WO2016142954A2 - IMPROVED PROCESS FOR THE PREPARATION OF [3R,5R]-2-FLUOROPHENYL-β,δ- DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(2-HYDROXYPHENYLAMINO)- CARBONYL]-1H-PYRROLE-1-HEPTANOIC ACID, SODIUM SALT - Google Patents

IMPROVED PROCESS FOR THE PREPARATION OF [3R,5R]-2-FLUOROPHENYL-β,δ- DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(2-HYDROXYPHENYLAMINO)- CARBONYL]-1H-PYRROLE-1-HEPTANOIC ACID, SODIUM SALT Download PDF

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WO2016142954A2
WO2016142954A2 PCT/IN2016/000062 IN2016000062W WO2016142954A2 WO 2016142954 A2 WO2016142954 A2 WO 2016142954A2 IN 2016000062 W IN2016000062 W IN 2016000062W WO 2016142954 A2 WO2016142954 A2 WO 2016142954A2
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formula
compound
phenyl
fluorophenyl
pyrrole
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PCT/IN2016/000062
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WO2016142954A3 (en
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Srinivasan Thirumalai Rajan
Muppa Kishore Kumar
Durgadas Shyla Prasad
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Msn Laboratories Private Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to an improved process for the preparation of [3R,5R]- 2-fluorophenyl-P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2-hydroxyphenylamino)- carbonyl]-l H-pyrrole- 1-heptanoic acid, sodium salt compound of formula- 1 represented by the following structural formula.
  • the present invention also relates to an amorphous [3R,5R]-2-fluorophenyl-P,6- dihydroxy-5 -( 1 -methylethyl)-3 -phenyl-4- [(2-hydroxyphenylamino)-carbonyl]- 1 H-pyrrole- 1 - heptanoic acid, sodium salt compound of formula- 1 and process for its preparation.
  • Atorvastatin ([R-(R*,R*)]-2-(4-fluorophenyl)-p,6-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-l H-pyrrole- 1-heptanoic acid), and its calcium salt are known in the art, and described, in U.S. Pat. No. 4,681 ,893 and US 5,273,995.
  • Atorvastatin is a member of the class of drugs called statins.
  • Statin drugs are currently the most therapeutically effective drugs available for reducing low density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease.
  • Atorvastatin hemi-calcium salt trihydrate is marketed under the name LIPITOR by Warner-Lambert Co.
  • Atorvastatin as well as some of its metabolites are pharmacologically active in humans and are thus useful as a hypolipidemic and hypocholesterolemic agent.
  • Atorvastatin is extensively metabolized to ortho- and para-hydroxylated derivatives by cytochrome P-450 3A4 (CYP 3A4) and to various beta-oxidation products.
  • CYP 3A4 cytochrome P-450 3A4
  • inhibition of HMG-CoA reductase by ortho- and para-hydroxylated metabolites is equivalent to that of atorvastatin.
  • Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to ortho- and para-hydroxylated derivative active metabolites.
  • WO2013/073775 Al discloses process for the preparation of atorvastatin metabolites using enzymes. Moreover carrying out the reactions in the enzymes, takes very long reaction times, low yields and also large dilutions are required in which it is necessary to work. Brief description of the Invention:
  • the first aspect of the present invention is to provide a process for the preparation of [3R,5R]-2-fluorophenyl- ,6-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2-hydroxyphenyl amino)-carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1.
  • the second aspect of the present invention is to provide amorphous [3R,5R]-2- fluorophenyl-P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2-hydroxyphenylamino)- carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1.
  • the third aspect of the present invention is to provide a process for the preparation of amorphous [3R,5R]-2-fluorophenyl-P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2- hydroxyphenylamino)-carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1.
  • the fourth aspect of the present invention is to provide a one-pot process for the preparation of compound of formula-13.
  • the fifth aspect of the present invention is to provide a process for the purification of N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)-l-(2-((2R,4R)-4-hydroxy-6-oxotetrahydro-2H- pyran-2-yl)ethyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxamide compound of formula-13.
  • Figure 1 Illustrates the PXRD pattern of amorphous [3R,5R]-2-fiuorophenyl-P,6-dihydroxy- 5-( 1 -methylethyl)-3 -phenyl-4- [(2-hydroxyphenylamino)-carbonyl] - 1 H-pyrrole- 1 -heptanoic acid, sodium salt.
  • suitable solvent refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, pentane, cycloheptane, methylcyclohexane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene and the like; "ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1
  • suitable base used herein the present invention until unless specified is selected from inorganic bases like "alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; ammonia; and organic bases such as triethyl amine, methyl amine, ethyl amine, 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-
  • suitable debenzylating reagents that can be used in the reaction include, but are not limited to, a noble metal catalyst such as nickel, palladium, platinum, iridium, ruthenium and the like, in combination with hydrogen.
  • the suitable acid source is selected from HC1 gas, aqueous HC1, dry HC1, ethyl acetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl.
  • the first aspect of the present invention provides a process for the preparation of [3R,5R]-2-fluorophenyl-P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2-hydroxyphenyl amino)-carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1, comprising of the following steps:
  • the suitable base is selected from organic base or inorganic base;
  • the suitable acid is selected from trifluoro acetic acid or hydrochloric acid; in step-f) the suitable acid is hydrochloric acid; in step-a) to step-j) the suitable solvent is selected from alcohol solvents, chloro solvents, ester solvents, polar aprotic solvents, ketone solvents, ether solvents, hydrocarbon solvents and polar solvent like water or mixture thereof.
  • the preferred embodiment of the present invention provides a process for the preparation of [3R,5R]-2-fluorophenyl- ,8-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2- hydroxyphenylamino)-carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1, comprising of the following steps:
  • impurities in API's result primarily from one of two sources, (I) the manufacturing process (or) synthesis of the API and (II) from the degradation of the API itself.
  • the present invention also involves the none of the ICH class 1 solvent in the manufacturing of [3R,5R]-2-fluorophenyl-p*6-dihydroxy-5-(l-methyl ethyl)-3-phenyl-4-[(2- hydroxyphenylamino)-carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1.
  • the second aspect of the present invention provides amorphous [3R,5R]-2- fluorophenyl-p,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2-hydroxyphenylamino)- carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1, which is characterized by P-XRD pattern as depicted in figure- 1.
  • the third aspect of the present invention provides a process for the preparation of amorphous [3R,5R]-2-fiuorophenyl-P,6-dihydroxy-5-( 1 -methylethyl)-3-phenyl-4-[(2- hydroxyphenylamino)-carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1, comprising of the following steps:
  • step-b) the suitable temperature is ranging from 0°C-20°C;
  • the suitable base is selected from organic or inorganic base
  • the suitable solvent is selected from alcohol solvents, chloro solvents, ester solvents, polar aprotic solvents, ketone solvents, ether solvents, hydrocarbon solvents and polar solvent like water or mixture thereof.
  • the preferred embodiment of the present invention provides a process for the preparation of amorphous [3R,5R]-2-fluorophenyl-P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(2-hydroxyphenylamino)-carbonyl]-lH-pyrrole-l -heptanoic acid, sodium salt compound of formula- 1, comprising of the following steps:
  • the fourth aspect of the present invention provides a one-pot process for the preparation of N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)-l-(2-((2R,4R)-4-hydroxy-6-oxo tetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl- 1 H-pyrrole-3 -carboxamide compound of formula- 13 , comprising of the following steps:
  • the suitable acid is hydrochloric acid; the suitable base is selected from
  • the suitable solvent is selected from selected from alcohol solvents, chloro solvents, ester solvents, polar aprotic solvents, ketone solvents, ether solvents, hydrocarbon solvents and polar solvent like water or their mixtures thereof.
  • the preferred embodiment of the present invention provides a one-pot process for the preparation of N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)- 1 -(2-((2R,4R)-4-hydroxy-6-oxo tetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl- 1 H-pyrrole-3 -carboxamide compound of formula- 13 , comprising of the following steps:
  • 2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula-10 in presence of pivalic acid in cyclohexane provide tert-butyl 2-((4R,6R)-6-(2-(3-(2-(benzyloxy)phenyl carbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-lH-pyrrol-l-yl)ethyl)-2,2- dimethyl-l,3-dioxan-4-yl)acetate compound of formula-11, which on hydrolysis in- situ by treating it with aqueous hydrochloric acid in acetonitrile to provide compound of formula- 12 and which on further treating with aqueous sodium hydroxide in methanol to provide N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)-l-(2-((2R,4R)-4- hydroxy-6-oxote
  • the fifth aspect of the present invention provides a process for the purification of N- (2-(benzyloxy)phenyl)-5-(4-fluorophenyl)-l-(2-((2R,4R)-4-hydroxy-6-oxotetrahydro-2H- pyran-2-yl)ethyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxamide compound of formula- 13, comprising of the following steps:
  • the suitable solvent is selected from alcohol solvents, chloro solvents, ester solvents, polar aprotic solvents, ketone solvents, ether solvents, hydrocarbon solvents and polar solvent like water or mixture thereof;
  • step-b) the suitable temperature is ranging from ambient temperature to reflux temperature of the solvent used in the reaction;
  • the suitable temperature is ranging from 0°C to 35°C.
  • the preferred embodiment of the present invention provides a process for the purification of N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)- 1 -(2-((2R,4R)-4-hydroxy-6-oxo tetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl-lH-pyrrole-3 -carboxamide compound of formula- 13, comprising of the following steps: a) Adding aqueous methanol to N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)-l-(2- ((2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl-lH- pyrrole-3 -carboxamide,
  • the invention also encompasses pharmaceutical compositions comprising the amorphous [3R,5R]-2-fluorophenyl-P,6-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2- hydroxyphenylamino)-carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt of the invention.
  • compositions containing the amorphous [3R,5R]-2-fluorophenyl- ,5- dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2-hydroxyphenylamino)-carbonyl]-lH-pyrrole-l- heptanoic acid, sodium salt of the invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants.
  • compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • Apparatus A liquid chromatographic system equipped with variable wavelength UV- detector; Column: Zorbax Bonus RP, 250 x 4.6 mm ID, 5 ⁇ (or) equivalent; Flow rate: 1.0 ml/min; Wavelength: 246 nm; Column Temperature: 35°C; Injection volume: 10 xL; Run time: 42 min; Diluent: Acetonitrile : Water (90:10 v/v); Needle wash: Diluent; Elution: Gradient; Mobile phase-A: Buffer: (100 %); Mobile phase-B: Acetonitrile : Buffer (70:25:05 v/v/v); Auto sample cooler 5°C; Buffer: Transfer accurately about 1000 ml of milli-Q-water and filter this solution through 0.22 ⁇ Nylon membrane filter paper and add 1 ml of perchloric acid and adjust its pH to 2.5 with dil. NaOH solution.
  • PXRD analysis of compounds produced by the present invention were carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° 'and continuous scan speed of 0.03°/min.
  • [3R,5R]-2-fluorophenyl-P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2 -hydroxy phenylamino)-carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1 produced by the present invention can be further micronized or milled by the conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • a mixture of methanol (200 ml) and tert-butyl 2-hydroxyphenylcarbamate (100 gms) were added to a solution of water (100 ml) and potassium carbonate (131.9 gms) at 25-30°C and stirred for 15 minutes at the same temperature.
  • Benzyl chloride (85 gms) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 10 hours at the same temperature. Cooled the reaction mixture to 25-30°C.
  • Purified water 500 ml was added to the reaction mixture and stirred for 15 minutes at the same temperature. Again cooled the reaction mixture to 2-5 °C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with chilled water followed by chilled petroleum ether and dried to get the title compound.
  • Dichloromethane 500 ml was added to tert-butyl 2-(benzyloxy)phenylcarbarnate (100 gms) at 25-30°C and stirred for 15 minutes at the same temperature.
  • Purified water 300 ml was added to the reaction mixture and stirred for 15 minutes at the same temperature. Basifying the reaction mixture using aqueous sodium hydroxide solution at 0-5°C and stirred for 15 minutes at the same temperature.
  • Example-6 Preparation of (4R-cis)-l,l-dimethylethyl-6-[2-[2-(4-fluorophenyl)-5-(l- methylethyl)-3-phenyI-4-[(4-benzyloxyphenyl)carbonyl]-lH-pyrrol-yl-]ethyl]-2,2- dimethyl- l,3-dioxane-4-acetate (Formula-11) A mixture of cyclohexane (500 ml) and (4R-cis)-l,l-dimethylethyl-6-(2-aminoethyl)- 2,2-dimethyl-l,3-dioxane-4-acetate (52.2 gms) were stirred for 10 minutes at 25-30°C.
  • N-(2- (benzyloxy)phenyl)-2-(2-(4-fluorophenyl)-2-oxo-l-phenylethyl)-4-methyl-3-oxopentanamide 100 gms was added to the reaction mixture at 25-30°C and stirred for 10 minutes at the same temperature.
  • Pivalic acid 9.8 gms was added to the reaction mixture. Heated the reaction mixture to 85-90°C and stirred for 40 hours at the same temperature. Cooled the reaction mixture to 55°C and distilled off the solvent completely under reduced pressure and cooled to 25-30°C.
  • Dichloromethane 1000 ml was added to the obtained compound at 25- 30°C and stirred for 20 minutes at the same temperature.
  • Acetonitrile (700 ml) was added to the compound obtained in example-6 at 25-30°C and stirred for 10 minutes at the same temperature.
  • Aqueous hydrochloric acid ⁇ hydrochloric acid (50 ml) in water (200 ml) ⁇ solution was slowly added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature.
  • Purified water was added to the reaction mixture and stirred for 15 minutes at the same temperature. Cooled the reaction mixture to 10-15°C. Basifying the reaction mixture using aqueous sodium carbonate at 10-15°C solution and stirred for 15 minutes at the same temperature.
  • Ethyl acetate (700 ml) was added to the reaction mixture at 10-15°C.
  • Example-8 Preparation of (2R-trans)-5-(4-fluorophenyl)-2-(l-methyIethyl)-N-(4- benzyloxyphenyl)-4-phenyl-l-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyraii-2-yl]ethyl]-lH- pyrrole-3-carboxamide (Formula-13)
  • Example-9 Purification of (2R-trans)-5-(4-fluorophenyl)-2-(l-methylethyl)-N-(4- benzyloxyphenyl)-4-phenyl-l-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-lH- pyrrole-3-carboxamide (Formula-13)
  • Pd/C (15 gms) was added to the reaction mixture.
  • the reaction mixture was hydrogenated for 12 hours under a hydrogen gas pressure 5.0-5.5 kg/cm 2 at 25-30°C. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Distilled off the solvent completely from the filtrate under reduced pressure below 40-45°C. Isopropanol (100 ml) was added to the obtained compound at 45°C and stirred for 15 minutes at the same temperature. Distilled off the solvent completely from the organic layer under reduced pressure. Heated the reaction mixture to 60-65°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 2 hours at the same temperature. Filtered the solid, washed with isopropanol and dried to get the title compound.
  • Example-11 Preparation of [3R,5R]-2-(4-fluorophenyl)-p,6-dihydroxy-5-(l -methyl ethyl)-3-phenyl-4-[(2-hydroxyphenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt (Formula-1)

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Abstract

The present invention relates to an improved process for the preparation of [3R,5R]-2-fluorophenyl-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(2-hydroxyphenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid sodium salt compound of formula- 1 represented by the following structural formula:

Description

Improved process for the preparation of f3R,5Rl-2-fluorophenyl-P,d- dihvdroxy-5-(l-methvIethvn-3-phenyl-4-[(2-hvdroxyphenylamino)- carbonyll-lH-pyrrole-l-heptanoic acid, sodium salt
Related Applications:
This application claims the benefit of priority of our Indian patent application number 1101/CHE/2015 filed on 6th Mar. 2015 which is incorporated herein by reference. Field of the Invention:
The present invention relates to an improved process for the preparation of [3R,5R]- 2-fluorophenyl-P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2-hydroxyphenylamino)- carbonyl]-l H-pyrrole- 1-heptanoic acid, sodium salt compound of formula- 1 represented by the following structural formula.
Figure imgf000002_0001
Formula- 1
The present invention also relates to an amorphous [3R,5R]-2-fluorophenyl-P,6- dihydroxy-5 -( 1 -methylethyl)-3 -phenyl-4- [(2-hydroxyphenylamino)-carbonyl]- 1 H-pyrrole- 1 - heptanoic acid, sodium salt compound of formula- 1 and process for its preparation.
Background of the Invention:
Atorvastatin, ([R-(R*,R*)]-2-(4-fluorophenyl)-p,6-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-l H-pyrrole- 1-heptanoic acid), and its calcium salt are known in the art, and described, in U.S. Pat. No. 4,681 ,893 and US 5,273,995.
Atorvastatin is a member of the class of drugs called statins. Statin drugs are currently the most therapeutically effective drugs available for reducing low density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease. Atorvastatin hemi-calcium salt trihydrate is marketed under the name LIPITOR by Warner-Lambert Co. Atorvastatin as well as some of its metabolites are pharmacologically active in humans and are thus useful as a hypolipidemic and hypocholesterolemic agent.
Hydroxylated derivatives of atorvastatin (hydroxy metabolites) are disclosed in U.S. Pat. No. 5,385,929.
Atorvastatin is extensively metabolized to ortho- and para-hydroxylated derivatives by cytochrome P-450 3A4 (CYP 3A4) and to various beta-oxidation products. In vitro, inhibition of HMG-CoA reductase by ortho- and para-hydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to ortho- and para-hydroxylated derivative active metabolites.
WO2013/073775 Al discloses process for the preparation of atorvastatin metabolites using enzymes. Moreover carrying out the reactions in the enzymes, takes very long reaction times, low yields and also large dilutions are required in which it is necessary to work. Brief description of the Invention:
The first aspect of the present invention is to provide a process for the preparation of [3R,5R]-2-fluorophenyl- ,6-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2-hydroxyphenyl amino)-carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1.
The second aspect of the present invention is to provide amorphous [3R,5R]-2- fluorophenyl-P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2-hydroxyphenylamino)- carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1.
The third aspect of the present invention is to provide a process for the preparation of amorphous [3R,5R]-2-fluorophenyl-P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2- hydroxyphenylamino)-carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1.
The fourth aspect of the present invention is to provide a one-pot process for the preparation of compound of formula-13.
The fifth aspect of the present invention is to provide a process for the purification of N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)-l-(2-((2R,4R)-4-hydroxy-6-oxotetrahydro-2H- pyran-2-yl)ethyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxamide compound of formula-13. Brief description of the Drawings:
Figure 1 : Illustrates the PXRD pattern of amorphous [3R,5R]-2-fiuorophenyl-P,6-dihydroxy- 5-( 1 -methylethyl)-3 -phenyl-4- [(2-hydroxyphenylamino)-carbonyl] - 1 H-pyrrole- 1 -heptanoic acid, sodium salt.
Detailed description of the Invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, pentane, cycloheptane, methylcyclohexane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene and the like; "ether solvents" such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1 ,2-dimethoxy ethane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethyl acetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t- butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2- methoxyethanol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; "polar solvents" such as water or mixtures thereof.
The term "suitable base" used herein the present invention until unless specified is selected from inorganic bases like "alkali metal hydroxides" such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; ammonia; and organic bases such as triethyl amine, methyl amine, ethyl amine, 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-Diazabicyclo(4.3.0)non-5-ene (DBN), lithium dioisoporpylamide (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine (DIPA), diisopropylethylamine (DIPEA), N-methylmorpholine (NMP), N- ethylmorpholine, piperidine, dimethylaminopyridine (DMAP), morpholine, pyridine, 2,6- lutidine, 2,4,6-collidine, imidazole, 1-methylimidazole, 1 ,2,4-triazole, 1,4- diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.
As used herein the term suitable debenzylating reagents that can be used in the reaction include, but are not limited to, a noble metal catalyst such as nickel, palladium, platinum, iridium, ruthenium and the like, in combination with hydrogen.
The suitable acid source is selected from HC1 gas, aqueous HC1, dry HC1, ethyl acetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl.
The first aspect of the present invention provides a process for the preparation of [3R,5R]-2-fluorophenyl-P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2-hydroxyphenyl amino)-carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1, comprising of the following steps:
a) Reacting 2-aminophenol compound of formula-2 with ditertiary butyldicarbonate in presence of a suitable solvent to provide tert-butyl 2-hydroxyphenylcarbamate compound of formula-3 and optionally purifying from a suitable solvent,
b) reacting the compound of formula-3 with benzyl chloride in presence of a suitable base in a suitable solvent to provide tert-butyl 2-(benzyloxy)phenylcarbamate compound formula-4,
c) treating of compound of formula-4 with a suitable acid in a suitable solvent to provide 2-(benzyloxy)aniline compound of formula-5,
d) reacting the compound of formula-5 with methyl 4-methyl-3-oxopentanoate compound of formula-6 in presence of a suitable base in a suitable solvent to provide N-(2-(benzyloxy)phenyl)-4-methyl-3-oxopentanamide compound of formula-7, e) reacting the compound of formula-7 with 2-bromo-l-(4-fluorophenyl)-2- phenylethanone compound of formula- 8 in presence of a suitable base in a suitable solvent to provide N-(2-(benzyloxy)phenyl)-2-(2-(4-fluorophenyl)-2-oxo-l -phenyl ethyl)-4-rnethyl-3-oxopentanamide compound of formula-9,
f) reacting the compound of formula-9 with tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2- dimethyl-l,3-dioxan-4-yl)acetate compound of formula- 10 in presence of pivalic acid in a suitable solvent to provide tert-butyl 2-((4R,6R)-6-(2-(3-(2-(benzyloxy)phenyl carbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2,2- dimethyl-l,3-dioxan-4-yl)acetate compound of formula-11, hydrolyzing the obtained compound by treating in-situ with a suitable acid in a suitable solvent gives compound of formula- 12 and which on further treatment with suitable base in a suitable solvent to provide N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)-l-(2-
((2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl-lH- pyrrole-3-carboxamide compound of formula- 13,
g) optionally, purifying the compound of formula- 13 from a suitable solvent to provide pure compound of formula- 13,
h) treating the compound of formula- 13 obtained in step-(f or (g) with palladium carbon in a suitable solvent to provide 5-(4-fluorophenyl)-l-(2-((2R,4R)-4-hydroxy-6- oxotetrahydro-2H-pyran-2-yl)ethyl)-N-(2-hydroxyphenyl)-2-isopropyl-4-phenyl-lH- pyrrole-3-carboxamide compound of formula- 14,
i) optionally, purifying the compound of formula- 14 from a suitable solvent to provide pure compound of formula- 14,
j) treating the compound of formula- 14 obtained in step-(h) or (i) with sodium hydroxide in a suitable solvent to provide [3R,5R]-2-fluorophenyl-P,5-dihydroxy-5- ( 1 -methylethyl)-3 -phenyl -4- [(2-hydroxyphenylamino)-carbonyl] - 1 H-pyrrole- 1 - heptanoic acid, sodium salt compound of formula- 1.
Wherein,
in step-b), d), e) and f) the suitable base is selected from organic base or inorganic base;
in step-c) the suitable acid is selected from trifluoro acetic acid or hydrochloric acid; in step-f) the suitable acid is hydrochloric acid; in step-a) to step-j) the suitable solvent is selected from alcohol solvents, chloro solvents, ester solvents, polar aprotic solvents, ketone solvents, ether solvents, hydrocarbon solvents and polar solvent like water or mixture thereof.
The preferred embodiment of the present invention provides a process for the preparation of [3R,5R]-2-fluorophenyl- ,8-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2- hydroxyphenylamino)-carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1, comprising of the following steps:
a) Reacting 2-aminophenol compound of formula-2 with ditertiary butyldicarbonate in presence of dichloromethane to provide tert-butyl 2-hydroxyphenylcarbamate compound of formula-3,
b) reacting the compound of formula-3 with benzyl chloride in presence of potassium carbonate in a mixture of water and methanol to provide tert-butyl 2-(benzyloxy) phenylcarbamate compound formula-4,
c) treating the compound of formula-4 with trifluoro acetic acid in a mixture of dichloromethane and water to provide 2-(benzyloxy)aniline compound of formula-5, d) reacting the compound of formula-5 with methyl 4-methyl-3-oxopentanoate compound of formula-6 in presence of ethylene diamine in toluene to provide N-(2- (benzyloxy)phenyl)-4-methyl-3-oxopentanamide compound of formula-7,
e) reacting the compound of formula-7 with 2-bromo-l-(4-fluorophenyl)-2- phenylethanone compound of formiila-8 in presence of potassium carbonate in isopropanol to provide N-(2-(benzyloxy)phenyl)-2-(2-(4-fluorophenyl)-2-oxo-l- phenylethyl)-4-methyl-3-oxopentanamide compound of formula-9,
f) reacting the compound of formula-9 with tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2- dimethyl-l,3-dioxan-4-yl)acetate compound of formula- 10 in presence of pivalic acid in cyclohexane to provide tert-butyl 2-((4R,6R)-6-(2-(3-(2-(benzyloxy)phenyl carbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2,2- dimethyl-l,3-dioxan-4-yl)acetate compound of formula-11, hydrolyzing the obtained compound by treating in-situ with an aqueous hydrochloric acid in acetonitrile provides compound of formula- 12 and which on further treating with aqueous sodium hydroxide in methanol to provide N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)-l-(2- ((2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl-lH- pyrrole-3-carboxamide compound of formula- 13,
g) purifying the compound of formula- 13 from toluene to provide pure compound of formula- 13,
h) treating the compound of formula- 13 with palladium carbon in a mixture of methanol and ethylacetate to provide 5-(4-fluorophenyl)-l-(2-((2R,4R)-4-hydroxy-6-oxo tetrahydro-2H-pyran-2-yl)ethyl)-N-(2-hydroxyphenyl)-2-isopropyl-4-phenyl-lH- pyrrole-3 -carboxamide compound of formula- 14,
i) purifying the compound of formula- 14 with isopropanol to provide pure compound of formula- 14,
j) treating the compound of formula- 14 with aqueous sodium hydroxide in presence of acetonitrile to provide [3R,5R]-2-fluorophenyl-P,6-dihydroxy-5-(i-methylethyl)-3- phenyl-4- [(2-hydroxyphenylamino)-carbonyl] - 1 H-pyrrole- 1 -heptanoic acid, sodium salt compound of formula- 1.
As is known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product. Therefore, impurities in API's result primarily from one of two sources, (I) the manufacturing process (or) synthesis of the API and (II) from the degradation of the API itself.
[3R,5R]-2-fluorophenyl- ,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2-hydroxy phenylamino)-carbonyl]-l H-pyrrole- 1 -heptanoic acid, sodium salt compound of formula- 1 of the present invention having the following process impurities not more than 1.0 %; pre
Figure imgf000008_0001
2-Hydroxy lactone Impurity 2-Hydroxydesfluoro Impurity
The [3R,5R]-2-fluorophenyl-p,6-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2- hydroxyphenylamino)-carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1 obtained according to the present invention having purity of more than 99.80%, preferably a purity of more than 99.85%, more preferably a purity of more than 99.95% as determined by HPLC area percentage.
The present invention also involves the none of the ICH class 1 solvent in the manufacturing of [3R,5R]-2-fluorophenyl-p*6-dihydroxy-5-(l-methyl ethyl)-3-phenyl-4-[(2- hydroxyphenylamino)-carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1. The second aspect of the present invention provides amorphous [3R,5R]-2- fluorophenyl-p,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2-hydroxyphenylamino)- carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1, which is characterized by P-XRD pattern as depicted in figure- 1. The third aspect of the present invention provides a process for the preparation of amorphous [3R,5R]-2-fiuorophenyl-P,6-dihydroxy-5-( 1 -methylethyl)-3-phenyl-4-[(2- hydroxyphenylamino)-carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1, comprising of the following steps:
a) Adding a suitable solvent to 5-(4-fluorophenyl)-l-(2-((2R,4R)-4-hydroxy-6-oxo tetrahydro-2H-pyran-2-yl)ethyl)-N-(2-hydroxyphenyl)-2-isopropyl-4-phenyl- 1 H- pyrrole-3-carboxamide,
b) cooling the reaction mixture to a suitable temperature,
c) stirring the reaction mixture and adding a suitable base to the reaction mixture, d) stirring the reaction mixture at a suitable temperature,
e) distilling off the solvent completely from the reaction mixture,
f) adding water to the obtained compound,
g) extracting the compound with a suitable solvent,
h) washing the organic layer with aqueous sodium chloride solution,
i) distilling off the solvent completely from the organic layer and then followed by co- distilling with water to get amorphous [3R,5R]-2-fluorophenyl-P,5-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(2-hydroxyphenylamino)-carbonyl]- 1 H-pyrrole- 1 - heptanoic acid, sodium salt compound of formula- 1.
Wherein,
in step-b) the suitable temperature is ranging from 0°C-20°C;
in step-c) the suitable base is selected from organic or inorganic base;
in step-a) and step-g) the suitable solvent is selected from alcohol solvents, chloro solvents, ester solvents, polar aprotic solvents, ketone solvents, ether solvents, hydrocarbon solvents and polar solvent like water or mixture thereof.
The preferred embodiment of the present invention provides a process for the preparation of amorphous [3R,5R]-2-fluorophenyl-P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(2-hydroxyphenylamino)-carbonyl]-lH-pyrrole-l -heptanoic acid, sodium salt compound of formula- 1, comprising of the following steps:
a) Adding acetonitrile to 5-(4-fluorophenyl)-l-(2-((2R,4R)-4-hydroxy-6-oxotetrahydro- 2H-pyran-2-yl)ethyl)-N-(2-hydroxyphenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3- carboxamide compound of formula- 14,
b) cooling the reaction mixture to 0°C to 5°C,
c) stirring the reaction mixture and adding aqueous sodium hydroxide solution to the reaction mixture,
d) stirring the reaction mixture at 25°C to 30°C,
e) distilling off the solvent completely from the reaction mixture,
f) adding water to the obtained compound,
g) extracting the compound with ethyl acetate,
h) washing the organic layer with aqueous sodium chloride solution,
i) distilling off the solvent completely from the organic layer and then followed by co- distilling with water to get amorphous [3R,5R]-2-fluorophenyl-p,6Tdihydroxy-5-(l- methylethyl)-3-phenyl-4-[(2-hydroxyphenylamino)-carbonyl]- 1 H-pyrrole- 1 - heptanoic acid, sodium salt compound of formula- 1.
The fourth aspect of the present invention provides a one-pot process for the preparation of N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)-l-(2-((2R,4R)-4-hydroxy-6-oxo tetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl- 1 H-pyrrole-3 -carboxamide compound of formula- 13 , comprising of the following steps:
a) Reacting the compound of formula-9 with tert-butyl 2-((4R,6R)-6-(2-aminoethyl)- 2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula-10 in presence of pivalic acid in a suitable solvent to provide tert-butyl 2-((4R,6R)-6-(2-(3-(2- (benzyloxy)phenyl carbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl- 1 H-pyrrol- l-yl)ethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula- 11, which on hydrolysis in-situ by treating it with suitable acid in a suitable solvent to provide compound of formula- 12 and which on further treating with a suitable base in a suitable solvent to provide N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)-l-(2- ((2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2ryl)ethyl)-2-isopropyl-4-phenyl- 1 H- pyrrole-3-carboxamide compound of formula-13,
b) optionally, purifying the compound of formula-13 from a suitable solvent to provide pure compound of formula-13.
Wherein,
in step-a) the suitable acid is hydrochloric acid; the suitable base is selected from
organic or inorganic base;
in step-a) and b) the suitable solvent is selected from selected from alcohol solvents, chloro solvents, ester solvents, polar aprotic solvents, ketone solvents, ether solvents, hydrocarbon solvents and polar solvent like water or their mixtures thereof.
The preferred embodiment of the present invention provides a one-pot process for the preparation of N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)- 1 -(2-((2R,4R)-4-hydroxy-6-oxo tetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl- 1 H-pyrrole-3 -carboxamide compound of formula- 13 , comprising of the following steps:
a) Reacting the compound of formula-9 with tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-
2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula-10 in presence of pivalic acid in cyclohexane provide tert-butyl 2-((4R,6R)-6-(2-(3-(2-(benzyloxy)phenyl carbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-lH-pyrrol-l-yl)ethyl)-2,2- dimethyl-l,3-dioxan-4-yl)acetate compound of formula-11, which on hydrolysis in- situ by treating it with aqueous hydrochloric acid in acetonitrile to provide compound of formula- 12 and which on further treating with aqueous sodium hydroxide in methanol to provide N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)-l-(2-((2R,4R)-4- hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl-lH-pyrrole-3- carboxamide compound of formula- 13,
b) purifying the compound of formula- 13 from toluene to provide pure compound of formula- 13,
The fifth aspect of the present invention provides a process for the purification of N- (2-(benzyloxy)phenyl)-5-(4-fluorophenyl)-l-(2-((2R,4R)-4-hydroxy-6-oxotetrahydro-2H- pyran-2-yl)ethyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxamide compound of formula- 13, comprising of the following steps:
a) Adding a suitable solvent to N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)-l-(2- ((2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl-lH- pyrrole-3 -carboxamide,
b) heating the reaction mixture to a suitable temperature,
c) stirring the reaction mixture,
d) cooling the reaction mixture,
e) stirring the reaction mixture,
f) filtering the solid and drying to get pure N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)- l-(2-((2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4- phenyl- lH-pyrrole-3 -carboxamide.
Wherein, in step-a) the suitable solvent is selected from alcohol solvents, chloro solvents, ester solvents, polar aprotic solvents, ketone solvents, ether solvents, hydrocarbon solvents and polar solvent like water or mixture thereof;
in step-b) the suitable temperature is ranging from ambient temperature to reflux temperature of the solvent used in the reaction;
in step-d) the suitable temperature is ranging from 0°C to 35°C.
The preferred embodiment of the present invention provides a process for the purification of N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)- 1 -(2-((2R,4R)-4-hydroxy-6-oxo tetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl-lH-pyrrole-3 -carboxamide compound of formula- 13, comprising of the following steps: a) Adding aqueous methanol to N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)-l-(2- ((2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl-lH- pyrrole-3 -carboxamide,
b) heating the reaction mixture to 60°C to 65 °C,
c) stirring the reaction mixture,
d) cooling the reaction mixture to 0°C to 5°C,
e) stirring the reaction mixture,
f) filtering the solid and drying to get pure N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)- l-(2-((2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4- phenyl- lH-pyrrole-3-carboxamide.
The invention also encompasses pharmaceutical compositions comprising the amorphous [3R,5R]-2-fluorophenyl-P,6-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2- hydroxyphenylamino)-carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt of the invention. Pharmaceutical compositions containing the amorphous [3R,5R]-2-fluorophenyl- ,5- dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2-hydroxyphenylamino)-carbonyl]-lH-pyrrole-l- heptanoic acid, sodium salt of the invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants. Various modes of administration of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
HPLC Method of Analysis [3R,5R]-2-fluorophenyl-p,6-dihydroxy-5-(l-methyIethyl)-3- phenyl-4-[(2-hydroxyphenylamino)-carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt:
Apparatus: A liquid chromatographic system equipped with variable wavelength UV- detector; Column: Zorbax Bonus RP, 250 x 4.6 mm ID, 5 μιη (or) equivalent; Flow rate: 1.0 ml/min; Wavelength: 246 nm; Column Temperature: 35°C; Injection volume: 10 xL; Run time: 42 min; Diluent: Acetonitrile : Water (90:10 v/v); Needle wash: Diluent; Elution: Gradient; Mobile phase-A: Buffer: (100 %); Mobile phase-B: Acetonitrile : Buffer (70:25:05 v/v/v); Auto sample cooler 5°C; Buffer: Transfer accurately about 1000 ml of milli-Q-water and filter this solution through 0.22 μπι Nylon membrane filter paper and add 1 ml of perchloric acid and adjust its pH to 2.5 with dil. NaOH solution.
P-XRD Method of Analysis:
PXRD analysis of compounds produced by the present invention were carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° 'and continuous scan speed of 0.03°/min.
[3R,5R]-2-fluorophenyl-P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2 -hydroxy phenylamino)-carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1 produced by the present invention can be further micronized or milled by the conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
The process of the present invention is schematically represented below:
Scheme-A:
Figure imgf000014_0001
Formula-4
DCM, TFA
Figure imgf000014_0002
Formula-7 Formula-5 cheme-B:
Figure imgf000015_0001
Formula-l
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples:
Example-1: Preparation of tert-butyl 2-hydroxyphenylcarbamate (Formula-3)
A mixture of dichloromethane (500 ml) and 2-aminophenol (100 gms) were stirred for 15 minutes at 25-30°C. Di-tert-butyl dicarbonate (240 gms) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 35-40°C and stirred for 10 hours at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Petroleum ether (200 ml) was added to the obtained compound at below 40°C and stirred for 15 minutes at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Petroleum ether (500 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the solid, washed with petroleum ether and dried to get the title compound. Yield: 180 gms; Melting point: 140-144°C.
Example-2: Preparation of tert-butyl 2-(benzyloxy)phenylcarbamate (Formula-4)
A mixture of methanol (200 ml) and tert-butyl 2-hydroxyphenylcarbamate (100 gms) were added to a solution of water (100 ml) and potassium carbonate (131.9 gms) at 25-30°C and stirred for 15 minutes at the same temperature. Benzyl chloride (85 gms) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 10 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Purified water (500 ml) was added to the reaction mixture and stirred for 15 minutes at the same temperature. Again cooled the reaction mixture to 2-5 °C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with chilled water followed by chilled petroleum ether and dried to get the title compound.
Yield: 120gms; Melting point: 70.5-75.4°C.
Example-3: Preparation of 2-(benzyloxy)aniline (Formula-5)
Dichloromethane (500 ml) was added to tert-butyl 2-(benzyloxy)phenylcarbarnate (100 gms) at 25-30°C and stirred for 15 minutes at the same temperature. A solution of trifluoroacetic acid (200 ml) and dichloromethane (200 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 0-5°C. Purified water (300 ml) was added to the reaction mixture and stirred for 15 minutes at the same temperature. Basifying the reaction mixture using aqueous sodium hydroxide solution at 0-5°C and stirred for 15 minutes at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 20 minutes at the same temperature. Both the organic and aqueous layers were separated and aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with 10% aqueous sodium chloride solution and dried over sodium sulfate. Distilled off the solvent completely from the organic layer under reduced pressure. Petroleum ether (100 ml) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Distilled off the solvent completely from the reaction mixture. Petroleum ether (300 ml) was added to the obtained compound at 25-30°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 3 hours at the same temperature. Filtered the solid, was,hed with chilled petroleum ether and dried to get the title compound. Yield: 62 gms; Melting point: 35.5-37.6°C.
Example-4: Preparation of N-(2-(benzyloxy)phenyl)-4-methyl-3-oxopentanamide (Formula-7)
Toluene (2500 ml) was added to 2-(benzyloxy)aniline (100 gms) at 25-30°C and stirred for 15 minutes at the same temperature. Methyl isobutyryl acetate (76.2 gms) compound of formula-6 and followed by ethylenediamine (0.34 gms) were added to the reaction mixture at 25-30°C and stirred for 20 minutes at the same temperature. Heated the reaction mixture to 110-112° C and stirred for 30 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Aqueous hydrochloric acid solution was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with aqueous sodium bicarbonate solution and then followed by purified water. Organic layer was dried over sodium sulfate and washed with toluene. Distilled off the solvent completely form the reaction mixture under reduced pressure and cooled to 40-45°C. Petroleum ether (100 ml) was added to the obtained compound and stirred for 15 minutes at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Petroleum ether (400 ml) was added to the obtained compound and stirred for 30 minutes at 40-45°C. Cooled the reaction mixture to 0-5°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with chilled petroleum ether and dried to get the title compound. Yield: 130 gms; Melting point: 50.5-55.6°C.
Example-5: Preparation of 4-Methyl-3-oxo-N-(2-benzyloxyphenyI)-2-[l-phenyl-2-(4- fluorophenyl)-2-oxo ethyl] pentanamide (Formula-9)
A mixture of N-(2-(benzyloxy)phenyl)-4-methyl-3-oxopentanamide (100 gms) and isopropanol (500 ml) were stirred for 15 minutes at 25-30°C. Cooled the reaction mixture to 5-10°C. Potassium carbonate (88.6 gms) was added to the reaction mixture at 25-30°C. Isopropanol (580 ml) was added to 2-bromo-l-(4-fluorophenyl)-2-phenylethanone (75.4 gms) at 25-30°C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 45-50°C and stirred for 20 minutes at the same temperature. Cooled the reaction mixture to 10-15°C and slowly added to the above reaction mixture at the same temperature. Stirred the reaction mixture for 12 hours at _0-15°C. Isopropanol (300 ml) was added to the reaction mixture at 10-15°C and stirred for 1 hour at the same temperature. Filtered the undissolved material and washed with isopropanol. Distilled off the solvent completely from the filtrate under reduced pressure and cooled to 25-30°C. Dichloromethane was added to the obtained compound at 25-30°C and stirred for 20 minutes at the same temperature. Purified water (200 ml) was added to the reaction mixture at 25-30°C and stirred for 20 minutes at the same temperature. Both the organic and aqueous layers were separated and organic layer was washed with purified water. The organic layer was dried over sodium sulfate. Distilled off the solvent completely from the organic layer under reduced pressure. Methyl tertiary butyl ether (100 ml) was added to the obtained compound at 40-45°C and stirred for 15 minutes at the same temperature. Distilled off the solvent completely from the organic layer under reduced pressure. Methyl tertiary butyl ether (200 ml) was added to the obtained compound and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 0-5°C and seeded with compound of formula-9 at the same temperature. Stirred the reaction mixture for 3 hours at 0-5°C. Filtered the precipitated solid, washed with chilled methyl tertiary butyl ether and dried to get the title compound. Yield: 55 gms; Melting point: 102-104°C.
Example-6: Preparation of (4R-cis)-l,l-dimethylethyl-6-[2-[2-(4-fluorophenyl)-5-(l- methylethyl)-3-phenyI-4-[(4-benzyloxyphenyl)carbonyl]-lH-pyrrol-yl-]ethyl]-2,2- dimethyl- l,3-dioxane-4-acetate (Formula-11) A mixture of cyclohexane (500 ml) and (4R-cis)-l,l-dimethylethyl-6-(2-aminoethyl)- 2,2-dimethyl-l,3-dioxane-4-acetate (52.2 gms) were stirred for 10 minutes at 25-30°C. N-(2- (benzyloxy)phenyl)-2-(2-(4-fluorophenyl)-2-oxo-l-phenylethyl)-4-methyl-3-oxopentanamide (100 gms) was added to the reaction mixture at 25-30°C and stirred for 10 minutes at the same temperature. Pivalic acid (9.8 gms) was added to the reaction mixture. Heated the reaction mixture to 85-90°C and stirred for 40 hours at the same temperature. Cooled the reaction mixture to 55°C and distilled off the solvent completely under reduced pressure and cooled to 25-30°C. Dichloromethane (1000 ml) was added to the obtained compound at 25- 30°C and stirred for 20 minutes at the same temperature. Purified water (200 ml) was added to the reaction mixture at 25-30°C and stirred for 20 minutes at the same temperature. Both the organic and aqueous layers were separated and organic layer was washed with 5% aqueous sodium bicarbonate solution. Organic layer was dried over sodium sulfate. Distilled off the solvent completely from the organic layer under reduced pressure below 45°C to get the title compound.
Example-7: Preparation of (3R,5R)-tert-butyl7-(3-(2-(benzyloxy)phenylcarbam6yl)-5- (4-fluorophenyl)-2-isopropyl-4-phenyl-lH-pyrrol-l-yl)-3,5-dihydroxyheptanoate
(FormuIa-12)
Acetonitrile (700 ml) was added to the compound obtained in example-6 at 25-30°C and stirred for 10 minutes at the same temperature. Aqueous hydrochloric acid {hydrochloric acid (50 ml) in water (200 ml)} solution was slowly added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Purified water was added to the reaction mixture and stirred for 15 minutes at the same temperature. Cooled the reaction mixture to 10-15°C. Basifying the reaction mixture using aqueous sodium carbonate at 10-15°C solution and stirred for 15 minutes at the same temperature. Ethyl acetate (700 ml) was added to the reaction mixture at 10-15°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 20 minutes at the same temperature. Both the organic and aqueous layers were separated and organic layer was washed with purified water and dried over sodium sulfate. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.
Example-8: Preparation of (2R-trans)-5-(4-fluorophenyl)-2-(l-methyIethyl)-N-(4- benzyloxyphenyl)-4-phenyl-l-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyraii-2-yl]ethyl]-lH- pyrrole-3-carboxamide (Formula-13)
Methanol (125 ml) was added to the compound obtained in example-7 at 25-30°C and stirred the reaction mixture for 10 minutes at the same temperature. Cooled the reaction mixture to 0-5°C. Aqueous sodium hydroxide {sodium hydroxide (11.5 gms) in water (250 ml)} solution was slowly added to the reaction mixture at 0-5°C and stirred for 1 hour at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Water was added to the reaction mixture and stirred for 15 minutes at 25-30°C. Toluene (375 ml) was added to the reaction mixture at 25-30°C and stirred for 20 minutes at the same temperature. Both the organic and aqueous layers were separated and aqueous layer was washed with toluene. Cooled the aqueous layer to 0°C to 5°C Acidifying the aqueous layer using aqueous hydrochloric acid solution at 0-5 °C and stirred for 15 minutes at the same temperature. Toluene (900 ml) was added to the reaction mixture at 0-5°C and stirred for 20 minutes at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 20 minutes at the same temperature. Both the organic and aqueous layers were separated and aqueous layer was extracted with toluene. Combined the total organic layers and dried over sodium sulfate. Heated the organic layer to 110-115°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 55-60°C. Distilled off the solvent completely from the organic layer under reduced pressure. Toluene (250 ml) was added to the obtained compound and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 3 hours at the same temperature. Filtered the solid, washed with toluene and dried to get the title compound. Yield: 53 gms.
Example-9: Purification of (2R-trans)-5-(4-fluorophenyl)-2-(l-methylethyl)-N-(4- benzyloxyphenyl)-4-phenyl-l-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-lH- pyrrole-3-carboxamide (Formula-13)
A mixture of methanol and water (500 ml) was added to (2R-trans)-5-(4-fluoro phenyl)-2-(l-methylethyl)-N-(4-benzyloxyphenyl)-4-phenyl-l-[2-(tetrahydro-4-hydroxy-6- oxo-2H-pyran-2-yl] ethyl]-lH-pyrrole-3-carboxamide (100 gms) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 60-65°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 2 hours at the sane temperature. Filtered the precipitated solid, washed with a mixture of chilled methanol and water. To the obtained wet compound, a mixture of methanol and water (450 ml) was added at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 60-65°C and stirred from 2 hours at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with a mixture of methanol and water and dried to get the title compound. Yield: 89 gms; Melting point: 167-170°C.
ExampIe-10: Preparation of (2R-trans)-5-(4-fluorophenyI)-2-(l-methylethyl)-N-(2- hydroxyphenyI)-4-phenyl-l-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-l- Hpyrrole-3-carboxamide (Formula-14)
Methanol (50 ml) and ethyl acetate (200 ml) were added to (2R-trans)-5-(4- fluorophenyl)-2-( 1 -methyl ethyl)-N-(4-benzyloxyphenyl)-4-phenyl- 1 - [2-(tetrahydro-4- hydroxy-6-oxo-2H-pyran-2-yl] ethyl] -lH-pyrrole-3-carboxamide (100 gms) at 25-30°C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 40-45 °C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C. Pd/C (15 gms) was added to the reaction mixture. The reaction mixture was hydrogenated for 12 hours under a hydrogen gas pressure 5.0-5.5 kg/cm2 at 25-30°C. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Distilled off the solvent completely from the filtrate under reduced pressure below 40-45°C. Isopropanol (100 ml) was added to the obtained compound at 45°C and stirred for 15 minutes at the same temperature. Distilled off the solvent completely from the organic layer under reduced pressure. Heated the reaction mixture to 60-65°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 2 hours at the same temperature. Filtered the solid, washed with isopropanol and dried to get the title compound.
Yield: 83 gms; Melting point 126.7-130.7°C.
Example-11: Preparation of [3R,5R]-2-(4-fluorophenyl)-p,6-dihydroxy-5-(l -methyl ethyl)-3-phenyl-4-[(2-hydroxyphenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt (Formula-1)
(2R-trans)-5-(4-fluorophenyl)-2-(l-methylethyl)-N-(2-hydroxyphenyl)-4-phenyl-l- [2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-l-Hpyrrole-3-carboxamide (100 gms) was added to a pre-cooled acetonitrile (1000 ml) at 0-5°C and stirred for 10 minutes at the same temperature. Aqueous sodium hydroxide {sodium hydroxide (1.08 gms) and water (500 ml)} solution was slowly added to the reaction mixture at 0-5 °C and stirred for 2 hours at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 6 hours at the same the same temperature. Distilled off the solvent completely from the organic layer under reduced pressure. Purified water (500 ml) was added to the obtained compound at 25-30°C and stirred for 20 minutes at the same temperature. Ethyl acetate (500 ml) was added to the reaction mixture at 25-30°C and stirred for 20 minutes at the same temperature. Both the organic and aqueous layers were separated and aqueous layer was extracted with ethyl acetate. Sodium chloride was added to the aqueous layer and stirred for 20 minutes at 25-30°C. Ethyl acetate was added to the aqueous layer and stirred for 20 minutes at 25-30°C. Both the organic and aqueous layers were separated and aqueous layer extracted with ethyl acetate. Combined the total organic layers and washed with 25% aqueous sodium chloride solution and dried over sodium sulfate. Filtered the organic layer through hyflow bed and washed with ethyl acetate. Distilled off the solvent completely from the organic layer under reduced pressure and then co-distilled with purified water to get the title compound.
Yield: 85-95 gms; Purity by HPLC: 99.90 %; 2-Hydroxy desfluoro impurity: 0.05 %; 2- Hydroxy lactone impurity: 0.03%; Unknown impurities: 0.02%.
The P-XRD pattern of the obtained compound was depicted in figure- 1.

Claims

We Claim:
1. Amorphous [3R,5R]-2-fluorophenyl- ,6-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2- hydroxyphenylamino)-carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1.
2. Amorphous [3R,5R]-2-fluorophenyl-P,5-dihydroxy-5-(l -methylethyl)-3-phenyl-4-[(2- hydroxyphenylamino)-carbonyl]-lH-pyrrole-l-heptanoic acid, sodium salt compound of formula- 1, characterized by its powder X-ray diffractogram as depicted in figure- 1.
3. A process for the preparation of [3R,5R]-2-fluorophenyl-P,5-dihydroxy-5-(l-methyl ethyl)-3-phenyl-4- [(2-hydroxyphenylamino)-carbonyl] - 1 H-pyrrole- 1 -heptanoic acid, sodium salt compound of formula- 1, comprising of the following steps:
a) Reacting the 2-aminophenol compound of formula-2 with ditertiary butyldicarbonate in a suitable solvent to provide tert-butyl 2-hydroxyphenylcarbamate compound of formula-3 and optionally purifying from a suitable solvent,
b) reacting the compound of formula-3 with benzyl chloride in presence of a suitable base in a suitable solvent to provide tert-butyl 2-(benzyloxy)phenylcarbamate compound formula-4,
c) treating the compound of formula-4 with a suitable acid in a suitable solvent to provide 2-(benzyloxy)aniline compound of formula-5,
d) reacting the compound of formula-5 with methyl 4-methyl-3-oxopentanoate compound of formula-6 in presence of a suitable base in a suitable solvent to provide N-(2-(benzyloxy)phenyl)-4-methyl-3-oxopentanamide compound of formula-7, e) reacting the compound of formula-7 with 2-bromo-l-(4-fluorophenyl)-2- phenylethanone compound of formula-8 in presence of a suitable base in a suitable solvent to provide N-(2-(benzyloxy)phenyl)-2-(2-(4-fluorophenyl)-2-oxo-l -phenyl ethyl)-4-methyl-3-oxopentanamide compound of formula-9,
f) reacting the compound of formula-9 with tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2- dimethyl-l,3-dioxan-4-yl)acetate compound of formula-10 in presence of pivalic acid in a suitable solvent to provide tert-butyl 2-((4R,6R)-6-(2-(3-(2-(benzyloxy)phenyl carbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2,2- dimethyl- 1, 3 -dioxan-4-yl)acetate compound of formula-11, hydrolyzing the obtained compound by treating in-situ with a suitable acid in a suitable solvent to provide compound of formula- 12 and which on further treating with suitable base in a suitable solvent to provide N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)-l-(2-((2R,4R)-4- hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl- 1 H-pyrrole-3 - carboxamide compound of formula- 13,
g) optionally, purifying the compound of formula- 13 from a suitable solvent to provide pure compound of formula- 13,
h) reacting the compound of formula- 13 obtained in step-(f) or step-(g) with palladium carbon in a suitable solvent to provide 5-(4-fluorophenyl)-l-(2-((2R,4R)-4-hydroxy- 6-oxotetrahydro-2H-pyran-2-yl)ethyl)-N-(2-hydroxyphenyl)-2-isopropyl-4-phenyl-
1 H-pyrrole-3 -carboxamide compound of formula- 14,
i) optionally, purifying the compound of formula- 14 from a suitable solvent to provide pure compound of formula- 14,
j) treating the compound of formula- 14 obtained in step-(h) or step-(i) with sodium hydroxide in a suitable solvent to provide amorphous [3R,5R]-2-fluorophenyl-P,6- dihydroxy-5-( 1 -methylethyl)-3-phenyl-4- [(2-hydroxyphenylamino)-carbonyl] - 1 H- pyrrole-l-heptanoic acid, sodium salt compound of formula- 1.
4. The process according to claim-3, wherein,
in step-b), d), e) and f) the suitable base is selected from organic base or inorganic base; in step-c) the suitable acid is selected from trifluoro acetic acid or hydrochloric acid; in step-a) to step-j) the suitable solvent is selected from alcohol solvents, chloro solvents, ester solvents, polar aprotic solvents, ketone solvents, ether solvents, hydrocarbon solvents and polar solvent like water or mixture thereof.
5. A process for the preparation of [3R,5R]-2-fluorophenyl-p,5-dihydroxy-5-(l -methyl ethyl)-3-phenyl-4-[(2-hydroxyphenylamino)-carbonyl]- 1 H-pyrrole- 1 -heptanoic acid, sodium salt compound of formula- 1, comprising of the following steps:
a) Reacting 2-aminophenol compound of formula-2 with ditertiary butyldicarbonate in dichloromethane to provide tert-butyl 2-hydroxyphenylcarbamate compound of formula-3,
b) reacting the compound of formula-3 with benzyl chloride in presence of potassium carbonate and in a mixture of water and methanol to provide tert-butyl 2- (benzyloxy)phenylcarbamate compound formula-4,
c) treating the compound of formula-4 with trifluoro acetic acid in a mixture of dichloromethane and water to provide 2-(benzyloxy)aniline compound of formula-5, d) reacting the compound of formula-5 with methyl 4-methyl-3-oxopentanoate compound of formula-6 in presence of ethylene diamine in toluene to provide N-(2- (benzyloxy)phenyl)-4-methyl-3-oxopentanamide compound of formula-7,
e) reacting the compound of formula-7 with 2-bromo-l-(4-fluorophenyl)-2- phenylethanone compound of formula- 8 in presence of potassium carbonate in isopropanol to provide N-(2-(benzyloxy)phenyl)-2-(2-(4-fluorophenyl)-2-oxo-l- phenylethyl)-4-methyl-3-oxopentanamide compound of formula-9,
f) reacting the compound of formula-9 with tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2- dimethyl-l,3-dioxan-4-yl)acetate compound of formula- 10 in presence of pivalic acid in cyclohexane to provide tert-butyl 2-((4R,6R)-6-(2-(3-(2-(benzyloxy)phenyl carbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2,2- dimethyl-l,3-dioxan-4-yl)acetate compound of formula-11, hydro lyzing the obtained compound by treating in-situ with an aqueous hydrochloric acid in acetonitrile to provide compound of formula- 12 and which on further treating with aqueous sodium hydroxide in methanol to provide N-(2-(benzyloxy)phenyl)-5-(4-fiuorophenyl)-l-(2- ((2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl-lH- pyrrole-3 -carboxamide compound of formula- 13,
g) purifying the compound of formula- 13 from toluene to provide pure compound of formula-13,
h) treating the compound of formula-13 with palladium carbon in a mixture of methanol and ethylacetate to provide 5-(4-fluorophenyl)-l-(2-((2R,4R)-4-hydroxy-6-oxo tetrahydro-2H-pyran-2-yl)ethyl)-N-(2-hydroxyphenyl)-2-isopropyl-4-phenyl-lH- pyrrole-3-carboxamide compound of formula- 14,
i) purifying the compound of formula- 14 from isopropanol to provide pure compound of formula- 14,
j) treating the compound of formula- 14 with aqueous sodium hydroxide in presence of acetonitrile to provide amorphous [3R,5R]-2-fluorophenyl-P,5-dihydroxy-5-(l- methylethyl)-3 -phenyl -4- [(2-hydroxyphenylamino)-carbonyl]- 1 H-pyrrole- 1 - heptanoic acid, sodium salt compound of formula- 1.
A process for the preparation of N-(2-(benzyloxy)phenyl)-2-(2-(4-fluorophenyl)-2-oxo-l- phenyl ethyl)-4-methyl-3-oxopentanamide compound of formula-9, comprising of treating the compound of formula-7 with 2-bromo-l-(4-fluorophenyl)-2-phenylethanone compound of formula-8 in presence of a suitable base selected from organic or inorganic base in a suitable solvent selected from alcohol solvents, chloro solvents, ester solvents, polar aprotic solvents, ketone solvents, ether solvents, hydrocarbon solvents and polar solvent like water or mixture thereof to provide N-(2-(benzyloxy)phenyl)-2-(2-(4- fluorophenyl)-2-oxo-l-phenylethyl)-4-methyl-3-oxopentan amide compound of formula-9.
A one-pot process for the preparation of N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)-l- (2-((2R,4R)-4-hydroxy-6-oxo tetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl- 1 H- pyrrole-3-carboxamide compound of formula-13, comprising of the following steps: a) Reacting the compound of formula-9 with tert-butyl 2-((4R,6R)-6-(2-aminoethyl)- 2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula- 10 in presence of pivalic acid in a suitable solvent to provide tert-butyl 2-((4R,6R)-6-(2-(3-(2-(benzyloxy) phenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl- 1 H-pyrrol- 1 -yl)ethyl)- 2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula-11, hydro lyzing the obtained compound by treating in-situ with a suitable acid in a suitable solvent to provide compound of formula- 12 and which on further treating with a suitable base in a suitable solvent to provide N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)-l-(2- ((2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl-lH- pyrrole-3-carboxamide compound of formula-13,
b) optionally, purifying the compound of formula-13 from a suitable solvent to provide pure compound of formula-13.
8. A one-pot process for the preparation of N-^-ibenzyloxy^henyO-S-^-fluorophenylH- ^-^R^R^-hydroxy-e-oxotetrahydro^H-pyran^-y ethyl)^-^^
pyrrole-3-carboxamide compound of formula-13, comprising of the following steps: a) Reacting the compound of formula-9 with tert-butyl 2-((4R,6R)-6-(2-aminoethyl)- 2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula- 10 in presence of pivalic acid in cyclohexane to provide tert-butyl 2-((4R,6R)-6-(2-(3-(2-(benzyloxy)phenyl carbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2,2- dimethyl-l,3-dioxan-4-yl)acetate compound of formula-11, hydrolyzing the obtained compound by treating in-situ with an aqueous hydrochloric acid in acetonitrile to provide compound of formula- 12 and which on further treating with aqueous sodium hydroxide in methanol to provide N-(2-(benzyloxy)phenyl)-5-(4-fiuorophenyl)-l-(2- ((2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl-lH- pyrrole-3-carboxamide compound of formula-13,
b) purifying the compound of formula-13 from toluene to provide pure compound of formula-13.
9. A process for the preparation of amorphous [3R,5R]-2-fluorophenyl-P,6-dihydroxy-5-(l- methylethyl)-3 -phenyl-4- [(2-hydroxyphenylamino)-carbonyl]- 1 H-pyrrole- 1 -heptanoic acid, sodium salt compound of formula- 1, comprising of the following steps:
a) Adding acetonitrile to 5-(4-fluorophenyl)-l-(2-((2R,4R)-4-hydroxy-6-oxotetrahydro- 2H-pyran-2-yl)ethyl)-N-(2-hydroxyphenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3- carboxamide compound of formula- 14,
b) cooling the reaction mixture to 0°C to 5°C,
c) stirring the reaction mixture and adding aqueous sodium hydroxide solution to the reaction mixture,
d) stirring the reaction mixture at 25°C to 30°C ,
e) distilling off the solvent completely from the reaction mixture,
f) adding water to the obtained compound,
g) extracting the compound with ethyl acetate,
h) washing the organic layer with aqueous sodium chloride solution,
i) distilling off the solvent completely from the organic layer and then followed by co- distilling with water to get amorphous [3R,5R]-2-fluorophenyl-P,6-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(2-hydroxyphenylamino)-carbonyl]- 1 H-pyrrole- 1 - heptanoic acid, sodium salt compound of formula- 1.
10. A process for the purification of N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)-l-(2- ((2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl-lH- pyrrole-3-carboxamide compound of formula-13, comprising of the following steps: a) Adding aqueous methanol to N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)-l-(2- ((2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4-phenyl-lH- pyrrole-3-carboxamide,
b) heating the reaction mixture to 60°C to 65°C,
c) stirring the reaction mixture,
d) cooling the reaction mixture to 0°C to 5°C,
e) stirring the reaction mixture,
f) filtering the solid and dried to get pure N-(2-(benzyloxy)phenyl)-5-(4-fluorophenyl)- l-(2-((2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-4- phenyl- 1 H-pyrrole-3 -carboxamide .
11. Amorphous [3R,5R]-2-fluorophenyl- ,6-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(2- hydroxyphenyl amino)-carbonyl]-l H-pyrrole- 1 -heptanoic acid, sodium salt compound of formula- 1, of the present invention is useful in the preparation of pharmaceutical formulation.
12. The compound of formula- 1 obtained according to any of the preceding claims having purity greater than 99.0% by HPLC; preferably greater than 99.50% by HPLC; more preferably greater than 99.75% by HPLC.
PCT/IN2016/000062 2015-03-06 2016-03-04 IMPROVED PROCESS FOR THE PREPARATION OF [3R,5R]-2-FLUOROPHENYL-β,δ- DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(2-HYDROXYPHENYLAMINO)- CARBONYL]-1H-PYRROLE-1-HEPTANOIC ACID, SODIUM SALT WO2016142954A2 (en)

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