Indian Patents. 268571:PROCESS FOR PREPARATION OF (3R, 5R)-7-[2-(4-FLUOROPHENYL) -5-ISOPROPYL-3-PHENYL-4-[(4-HYDROXY METHYL PHENYL AMINO) CARBONYL]-PYRROL-1-Y1]-3,5-DIHYDROXY-HEPTANOIC ACID HEMI CALCIUM SALT

Title of Invention	PROCESS FOR PREPARATION OF (3R, 5R)-7-[2-(4-FLUOROPHENYL) -5-ISOPROPYL-3-PHENYL-4-[(4-HYDROXY METHYL PHENYL AMINO) CARBONYL]-PYRROL-1-Y1]-3,5-DIHYDROXY-HEPTANOIC ACID HEMI CALCIUM SALT
Abstract	The present invention relates to processes for the preparation of (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt.

Full Text	Field of the Invention The present invention relates to processes for the preparation of (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt. Background of the Invention (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt acts an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A- (HMG-CoA) reductase, a coenzyme catalyzing the intracellular synthesis of cholesterol, and thus is useful as hypolipidemic and hypocholesterol-emic agent, as discussed in PCT Publication No. 04/106299. 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 multi-factorial 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. A synthetic procedure for preparing (3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt has been disclosed in PCT Publication No. WO 04/106299. The aforementioned procedure involves multiple steps involving selective hydrolysis of two chemically similar functionalities e.g. hydrolysis of methyl ester in the presence of tert. -butyl ester, and reduction with sodium borohydride in the presence of iodine or with borane dimethyl sulphide which are expensive reagents and are air- and moisture-sensitive, hence difficult to handle. Summary of the Invention Accordingly, herein are provided processes for preparing (3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pvrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt by using synthetic procedure incorporating particular intermediates. Further, herein are provided processes which are simple and economical, avoid the use of expensive and air- and moisture-sensitive reagents, and avoid selective hydrolysis of methyl ester in the presence of tert-butyl ester. Further, herein are provided processes for the preparation of a compound of Formula I (Formula Removed) which processes compris: (a) reacting an amine of Formula II with methyl isobutyryl acetate of Formula III (Formula Removed) to form a compound of Formula of IV (wherein R is a hydroxy protecting group, for example, acetyl, benzoyl, tetrahydiopyranyl, methoxy methyl, methoxy ethoxymethyl, benzyl); (Formula Removed) b) reacting the compound of Formula IV with benzaldehyde to form a compound of Fonnula V; (Formula Removed) c) reacting the compound of Formula V with 4-fluorobenzaldehyde to form a compound of Fonnula VI; d) reacting the compound of Formula VI with a compound of Formula VII (Formula Removed) to form a compound of Formula VIH; (Formula Removed) e) subjecting the compound of Formula VIH simultaneously to acid-catalyzed cleavage of ketal and hydroxy protecting group (when R is tetrahydropyranyl) to form a compound of Formula DC; (Formula Removed) f) subjecting me compound of Formula DC to base-catalyzed hydrolysis to form a compound of Formula X; and (Formula Removed) g) reacting the compound of Formula X with an aqueous solution of calcium acetate to form a compound of Formula I. This process may involve one or more of the following features. For example, reaction of an amine of Formula II can be carried out in the presence of one or more organic bases such as, for example, triethylamine, pyridine, 1,2-ethylenediamine or mixtures thereof, in one or more aromatic solvents, for example, xylene, toluene or mixtures thereof. In another feature, the reaction of a compound of Formula IV can be carried out in the presence of one or more organic bases such as, for example, piperidine, pyridine, P-alanine or mixtures thereof, one or more organic acids such as, for example, glacial acetic acid or benzoic acid or mixture of organic bases and organic acids, in one or more solvents such as, for example, hydrocarbon solvents (e.g., hexane or heptane), halogenated solvents {e.g., dichloromethane, dichloroethane or chloroform), aromatic solvents (e.g„ toluene or xylene) or mixtures thereof. In another feature, the reaction of a compound of Formula V can be carried out in the presence of one or more catalysts such as, for example, sodium cyanide, 3-ethyl-5- (2-hydroxyethyl)-4-methyl thiazotium bromide, 3-benzyl-5-(2-hydroxyethyl)-4-methyl thiazolium chloride or mixtures thereof, one or more organic bases such as, for example, triethylamine, pyridine or mixtures thereof, in a solvent-free condition or in one or more solvents such as, for example, protic polar solvents (e.g., methanol, ethanol, propanol, isopropanol or water), ethers (e.g., dioxan or tetrahydrofuran) or mixtures thereof. In another feature, the reaction of a compound of Formula VI can be carried out in the presence of one or more organic acids such as, for example, pivalic acid, p-toluene sulfonic acid or mixtures thereof, in one or more solvents such as, for example, aromatic solvents (e.g., xylene or toluene), hydrocarbon solvents (e.g., hexane or heptane), ethers (e.g., tetrahydrofuran, dioxane or diethyl ether) or mixtures thereof. In another feature, the cleavage of ketal and hydroxy protecting group of a compound of Formula VIA can be carried out in the presence of one or more mineral acids such as, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid or mixtures thereof, in one or more solvents such as, for example, protic polar solvents (e.g., methanol, ethanol, propanol or water), ethers (e.g., tetrahydrofuran or diethyl ether) or mixtures thereof. In yet another feature, the hydrolysis of a compound of Formula IX can be carried out in the presence of one or more bases such as, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide or mixtures thereof, in one or more solvents such as, for example, protic polar solvents (e.g., methanol, ethanol, propanol, isopropanol or water), ethers (e.g., tetrahydrofuran or diethyl ether) or mixtures thereof. Detailed Description of the Invention (3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt described herein may be prepared by following, for example, reaction sequences as depicted in Scheme I. (Scheme Removed) (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt of Formula I can be prepared, for example, according to Scheme I. Thus, an amine of Formula I can be reacted with methyl isobutyryl acetate of Formula HI to form a compound of Formula of IV (wherein R is the same as defined earlier). The compound of Formula IV can be reacted with benzaldehyde to form a compound of Formula V. The compound of Formula V can be reacted with 4-fluorobenzaldehyde to form a compound of Formula VI. The compound of Formula VI can be reacted with a compound of Formula VTI to form a compound of Formula VDI. The compound of Formula VDI can be simultaneously subject to acid catalyzed cleavage of ketal and hydroxy protecting group (when R is tetrahydropyranyl) to form a compound of Formula IX. The compound of Formula DC can be subject to alkali base catalyzed hydrolysis to form a compound of Formula X. The compound of Formula X can be further converted to hemi calcium salt of Formula I by following procedures known to those of skill in the art. The reaction of an amine of Formula II can be carried out in one or more aromatic solvents, for example, xylene, toluene or mixtures thereof. The reaction can also be carried out in the presence of one or more organic bases, for example, triethylamine, pyridine, 1,2-ethylenediamine or mixtures thereof. The reaction of a compound of Formula TV can be carried out in one or more solvents, for example, hydrocarbon solvents (e.g., hexane or heptane), or halogenated solvents (e.g., dichloromethane, dichloroethane or chloroform), aromatic solvents (e.g., toluene or xylene) or mixtures thereof. The reaction can also be carried out in the presence of one or more organic bases, for example, piperidine, pyridine or ß-lanine, one or more organic acids, for example, glacial acetic acid or benzoic acid or mixtures of organic bases and organic acids. The reaction of a compound of Formula V can be carried out in the presence of one or more catalysts, for example, sodium cyanide, 3-ethyl-5- (2-hydroxyethyl)-4-methyl thiazolium bromide, 3-benzyl-5- (2-hydroxyethyl)-4-methyl thiazolium chloride or mixtures thereof. The reaction can also be carried out in the presence of one or more organic bases, for example, triethylamine, pyridine or mixture thereof, in a solvent-free condition or in one or more solvents, for example, protic polar solvents (e.g„ methanol, ethanol, propanol, isopropanol or water), ethers (e.g., dioxan or tetrahydrofuran) or mixtures thereof. The reaction of a compound of Formula VI can be carried out in one or more solvents, for example, aromatic solvents (e.g„ xylene or toluene), hydrocarbon solvents (e.g., hexane or heptane), ethers (e.g., tetrahydrofuran, dioxane or diethyl ether) or mixtures thereof. The reaction can also be carried out in the presence of one or more organic acids, for example, pivalic acid, p-toluene sulfonic acid or mixtures thereof. The cleavage of ketal and hydroxy protecting group of a compound of Formula Vm can be carried out in the presence of one or more mineral acids, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid or mixtures thereof. The reaction can also be carried out in one or more solvents, for example, protic polar solvents (e.g., methanol, ethanol, propanol or water), ethers (e.g., tetrahydrofuran or diethyl ether) or mixtures thereof. The cleavage of ketal and hydroxy protecting group can also be carried out by any other cleavage method known to those of skill in the art. The hydrolysis of a compound of Formula IX can be carried out in the presence of one or more bases, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide or mixtures thereof. The reaction can also be carried out in one or more solvents, for example, protic polar solvents (e.g, methanol, ethanol, propanol, isopropanol or water), ethers (e.g., tetrahydrofuran or diethyl ether) or mixtures thereof. The compound of Formula X can be converted into its corresponding hemi calcium salt of Formula I by following procedure known to those of skill in the art. In the above schemes, 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 within the scope of the present invention. Examples Example 1: Preparation of 4-methvl-3-oxo-pentanoic acid r4-(tetrahvdropvran-2-yloxymethvfl phenyl") amide A mixture of 4-(tetrahydropyran-2-yloxymethyl) phenyl amine (70 g, 0.34 mol, 1 equiv (prepared following the procedure mentioned in JMed. Chenu, 41,26, (1998), 5297-5309; and Tetrahedron Lett., 41, 30, (2002), 5353), methyl isobutyryl acetate (49 g, 0.34 mol, 1 equiv.), toluene (600 mL) and 1,2-ethylenediamine (2.0 g, 0.034 mol, 0.1 equiv.) was placed in a 2-necked round bottom flask and the reaction mixture was refluxed under a Dean-Stark set up. After completion of the reaction, the solvent was removed under vacuum. The crude product was taken as such for next step. Yield: 116g (crude) MS (-Honmode): m /z 320.16 (M+ 1); !HNMR(CDCl3, 300Hz): S 1.27(d, J=6Hz, 6H); 1.33(s, 2H); 1.54-1.72(m, 7H); 2.74(sep, J=6Hz, 1H); 3.52-3.56(m, 1H); 3.61(s, 2H); 3.87-3.95(m, 1H); 4.47(d, J»12Hz, 1H); 4.68(m, 1H); 4.74(d, J=12Hz, 1H); 7.32(d, J=9Hz, 2H); 7.53(d, J=6Hz, 2H); 9.22(brs, 1H). Example 2: Preparation of 2-benzvlidine-4-methyl-3-oxo-pentanoic acid [4-(tetrahydro-pyran-2-vloxv methyl phenyl] amide A mixture of crude 4-methyl-3-oxo-pentanoic acid [4-(tetrahydropyran-2-yloxy methyl) phenyl] amide (100 g, 0.31 mol, 1 equiv.), B-alanine (5.6 g, 0.063 mol, 0.2 equiv.), benzaldehyde (30.5 mL, 0.31 mol, 1 equiv.), glacial acetic acid (10.6 mL, 0.19 mol, 0.6 equiv.) and hexane (500 mL) was placed in a 2 necked-flask equipped with a Dean-Stark setup. The reaction mixture was refluxed with azeotropic removal of water. At the end of the reaction (TLC monitoring) the solvent was evaporated under reduced pressure to give solid, which was washed with hot hexane, and the solid was collected on a Buchner funnel. The crude compound was purified on column (silioa gel, 100-200 mesh, 15% ethyl acetate/hexane) to afford the pure product. Yield: 66.81 g (52.36%). MS (+ion mode): m/z 408.12 (M+ 1); JH NMR(CDC13,300Hz): 5 1.22(d, J=6.0Hz, 6H); 1.52-1.85(m, 8H); 3.35(sep, J=6Hz, 1H); 3.52-3.56(m, 1H); 3.87-3.91(m, 1H); 4.47(d, J=12Hz, 1H); 4.68-4.7(m, 1H); 4.75(d, J=12Hz, 1H); 7.32-7.64(m, 11H). Example 3: Preparation of 2-[2-f4-fluorophenvlV2-pxo-l-phenylethvl1-4-methyl-3-oxo-pentanoic acid T4-f tetrahydropyran-2-vloxv methvl phenyl! amide A mixture of 2-benzylidine-4-methyl-3-oxo-pentanoic acid [4-(tetrahydropyran-2-yloxy methyl) phenyl] amide (5.0 g, 0.012 mol, 1 equiv.), 4-fluorobenzaldehyde (1.5 mL, 0.0013 mol, 1.1 equiv.), 3-ethyl-5- (2-hydroxyethyl)-4-methylthiazolium bromide (0.77 g, 0.0003 mol, 0.25 equiv.), triethyl amine (dry, 10 mL, 0.0072 mol, 5.8 equiv.) were placed in round bottom flask, and purged with nitrogen gas. The reaction mixture was refluxed at 90° C for about 6 hours. After the reaction was over, the reaction mixture was extracted with ethyl acetate and washed with water, and dried over anhydrous sodium sulphate. Organic layer was concentrated and the crude mixture was purified on column (silica gel, 100-200 mesh, 17% ethyl acetate/hexane) to afford the pure product. Yield: 2.52g (38.6%) MS (+ionmode): m/z 532.17 (M+ 1); 'HNMR(CDCl3, 300Hz): 8 1.15(d,J=6.0Hz,3H); 1.23(d,J=6.0Hz,3H); 1.45-1.851(m, 6 H); 2.85-3.05(m, 1H); 3.20-3.55(m, 1H); 3.70-3.95(m, 1H); 4.40-4.53(m, 2H); 4.67-4.72(m, 2H); 5.34(d,J=9.0Hz, 1H); 7.01-7.28(m, 12H); 7.95-8.00(m, 2H). Example 4: Preparation of rf4R.6RV6-f2-(2-(4-fluorophenvl)-5-isopropvl-3-phenvl-4-r4-ftetrahvdropyran-2-yloxy methyD phenyl anuno^carbnovl]pyrrol-l-vl>emvlV2.2-dimethyl-n.Sldioxan^-yll-acetic acid tert-butvl ester A mixture of 2-[2-(4-fluorophenyl)-2-oxo-l-phenylethyl]-4-methyl-3-oxo-pentanoic acid [4-(tetrahydropyran-2-yloxy methyl)phenyl] amide (2.0 g, 0.004 mol, 1 equiv.), an amine of Formula IX (1.5 g, 0.006 mol, 1.5 equiv.), pivalic aoid (0.45 mL, 0.004 mol, 1.03 equiv.), and heptane:toluene:tetrahydrofuran (4:1:1,24 ml) was placed in a round bottom flask equipped with a Dean-Stark setup. The reaction mixture was refluxed at with azeotropic removal of water. After the completion of reaction (TLC monitoring), the solvents were removed on a rotary evaporator. The residue was diluted with ethyl acetate and a saturated solution of sodium bicarbonate was added to this solution. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated. The crude mixture was purified on column (silica gel, 100-200 mesh, 15% ethyl acetate/hexane) to obtain the pure product. Yield: 1.0 g (34.6%). MS (-Honmode): m/z769.45 (M+ 1); lHNMR(CDCl3, 300Hz): 8 0.9-l.l(m, 2H); 1.30(s, 1H), 1.36(s, 3H); 1.43(s, 9H); 1.50-1.77(m,14 6H); 2.20-2.40(m, 2H); 3.52-3.70(m, 3H); 3.85-3.89(m, 2H); 4.05-4.25(m, 2H); 4.40(d, J=12 Hz,lH);4.64-4.70(m, 2H); 6.86-7.25(m, 14H). Example 5: Preparation of r3R.5RV7-\|"2-(4-fluor7phenvl)-4-(4-hydroxvmethvl- phenvlamino) oarbnovlV5-isopropyl-3-phenvlpyrrol-l-vll-3.5-djhydroxv heptanoio acid tert-butvl ester A mixture of [(4R, 6R)-6-(2- {2-(4-fiuorophenyl)-5-isopropyl-3-phenyl-4- [4-(tetrahydro-pyran-2-yloxy methyl) phenyl amino) catbnoyl]-pyrrol-l-yl}ethyl)-2,2-dimethyl- [1,3] dioxan-4-yl]-acetic acid tert-butyl ester (0.8 g, 0.0015 mol, 1 equiv.) and a mixture of IN hydrochloric acid:methanol:tetrahydrofuran in the ratio 2:5:5 (24 mL) was placed in a single neck flask. The reaction mixture was stirred at room temperature. Reaction mixture was concentrated by evaporating solvent under reduced pressure. The crude compound was extracted with ethyl acetate and the ethyl acetate layer was washed with brine, dried over anhydrous sodium sulphate and concentrated. The crude mixture was purified on column (silica gel, 100-200 mesh, 60% ethyl acetate/hexane) to obtain the pure product. Yield: 446 mg (66.56%). MS (-Honmode): m/z 645.32 (M+ 1); 'H:NMR(CDC13, 300Hz): 8 1.15-1.30(m, 2H); 1.45(s, 9H); 1.47-1.62(m, 8H);2.32(d,J=6.0Hz,2H); 3.53-3.60(m, 2H); 3.69-3.92(m, 1H); 4.08-4.13(m, 2H); 4.58(s, 2H); 6.87(s, 1H); 6.97-7.25(m, 13H). Example 6: Preparation of f3R.5RV7-[2-(4-fluorophenvl)-4-(4-hvdroxv methyl- phenv lamino) carbnoyl)-5-isopropvl-3-phenyl-pyn:ol-l-vl1-3,5-dihvdroxv-heptanoic acid hemi calcium salt Step 1: (3R, 5R)-7-[2-(4-fluorophenyl)-4-(4-hydroxy methyl phenyl amino) carbnoyl)-5-isopropyl-3-phenylpyrrol-l-yl]-3,5-dihydroxyheptanoic acid tert-butyl ester in a mixture of methanol-tetrahydrofuran (1:1) was cooled to 0°C and sodium hydroxide pellets were added. The reaction mixture was then stirred at an ambient temperature. At the end of ester hydrolysis, solvents were removed and the residue was dissolved in water, and the aqueous layer was washed with ether. Step 2: To an aqueous solution of sodium salt of (3R,5R)-7-[2-(4-fluorophenyl)-4-(4-hydroxy methyl- pheny lamino) carbnoyl)-5-isopropyl-3-phenyl-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid was added drop wise an aqueous solution (1M) of calcium acetate (0.55 equiv.). White precipitate was obtained, which was filtered off, washed with copious amount of water, and dried in vacuo. Yield— 63.4% MS (positive ion mode): m/z 589 (Acid+1); m.p. - 189-204°C; lHNMR (DMSO-d6):δ 1.22-1.62 (m, 11H), 1.98 (dd, J=15 & 8.1Hz, 1H), 2.06-2.16 (m, 1H), 3.25-3.37 (m, 2H), 3.57 (brs, 2H), 3.80 (brs, IH), 4.43 (s, 2H), 7.03-7.28 (m, 12H), 7.50 (d, J=6H, 2H), 9.80 (s, IH) We Claim: 1. A method for the preparation of (3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt of Formula I, (Formula Removed) compnsmg: (a) reacting an amine of Formula II with methyl isobutyryl acetate of Formula III (Formula Removed) to form a compound of Formula of IV (wherein R is a hydroxy protecting group selected from acetyl, benzoyl, tetrahydropyranyl, .methoxy methyl, methoxy ethoxymethyl or benzyl); (Formula Removed) b) reacting the compound of Fonnula IV with benzaldehyde to form a compound of Formula V; (Formula Removed) c) reacting the compound of Fonnula 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 VII (Formula Removed) to form a compound of Formula VIII; (Formula Removed) e) subjecting the compound of Fonnula VIII simultaneously to acid-catalyzed cleavage of ketal and hydroxy protecting group (when R is tetrahydropyranyl) to form a compound of Formula DC; (Formula Removed) f) subjecting the compound of Formula DC to base-oatalyzed hydrolysis to form a compound of Formula X; and (Formula Removed) g) reacting the compound of Formula X with aqueous solution of calcium acetate to form a compound of Formula I. 2. The process of claim 1, wherein the reaction of an amine of Formula II is carried out i) in the presence of one or more organic bases; and ii) in one or more aromatic solvents. The process of claim 1, wherein the reaction of a compound of Formula IV is carried out i) in the presence of one or more organic bases selected from piperidine, pyridine or P-alanine; or in the presence off one or more organic acids selected from glacial acetic acid or benzoic acid or in the presence of a mixture of organic bases or organic acids; and ii) in one or more solvents selected from hydrocarbon solvents (selected from hexane or heptane), halogenated solvents (selected from dichloromethane, dichloroethane or chloroform), aromatic solvents (selected from toluene or xylene) or mixtures thereof. The process of claim 1, wherein the reaction of a compound of Formula V is carried out i) in the presence of one or more catalysts selected from sodium cyanide, 3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazolium bromide, 3-benzyl-5- (2-hydroxyethyl)-4-methyl thiazolium chloride or mixtures thereof; ii) in the presence of one or more organic bases selected from triethylamine, pyridine or mixtures thereof; and iii) in a solvent-free condition or in one or more solvents selected from protic polar solvents (selected from methanol, ethanol, propanol, isopropanol or water), ethers (selected from dioxan or tetrahydrofuran) or mixtures thereof. The process of claim 1, wherein the reaction of a compound of Formula VI is carried out i) in the presence of one or more organic acids selected from pivalic acid, p-toluene sulfonic acid or mixtures thereof; and ii) in the presence of one or more solvents selected from aromatic solvents (selected from xylene or toluene), hydrocarbon solvents (selected from hexane or heptane), ethers (selected from tetrahydrofuran, dioxane or diethyl ether) or mixtures thereof. The process of claim 1, wherein the cleavage of ketal and hydroxy protecting group of a compound of Formula VIII is carried out i) in the presence of one or more mineral acids selected from hydrochloric acid, hydrobromic acid, hydroiodic acid or mixtures thereof; and ii) in the presence of one or more solvents selected from protic polaT solvents (selected from methanol, ethanol, propanol or water), ethers (selected from tetrahydrofuran or diethyl ether) or mixtures thereof. 7. The process of claim 1, wherein the hydrolysis of a compound of Formula DC is carried out i) in the presence of one or more bases selected from lithium hydroxide, sodium hydroxide, potassium hydroxide or mixtures thereof; and ii) in the presence of one or more solvents selected from protic polar solvents (selected from methanol, ethanol, propanol, isopropanol or water), ethers (selected from tetrahydrofuran or diethyl ether) or mixtures thereof.

Full Text

Field of the Invention
The present invention relates to processes for the preparation of (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt.
Background of the Invention
(3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt acts an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A- (HMG-CoA) reductase, a coenzyme catalyzing the intracellular synthesis of cholesterol, and thus is useful as hypolipidemic and hypocholesterol-emic agent, as discussed in PCT Publication No. 04/106299.
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 multi-factorial 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.
A synthetic procedure for preparing (3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt has been disclosed in PCT Publication No. WO 04/106299. The aforementioned procedure involves multiple steps involving selective hydrolysis of two chemically similar functionalities e.g. hydrolysis of methyl ester in the presence of tert. -butyl ester, and reduction with sodium borohydride in the presence of iodine or with borane dimethyl sulphide which are expensive reagents and are air- and moisture-sensitive, hence difficult to handle.
Summary of the Invention
Accordingly, herein are provided processes for preparing (3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pvrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt by using synthetic procedure incorporating particular intermediates.
Further, herein are provided processes which are simple and economical, avoid the use of expensive and air- and moisture-sensitive reagents, and avoid selective hydrolysis of methyl ester in the presence of tert-butyl ester.
Further, herein are provided processes for the preparation of a compound of Formula I
(Formula Removed)
which processes compris:
(a) reacting an amine of Formula II with methyl isobutyryl acetate of Formula III
(Formula Removed)
to form a compound of Formula of IV (wherein R is a hydroxy protecting group, for example, acetyl, benzoyl, tetrahydiopyranyl, methoxy methyl, methoxy ethoxymethyl, benzyl);

(Formula Removed)
b) reacting the compound of Formula IV with benzaldehyde to form a compound of Fonnula V;
(Formula Removed)
c) reacting the compound of Formula V with 4-fluorobenzaldehyde to form a compound of Fonnula VI;
d) reacting the compound of Formula VI with a compound of Formula VII
(Formula Removed)
to form a compound of Formula VIH;

(Formula Removed)
e) subjecting the compound of Formula VIH simultaneously to acid-catalyzed cleavage of ketal and hydroxy protecting group (when R is tetrahydropyranyl) to form a compound of Formula DC;
(Formula Removed)
f) subjecting me compound of Formula DC to base-catalyzed hydrolysis to form a

compound of Formula X; and
(Formula Removed)
g) reacting the compound of Formula X with an aqueous solution of calcium acetate to form a compound of Formula I.
This process may involve one or more of the following features. For example, reaction of an amine of Formula II can be carried out in the presence of one or more organic bases such as, for example, triethylamine, pyridine, 1,2-ethylenediamine or mixtures thereof, in one or more aromatic solvents, for example, xylene, toluene or mixtures thereof. In another feature, the reaction of a compound of Formula IV can be carried out in the presence of one or more organic bases such as, for example, piperidine, pyridine, P-alanine or mixtures thereof, one or more organic acids such as, for example, glacial acetic acid or benzoic acid or mixture of organic bases and organic acids, in one or more solvents such as, for example, hydrocarbon solvents (e.g., hexane or heptane), halogenated solvents {e.g., dichloromethane, dichloroethane or chloroform), aromatic solvents (e.g„ toluene or xylene) or mixtures thereof. In another feature, the reaction of a compound of Formula V can be carried out in the presence of one or more catalysts such as, for example, sodium cyanide, 3-ethyl-5- (2-hydroxyethyl)-4-methyl thiazotium bromide, 3-benzyl-5-(2-hydroxyethyl)-4-methyl thiazolium chloride or mixtures thereof, one or more organic bases such as, for example, triethylamine, pyridine or mixtures thereof, in a solvent-free condition or in one or more solvents such as, for example, protic polar solvents (e.g., methanol, ethanol, propanol, isopropanol or water), ethers (e.g., dioxan or tetrahydrofuran) or mixtures thereof. In another feature, the reaction of a compound of Formula VI can be carried out in the presence of one or more organic acids such as, for example, pivalic acid, p-toluene sulfonic acid or mixtures thereof, in one or more solvents such as, for example, aromatic solvents (e.g., xylene or toluene), hydrocarbon solvents (e.g., hexane or heptane), ethers (e.g., tetrahydrofuran, dioxane or diethyl ether) or mixtures thereof. In another feature, the cleavage of ketal and hydroxy protecting group of a compound of Formula VIA can be carried out in the presence of one or more mineral acids such as, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid or mixtures thereof, in one or more solvents such as, for example, protic polar solvents (e.g., methanol, ethanol, propanol or water), ethers (e.g., tetrahydrofuran or diethyl ether) or mixtures thereof. In yet another feature, the hydrolysis of a compound of Formula IX can be carried out in the presence of one or more bases such as, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide or mixtures thereof, in one or more solvents such as, for example, protic
polar solvents (e.g., methanol, ethanol, propanol, isopropanol or water), ethers (e.g., tetrahydrofuran or diethyl ether) or mixtures thereof.
Detailed Description of the Invention (3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt described herein may be prepared by following, for example, reaction sequences as depicted in Scheme I.
(Scheme Removed)
(3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt of Formula I can be prepared, for example, according to Scheme I. Thus, an amine of Formula I can be reacted with methyl isobutyryl acetate of Formula HI to form a compound of Formula of IV (wherein R is the same as defined earlier). The compound of Formula IV can be reacted with benzaldehyde to form a compound of Formula V. The compound of Formula V can be reacted with 4-fluorobenzaldehyde to form a compound of Formula VI. The compound of Formula VI can be reacted with a compound of Formula VTI to form a compound of Formula VDI. The compound of Formula VDI can be simultaneously subject to acid catalyzed cleavage of ketal and hydroxy protecting group (when R is tetrahydropyranyl) to form a compound of Formula IX. The compound of Formula DC can be subject to alkali base catalyzed hydrolysis to form a compound of Formula X. The compound of Formula X can be further converted to hemi calcium salt of Formula I by following procedures known to those of skill in the art.
The reaction of an amine of Formula II can be carried out in one or more aromatic solvents, for example, xylene, toluene or mixtures thereof. The reaction can also be carried out in the presence of one or more organic bases, for example, triethylamine, pyridine, 1,2-ethylenediamine or mixtures thereof.
The reaction of a compound of Formula TV can be carried out in one or more solvents, for example, hydrocarbon solvents (e.g., hexane or heptane), or halogenated solvents (e.g., dichloromethane, dichloroethane or chloroform), aromatic solvents (e.g., toluene or xylene) or mixtures thereof. The reaction can also be carried out in the presence of one or more organic bases, for example, piperidine, pyridine or ß-lanine, one or more organic acids, for example, glacial acetic acid or benzoic acid or mixtures of organic bases and organic acids.
The reaction of a compound of Formula V can be carried out in the presence of one or more catalysts, for example, sodium cyanide, 3-ethyl-5- (2-hydroxyethyl)-4-methyl thiazolium bromide, 3-benzyl-5- (2-hydroxyethyl)-4-methyl thiazolium chloride or mixtures thereof. The reaction can also be carried out in the presence of one or more organic bases, for example, triethylamine, pyridine or mixture thereof, in a solvent-free condition or in one or more solvents,
for example, protic polar solvents (e.g„ methanol, ethanol, propanol, isopropanol or water), ethers (e.g., dioxan or tetrahydrofuran) or mixtures thereof.
The reaction of a compound of Formula VI can be carried out in one or more solvents, for example, aromatic solvents (e.g„ xylene or toluene), hydrocarbon solvents (e.g., hexane or heptane), ethers (e.g., tetrahydrofuran, dioxane or diethyl ether) or mixtures thereof. The reaction can also be carried out in the presence of one or more organic acids, for example, pivalic acid, p-toluene sulfonic acid or mixtures thereof.
The cleavage of ketal and hydroxy protecting group of a compound of Formula Vm can be carried out in the presence of one or more mineral acids, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid or mixtures thereof. The reaction can also be carried out in one or more solvents, for example, protic polar solvents (e.g., methanol, ethanol, propanol or water), ethers (e.g., tetrahydrofuran or diethyl ether) or mixtures thereof. The cleavage of ketal and hydroxy protecting group can also be carried out by any other cleavage method known to those of skill in the art.
The hydrolysis of a compound of Formula IX can be carried out in the presence of one or more bases, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide or mixtures thereof. The reaction can also be carried out in one or more solvents, for example, protic polar solvents (e.g, methanol, ethanol, propanol, isopropanol or water), ethers (e.g., tetrahydrofuran or diethyl ether) or mixtures thereof.
The compound of Formula X can be converted into its corresponding hemi calcium salt of Formula I by following procedure known to those of skill in the art.
In the above schemes, 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 within the scope of the present invention.
Examples
Example 1: Preparation of 4-methvl-3-oxo-pentanoic acid r4-(tetrahvdropvran-2-yloxymethvfl phenyl") amide
A mixture of 4-(tetrahydropyran-2-yloxymethyl) phenyl amine (70 g, 0.34 mol, 1 equiv (prepared following the procedure mentioned in JMed. Chenu, 41,26, (1998), 5297-5309; and Tetrahedron Lett., 41, 30, (2002), 5353), methyl isobutyryl acetate (49 g, 0.34 mol, 1 equiv.), toluene (600 mL) and 1,2-ethylenediamine (2.0 g, 0.034 mol, 0.1 equiv.) was placed in a 2-necked round bottom flask and the reaction mixture was refluxed under a Dean-Stark set up. After completion of the reaction, the solvent was removed under vacuum. The crude product was taken as such for next step. Yield: 116g (crude)
MS (-Honmode): m /z 320.16 (M+ 1); !HNMR(CDCl3, 300Hz): S 1.27(d, J=6Hz, 6H); 1.33(s, 2H); 1.54-1.72(m, 7H); 2.74(sep, J=6Hz, 1H); 3.52-3.56(m, 1H); 3.61(s, 2H); 3.87-3.95(m, 1H); 4.47(d, J»12Hz, 1H); 4.68(m, 1H); 4.74(d, J=12Hz, 1H); 7.32(d, J=9Hz, 2H); 7.53(d, J=6Hz, 2H); 9.22(brs, 1H).
Example 2: Preparation of 2-benzvlidine-4-methyl-3-oxo-pentanoic acid [4-(tetrahydro-pyran-2-vloxv methyl phenyl] amide
A mixture of crude 4-methyl-3-oxo-pentanoic acid [4-(tetrahydropyran-2-yloxy methyl) phenyl] amide (100 g, 0.31 mol, 1 equiv.), B-alanine (5.6 g, 0.063 mol, 0.2 equiv.), benzaldehyde (30.5 mL, 0.31 mol, 1 equiv.), glacial acetic acid (10.6 mL, 0.19 mol, 0.6 equiv.) and hexane (500 mL) was placed in a 2 necked-flask equipped with a Dean-Stark setup. The reaction mixture was refluxed with azeotropic removal of water. At the end of the reaction (TLC monitoring) the solvent was evaporated under reduced pressure to give solid, which was washed with hot hexane, and the solid was collected on a Buchner funnel. The crude compound was purified on column (silioa gel, 100-200 mesh, 15% ethyl acetate/hexane) to afford the pure product. Yield: 66.81 g (52.36%).
MS (+ion mode): m/z 408.12 (M+ 1); JH NMR(CDC13,300Hz): 5 1.22(d, J=6.0Hz, 6H); 1.52-1.85(m, 8H); 3.35(sep, J=6Hz, 1H); 3.52-3.56(m, 1H); 3.87-3.91(m, 1H); 4.47(d, J=12Hz, 1H); 4.68-4.7(m, 1H); 4.75(d, J=12Hz, 1H); 7.32-7.64(m, 11H).
Example 3: Preparation of 2-[2-f4-fluorophenvlV2-pxo-l-phenylethvl1-4-methyl-3-oxo-pentanoic acid T4-f tetrahydropyran-2-vloxv methvl phenyl! amide
A mixture of 2-benzylidine-4-methyl-3-oxo-pentanoic acid [4-(tetrahydropyran-2-yloxy methyl) phenyl] amide (5.0 g, 0.012 mol, 1 equiv.), 4-fluorobenzaldehyde (1.5 mL, 0.0013 mol, 1.1 equiv.), 3-ethyl-5- (2-hydroxyethyl)-4-methylthiazolium bromide (0.77 g, 0.0003 mol, 0.25 equiv.), triethyl amine (dry, 10 mL, 0.0072 mol, 5.8 equiv.) were placed in round bottom flask, and purged with nitrogen gas. The reaction mixture was refluxed at 90° C for about 6 hours. After the reaction was over, the reaction mixture was extracted with ethyl acetate and washed with water, and dried over anhydrous sodium sulphate. Organic layer was concentrated and the crude mixture was purified on column (silica gel, 100-200 mesh, 17% ethyl acetate/hexane) to afford the pure product. Yield: 2.52g (38.6%)
MS (+ionmode): m/z 532.17 (M+ 1); 'HNMR(CDCl3, 300Hz): 8 1.15(d,J=6.0Hz,3H); 1.23(d,J=6.0Hz,3H); 1.45-1.851(m, 6 H); 2.85-3.05(m, 1H); 3.20-3.55(m, 1H); 3.70-3.95(m, 1H); 4.40-4.53(m, 2H); 4.67-4.72(m, 2H); 5.34(d,J=9.0Hz, 1H); 7.01-7.28(m, 12H); 7.95-8.00(m, 2H).
Example 4: Preparation of rf4R.6RV6-f2-(2-(4-fluorophenvl)-5-isopropvl-3-phenvl-4-r4-ftetrahvdropyran-2-yloxy methyD phenyl anuno^carbnovl]pyrrol-l-vl>emvlV2.2-dimethyl-n.Sldioxan^-yll-acetic acid tert-butvl ester
A mixture of 2-[2-(4-fluorophenyl)-2-oxo-l-phenylethyl]-4-methyl-3-oxo-pentanoic acid [4-(tetrahydropyran-2-yloxy methyl)phenyl] amide (2.0 g, 0.004 mol, 1 equiv.), an amine of Formula IX (1.5 g, 0.006 mol, 1.5 equiv.), pivalic aoid (0.45 mL, 0.004 mol, 1.03 equiv.), and heptane:toluene:tetrahydrofuran (4:1:1,24 ml) was placed in a round bottom flask equipped with a Dean-Stark setup. The reaction mixture was refluxed at with azeotropic removal of water. After the completion of reaction (TLC monitoring), the solvents were removed on a rotary evaporator. The residue was diluted with ethyl acetate and a saturated solution of sodium bicarbonate was added to this solution. The aqueous layer was extracted with ethyl acetate and
the organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated. The crude mixture was purified on column (silica gel, 100-200 mesh, 15% ethyl acetate/hexane) to obtain the pure product. Yield: 1.0 g (34.6%).
MS (-Honmode): m/z769.45 (M+ 1); lHNMR(CDCl3, 300Hz): 8 0.9-l.l(m, 2H); 1.30(s, 1H), 1.36(s, 3H); 1.43(s, 9H); 1.50-1.77(m,14 6H); 2.20-2.40(m, 2H); 3.52-3.70(m, 3H); 3.85-3.89(m, 2H); 4.05-4.25(m, 2H); 4.40(d, J=12 Hz,lH);4.64-4.70(m, 2H); 6.86-7.25(m, 14H).
Example 5: Preparation of r3R.5RV7-|"2-(4-fluor7phenvl)-4-(4-hydroxvmethvl- phenvlamino) oarbnovlV5-isopropyl-3-phenvlpyrrol-l-vll-3.5-djhydroxv heptanoio acid tert-butvl ester
A mixture of [(4R, 6R)-6-(2- {2-(4-fiuorophenyl)-5-isopropyl-3-phenyl-4- [4-(tetrahydro-pyran-2-yloxy methyl) phenyl amino) catbnoyl]-pyrrol-l-yl}ethyl)-2,2-dimethyl- [1,3] dioxan-4-yl]-acetic acid tert-butyl ester (0.8 g, 0.0015 mol, 1 equiv.) and a mixture of IN hydrochloric acid:methanol:tetrahydrofuran in the ratio 2:5:5 (24 mL) was placed in a single neck flask. The reaction mixture was stirred at room temperature. Reaction mixture was concentrated by evaporating solvent under reduced pressure. The crude compound was extracted with ethyl acetate and the ethyl acetate layer was washed with brine, dried over anhydrous sodium sulphate and concentrated. The crude mixture was purified on column (silica gel, 100-200 mesh, 60% ethyl acetate/hexane) to obtain the pure product. Yield: 446 mg (66.56%).
MS (-Honmode): m/z 645.32 (M+ 1); 'H:NMR(CDC13, 300Hz): 8 1.15-1.30(m, 2H); 1.45(s, 9H); 1.47-1.62(m, 8H);2.32(d,J=6.0Hz,2H); 3.53-3.60(m, 2H); 3.69-3.92(m, 1H); 4.08-4.13(m, 2H); 4.58(s, 2H); 6.87(s, 1H); 6.97-7.25(m, 13H).
Example 6: Preparation of f3R.5RV7-[2-(4-fluorophenvl)-4-(4-hvdroxv methyl- phenv lamino) carbnoyl)-5-isopropvl-3-phenyl-pyn:ol-l-vl1-3,5-dihvdroxv-heptanoic acid hemi calcium salt
Step 1: (3R, 5R)-7-[2-(4-fluorophenyl)-4-(4-hydroxy methyl phenyl amino) carbnoyl)-5-isopropyl-3-phenylpyrrol-l-yl]-3,5-dihydroxyheptanoic acid tert-butyl ester in a mixture of methanol-tetrahydrofuran (1:1) was cooled to 0°C and sodium hydroxide pellets were added. The reaction mixture was then stirred at an ambient temperature. At the end of ester hydrolysis, solvents were removed and the residue was dissolved in water, and the aqueous layer was washed with ether.
Step 2: To an aqueous solution of sodium salt of (3R,5R)-7-[2-(4-fluorophenyl)-4-(4-hydroxy methyl- pheny lamino) carbnoyl)-5-isopropyl-3-phenyl-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid was added drop wise an aqueous solution (1M) of calcium acetate (0.55 equiv.). White precipitate was obtained, which was filtered off, washed with copious amount of water, and dried in vacuo. Yield— 63.4%
MS (positive ion mode): m/z 589 (Acid+1); m.p. - 189-204°C; lHNMR (DMSO-d6):δ 1.22-1.62 (m, 11H), 1.98 (dd, J=15 & 8.1Hz, 1H), 2.06-2.16 (m, 1H), 3.25-3.37 (m, 2H), 3.57 (brs, 2H), 3.80 (brs, IH), 4.43 (s, 2H), 7.03-7.28 (m, 12H), 7.50 (d, J=6H, 2H), 9.80 (s, IH)

We Claim:
1. A method for the preparation of (3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt of Formula I,
(Formula Removed)
compnsmg:
(a) reacting an amine of Formula II with methyl isobutyryl acetate of Formula III
(Formula Removed)
to form a compound of Formula of IV (wherein R is a hydroxy protecting group selected from acetyl, benzoyl, tetrahydropyranyl, .methoxy methyl, methoxy ethoxymethyl or benzyl);
(Formula Removed)
b) reacting the compound of Fonnula IV with benzaldehyde to form a compound of Formula V;
(Formula Removed)
c) reacting the compound of Fonnula 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 VII
(Formula Removed)
to form a compound of Formula VIII;
(Formula Removed)
e) subjecting the compound of Fonnula VIII simultaneously to acid-catalyzed cleavage of ketal and hydroxy protecting group (when R is tetrahydropyranyl) to form a compound of Formula DC;
(Formula Removed)
f) subjecting the compound of Formula DC to base-oatalyzed hydrolysis to form a compound of Formula X; and
(Formula Removed)
g) reacting the compound of Formula X with aqueous solution of calcium acetate to form a compound of Formula I.
2. The process of claim 1, wherein the reaction of an amine of Formula II is carried out
i) in the presence of one or more organic bases; and
ii) in one or more aromatic solvents.
The process of claim 1, wherein the reaction of a compound of Formula IV is carried out
i) in the presence of one or more organic bases selected from piperidine, pyridine or P-alanine; or in the presence off one or more organic acids selected from glacial acetic acid or benzoic acid or in the presence of a mixture of organic bases or organic acids; and
ii) in one or more solvents selected from hydrocarbon solvents (selected from hexane or heptane), halogenated solvents (selected from dichloromethane, dichloroethane or chloroform), aromatic solvents (selected from toluene or xylene) or mixtures thereof.
The process of claim 1, wherein the reaction of a compound of Formula V is carried out
i) in the presence of one or more catalysts selected from sodium cyanide, 3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazolium bromide, 3-benzyl-5- (2-hydroxyethyl)-4-methyl thiazolium chloride or mixtures thereof;
ii) in the presence of one or more organic bases selected from triethylamine, pyridine or mixtures thereof; and
iii) in a solvent-free condition or in one or more solvents selected from protic polar solvents (selected from methanol, ethanol, propanol, isopropanol or water), ethers (selected from dioxan or tetrahydrofuran) or mixtures thereof.
The process of claim 1, wherein the reaction of a compound of Formula VI is carried out
i) in the presence of one or more organic acids selected from pivalic acid, p-toluene
sulfonic acid or mixtures thereof; and
ii) in the presence of one or more solvents selected from aromatic solvents (selected from xylene or toluene), hydrocarbon solvents (selected from hexane or heptane), ethers (selected from tetrahydrofuran, dioxane or diethyl ether) or mixtures thereof.
The process of claim 1, wherein the cleavage of ketal and hydroxy protecting group of a compound of Formula VIII is carried out
i) in the presence of one or more mineral acids selected from hydrochloric acid, hydrobromic acid, hydroiodic acid or mixtures thereof; and
ii) in the presence of one or more solvents selected from protic polaT solvents (selected from methanol, ethanol, propanol or water), ethers (selected from tetrahydrofuran or diethyl ether) or mixtures thereof.
7. The process of claim 1, wherein the hydrolysis of a compound of Formula DC is carried out
i) in the presence of one or more bases selected from lithium hydroxide, sodium hydroxide, potassium hydroxide or mixtures thereof; and
ii) in the presence of one or more solvents selected from protic polar solvents (selected from methanol, ethanol, propanol, isopropanol or water), ethers (selected from tetrahydrofuran or diethyl ether) or mixtures thereof.

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Patent Number

268571

Indian Patent Application Number

3930/DELNP/2008

PG Journal Number

36/2015

Publication Date

04-Sep-2015

Grant Date

03-Sep-2015

Date of Filing

07-May-2008

Name of Patentee

RANBAXY LABORATORIES LIMITED

Applicant Address

PLOT NO, 90, SECTOR-32, GURGAON 122001, HARYANA, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	SETHI, SACHIN	C-II-50, CHHACHHRAULI GATE JAGADHRI, YAMUNA NAGAR 135003, HARYANA (IN)
2	KISHORE, KAUSHAL	ORIAWAN POST, EKANGER SARAI (VIA), NALANDA 801301, BIHAR (IN)
3	SATTIGERI, JITENDRA, ANANT	N-323, VIJAY RATTAN VIHAR, SECTOR 15-II GURGAON 122001, HARYANA, INDIA.

PCT International Classification Number

C07D 207/34

PCT International Application Number

PCT/IB2006/003153

PCT International Filing date

2006-11-08

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2964/DEL/2005	2005-11-08	India
2	2967/DEL/2005	2005-11-08	India
3	3033/DEL/2005	2005-11-14	India