaction can be carried out in presence of excess base for example triethylamine which itself acts as a solvent
The reaction of a compound of Formula VI with a compound of Formula VII can be carried out in one or more solvents, for example, hydrocarbon solvents (e g, xylene, toluene, hexane or heptane), ether solvents (eg, tetrahydrofuran or dioxane) or mixtures thereof, in presence of an organic acid, for example, pivalic acid or p-toluene sulfonic acid
The deprotection of a compound of Formula VIM can be carried out at temperatures ranging from 10°C to the reflux temperature, preferably at temperatures ranging from 40 to 50 °C in presence of an inorganic base (e g, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate), in one or more solvents, for example, polar solvents (e g, methanol, ethanol, acetonitnle, isopropyl alcohol or t-butanol) or ether solvents (e g, tetrahydrofuran, diethyl ether or dioxane) or mixture thereof Alternatively, deprotection can be carried out under phase transfer catalysis using TBAB in aqueous alcoholic solvents, for example, ethanol or methanol at reflux temperatures
The reduction of compound of Formula IX can be carried out in presence of a reducing agent (e g, boron-dimethylsulfide complex or boron-tetrahydrofuran complex), in one or more solvents, for example, hydrocarbon solvents (e g, hexane, n-heptane or toluene), ether solvents (eg, tetrahydrofuran, dioxane or diethyl ether) or mixture thereof
The cleavage of ketal group of a compound of Formula X with an acid (e g, hydrochloric acid) can be carried out at temperatures ranging from room temperature (~25°C) to reflux temperature, preferably at temperatures ranging from 40 to 55 °C in one or more solvents, for example, polar solvents (e g, methanol, ethanol or isopropyl alcohol), ether solvents (e g, tetrahydrofuran, dioxane or diethyl ether) or combination thereof
The compound of Formula XI can be converted into its corresponding hemi calcium salt of formula I either
i) by first converting Formula XI compound into its sodium salt by treatment with NaOH at temperature ranging from 0 to 30 °C, preferably at temperature ranging from 0 to 10 °C and subsequent displacement of sodium with calcium using calcium acetate or
n) by subjecting Formula XI compound to phase transfer catalysis using
tetrabutylammonium bromide as the catalyst and calcium hydroxide as the base in refluxing aqueous alcoholic solvent, for example, methanol or ethanol
The process described above may involve one or more of the following embodiments For example, the reaction of the compound of Formula II can be carried out in toluene The reaction of the compound of Formula IV can be carried out in presence of triethylamine, which itself acts as a solvent The reaction of the compound of Formula VIM can be carried out in acetonitnle or methanol tetrahydrofuran (3 1), in presence of sodium hydroxide at temperatures ranging from 50 to 55 °C for about 4-5 hours or at 30°C for about 8-10 hours The reaction of the compound of Formula IX can be carried out at temperatures ranging from 40 to 45°C for about 5 hours The reaction of the compound of Formula X can be carried out in methanol tetrahydrofuran water (111) The reaction of the compound of Formula XI can be carried out tetrahydrofuran de-ionized water (11) or ethanol water (4 1), in presence of tetrabutylammonium bromide at a temperature ranging from 30 to 50 °C for about 2-8 hours
The process as enumerated above has an advantage that, none of the steps involve the use of column chromatography as a purification method, thus enables to achieve high yields and makes it amenable to large-scale production
The compound of Formula IV is purified by dissolving the crude product of Formula IV in ethyl acetate and washing the ethyl acetate layer successively with an acid then by de-ionized water, the excess acid is removed by washing the solution successively with sodium bicarbonate solution, de-ionized water, concentrated to
obtain a solid, which is added to hexane and stirred till the product precipitates out, which is filtered and dried
The compound of Formula V is purified by washing the crude product of Formula V with hexane to remove the organic impurities followed by drying the product, which is dissolved in ethyl acetate and partitioned with de-ionized water to remove the inorganic impurities, the organic layer is separated, dried and dissolved in isopropyl alcohol with heating, which on cooling gives the solid product, filtered and dried in vacuum tray drier at temperatures ranging from 40 to 50 °C for about 6 hours
The compound of Formula VI is purified by dissolving the crude product of Formula VI and activated charcoal in a solvent system of methanol and water and refluxing the reaction mixture, filtered and the residue so obtained is washed with solvent methanol water (9 1), the filtrate is concentrated to obtain a solid, slurred in hexane, filtered, and concentrated under vacuum
The compound of Formula VIII is purified by cooling the reaction mixture to 0°C and stirring till the product precipitates, which is filtered, washed with hexane, and dried
The compound of Formula IX is purified by a) cooling the reaction mixture to room temperature and acidifying it, filtering to get the solid and washing it with de-lonized water and acetonitnle, the solid is further refluxed in denatured spirit, cool till the product precipitates out, filtered, washed with denatured spirit, and dried under vacuum, b) concentrating the reaction mixture and extracting it into a solvent system of ethyl acetate and water, separating the ethyl acetate layer and washing it with brine, the organic layer is further acidified wherein, the excess acid is neutralized by a base and washed with de-ionized water, the reaction mixture is concentrated and the residue is triturated with hexane to form solid, filtered, and dried under vacuum
The compound of Formula X is purified by a) dissolving the crude product in ethyl acetate and washing the layer successively with de-ionized water, sodium
bicarbonate and brine, concentrated to obtain a solid, which is slurred in hexane, filtered and dried under vacuum, b) dissolving the crude product in the solvent system of isopropyl alcohol, de-ionized water and acetic acid, and refluxing it with concurrent addition of calcium hydroxide, the hot solution is filtered, the filtrate so obtained is cooled to room temperature till the solid precipitates out, filtered, washed with ice-cold isopropyl alcohol and water, dried in vacuum tray drier at about 60°C for about 7-8 hours
The compound of Formula XI is purified by a) dissolving the crude product in a solvent system of ethyl acetate and toluene (1 2) and washing the layer successively with de-ionized water and brine, the product is isolated, slurred in hexane at about 40°C for about 1 hour, cooled, filtered and dried in vacuum tray drier at 60°C for 3 hours, b)
dissolving the crude product in (10 %) ethyl acetate-hexane solvent system with concurrent heating at temperatures ranging from 40 to 50 °C for about 1 hour, cooled to room temperature (about 25°C) and stirred for about 1 hour or till the product precipitates, the solid so obtained is filtered, washed with water and hexane and dried in vacuum tray drier
The compound of Formula I is purified by a) washing the crude product with ethyl acetate and drying it under vacuum at temperatures ranging from 60 to 70 °C for about 10 hours, dissolved in methanol and to it is added butylated hydroxy anisole, the solution is filtered to obtain a solid, which is dried in vacuum tray drier at temperatures ranging from 40 to 50 °C to form pure amorphous compound, b) refluxing the crude calcium salt in a solvent system of ethyl acetate and water (1 1) and butylated hydroxy anisole, the hot solution is filtered, the filtrate is cooled till the product completely precipitates out, filtered, washed with ethyl acetate and dried under vacuum to form pure amorphous compound, c) filtering the hot reaction mixture, the filtrate so obtained is cooled and to it is added de-ionized water, the product precipitates out, filtered, subjected to reflux in ethyl acetate and water mixture (1 1), the reaction mixture is cooled till the product precipitates out, which is followed by isolating the product, washing it with ethyl acetate and drying it in vacuum tray drier to form pure amorphous compound
In the above reaction scheme, where specific reducing agents, solvents, bases, catalysts, acids etc , are mentioned, it is to be understood that other reducing agents, solvents, bases, catalysts, acids etc, known to those skilled in the art may be used Similarly, the reaction temperature and duration may be adjusted
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention
EXAMPLE 1
Preparation of Methyl 4-[(4-methyl-3-oxopentanoyl) ammo] benzoate of Formula IV
To a solution of methyl-4-aminobenzoate (250 g, 1 65 moles) in toluene (2 4 Lt) was added methyl-4-methyl-3-oxopentanoate (237 7 gms, 1 648 moles) and ethylene
diamine (1 15 ml, 0 016 moles) The reaction mixture was refluxed for about 20-25 hours The solvent was removed under reduced pressure to obtain a solid residue The residue was dissolved in ethyl acetate (2 4 Lt) The organic phase was washed with an acid (e g , 20 % w/w hydrochloric acid 0 5 Lt) followed by de-ionized water It was further washed with a 10 % sodium bicarbonate solution, followed by de-ionized water and saturated brine The solvent was removed under reduced pressure To this was added hexane while stirring and the solid precipitated out completely The solid was filtered and washed with hexane The solid was dried to yield the titled product in 99 45 % purity
Yield 358 gms (1 5, w/w)
LCMS m/z(M+1)265 09
Melting range 54-56 °C
1H NMR (CDCI3) δ 1 16-1 18 (d,6H,-CH(CH3)2 ), 2 75-2 70 (m,1H, -CH(CH3)2 ), 3 62
(s,2H,CH2), 3 89 (s,3H, OCH3), 7 62-7 65 (d,2H, ArH), 7 98-8 01 (d,2H, ArH), 9 51 (bs,
NHCO)
EXAMPLE 2
Preparation of Methyl 4-{[-2-benzyhdene-4-methyl-3-oxopentanoyl] amino} benzoate of Formula V
To a mixture of compound of Formula IV (400 gms, 1 52 moles) and benzaldehyde (177 gms, 1 67 moles) in hexane (5 4 Lt) was added p-alanine (27 gms, 0 3 moles) followed by glacial acetic acid (54 6 gms, 0 91 moles) while under stirring The reaction mixture was refluxed for about 24 hours with constant removal of moisture with the help of dean stark apparatus At the end of the reaction, solid precipitated The solid was filtered and washed with hexanes (0 6 Lt) The solid was dissolved in ethyl acetate (3 6 Lt) followed by addition of de-ionized water (1 2 Lt) with stirring The layers were separated and the organic layer was washed with brine The solvent was removed under reduced pressure to obtain a solid product, which was dissolved in isopropyl alcohol (0 85 Lt) on heating The solution was cooled to room temperature and the solid precipitated The solid was filtered and successively washed with ice-cold isopropyl alcohol and hexanes The solid was dried under vacuum (10 mbar) at about 40-50°C for about 6 hrs to obtain the desired product as a mixture of E & Z isomers
Yield 338 gm (0 84, w/w) LCMS m/z (M+1) 352 1 Melting range 154-156 °C
1H NMR (CDCl3) E isomer 8 1 21-1 23 (d,6H,-CH(CH3)2), 3 32-3 39 (m,1H, -CH(CH3)2), 3 90 (s,3H, OCH3), 7 33-7 39 (m,3H, ArH), 7 53-7 59 (m,4H, ArH),7 93 (s,1H, vinyhc H), 8 00-8 02 (d,2H, ArH) (melting range of analytical sample, 155 0-156 2
Z isomer δ 1 03-1 05 (d,6H,-CH(CH3)2 ), 2 62-2 65 (m,1H, -CH(CH3)2 )■ 3 91 (s,3H, OCH3), 7 30-7 32 (m,2H, ArH), 7 42-7 45 (m,3H, ArH),7 71-7 73 (d,2H,ArH), 8 03-8 05 (d,2H,ArH), 8 21 (s,1H, vinylic H) ) (Melting range of analytical sample, 145 6-146 3 °C)
EXAMPLE 3
Preparation of Methyl 4-({2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxopentanoyl} amino) benzoate of Formula VI
To a mixture of compound of Formula V (100 gms, 0 285 moles) in triethylamine (0 2 Lt) was added thiazohum bromide (17 94 gms, 0 071 moles) and 4-fluorobenzaldehyde (38 82 gms, 0 313 moles) The reaction mixture was subjected to reflux for about 8 hours At the end of the reaction, as indicated by TLC or reaction monitoring by HPLC, triethylamine was removed under reduced pressure The solid so obtained was dissolved in ethyl acetate (0 75 Lt) followed by the addition of de-ionized water (0 25 Lt) The organic phase was then separated and the aqueous layer was washed with ethyl acetate The combined organic layer was washed successively with de-ionized water, acid (eg, 10 % hydrochloric acid 02 Lt), base (eg, 10 % sodium bicarbonate) and brine The solvent was removed under reduced pressure to obtain a solid product The solid was dissolved in a solvent system of methanol and water (9 1, 0 75 Lt) on heating with added activated charcoal (7 5 gm) and brought to reflux The hot solution was filtered and the residue was washed with solvent system of methanol and water (9 1) The filtrate was further cooled to about 0-5 °C and the solid that precipitated was filtered The solid was slurred with hexanes (0 4 Lt) at 40°C for 1 hr and is filtered The product was dried under vacuum (10 mbar) at about 50°C for about 10-12 hrs to give the product of desired quality
Yield 156 gm (0 93, w/w)
Melting range 168 5-170°C
LCMS m/z(M+1)476 21
1H NMR (CDCI3) 8 115-118 (d,3H,-CH3), 1 22-1 25 (d,3H,-CH3), 2 96-
3 02(m,1 H,CH(CH3)2), 3 89 (s,3H,-OCH3), 4 54-4 56 (d,1H,-CO-CH-Ph), 5 33-5 36
(d,1H,-CO-CH-CO-), 7 01-7 99 (m,14H,Ar-H and -NH)
EXAMPLE 4
Preparation of Methyl 4-({[1-{2-[(4R6R)-6-(2-tert-butoxy-2-oxoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]ethyl}-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-3-yl]carbonyl}amino)benzoate of Formula VIII
Pivahc acid (44 2 gms, 0 433 moles) was added to a mixture of a compound of Formula VI (200 gms, 0 421 moles) and [6-(2-Ammo-ethyl)-2, 2-dimethyl-[1, 3-dioxan-4-yl]-acetic acid f-butyl ester of Formula VII (137 9 gms, 0 505 moles) in solvent system of heptane, toluene and tetrahydrofuran in the ratio of 4 1 1 (2 52 Lt) The reaction mixture was refluxed for about 28-35 hours The reaction mixture was cooled to about 0°C and stirred till the product precipitates The precipitated product was filtered and washed with hexanes (1 Lt) The solid was dried under vacuum (10mbar) at 50°C to obtain the desired product
Yield 210 gms (1 05, w/w) LCMS m/z(M+1)713 2 Melting range 158 8 - 159 5°C
1H NMR (CDCI3) δ 1 03-1 06 (m,1H,>NCH2CH2-), 1 30-1 36 (2xs,6H, >C(CH3)2 & m,1H,>NCH2CH2- merged together), 1 43 (s,9H, -C(CH3)3), 1 52-1 54 (d,6H, -CH(CH3)2), 1 66(m,2H,C-5 -CH2-), 2 2-2 4 (m,2H,-CH2COOtBu), 3 6 (m,1H, -CH(CH3)2), 3 7(m,1H,C-4 >CHO-), 3 85 (s,3H,-OCH3), 3 85 (m,1H,C-6 >CHO-), 4 1 (m,2H,>NCH2-), 6 97-7 85 (m,14H,Ar-H and -NH)
EXAMPLE 5
Preparation of 4-({[1-{2-[(4f?, 6R)-6-(2-te/f-butoxy-2-oxoethyl)-2,2-dimethyl-1,3-dioxan-4-yl] ethyl}-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1 H-pyrrol-3-yl] carbonyl} amino)benzoic acid of Formula IX
Sodium hydroxide (2 5 molar equivalents, 1N aq solution) was added to a solution of compound of Formula VIII (425 gms, 0 596 moles) in acetonitnle (4 25 Lt) and the reaction mixture was stirred at about 50-55°C for about 4-5 hours The reaction mixture was cooled to about 25°C and the pH adjusted to 5 5-6 with 20% acetic acid solution when the product precipitates out The solid was then filtered and washed with de-ionized water and acetonitnle The crude product obtained was refluxed in denatured spirit (7 2 Lt) for about 1 hour The reaction mixture was cooled to about 25 °C and stirred for about 5 hours till the solid precipitates out completely The solid was filtered and washed with denatured spirit (0 42 Lt) The solid was further dried under vacuum (10 mbar) at about 50°C for about 6 hrs to obtain the desired product
Yield 324 95 gms (0 76, w/w) LCMS m/z(M+1)699 3 Melting range 239 9-241 7°C
1H NMR (CDCI3) δ 1 03-1 06 (m,1H,>NCH2CH2-),1 30-1 36 (2xs,6H, >C(CH3)2 & m,1H,>NCH2CH2- merged together), 1 43 (s,9H, -C(CH3)3), 1 52-1 54 (d,6H, -CH(CH3)2), 1 64-1 68 (m,2H,C-5 -CHr), 2 2-2 4 (m1H.-CHzCOO'Bu), 3 6 (m,1H,-CH(CH3)2), 3 7(m,1H,C-4 >CHO-), 3 8 (m,1H,C-6 >CHO-), 4 15-417 (m^H^NCHz-), 6 97-7 92 (m,14H,ArH and -NH)
Alternatively, sodium hydroxide (2 5 molar equivalents, 1N aq solution) was added to a solution of compound of Formula VIII (100 gms, 0 14 moles) in a mixture of tetrahydrofuran and methanol (1 0 Lt, 3 1) and the reaction mixture was stirred at room temperature (30°C) for about 8-10 hours The volatilities were distilled off at reduced pressure and ethyl acetate and water (1 1) charged under stirring at room temperature The organic phase was separated and washed with saturated brine, any insoluble material that precipitated was filtered The pH of the organic phase was adjusted to 5 5-6 with 20% acetic acid solution and subsequently washed with de-lonized water and bicarbonate solution The organic volatilities were removed under reduced pressure and the residue was triturated with hexanes to give the solid, which was filtered and washed with hexanes The solid was further dried under vacuum (10 mbar) at about 50°C for about 6 hrs to obtain the desired product Yield 60 gms (0 6, w/w)
EXAMPLE 6
Preparation of tert-butyl ((4/?, 6R)-6-{2-[2-(4-fluorophenyl)-4-({[4-(hydroxymethyl) phenyl] amino} carbonyl)-5-isopropyl-3-phenyl-1H-pyrrol-1-yl] ethyl}-2, 2-dimethyl-1, 3-dioxan-4-yl) acetate of Formula X
A solution of a compound of Formula IX (100gms, 0 14 moles) in tetrahydrofuran (0 7 Lt), was heated to about 40-45 °C To it was added boron-dimethyl sulfide complex (BMS complex 2 3 molar equivalents, 2M sol in tetrahydrofuran) The reaction mixture was stirred at this same temperature for about 5 hours The reaction mixture was cooled to about 20-25 °C and to it was added methanol to destroy excess BMS complex* The organic volatilities were removed under vacuum and the residue so obtained was dissolved in ethyl acetate The organic phase was successively washed with de-ionized water, sodium bicarbonate and brine On distilling off the solvent under reduced pressure (10 mbar) at 50°C the desired product obtained was a solid The solid reaction mass was slurred in hexanes and filtered The product so obtained was dried under vacuum (10 mbar) at about 60°C for about 7-8 hrs and used for next step
Yield 95 gms, (0 95, w/w) LCMS m/z(M+1)685 3
Melting range 193 8-194 6°C
1H NMR (CDCI3) δ 1 03-1 06 (m,1H,>NCH2CH2-), 1 30-1 36 (2xs,6H,>C(CH3)2 & m,1H,>NCH2CH2- merged together), 1 43 (s,9H,-C(CH3)3), 1 52-1 54 (d,6H,-CH(CH3)2), 1 66-1 67 (m,2H,C-5 -CHr), 2 2-2 4 (m,2H,-CH2COO'Bu), 3 58 (m,1H,-CH(CH3)2), 3 68 (m,1H,C-6 >CHO-), 3 82 (m,1H,C-4 >CHO-),4 07-4 17(m,2H,>NCH2-), 4 57 (s,2H, -PhChbOH), 6 87-7 21 (m,14H,ArH and -NH)
Alternatively, the reaction mixture after quenching with methanol to destroy the excess BMS complex is subjected to distillation under reduced pressure to reduce the volatilities to a minimum and allowed to attain ambient temperature Acetic acid is added to the reaction mixture along with isopropyl alcohol and de-ionized water The reaction mixture is heated to reflux and calcium hydroxide charged The reaction mixture is filtered hot and the filtrate on cooling to 20-25°C results in the precipitation of the solid product which is filtered and washed with a mixture of chilled isopropyl alcohol and water The product so obtained is dried under vacuum (10 mbar) at 60°C for 7-8 hrs and the desired product, so obtained is used for the next step
EXAMPLE 7
Preparation of (3R, 5R)-7-[2-(4-fluorophenyl)-4-({[4-(hydroxymethyl) phenyl] ammo} carbonyl)-5-isopropyl-3-phenyl-1/-/-pyrrol-1-yl]-3, 5-dihydroxyheptanoic acid t-butyl ester of Formula XI
Hydrochloric acid (1N, aq sol) was added to a solution of a compound of Formula X (25 gms, 0 036 moles) in a solvent system of methanol and tetrahydrofuran (1 1), 0 125 Lt at room temperature The reaction mixture was stirred for about 5 hrs or till the completion of the reaction The reaction mixture was quenched with sodium bicarbonate (1 53 gms, 0 018 moles) and subjected to removal of the organic volatilities under reduced pressure The residue so obtained was taken up in ethyl acetate and toluene (12, 0 5 Lt) The organic phase was washed successively with de-ionized water and brine Removal of the solvent under vacuum resulted in a solid product The solid obtained was slurred in hexane at about 40°C for about 1 hr, followed by cooling to ~ 25°C and filtration The solid obtained was dried under vacuum (20 mm) at about 60°C for about 3 hrs
Yield 22 gms, (0 88, w/w)
LCMS m/z(M+1)645 2
Melting range 144 6-146 1°C
1H NMR (CDCI3) 8 1 20-1 24 (m,1H,>NCH2CH2-), 1 40-1 45 (s,9H,-C(CH3)3 &
m,1H,>NCH2CH2- merged together), 1 52-1 54 (d,6H,-CH(CH3)2), 1 62 (m,2H,C-4
CHj>(-CHOH)2), 2 3-2 32 (d^H.-C^COO'Bu), 3 56-3 59 (m,1H,-CH(CH3)2), 3 72
(bs,2H,2xOH), 3 78 (m,1H,C-5 >CHOH), 3 93 (m,1H,C-3 >CHOH), 4 07-
4 14(m,2H,>NCH2-), 4 57 (s,2H, -PhCHzOH), 6 87-7 19 (m,14H,ArH and -NH)
Alternatively, the compound of formula X (200 gms, 0 29 moles) on subjecting to acid hydrolysis in a mixture of tetrahydrofuran methanol water (1 1 1, 3 Lt) at about 50°C in presence of 1N HCI (0 5, molar equivalents) for about 1-2 hrs affords the desired compound in solution The reaction mixture was quenched with sodium bicarbonate (15 96 gms, 0 19 moles) and the organic volatilities were distilled off leaving behind 50% of the total reaction volume To the reaction mixture was added 10% ethyl acetate in hexanes (2 Lt) and subjected to a temperature of about 40-50°C for about 1 hr The reaction mixture was then cooled to ~25°C and stirred at this temperature for about 1 hr for complete precipitation The product so obtained was filtered and washed with water (0 2 Lt) and hexanes (0 4 Lt) The solid obtained was dried under vacuum (20 mm) at about 60°C for about 3 hrs Yield 0 87(w/w)
EXAMPLE 8
Preparation of (3R, 5R)-7-[2-(4-fluorophenyl)-4-({[4-(hydroxymethyl) phenyl] ammo} carbonyl)-5-isopropyl-3-phenyl-1H-pyrrol-1-yl]-3, 5-dihydroxyheptanoic acid hemi calcium salt of Formula I
A solution of a compound of Formula XI (60 gms, 0 093 moles) in methanol and tetrahydrofuran (1 1, 0 3 Lt) was stirred at room temperature The reaction mixture was cooled to 0°C A solution of sodium hydroxide (1N aq sol, 1 2 molar equivalents) was added to the reaction mixture and the temperature was not allowed to exceed 10 °C during addition The reaction mixture was stirred for about 3 hours at about 5-10 °C The solvent was then removed under reduced pressure The solid product obtained was dissolved in ethyl acetate (0 3 Lt), to it was added de-ionized water (0 6 Lt) The aqueous layer containing the desired product was separated and washed with ethyl acetate To this aqueous layer was added calcium acetate solution (0 66 Lt, 0 6 molar equivalents) and stirred till product of Formula I precipitated out The product was filtered and washed with ethyl acetate The product was dried under vacuum (10mm) at 60-70°C for about 10 hours The product obtained above (50 gms, yield 0 833, w/w) was dissolved in methanol (0 245 Lt) and butylated hydroxy anisole (BHA, 0 05 m0l%) was added, the solution so obtained was filtered and evaporated to dryness under vacuum (10 mm) at 40-50°C to get the desired amorphous form of the compound of Formula I (44 gms)
Over all yield 44 gms, (0 73, w/w)
LCMS m/z(M+1)589 1
1H NMR (CD3OD) δ 1 36-1 39 (m,1H,C-6 >NCH2CH2), 1 46-1 47 (d,6H,CH(CH3)2), 1 51-1 53 (m,1H, C-6 >NCH2CH2 merged with CH(CH3)2), 1 67-1 68 (m,2H,C-4 CH2(-CHOH)2) 2 22-2 32 (m,2H,C-2 -CfcbCOO), 3 33-3 37 (m,1H,CH(CH3)2), 3 64-3 65 (m,1H,C-5 >CHOH), 3 89 (m,1H, C-3 >CHOH), 3 99-4 06 (m,2H,C-7 >NCtU-), 4 51 (s,2H, -PhChbOH), 7 02-7 12 (m,7H,ArH), 7 20-7 24 (m,4H,ArH), 7 27-7 29 (m,2H,ArH)
Alternatively, the compound of Formula XI (80 gms, 0124 moles) in tetrahydrofuran and deionized water (1 1, 0 8 Lt) was stirred at room temperature in presence of sodium hydroxide (1N aq sol, 1 2 molar equivalents) for about 2- 3 hours at about 30°C The solvent tetrahydrofuran was then removed under reduced pressure and the residue taken up in ethyl acetate water mixture The aqueous layer containing the desired product was separated and washed with ethyl acetate To this aqueous layer was added calcium acetate (0 6 molar equivalents) under stirring The desired product precipitated out To the precipitated product in aqueous solution was added ethyl acetate such that the ratio of ethyl acetate and water is 1 1 and butylated hydroxyl anisole (0 05 mol %) and the reaction mixture was refluxed to dissolve the solids The hot solution was filtered and allowed to cool to room temperature (25-30°C) under stirring when the desired Ca-salt of compound of Formula I precipitated out The product was filtered and washed with ethyl acetate The product was dried under vacuum (10mm) at 55-65°C for 10-12 hrs, (yield, 60gms, 0 75 w/w) The desired compound of Formula I, was obtained above, and was treated further to produce one single morph consistently, i e , amorphous form of compound of Formula I Thus, to a solution of the compound of Formula I (25 gms) in methanol (500 ml) was added butylated hydroxyl anisole (0 05 mol %), filtered and subjected to spray drying technique to give the desired amorphous form (20 5 gms)
Yield 0 82 w/w Overall yield 0 61
Alternatively, a mixture of compound of Formula XI (80 gms, 0 124 moles), calcium hydroxide (13 8 gm, 0 186 moles) and tetrabutylammonium bromide (2 gm, 5 mol %) in ethanol water mixture (4 1, 0 8 Lt) was heated to about 50°C for about 5-8 hours under stirring Reaction mixture shows consumption of the starting material as indicated by TLC or by HPLC The reaction mixture was filtered hot (~ 50°C) The filtrate was cooled to room temperature (~25°C) and charged to deionized water (2 4 Lt)
under stirring The precipitated product was filtered and washed with water (0 16 Lt) and sucked dry The wet cake was refluxed in ethyl acetate water mixture (1 1, 1 6 Lt) till the complete dissolution of solids The reaction mixture was cooled to 25°C under stirring for about 2 hours to afford the compound of Formula I of desired quality The solid was filtered and washed with ethyl acetate (0 32 Lt), sucked dry and further dried under the above said conditions, yield, 50 5 gms (0 63, w/w) Further treatment of the product as described above affords the amorphous compound of Formula I.

WE CLAIM :
1 An improved process for the manufacture of 3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt of Formula I,
(Formula Removed)
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, pro-drugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof, which method comprises of (a) reacting the compound of Formula II with compound of Formula III,
(Formula Removed)
to form a compound of Formula of IV (wherein R is alkyl, aryl or arylalkyl),

(Formula Removed)
(b) reacting the compound of Formula IV with benzaldehyde to form a compound of Formula V,
(Formula Removed)
(c) reacting the compound of Formula V with 4-fluorobenzaldehyde to form a compound of Formula VI,
(Formula Removed)
(d) reacting the compound of Formula VI with a compound of Formula,
(Formula Removed)
form the compound of Formula VIM,

(Formula Removed)
(e) deprotecting the compound of Formula VIII to form a compound of Formula IX,
(Formula Removed)
(f) reducing the compound of Formula IX to form a compound of Formula X,
(Formula Removed)
(g) deprotecting the compound of Formula X to form a compound of Formula XI,
(Formula Removed)
(h) converting the compound of Formula XI to compound of Formula I,
which process is characterized by the fact that, the purification of products of the steps (a) to (h) is carried out without using column chromatography as purification methods, and the reaction in step (h) involves one-pot conversion of compound of Formula XI to the desired calcium salt of Formula I
2 The process according to claim 1, wherein the solvent in step (a) is toluene
3 The process according to claim 1, wherein the base in step (c) is tnethylamine, which acts as a solvent
4 The process according to claim 1, wherein the reaction of step (e) is carried out in one or more solvent selected from acetonitnle, propionitnle, dimethylsulfoxide,
dimethylformamide and dimethoxyethane or methanol tetrahydrofuran (3 1), in presence of sodium hydroxide, at temperatures ranging from 50 to 55 °C for about 4-5 hours, or at 30°C for about 8-10 hours
5 The process according to claim 1, wherein the step (f) is carried out at temperatures ranging from 40 to 45 °C for about 5 hours
6 The process according to claim 1, wherein the reaction of step (g) is carried out in methanol tetrahydrofuran water (1 1 1)
7 The process according to claim 1, wherein the reaction of step (h) is carried out in tetrahydrofuran de-ionized water (1 1)
8 The process according to claim 1, wherein the reaction of step (h) is carried out in ethanol water (4 1) in presence of calcium hydroxide and a phase transfer catalyst selected from tetraalkylammonium hahde, tetrabutylammonium hydrogen sulfate, tetrabutylammonium thiocyanate, tetrabutylammonium tetrafluoroborate, benzyltributylammonium chloride and tetraalkylphosphonium halide
9 The process according to claim 1, wherein the reaction of step (h) is carried out at a temperature ranging from 30 to 50 °C for about 2-8 hours
10 The product of step (h) is amorphous